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Yu Q, Zhu Q, Huang X, Wu J, Zhou Q, Chen T, Zhu C, Ding L, Deng G, Wang Y, Zhang Z, Zhang B. Preparation of bovine coronavirus virus-like particles and its immunogenicity in mice and cattle. Microb Pathog 2024; 197:107062. [PMID: 39442811 DOI: 10.1016/j.micpath.2024.107062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/21/2024] [Revised: 10/07/2024] [Accepted: 10/20/2024] [Indexed: 10/25/2024]
Abstract
The widespread prevalence of bovine coronavirus (BCoV) disease worldwide has impacted the livestock industry economically. No effective vaccine is available in China. In this study, we produced BCoV virus-like particles (VLPs) containing E, M, N, S, and hemagglutinin-esterase (HE) proteins using a baculovirus expression system. Five recombinant baculoviruses were co-infected with Sf9 cells, and the VLPs were assembled and characterized. Mice and cattle were immunized by VLPs mixed with MF59 and CpG 55.2 adjuvants. Two doses of the VLPs/MF59/CpG vaccine were administered in mice and cattle. The immune effect of the VLPs/MF59/CpG vaccine was measured using indirect ELISA and neutralization assays. After immunization, the serum IgG-specific antibody titer against S protein and neutralization antibody titer increased to 1:1.28 × 104 (p < 0.01) and 1:128 (p < 0.01) in mice, respectively. Interestingly, the high IgG antibody and neutralizing antibody titers were maintained for seven days in mice. In addition, the serum IgG-specific antibody titer against S proteins and neutralization antibody titer increased to 1:1.024 × 105 and 1:512 (p < 0.05) in cattle, respectively. The high IgG antibody and neutralizing antibody titers were maintained for 21 days in cattle. Notably, BCoV VLPs group interferon-gamma (IFN-γ) lymphocytes in spleens were significantly increased (p < 0.01). These findings suggest that BCoV VLPs induced strong cellular and humoral immune responses in mice and cattle. These findings suggest that BCoV VLPs could serve as a potent immunogen for vaccine development.
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Affiliation(s)
- Qisheng Yu
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
| | - Qing Zhu
- Center for Animal Disease Control and Prevention, Ganzi Tibetan Autonomous Prefecture, Kangding, 626000, China.
| | - Xiangyue Huang
- Animal Husbandry Science Institute of Aba Autonomous Prefecture, Hongyuan, 624400, China.
| | - Jinbo Wu
- Animal Husbandry Science Institute of Aba Autonomous Prefecture, Hongyuan, 624400, China.
| | - Qun Zhou
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
| | - Taoyun Chen
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
| | - Chenxi Zhu
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
| | - Lu Ding
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
| | - Gunan Deng
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
| | - Yi Wang
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China.
| | - Zhaohui Zhang
- Center for Animal Disease Control and Prevention, Ganzi Tibetan Autonomous Prefecture, Kangding, 626000, China.
| | - Bin Zhang
- College of Animal and Veterinary Sciences, Southwest Minzu University, Chengdu, 610041, China; Key Laboratory of Ministry of Education and Sichuan Province for Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, 610041, China.
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Lensch V, Gabba A, Hincapie R, Bhagchandani SH, Basak A, Alam MM, Noble J, Irvine DJ, Shalek AK, Johnson JA, Finn MG, Kiessling LL. Carbohydrate-Lectin Interactions Reprogram Dendritic Cells to Promote Type 1 Anti-Tumor Immunity. ACS NANO 2024; 18:26770-26783. [PMID: 39283240 PMCID: PMC11646345 DOI: 10.1021/acsnano.4c07360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 10/02/2024]
Abstract
Cancer vaccine development is inhibited by a lack of strategies for directing dendritic cell (DC) induction of effective tumor-specific cellular immunity. Pathogen engagement of DC lectins and toll-like receptors (TLRs) is thought to shape immunity by directing T cell function. Controlling downstream responses, however, remains a major challenge. A critical goal in advancing vaccine development involves the identification of receptors that drive type 1 cellular immunity. The immune system monitors cells for aberrant glycosylation (a sign of a foreign entity), but potent activation occurs when a second signal, such as single-stranded RNA or lipopolysaccharide, is present to activate TLR signaling. To exploit dual signaling, we engineered a glycan-costumed virus-like particle (VLP) vaccine that displays a DC-SIGN-selective aryl mannose ligand and encapsulates TLR7 agonists. These VLPs deliver programmable peptide antigens to induce robust DC activation and type 1 cellular immunity. In contrast, VLPs lacking this critical DC-SIGN ligand promoted DC-mediated humoral immunity, offering limited tumor control. Vaccination with glycan-costumed VLPs generated tumor antigen-specific Th1 CD4+ and CD8+ T cells that infiltrated solid tumors, significantly inhibiting tumor growth in a murine melanoma model. The tailored VLPs also afforded protection against the reintroduction of tumor cells. Thus, DC lectin-driven immune reprogramming, combined with the modular programmability of VLP platforms, provides a promising framework for directing cellular immunity to advance cancer immunotherapies and vaccines.
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Affiliation(s)
- Valerie Lensch
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Adele Gabba
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Robert Hincapie
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Sachin H Bhagchandani
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Ankit Basak
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Mohammad Murshid Alam
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
| | - Jeffery Noble
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Darrell J Irvine
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
- Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, United States
| | - Alex K Shalek
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - Jeremiah A Johnson
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
| | - M G Finn
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, Georgia 30332, United States
| | - Laura L Kiessling
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
- Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts 02139, United States
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, United States
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3
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Lampinen V, Gröhn S, Lehmler N, Jartti M, Hytönen VP, Schubert M, Hankaniemi MM. Production of norovirus-, rotavirus-, and enterovirus-like particles in insect cells is simplified by plasmid-based expression. Sci Rep 2024; 14:14874. [PMID: 38937523 PMCID: PMC11211442 DOI: 10.1038/s41598-024-65316-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/29/2024] [Accepted: 06/19/2024] [Indexed: 06/29/2024] Open
Abstract
Insect cells have long been the main expression host of many virus-like particles (VLP). VLPs resemble the respective viruses but are non-infectious. They are important in vaccine development and serve as safe model systems in virus research. Commonly, baculovirus expression vector system (BEVS) is used for VLP production. Here, we present an alternative, plasmid-based system for VLP expression, which offers distinct advantages: in contrast to BEVS, it avoids contamination by baculoviral particles and proteins, can maintain cell viability over the whole process, production of alphanodaviral particles will not be induced, and optimization of expression vectors and their ratios is simple. We compared the production of noro-, rota- and entero-VLP in the plasmid-based system to the standard process in BEVS. For noro- and entero-VLPs, similar yields could be achieved, whereas production of rota-VLP requires some further optimization. Nevertheless, in all cases, particles were formed, the expression process was simplified compared to BEVS and potential for the plasmid-based system was validated. This study demonstrates that plasmid-based transfection offers a viable option for production of noro-, rota- and entero-VLPs in insect cells.
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Affiliation(s)
- Vili Lampinen
- Virology and Vaccine Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Protein Dynamics, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Stina Gröhn
- Virology and Vaccine Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Nina Lehmler
- Department of Biotechnology, Institute for Biochemistry, Biotechnology and Bioinformatics, TU Braunschweig, Braunschweig, Germany
| | - Minne Jartti
- Virology and Vaccine Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Vesa P Hytönen
- Protein Dynamics, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Fimlab Laboratories, Tampere, Finland
| | - Maren Schubert
- Department of Biotechnology, Institute for Biochemistry, Biotechnology and Bioinformatics, TU Braunschweig, Braunschweig, Germany.
| | - Minna M Hankaniemi
- Virology and Vaccine Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.
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Qi SY, Yang MM, Li CY, Yu K, Deng SL. The HPV viral regulatory mechanism of TLRs and the related treatments for HPV-associated cancers. Front Immunol 2024; 15:1407649. [PMID: 38812510 PMCID: PMC11133576 DOI: 10.3389/fimmu.2024.1407649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/27/2024] [Accepted: 05/01/2024] [Indexed: 05/31/2024] Open
Abstract
Infection with human papillomavirus (HPV) typically leads to cervical cancer, skin related cancers and many other tumors. HPV is mainly responsible for evading immune tumor monitoring in HPV related cancers. Toll like receptors (TLRs) are particular pattern recognition molecules. When the body is facing immune danger, it can lead to innate and direct adaptive immunity. TLR plays an important role in initiating antiviral immune responses. HPV can affect the expression level of TLR and interfere with TLR related signaling pathways, resulting in sustained viral infection and even carcinogenesis. This paper introduces the HPV virus and HPV related cancers. We discussed the present comprehension of TLR, its expression and signaling, as well as its role in HPV infection. We also provided a detailed introduction to immunotherapy methods for HPV related diseases based on TLR agonists. This will provide insights into methods that support the therapeutic method of HPV related conditions with TLR agonists.
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Affiliation(s)
- Shi-Yu Qi
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Miao-Miao Yang
- College of Chemical and Pharmaceutical Engineering, Jilin Institute of Chemical Technology, Jilin, China
| | - Chong-Yang Li
- Institute of Animal Sciences (IAS), Chinese Academy of Agricultural Sciences (CAAS), Beijing, China
| | - Kun Yu
- College of Animal Science and Technology, China Agricultural University, Beijing, China
| | - Shou-Long Deng
- National Center of Technology Innovation for animal model, National Health Commission of China (NHC) Key Laboratory of Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China
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Bobadilla ML, Villagra V, Castro H, von Horoch M, Araya S, Deluca G, de Paula VS. Human Papillomavirus (HPV) Infection and Risk Behavior in Vaccinated and Non-Vaccinated Paraguayan Young Women. Pathogens 2024; 13:209. [PMID: 38535552 PMCID: PMC10974315 DOI: 10.3390/pathogens13030209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/29/2023] [Revised: 01/27/2024] [Accepted: 01/29/2024] [Indexed: 02/11/2025] Open
Abstract
Cervical cancer is a global health concern and ranks fourth among the most prevalent cancers in women worldwide. Human papillomavirus (HPV) infection is a known precursor of cervical cancer and preventive measures include prophylactic vaccines. This study focused on sexually active Paraguayan women aged 18-25 years, exploring the intersection of HPV vaccination and sexual behavior. Among 254 participants, 40.9% received the Gardasil-4 vaccine, with no significant differences in sexual behavior between the vaccinated and unvaccinated sexually active groups. However, a notable decrease in the prevalence of HPV among the vaccinated women highlights the efficacy of this vaccine in reducing infections. The prevalence of any HPV type was 37.5% in vaccinated participants compared to 56.7% in unvaccinated participants (p = 0.0026). High-risk HPV types showed a significant difference, with a prevalence of 26.0% in vaccinated women compared with 52.7% in unvaccinated women (p < 0.001). Although a potential decline in genital warts was observed among the vaccinated individuals, statistical significance (p = 0.0564) was not reached. Despite the challenges in achieving high vaccination coverage, the observed reduction in HPV prevalence underscores the importance of ongoing monitoring, healthcare professional recommendations, and comprehensive risk management. These findings contribute to dispelling concerns about HPV vaccination influencing sexual behavior, advocating further large-scale research to explore the impact of vaccines on various HPV types and potential cross-protection.
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Affiliation(s)
- María Liz Bobadilla
- Laboratory of Immunology, Central Laboratory of Public Health, Minister of Public Health and Social Welfare, Asunción 1429, Paraguay;
- Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil;
| | - Verónica Villagra
- Laboratory of Immunology, Central Laboratory of Public Health, Minister of Public Health and Social Welfare, Asunción 1429, Paraguay;
| | - Héctor Castro
- Expanded Immunization Program, Minister of Public Health and Social Welfare, Asunción 1429, Paraguay; (H.C.); (M.v.H.); (S.A.)
| | - Marta von Horoch
- Expanded Immunization Program, Minister of Public Health and Social Welfare, Asunción 1429, Paraguay; (H.C.); (M.v.H.); (S.A.)
| | - Soraya Araya
- Expanded Immunization Program, Minister of Public Health and Social Welfare, Asunción 1429, Paraguay; (H.C.); (M.v.H.); (S.A.)
| | - Gerardo Deluca
- Molecular Applications Laboratory, Faculty of Medicine, Northeast National University, Corrientes 1240, Argentina;
| | - Vanessa Salete de Paula
- Laboratory of Molecular Virology and Parasitology, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil;
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Lensch V, Gabba A, Hincapie R, Bhagchandani SH, Basak A, Alam MM, Irvine DJ, Shalek AK, Johnson JA, Finn MG, Kiessling LL. Glycan-costumed virus-like particles promote type 1 anti-tumor immunity. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.18.575711. [PMID: 38293025 PMCID: PMC10827186 DOI: 10.1101/2024.01.18.575711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 02/01/2024]
Abstract
Cancer vaccine development is inhibited by a lack of strategies for directing dendritic cell (DC) induction of effective tumor-specific cellular immunity. Pathogen engagement of DC lectins and toll-like receptors (TLRs) shapes immunity by directing T cell function. Strategies to activate specific DC signaling pathways via targeted receptor engagement are crucial to unlocking type 1 cellular immunity. Here, we engineered a glycan-costumed virus-like particle (VLP) vaccine that delivers programmable peptide antigens to induce tumor-specific cellular immunity in vivo. VLPs encapsulating TLR7 agonists and decorated with a selective mannose-derived ligand for the lectin DC-SIGN induced robust DC activation and type 1 cellular immunity, whereas VLPs lacking this key DC-SIGN ligand failed to promote DC-mediated immunity. Vaccination with glycan-costumed VLPs generated tumor antigen-specific Th1 CD4+ and CD8+ T cells that infiltrated solid tumors, inhibiting tumor growth in a murine melanoma model. Thus, VLPs employing lectin-driven immune reprogramming provide a framework for advancing cancer immunotherapies.
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Affiliation(s)
- Valerie Lensch
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Adele Gabba
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Robert Hincapie
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA
| | - Sachin H. Bhagchandani
- Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ankit Basak
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | | | - Darrell J. Irvine
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, USA
| | - Alex K. Shalek
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA
- Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Jeremiah A. Johnson
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - M. G. Finn
- School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA, USA
| | - Laura L. Kiessling
- Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA
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Orji AF, Gimm G, Desai A, Parekh T. The Association of Cervical Cancer Screening With Disability Type Among U.S. Women (Aged 25-64 Years). Am J Prev Med 2024; 66:83-93. [PMID: 37582416 DOI: 10.1016/j.amepre.2023.08.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 12/08/2022] [Revised: 08/08/2023] [Accepted: 08/08/2023] [Indexed: 08/17/2023]
Abstract
INTRODUCTION Despite a gradual decline in cervical cancer mortality because of greater use of screening, including Pap and human papillomavirus (HPV) tests, disparities in screening among adult women by disability type have not been examined. This study aims to assess the odds of cervical cancer screening using HPV tests by disability type among U.S. women aged 25-64 years. METHODS This study was analyzed in 2022 using pooled data from 2018 and the 2020 Behavioral Risk Factor and Surveillance System. The analytic sample included 189,795 women aged 25-64 years. Disability was defined as having any sensory disability, cognitive disability, physical disability, ≥2 disabilities, or no disability adapted from a standardized questionnaire. Descriptive analyses were used to estimate the proportion of HPV tests on the basis of 2020 American Cancer Society guidelines, which recommend testing within five years for all women aged 25-65 years. Multivariable analyses were conducted to estimate AORs of cervical cancer screening by disability type. RESULTS Overall, 53.8% of women met recommended 2020 American Cancer Society guidelines for cervical cancer screening using HPV tests. The proportion of HPV tests was higher in women with a cognitive disability (55.9%) and lower in those with sensory (49.7%), physical (48.2%), and ≥2 disabilities (47.8%) than in those without disabilities (54.8%). In adjusted analyses, women with any disability (AOR=0.95, 95% CI=0.88, 0.97), physical disability (AOR=0.96, 95% CI=0.80, 0.98), and ≥2 disabilities (AOR=0.88, 95% CI=0.78, 0.97) had lower odds of receiving cervical cancer screening with HPV testing than women without disabilities. CONCLUSIONS Disparities in screening with HPV tests among women with physical and ≥2 disabilities suggest the need for a targeted approach to improve prevention screening awareness, access, and availability in this population.
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Affiliation(s)
- Amarachukwu F Orji
- Department of Global and Community Health, George Mason University, Fairfax, Virginia
| | - Gilbert Gimm
- Department of Health Administration and Policy, George Mason University, Fairfax, Virginia
| | - Aakash Desai
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota
| | - Tarang Parekh
- College of Health Science, University of Delaware, Newark, Delaware.
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Skolnik JM, Morrow MP. Vaccines for HPV-associated diseases. Mol Aspects Med 2023; 94:101224. [PMID: 37931422 DOI: 10.1016/j.mam.2023.101224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/06/2023] [Revised: 10/19/2023] [Accepted: 10/24/2023] [Indexed: 11/08/2023]
Abstract
Human papillomavirus (HPV) infection represents a significant global health concern owing to its role in the etiology of conditions ranging from benign low-grade lesions to cancers of the cervix, head and neck, anus, vagina, vulva, and penis. Prophylactic vaccination programs, primarily targeting adolescent girls, have achieved dramatic reductions in rates of HPV infection and cervical cancer in recent years. However, there is a clear demand for a strategy to manage the needs of the many people who are already living with persistent HPV infection and/or HPV-associated conditions. Unlike prophylactic vaccines, which act to prevent HPV infection, therapeutic vaccination presents an opportunity to induce cellular immunity against established HPV infections and lesions and prevent progression to cancer. Several HPV vaccines are undergoing clinical development, using a range of platforms. Peptide- or protein-based vaccines, vector-based vaccines, whole-cell vaccines, and nucleic acid vaccines each offer relative merits and limitations for the delivery of HPV antigens and the subsequent generation of targeted immune responses. There has been particular interest in DNA-based vaccines, which elicit both cellular and humoral immune responses to provide long-lasting immunity. DNA vaccines offer several practical advantages over other vaccine platforms, including the potential for rapid and scalable manufacturing, targeting of many different antigens, and potential for repeat boosting. Furthermore, unlike vectored approaches, DNA vaccines are thermostable over extended time periods, which may enable shipping and storage. Several delivery strategies are available to address the main challenge of DNA vaccines, namely their relatively low transfection efficiency. We review the latest clinical data supporting the development of DNA vaccines and reflect on this exciting prospect in the management of HPV-related disease.
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Ma F, Chen A, Yao L, Gao H, Zhang Q, Hou W, Zheng L. Immunogenicity and protective efficacy of human metapneumovirus virus-like particles produced by a recombinant baculovirus in mice. Virus Res 2023; 336:199215. [PMID: 37657510 PMCID: PMC10491852 DOI: 10.1016/j.virusres.2023.199215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/03/2023] [Revised: 07/19/2023] [Accepted: 08/29/2023] [Indexed: 09/03/2023]
Abstract
BACKGROUND Human metapneumovirus (HMPV) causes respiratory tract infections among infant, elderly, and immunocompromised patients, with significant mortality. Currently no licensed vaccines or therapeutic agents of HMPV exist. METHODS HMPV virus-like particle (VLP) was constructed by co-expressing fusion protein of HMPV and matrix 1 protein of influenza virus using the baculovirus expression. Mice were immunized with VLP with or without aluminum hydroxide (alum) adjuvant by intramuscular route respectively. Sera were determined for titers of IgG and neutralizing antibody. Splenic lymphocytes were determined by IFN-γ and IL-4 ELISPOT. Mice were challenged with HMPV, and protective efficacy was evaluated. RESULTS We generated HMPV VLP in baculovirus expression system. After three times immunization, IgG antibody titers induced by VLP formulated with or without alum adjuvant group were 273,066 ± 100,331 and 136,533 ± 47,269 respectively, there was no difference (p ˃ 0.05); the neutralizing antibody titers vaccinated with VLP plus with alum adjuvant (266 ± 92) were higher than those of the VLP alone group (106 ± 37). For IFN-γ, mice vaccinated with VLP with or without alum adjuvant are 151 ± 36.4 and 77.0 ± 17.1SFC/106 respectively, there was difference (p = 0.03); For IL-4, they are 261.3 ± 38.7 versus 125.67 ± 29.78SFC/106 respectively, the difference was significant (p = 0.009). After challenge, in pathological analysis, the overall lesion scores in the VLP plus with and without alum adjuvant were 3.25 and 5.6 respectively, those of control group is 8. For immunohistochemical analyses, the average optical density of the lungs in the VLP immunized group containing adjuvant (9.07 ± 1.74) was lower than that in the VLP group without adjuvant (12.83 ± 2.31, p = 0.14). CONCLUSIONS This is the first study to demonstrate that HMPV VLP was successfully prepared in the baculovirus expression system. HMPV VLP could induce specific humoral and cellular immune responses as well as protective efficacy, and aluminum hydroxide may be an effective adjuvant in mice.
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Affiliation(s)
- Fenlian Ma
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, 100 Ying-Xin St., Xi-Cheng District, Beijing 100052, China
| | - Aijun Chen
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, 100 Ying-Xin St., Xi-Cheng District, Beijing 100052, China
| | - Lihong Yao
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, 100 Ying-Xin St., Xi-Cheng District, Beijing 100052, China
| | - Hanchun Gao
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, 100 Ying-Xin St., Xi-Cheng District, Beijing 100052, China
| | - Qian Zhang
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, 100 Ying-Xin St., Xi-Cheng District, Beijing 100052, China
| | - Wenzhe Hou
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, 100 Ying-Xin St., Xi-Cheng District, Beijing 100052, China
| | - Lishu Zheng
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, China CDC, 100 Ying-Xin St., Xi-Cheng District, Beijing 100052, China.
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Li J, Xie H, Fu L, Guo X, Dong J, Xu M, Wang G, Zhao A. Comparison of the Immune Responses to Different Formulations of BC02-Adjuvanted HPV Types 16 and 18 Bivalent Vaccines in Mice. Vaccines (Basel) 2023; 11:1553. [PMID: 37896956 PMCID: PMC10611034 DOI: 10.3390/vaccines11101553] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/09/2023] [Revised: 09/25/2023] [Accepted: 09/28/2023] [Indexed: 10/29/2023] Open
Abstract
To achieve maximum efficacy, vaccines, such as subunit, recombinant, and conjugate vaccines, necessitate the incorporation of immunostimulators/adjuvants. Adjuvants play a vital role in bolstering and extending the strength of the immune response while also influencing its type. As antigen and adjuvant formulations become more intricate, it becomes imperative to establish a well-characterized and robust formulation to ensure consistent and reproducible outcomes in preclinical and clinical studies. In the present study, an HPV bivalent vaccine was developed using a BC02 adjuvant in conjunction with HPV 16 and 18 L1 VLP antigens produced from an E. coli expression system. The study involved evaluating the adjuvant formulation and in vivo immunogenicity in mice. Remarkably, a medium-dose of BCG-CpG-DNA combined with a low-dose of aluminum hydroxide substantially enhanced the immunogenicity of HPV16 and 18 VLPs, resulting in improved cellular and humoral immune responses.
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Affiliation(s)
- Junli Li
- Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China; (J.L.); (H.X.); (L.F.); (X.G.); (J.D.); (M.X.); (G.W.)
- Key Laboratory for Quality Research and Evaluation of Biological Products, National Medical Products Administration (NMPA), Beijing 102629, China
- Key Laboratory of Research on Quality and Standardization of Biotech Products, National Health Commission (NHC), Beijing 102629, China
| | - Huicong Xie
- Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China; (J.L.); (H.X.); (L.F.); (X.G.); (J.D.); (M.X.); (G.W.)
- Key Laboratory for Quality Research and Evaluation of Biological Products, National Medical Products Administration (NMPA), Beijing 102629, China
- Key Laboratory of Research on Quality and Standardization of Biotech Products, National Health Commission (NHC), Beijing 102629, China
| | - Lili Fu
- Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China; (J.L.); (H.X.); (L.F.); (X.G.); (J.D.); (M.X.); (G.W.)
- Key Laboratory for Quality Research and Evaluation of Biological Products, National Medical Products Administration (NMPA), Beijing 102629, China
- Key Laboratory of Research on Quality and Standardization of Biotech Products, National Health Commission (NHC), Beijing 102629, China
| | - Xiaonan Guo
- Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China; (J.L.); (H.X.); (L.F.); (X.G.); (J.D.); (M.X.); (G.W.)
- Key Laboratory for Quality Research and Evaluation of Biological Products, National Medical Products Administration (NMPA), Beijing 102629, China
- Key Laboratory of Research on Quality and Standardization of Biotech Products, National Health Commission (NHC), Beijing 102629, China
| | - Jiaxin Dong
- Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China; (J.L.); (H.X.); (L.F.); (X.G.); (J.D.); (M.X.); (G.W.)
- Key Laboratory for Quality Research and Evaluation of Biological Products, National Medical Products Administration (NMPA), Beijing 102629, China
- Key Laboratory of Research on Quality and Standardization of Biotech Products, National Health Commission (NHC), Beijing 102629, China
| | - Miao Xu
- Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China; (J.L.); (H.X.); (L.F.); (X.G.); (J.D.); (M.X.); (G.W.)
- Key Laboratory for Quality Research and Evaluation of Biological Products, National Medical Products Administration (NMPA), Beijing 102629, China
- Key Laboratory of Research on Quality and Standardization of Biotech Products, National Health Commission (NHC), Beijing 102629, China
| | - Guozhi Wang
- Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China; (J.L.); (H.X.); (L.F.); (X.G.); (J.D.); (M.X.); (G.W.)
- Key Laboratory for Quality Research and Evaluation of Biological Products, National Medical Products Administration (NMPA), Beijing 102629, China
- Key Laboratory of Research on Quality and Standardization of Biotech Products, National Health Commission (NHC), Beijing 102629, China
| | - Aihua Zhao
- Division of Tuberculosis Vaccine and Allergen Products, Institute of Biological Product Control, National Institutes for Food and Drug Control, Beijing 102629, China; (J.L.); (H.X.); (L.F.); (X.G.); (J.D.); (M.X.); (G.W.)
- Key Laboratory for Quality Research and Evaluation of Biological Products, National Medical Products Administration (NMPA), Beijing 102629, China
- Key Laboratory of Research on Quality and Standardization of Biotech Products, National Health Commission (NHC), Beijing 102629, China
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11
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Williamson AL. Recent Developments in Human Papillomavirus (HPV) Vaccinology. Viruses 2023; 15:1440. [PMID: 37515128 PMCID: PMC10384715 DOI: 10.3390/v15071440] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/27/2023] [Revised: 06/14/2023] [Accepted: 06/15/2023] [Indexed: 07/30/2023] Open
Abstract
Human papillomavirus (HPV) is causally associated with 5% of cancers, including cancers of the cervix, penis, vulva, vagina, anus and oropharynx. The most carcinogenic HPV is HPV-16, which dominates the types causing cancer. There is also sufficient evidence that HPV types 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 cause cervical cancer. The L1 protein, which, when assembled into virus-like particles, induces HPV-type-specific neutralising antibodies, forms the basis of all commercial HPV vaccines. There are six licensed prophylactic HPV vaccines: three bivalent, two quadrivalent and one nonavalent vaccine. The bivalent vaccines protect from HPV types 16 and 18, which are associated with more than 70% of cervical cancers. Prophylactic vaccination targets children before sexual debut, but there are now catch-up campaigns, which have also been shown to be beneficial in reducing HPV infection and disease. HPV vaccination of adults after treatment for cervical lesions or recurrent respiratory papillomatosis has impacted recurrence. Gender-neutral vaccination will improve herd immunity and prevent infection in men and women. HPV vaccines are immunogenic in people living with HIV, but more research is needed on the long-term impact of vaccination and to determine whether further boosters are required.
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Affiliation(s)
- Anna-Lise Williamson
- Institute of Infectious Disease and Molecular Medicine/SAMRC Gynaecological Cancer Research Centre/Division of Medical Virology, Department of Pathology, University of Cape Town, Cape Town 7925, South Africa
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12
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Hashemzadeh MS, Gharari N. Biosynthesis of a VLP-type nanocarrier specific to cancer cells using the BEVS expression system for targeted drug delivery. J Genet Eng Biotechnol 2023; 21:20. [PMID: 36795253 PMCID: PMC9932404 DOI: 10.1186/s43141-023-00479-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/03/2023] [Accepted: 02/08/2023] [Indexed: 02/17/2023]
Abstract
OBJECTIVE Canine parvovirus (CPV) is a small virus without an envelope that consists of three viral proteins including VP1, VP2, and VP3. Exclusively, the VP2 can form a typically CPV-sized virus-like particle (CPV-VLP) that can be used as a biological nanocarrier for diagnostic and therapeutic purposes since these VLPs can target cancer cells specially through the transferrin surface receptors (TFRs). Consequently, we aimed to produce these nanocarriers to be used for specific targeting of cancer cells. METHODS Sf9 insect cells were transfected with constructed recombinant bacmid shuttle vector encoding an enhanced green fluorescent protein (EGFP) and CPV-VP2 by the cationic lipids of Cellfectin II. Subsequently, two recombinant baculoviruses expressing EGFP and VP2 were produced and expression of VP2 was increased under the optimal condition. In consequence, the CPV-VLP nanoparticles composed of recombinant VP2 subunits were extracted. The purity of VLPs was then evaluated by SDS-PAGE, and the structural integrity and quality of the final product were evaluated by TEM and HA methods. Eventually, the size distribution of the produced biological nanoparticles and their uniformity were determined by the DLS method. RESULTS The expression of EGFP protein was confirmed by fluorescent microscopy, and the expression of VP2 protein was evaluated by SDS-PAGE and western blotting. Infected Sf9 insect cells also showed cytopathic effects (CPEs), and the maximum expression of VP2 occurred at MOI of 10 (pfu/cell) at the harvest time of 72 h post-infection (hpi). After performing various stages of purification, buffer exchange, and concentration, the quality and structural integrity of the VLP product were confirmed. The results of the DLS technique showed the presence of uniform particles (PdI below 0.5) with an approximate size of 25 nm. CONCLUSION The results indicate BEVS as an appropriate and efficient system for generating CPV-VLPs, and the used method based on two-stage ultracentrifugation was appropriate for purifying these nanoparticles. Produced nanoparticles can be used as the biologic nano-carriers in future studies.
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Affiliation(s)
| | - Nariman Gharari
- grid.7605.40000 0001 2336 6580Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
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13
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Seoud M, Jaafar I, Ghanem R, Soubhieh C, Adra A, Nassar A, Khalil A. Outcomes of Human Papilloma Virus Vaccination in a Private Women Health Clinic in Lebanon. Obstet Gynecol Int 2022; 2022:7342061. [PMID: 36274656 PMCID: PMC9581706 DOI: 10.1155/2022/7342061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/11/2022] [Accepted: 09/19/2022] [Indexed: 12/03/2022] Open
Abstract
Objectives The study aims to report on the feasibility and associated adverse events of HPV-Vaccination (HPVV) in a private clinic setting in Lebanon and, when available, the results of subsequent cervical cancer screening. Methods Opportunistic HPV vaccination is offered at the Women's Health Center of the AUBMC. We retrospectively reviewed the patients' demographic data, the incidence of adverse events, and their cytological screening. Results A cohort of healthy women (n = 1013) aged 26.2 years (12-54 years) were opportunistically vaccinated with one of two HPV vaccines; 845 (83.4%) received the quadrivalent vaccine (Q4V), and 151 (14.1%) received the bivalent vaccine (B2V). The majority (75.8%) received three doses while 16% received two doses. Out of these women, 26.3% (267) became sexually active postvaccination (NS2), whereas 17% (174) were sexually active prior to vaccination (SA) and the rest 57% (572) reported no sexual activity (NS1). Among the SA group, 26% (46/147) presented with abnormal cytology at time of vaccination. As for the NS2 women, 5% (14/267) had subsequently abnormal screening within 37 (12-103) months following vaccination. Conclusions In this observational study, we report the successful introduction of HPVV with negligible adverse events. The incidence of abnormal cervical cytology was low among our patients.
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Affiliation(s)
- Muhieddine Seoud
- American University of Beirut Medical Center (AUBMC), Department of Obstetrics and Gynecology, Beirut, Lebanon
| | - Iman Jaafar
- American University of Beirut Medical Center (AUBMC), Department of Obstetrics and Gynecology, Beirut, Lebanon
| | - Rayan Ghanem
- American University of Beirut Medical Center (AUBMC), Department of Obstetrics and Gynecology, Beirut, Lebanon
| | - Christiane Soubhieh
- American University of Beirut Medical Center (AUBMC), Department of Obstetrics and Gynecology, Beirut, Lebanon
| | - Abdallah Adra
- American University of Beirut Medical Center (AUBMC), Department of Obstetrics and Gynecology, Beirut, Lebanon
| | - Anwar Nassar
- American University of Beirut Medical Center (AUBMC), Department of Obstetrics and Gynecology, Beirut, Lebanon
| | - Ali Khalil
- American University of Beirut Medical Center (AUBMC), Department of Obstetrics and Gynecology, Beirut, Lebanon
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14
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Enhanced Immunogenicity of Adjuvanted Microparticulate HPV16 Vaccines Administered via the Transdermal Route. Pharmaceuticals (Basel) 2022; 15:ph15091128. [PMID: 36145349 PMCID: PMC9503878 DOI: 10.3390/ph15091128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/10/2022] [Revised: 07/28/2022] [Accepted: 08/26/2022] [Indexed: 11/17/2022] Open
Abstract
Human papillomavirus (HPV) causes cervical cancer among women and is associated with other anogenital cancers in men and women. Prophylactic particulate vaccines that are affordable, self-administered and efficacious could improve uptake of HPV vaccines world-wide. The goal of this research is to develop a microparticulate HPV16 vaccine for transdermal administration using AdminPatch® and assess its immunogenicity in a pre-clinical mouse model. HPV16 microparticles were prepared using a biocompatible polymer and characterized in terms of size, zeta potential, encapsulation efficiency and microparticle yield. Scanning and transmission electron microscopy were conducted to confirm particle image and to visualize the conformation of HPV16 vaccine particles released from microparticle formulation. In vivo studies performed to evaluate the potential of the microparticulate vaccine initiated a robust and sustained immune response. HPV16 IgG antibodies were significantly elevated in the microparticle group compared to antigen solutions administered by the transdermal route. Results show significant expansion of CD4+, CD45R, CD27 and CD62L cell populations in the vaccinated mice group, indicating the high efficacy of the microparticulate vaccine when administered via transdermal route. The findings of this study call attention to the use of minimally invasive, pain-free routes to deliver vaccine.
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15
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Levit R, Cortes-Perez NG, de Moreno de Leblanc A, Loiseau J, Aucouturier A, Langella P, LeBlanc JG, Bermúdez-Humarán LG. Use of genetically modified lactic acid bacteria and bifidobacteria as live delivery vectors for human and animal health. Gut Microbes 2022; 14:2110821. [PMID: 35960855 PMCID: PMC9377234 DOI: 10.1080/19490976.2022.2110821] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 02/04/2023] Open
Abstract
There is now strong evidence to support the interest in using lactic acid bacteria (LAB)in particular, strains of lactococci and lactobacilli, as well as bifidobacteria, for the development of new live vectors for human and animal health purposes. LAB are Gram-positive bacteria that have been used for millennia in the production of fermented foods. In addition, numerous studies have shown that genetically modified LAB and bifodobacteria can induce a systemic and mucosal immune response against certain antigens when administered mucosally. They are therefore good candidates for the development of new mucosal delivery strategies and are attractive alternatives to vaccines based on attenuated pathogenic bacteria whose use presents health risks. This article reviews the most recent research and advances in the use of LAB and bifidobacteria as live delivery vectors for human and animal health.
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Affiliation(s)
- Romina Levit
- Centro de Referencia para Lactobacilos (CERELA-CONICET), Chacabuco 145, (T4000ILC) San Miguel de Tucumán, Tucumán, Argentina
| | - Naima G. Cortes-Perez
- Université Paris-Saclay, INRAE, AgroParisTech, UMR 0496, 78350 Jouy-en-Josas, France
| | - Alejandra de Moreno de Leblanc
- Centro de Referencia para Lactobacilos (CERELA-CONICET), Chacabuco 145, (T4000ILC) San Miguel de Tucumán, Tucumán, Argentina
| | - Jade Loiseau
- Micalis Institute, Université Paris-Saclay, INRAE, AgroParisTech, 78350 Jouy-en-Josas, France
| | - Anne Aucouturier
- Micalis Institute, Université Paris-Saclay, INRAE, AgroParisTech, 78350 Jouy-en-Josas, France
| | - Philippe Langella
- Micalis Institute, Université Paris-Saclay, INRAE, AgroParisTech, 78350 Jouy-en-Josas, France
| | - Jean Guy LeBlanc
- Centro de Referencia para Lactobacilos (CERELA-CONICET), Chacabuco 145, (T4000ILC) San Miguel de Tucumán, Tucumán, Argentina
| | - Luis G. Bermúdez-Humarán
- Micalis Institute, Université Paris-Saclay, INRAE, AgroParisTech, 78350 Jouy-en-Josas, France,CONTACT Luis G. Bermúdez-Humarán Micalis Institute, Université Paris-Saclay, INRAE, AgroParisTech, 78350 Jouy-en-Josas, France
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Ba DM, McCall-Hosenfeld JS, Ssentongo P, Chinchilli VM, Agbese E, Liu G, Leslie DL, Du P. Cervical cancer screening varies by HPV vaccination status among a National Cohort of privately insured young women in the United States 2006-2016. Medicine (Baltimore) 2021; 100:e27457. [PMID: 34731120 PMCID: PMC8519251 DOI: 10.1097/md.0000000000027457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 05/21/2021] [Accepted: 09/21/2021] [Indexed: 01/05/2023] Open
Abstract
Human papillomavirus (HPV) vaccination in young women is low. Women aged 21 to 65 years in the United States (U.S.) have not reached the Healthy People 2020 objective of 93% for cervical cancer screening. The main aim of this study was to investigate the association between HPV vaccination status and cervical cancer screening among privately insured women aged 21 to 26 years in the U.S.This was a retrospective cohort study using the IBM MarketScan database (2006-2016). The study population included 190,982 HPV-vaccinated women and 763,928 matched unvaccinated women. Adjusted incidence rate ratio (IRR) and the 95% confidence intervals (CIs) were obtained using the generalized estimating equations models with a Poisson distribution.Among a total of 954,910 women included in the analysis, age (mean [SD]) was 23.3 [1.6] years. During 967,317 person-years of follow-up, a total of 475,702 incidents of cervical cancer screening were identified. The incidence density rates of cervical cancer screening were 461 per 1000 person-years (PY) for unvaccinated women and 787 per 1000 PY for those who received 3 doses of the HPV vaccine. After adjusting for other covariates, the IRR of cervical cancer screening was 34% higher among HPV-vaccinated women with at least one vaccine dose than unvaccinated women (adjusted IRR = 1.34, 95% CI: 1.33-1.35; P < .0001). The IRR of cervical cancer screening varied by the dose of HPV vaccination. There was evidence of a linear dose-response relationship between the number of HPV vaccine doses and cervical cancer screening (P-trend < .0001). Compared with unvaccinated women, the IRR of cervical cancer screening were 14%, 39%, and 60% higher among those who received 1, 2, and 3 doses of the HPV vaccine, respectively.In this large retrospective cohort study of privately insured women, HPV-vaccinated women were more likely to be screened for cervical cancer compared with unvaccinated women.
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Affiliation(s)
- Djibril M. Ba
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA
- Center for Applied Studies in Health Economics (CASHE), Penn State College of Medicine, Hershey, PA
| | - Jennifer S. McCall-Hosenfeld
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA
- Department of Medicine, Penn State College of Medicine, Hershey, PA
| | - Paddy Ssentongo
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA
| | - Vernon M. Chinchilli
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA
| | - Edeanya Agbese
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA
- Center for Applied Studies in Health Economics (CASHE), Penn State College of Medicine, Hershey, PA
| | - Guodong Liu
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA
- Center for Applied Studies in Health Economics (CASHE), Penn State College of Medicine, Hershey, PA
| | - Douglas L. Leslie
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA
- Center for Applied Studies in Health Economics (CASHE), Penn State College of Medicine, Hershey, PA
| | - Ping Du
- Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA
- Department of Medicine, Penn State College of Medicine, Hershey, PA
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Kuguyo O, Dube Mandishora RS, Thomford NE, Makunike-Mutasa R, Nhachi CFB, Matimba A, Dandara C. High-risk HPV genotypes in Zimbabwean women with cervical cancer: Comparative analyses between HIV-negative and HIV-positive women. PLoS One 2021; 16:e0257324. [PMID: 34582476 PMCID: PMC8478215 DOI: 10.1371/journal.pone.0257324] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/05/2021] [Accepted: 08/30/2021] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND High-risk human papillomavirus HPV (HR-HPV) modifies cervical cancer risk in people living with HIV, yet African populations are under-represented. We aimed to compare the frequency, multiplicity and consanguinity of HR-HPVs in HIV-negative and HIV-positive Zimbabwean women. METHODS This was a cross-sectional study consisting of women with histologically confirmed cervical cancer attending Parirenyatwa Group of Hospitals in Harare, Zimbabwe. Information on HIV status was also collected for comparative analysis. Genomic DNA was extracted from 258 formalin fixed paraffin embedded tumour tissue samples, and analysed for 14 HR-HPV genotypes. Data was analysed using Graphpad Prism and STATA. RESULTS Forty-five percent of the cohort was HIV-positive, with a median age of 51 (IQR = 42-62) years. HR-HPV positivity was detected in 96% of biospecimens analysed. HPV16 (48%), was the most prevalent genotype, followed by HPV35 (26%), HPV18 (25%), HPV58 (11%) and HPV33 (10%), irrespective of HIV status. One third of the cohort harboured a single HPV infection, and HPV16 (41%), HPV18 (21%) and HPV35 (21%) were the most prevalent. HIV status did not influence the prevalence and rate of multiple HPV infections (p>0.05). We reported significant (p<0.05) consanguinity of HPV16/18 (OR = 0.3; 95% CI = 0.1-0.9), HPV16/33 (OR = 0.3; 95% CI = 0.1-1.0), HPV16/35 (OR = 3.3; 95% CI = 2.0-6.0), HPV35/51 (OR = 6.0; 95%CI = 1.8-15.0); HPV39/51 (OR = 6.4; 95% CI = 1.8-15), HPV31/52 (OR = 6.2; 95% CI = 1.8-15), HPV39/56 (OR = 11 95% CI = 8-12), HPV59/68 (OR = 8.2; 95% CI = 5.3-12.4), HPV66/68 (OR = 7; 95% CI = 2.4-13.5), independent of age and HIV status. CONCLUSION We found that HIV does not influence the frequency, multiplicity and consanguinity of HR-HPV in cervical cancer. For the first time, we report high prevalence of HPV35 among women with confirmed cervical cancer in Zimbabwe, providing additional evidence of HPV diversity in sub-Saharan Africa. The data obtained here probes the need for larger prospective studies to further elucidate HPV diversity and possibility of selective pressure on genotypes.
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Affiliation(s)
- Oppah Kuguyo
- Department of Clinical Pharmacology, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
- Division of Human Genetics, Department of Pathology, Pharmacogenomics and Drug Metabolism Group, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Cape Town, South Africa
| | - Racheal S. Dube Mandishora
- Faculty of Health Sciences, Department of Medical Microbiology Unit, University of Zimbabwe College of Health Sciences, Harare Zimbabwe University of Zimbabwe, Medical Microbiology Unit, Harare, Zimbabwe
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Nicholas Ekow Thomford
- Division of Human Genetics, Department of Pathology, Pharmacogenomics and Drug Metabolism Group, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Cape Town, South Africa
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, PMB, Ghana
| | - Rudo Makunike-Mutasa
- Department of Pathology, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
| | - Charles F. B. Nhachi
- Department of Clinical Pharmacology, University of Zimbabwe College of Health Sciences, Harare, Zimbabwe
| | - Alice Matimba
- Advanced Courses and Scientific Conferences, Wellcome Genome Campus, Hinxton, United Kingdom
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology, Pharmacogenomics and Drug Metabolism Group, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Cape Town, South Africa
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18
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Lisco A, Hsu AP, Dimitrova D, Proctor DM, Mace EM, Ye P, Anderson MV, Hicks SN, Grivas C, Hammoud DA, Manion M, Starrett GJ, Farrel A, Dobbs K, Brownell I, Buck C, Notarangelo LD, Orange JS, Leonard WJ, Orestes MI, Peters AT, Kanakry JA, Segre JA, Kong HH, Sereti I. Treatment of Relapsing HPV Diseases by Restored Function of Natural Killer Cells. N Engl J Med 2021; 385:921-929. [PMID: 34469647 PMCID: PMC8590529 DOI: 10.1056/nejmoa2102715] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 11/19/2022]
Abstract
Human papillomavirus (HPV) infections underlie a wide spectrum of both benign and malignant epithelial diseases. In this report, we describe the case of a young man who had encephalitis caused by herpes simplex virus during adolescence and currently presented with multiple recurrent skin and mucosal lesions caused by HPV. The patient was found to have a pathogenic germline mutation in the X-linked interleukin-2 receptor subunit gamma gene (IL2RG), which was somatically reverted in T cells but not in natural killer (NK) cells. Allogeneic hematopoietic-cell transplantation led to restoration of NK cytotoxicity, with normalization of the skin microbiome and persistent remission of all HPV-related diseases. NK cytotoxicity appears to play a role in containing HPV colonization and the ensuing HPV-related hyperplastic or dysplastic lesions. (Funded by the National Institutes of Health and the Herbert Irving Comprehensive Cancer Center Flow Cytometry Shared Resources.).
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Affiliation(s)
- Andrea Lisco
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Amy P Hsu
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Dimana Dimitrova
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Diana M Proctor
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Emily M Mace
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Peiying Ye
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Megan V Anderson
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Stephanie N Hicks
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Christopher Grivas
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Dima A Hammoud
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Maura Manion
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Gabriel J Starrett
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Alvin Farrel
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Kerry Dobbs
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Isaac Brownell
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Christopher Buck
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Luigi D Notarangelo
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Jordan S Orange
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Warren J Leonard
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Michael I Orestes
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Anju T Peters
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Jennifer A Kanakry
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Julia A Segre
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Heidi H Kong
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
| | - Irini Sereti
- From the Laboratories of Immunoregulation (A.L., P.Y., M.V.A., C.G., M.M., I.S.) and Clinical Immunology and Microbiology (A.P.H., K.D., L.D.N.), National Institute of Allergy and Infectious Diseases, the Experimental Transplantation and Immunotherapy Branch (D.D., S.N.H., J.A.K.) and the Laboratory of Cellular Oncology (G.J.S., C.B.), National Cancer Institute, the Translational and Functional Genomics Branch, National Human Genome Research Institute (D.M.P., J.A.S.), the Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute (A.F., W.J.L.), the Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases (H.H.K., I.B.), and the Center for Infectious Disease Imaging (D.A.H.), National Institutes of Health, and Walter Reed National Military Medical Center (M.I.O.) - all in Bethesda, MD; Vagelos College of Physicians and Surgeons, Columbia University, New York (E.M.M., J.S.O.); and the Department of Medicine and Department of Otolaryngology-Head and Neck Surgery, Northwestern University Feinberg School of Medicine, Chicago (A.T.P.)
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Peng T, Phasouk K, Bossard E, Klock A, Jin L, Laing KJ, Johnston C, Williams NA, Czartoski JL, Varon D, Long AN, Bielas JH, Snyder TM, Robins H, Koelle DM, McElrath MJ, Wald A, Corey L, Zhu J. Distinct populations of antigen-specific tissue-resident CD8+ T cells in human cervix mucosa. JCI Insight 2021; 6:149950. [PMID: 34156975 PMCID: PMC8410090 DOI: 10.1172/jci.insight.149950] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/25/2021] [Accepted: 06/18/2021] [Indexed: 11/17/2022] Open
Abstract
The ectocervix is part of the lower female reproductive tract (FRT), which is susceptible to sexually transmitted infections (STIs). Comprehensive knowledge of the phenotypes and T cell receptor (TCR) repertoire of tissue-resident memory T cells (TRMs) in the human FRT is lacking. We took single-cell RNA-Seq approaches to simultaneously define gene expression and TCR clonotypes of the human ectocervix. There were significantly more CD8+ than CD4+ T cells. Unsupervised clustering and trajectory analysis identified distinct populations of CD8+ T cells with IFNGhiGZMBloCD69hiCD103lo or IFNGloGZMBhiCD69medCD103hi phenotypes. Little overlap was seen between their TCR repertoires. Immunofluorescence staining showed that CD103+CD8+ TRMs were preferentially localized in the epithelium, whereas CD69+CD8+ TRMs were distributed evenly in the epithelium and stroma. Ex vivo assays indicated that up to 14% of cervical CD8+ TRM clonotypes were HSV-2 reactive in HSV-2-seropositive persons, reflecting physiologically relevant localization. Our studies identified subgroups of CD8+ TRMs in the human ectocervix that exhibited distinct expression of antiviral defense and tissue residency markers, anatomic locations, and TCR repertoires that target anatomically relevant viral antigens. Optimization of the location, number, and function of FRT TRMs is an important approach for improving host defenses to STIs.
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Affiliation(s)
- Tao Peng
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Laboratory Medicine and Pathology and
| | - Khamsone Phasouk
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Emily Bossard
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Alexis Klock
- Department of Laboratory Medicine and Pathology and
| | - Lei Jin
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Kerry J. Laing
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Christine Johnston
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Noel A. Williams
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Julie L. Czartoski
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Dana Varon
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Annalyssa N. Long
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jason H. Bielas
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | | | | | - David M. Koelle
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Laboratory Medicine and Pathology and
- Department of Medicine, University of Washington, Seattle, Washington, USA
- Department of Global Health, University of Washington, Seattle, Washington, USA
- Benaroya Research Institute, Seattle, Washington, USA
| | - M. Juliana McElrath
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Laboratory Medicine and Pathology and
- Department of Medicine, University of Washington, Seattle, Washington, USA
- Department of Global Health, University of Washington, Seattle, Washington, USA
| | - Anna Wald
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Laboratory Medicine and Pathology and
- Department of Medicine, University of Washington, Seattle, Washington, USA
- Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Lawrence Corey
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Laboratory Medicine and Pathology and
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Jia Zhu
- Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
- Department of Laboratory Medicine and Pathology and
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Venkataraman S, Hefferon K, Makhzoum A, Abouhaidar M. Combating Human Viral Diseases: Will Plant-Based Vaccines Be the Answer? Vaccines (Basel) 2021; 9:vaccines9070761. [PMID: 34358177 PMCID: PMC8310141 DOI: 10.3390/vaccines9070761] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/14/2021] [Revised: 07/02/2021] [Accepted: 07/04/2021] [Indexed: 12/28/2022] Open
Abstract
Molecular pharming or the technology of application of plants and plant cell culture to manufacture high-value recombinant proteins has progressed a long way over the last three decades. Whether generated in transgenic plants by stable expression or in plant virus-based transient expression systems, biopharmaceuticals have been produced to combat several human viral diseases that have impacted the world in pandemic proportions. Plants have been variously employed in expressing a host of viral antigens as well as monoclonal antibodies. Many of these biopharmaceuticals have shown great promise in animal models and several of them have performed successfully in clinical trials. The current review elaborates the strategies and successes achieved in generating plant-derived vaccines to target several virus-induced health concerns including highly communicable infectious viral diseases. Importantly, plant-made biopharmaceuticals against hepatitis B virus (HBV), hepatitis C virus (HCV), the cancer-causing virus human papillomavirus (HPV), human immunodeficiency virus (HIV), influenza virus, zika virus, and the emerging respiratory virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been discussed. The use of plant virus-derived nanoparticles (VNPs) and virus-like particles (VLPs) in generating plant-based vaccines are extensively addressed. The review closes with a critical look at the caveats of plant-based molecular pharming and future prospects towards further advancements in this technology. The use of biopharmed viral vaccines in human medicine and as part of emergency response vaccines and therapeutics in humans looks promising for the near future.
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Affiliation(s)
- Srividhya Venkataraman
- Virology Laboratory, Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3B2, Canada; (K.H.); (M.A.)
- Correspondence:
| | - Kathleen Hefferon
- Virology Laboratory, Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3B2, Canada; (K.H.); (M.A.)
| | - Abdullah Makhzoum
- Department of Biological Sciences & Biotechnology, Botswana International University of Science & Technology, Palapye, Botswana;
| | - Mounir Abouhaidar
- Virology Laboratory, Department of Cell & Systems Biology, University of Toronto, Toronto, ON M5S 3B2, Canada; (K.H.); (M.A.)
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21
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Microparticles and Nanoparticles from Plants-The Benefits of Bioencapsulation. Vaccines (Basel) 2021; 9:vaccines9040369. [PMID: 33920425 PMCID: PMC8069552 DOI: 10.3390/vaccines9040369] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/13/2021] [Revised: 04/04/2021] [Accepted: 04/09/2021] [Indexed: 11/25/2022] Open
Abstract
The efficacy of drugs and vaccines depends on their stability and ability to interact with their targets in vivo. Many drugs benefit from encapsulation, which protects them from harsh conditions and allows targeted delivery and controlled release. Although many encapsulation methods are inexpensive, such as the formulation of tablets for oral delivery, others require complex procedures that add significantly to production costs and require low-temperature transport and storage, making them inaccessible in developing countries. In this review we consider the benefits of encapsulation technologies based on plants. Plant-derived biopolymers such as starch and the maize storage protein zein are already used as protective coatings, but plant cells used as production host provide natural in vivo bioencapsulation that survives passage through the stomach and releases drugs in the intestine, due to the presence of microbes that can digest the cell wall. Proteins can also be encapsulated in subcellular compartments such as protein bodies, which ensure stability and activity while often conferring additional immunomodulatory effects. Finally, we consider the incorporation of drugs and vaccines into plant-derived nanoparticles assembled from the components of viruses. These are extremely versatile, allowing the display of epitopes and targeting peptides as well as carrying cargoes of drugs and imaging molecules.
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Han KH, Jang MS, Han HY, Im WJ, Jung KJ, Park KS, Choi D, Jeong HG, Kim SK, Moon KS. Preclinical safety assessment of a therapeutic human papillomavirus DNA vaccine combined with intravaginal interleukin-7 fused with hybrid Fc in female rats. Toxicol Appl Pharmacol 2021; 413:115406. [PMID: 33434572 DOI: 10.1016/j.taap.2021.115406] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/11/2020] [Revised: 01/03/2021] [Accepted: 01/07/2021] [Indexed: 11/19/2022]
Abstract
This study was conducted to establish the toxicological profile of combination treatment with therapeutic HPV DNA vaccines (GX-188E) and the long-acting form of recombinant human interleukin-7 fused with hybrid Fc (IL-7hyFc). GX-188E was administered intramuscularly by electroporation with or without IL-7hyFc intravaginally once per 2 weeks for 8 weeks (five times) in female Sprague-Dawley rats. Because up-regulation of immune responses and migration of antigen-specific T cells in cervicoviginal tissue were predicted as therapeutic effects, we distinguished adverse effects from therapeutic effects based on the severity of the systemic immune response, reversibility of lymphoid tissue changes, target tissue damage, and off-target immune responses. We observed that the number of neutrophils was increased, and the number of lymphocytes was decreased in the blood. Further, myofiber degeneration, necrosis, fibroplasia, and cell infiltration were observed at the GX-188E administration site. These changes were fully or partially recovered over a 4-week period. Analysis of lymphocytes in spleen revealed that CD4+ T cells and total T cells decreased in rats treated with GX-188E in combination with a high dose of IL-7hyFc (1.25 mg/animal). However, these changes were not considered adverse because they were transient and may have been related to electroporation-mediated DNA delivery or the local migration of lymphocytes induced by IL-7. Therefore, the potential toxicity of the combination of GX-188E and IL-7hyFc treatment was comparable to that of GX-188E treatment alone, and the no observed adverse effect level for GX-188E with IL-7hyFc was considered as 320 μg/animal for GX-188E and 1.25 mg/animal for IL-7hyFc.
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Affiliation(s)
- Kang-Hyun Han
- College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea; Department of Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Min Seong Jang
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Hyoung-Yun Han
- Department of Predictive Toxicology, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Wan-Jung Im
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Kyung Jin Jung
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea
| | - Ki Seok Park
- Research Institute, Genexine Inc., Korea Bio Park, Seongnam, Gyeonggi-do 13488, Republic of Korea
| | - Donghoon Choi
- Research Institute, NeoImmunetech, Inc., Rm501-1 Uspace2 B, Seongnam, Gyeonggi-do 13494, Republic of Korea
| | - Hye Gwang Jeong
- College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea
| | - Sang Kyum Kim
- College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, Republic of Korea.
| | - Kyoung-Sik Moon
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea; Human and Environmental Toxicology, University of Science and Technology, Daejeon 34114, Republic of Korea.
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Naupu PN, van Zyl AR, Rybicki EP, Hitzeroth II. Immunogenicity of Plant-Produced Human Papillomavirus (HPV) Virus-Like Particles (VLPs). Vaccines (Basel) 2020; 8:vaccines8040740. [PMID: 33291259 PMCID: PMC7762164 DOI: 10.3390/vaccines8040740] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/22/2020] [Revised: 11/16/2020] [Accepted: 11/29/2020] [Indexed: 12/14/2022] Open
Abstract
Cervical cancer is ranked fourth among the top cancers in women and is the second most common cancer in low- and middle-income regions, with ~570,000 new cases reported in 2018, which attributed to 84% of worldwide cervical cancer cases. Three commercially available prophylactic Human papillomavirus (HPV) vaccines are effective at preventing HPV infections. However, these vaccines are expensive due to their complex production systems, therefore limiting their use in developing countries. Recently, the use of plants to produce vaccines has emerged as a cost-effective alternative to conventionally used expression systems. Here, L1 proteins of eight high-risk (HPV 16, 18, 31, 33, 35, 45, 52, and 58) and two low risk (HPV 6 and 34) HPV types were successfully expressed in Nicotiana benthamiana, and transmission electron microscopy (TEM) analysis showed the presence of VLPs and/or capsomeres. Immunogenicity studies were conducted in mice utilizing HPV 35, 52, and 58 and showed that type-specific L1-specific antibodies were produced which were able to successfully neutralize homologous HPV pseudovirions in pseudovirion-based neutralization assays (PBNAs). This work demonstrated the potential for using plant-based transient expression systems to produce affordable and immunogenic HPV vaccines, particularly for developing countries.
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Affiliation(s)
- Paulina N. Naupu
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa; (P.N.N.); (E.P.R.); (I.I.H.)
| | - Albertha R. van Zyl
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa; (P.N.N.); (E.P.R.); (I.I.H.)
- Correspondence: ; Tel.: +27-21-650-5232
| | - Edward P. Rybicki
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa; (P.N.N.); (E.P.R.); (I.I.H.)
- Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa
| | - Inga I. Hitzeroth
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch 7701, South Africa; (P.N.N.); (E.P.R.); (I.I.H.)
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Development of HPV 16,18,31,45 E5 and E7 peptides-based vaccines predicted by immunoinformatics tools. Biotechnol Lett 2020; 42:403-418. [PMID: 31915962 PMCID: PMC7087594 DOI: 10.1007/s10529-020-02792-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/23/2019] [Accepted: 01/02/2020] [Indexed: 12/17/2022]
Abstract
Objectives Viral oncoproteins are ideal targets in therapeutic vaccines for functional inhibition of human papillomaviruses (HPVs). Herein, we designed the peptide constructs derived from E5 and E7 oncoproteins of high-risk HPV types 16, 18, 31 and 45 using the bioinformatics tools and investigated their potency in mice. Results The framework of the combined in silico/in vivo analysis included (1) to determine physicochemical properties of the designed constructs, (2) to identify potential IFN-γ-inducing epitopes, (3) to assess allergenicity, (4) to recognize linear and discontinuous B cell epitopes using modeling and validation of 3D structure of the designed constructs, and (5) to evaluate immune responses and tumor growth in vivo. Our in silico data determined high potency of the HPV16,18,31,45 E5 and HPV16,18,31,45 E7 peptides for trigger B- and T-cell responses, and IFN-γ secretion. In vivo study indicated that the mixture of E5 and E7 immunodominant peptides from four types of high-risk HPV could induce Th1 immune response, and protect completely mice against TC-1 tumor cells. Conclusion Generally, the combined in silico/in vivo approaches showed the ability of the designed E5 and E7 peptide constructs from four major high-risk HPV types for development of therapeutic vaccines. Electronic supplementary material The online version of this article (10.1007/s10529-020-02792-6) contains supplementary material, which is available to authorized users.
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Seong J, Ryou S, Yoo M, Lee J, Kim K, Jee Y, Cho CH, Kim SM, Hong SR, Jeong DH, Lee WC, Park JS, Kim TJ, Kee MK. Status of HPV vaccination among HPV-infected women aged 20-60 years with abnormal cervical cytology in South Korea: a multicenter, retrospective study. J Gynecol Oncol 2019; 31:e4. [PMID: 31788994 PMCID: PMC6918886 DOI: 10.3802/jgo.2020.31.e4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/01/2019] [Revised: 06/12/2019] [Accepted: 06/19/2019] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVES Since 2007, human papillomavirus (HPV) vaccines have been administered for the prevention of cervical cancer in Korea. We investigated the status of HPV vaccination among HPV-infected adult women with abnormal cervical cytology before the introduction of National Immunization Program. METHODS From 2010 to 2016, HPV-positive women (age, 20-60 years) with atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion (LSIL) were enrolled from five hospitals across Korea. Their HPV genotype, epidemiologic, and clinical data, including HPV vaccination history, were obtained. We compared the epidemiological characteristics and prevalence of HPV-16/18 genotypes between vaccinated and unvaccinated women. RESULTS Among the 1,300 women, approximately 26% had a history of vaccination. Vaccinated patients were significantly younger, unmarried, and had a higher education level than unvaccinated women. For HPV-vaccinated individuals by vaccine dose, there was a significant younger age at vaccination initiation (p=0.025), longer duration from HPV vaccination to Pap test date (p=0.001), and lower proportion of HPV-16/18 (p=0.028) in the women with three doses. There was a significantly lower prevalence of HPV-16/18 genotypes in women who were vaccinated at least 12 months prior than in unvaccinated women (adjusted prevalence ratio [aPR]=0.51; 95% confidence interval [CI]=0.29-0.88). For women with LSIL, the prevalence of the HPV-16/18 genotypes was significantly lower in women who were vaccinated more than 12 months prior than in unvaccinated women (aPR=0.35; 95% CI=0.13-0.96). CONCLUSION This study highlighted the status of HPV vaccination and the prevalence of HPV-16/18 genotypes among HPV-infected women with abnormal cervical cytology according to HPV vaccination. It provides preliminary information regarding the status of HPV vaccination among Korean adult women.
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Affiliation(s)
- Jaehyun Seong
- Division of Viral Diseases Research, Center for Infectious Diseases Research, Korea National Institute of Health, Cheongju, Korea
| | - Sangmi Ryou
- Division of Viral Diseases Research, Center for Infectious Diseases Research, Korea National Institute of Health, Cheongju, Korea
| | - Myeongsu Yoo
- Division of Viral Diseases Research, Center for Infectious Diseases Research, Korea National Institute of Health, Cheongju, Korea
| | - JeongGyu Lee
- Division of Viral Diseases Research, Center for Infectious Diseases Research, Korea National Institute of Health, Cheongju, Korea
| | - Kisoon Kim
- Division of Viral Diseases Research, Center for Infectious Diseases Research, Korea National Institute of Health, Cheongju, Korea
| | - Youngmee Jee
- Center for Infectious Diseases Research, Korea National Institute of Health, Cheongju, Korea
| | - Chi Heum Cho
- Department of Obstetrics and Gynecology, Keimyung University Dongsan Medical Center, Daegu, Korea
| | - Seok Mo Kim
- Department of Obstetrics and Gynecology, Chonnam National University Medical School, Gwangju, Korea
| | - Sung Ran Hong
- Department of Pathology, Cheil General Hospital and Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea
| | - Dae Hoon Jeong
- Department of Obstetrics and Gynecology, Inje University Busan Paik Hospital, University College of Medicine, Busan, Korea
| | - Won Chul Lee
- Department of Preventive Medicine, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Jong Sup Park
- Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, The Catholic University of Korea College of Medicine, Seoul, Korea
| | - Tae Jin Kim
- Department of Obstetrics and Gynecology, Cheil General Hospital and Women's Healthcare Center, Dankook University, Seoul, Korea
| | - Mee Kyung Kee
- Division of Viral Diseases Research, Center for Infectious Diseases Research, Korea National Institute of Health, Cheongju, Korea.
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Taleghani N, Bozorg A, Azimi A, Zamani H. Immunogenicity of HPV and HBV vaccines: adjuvanticity of synthetic analogs of monophosphoryl lipid A combined with aluminum hydroxide. APMIS 2019; 127:150-157. [PMID: 30746792 DOI: 10.1111/apm.12927] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/01/2018] [Accepted: 12/28/2018] [Indexed: 11/29/2022]
Abstract
Monophosphoryl lipid A (MPL), a purified and detoxified product of lipopolysaccharide (LPS) of Salmonella minnesota R595, has been used as an adjuvant in different vaccines. In this study, the efficacy of human papillomaviruses (HPV) and hepatitis B virus (HBV) vaccines formulated with aluminum hydroxide combined with two different synthetic MPLs, 3D-(6-acyl)-PHAD or 3D-PHAD, or aluminum hydroxide combined with the mixtures of such MPLs, has been assessed. The immunogenicity in female BALB/c mice was verified by two intramuscular injections of differently formulated HPV and HBV vaccines and the total immunoglobulin G (IgG) antibody response was considered to compare the employed adjuvants. As verified experimentally, a mixture of 3D-(6-acyl)-PHAD and 3D-PHAD was able to induce significantly higher antibody titer than that of either 3D-(6-acyl)-PHAD or 3D-PHAD, when used individually. Interestingly, based on the responses achieved in terms of the total antibody levels, such mixture of synthetic MPLs was found to be even more effective than the bacterially derived MPL. Accordingly, the obtained results indicated that, if designed appropriately, synthetic MPL molecules could provide improved adjuvanticity with high level of consistency.
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Affiliation(s)
- Nastaran Taleghani
- Biotechnology Department, College of Science, University of Tehran, Tehran, Iran
| | - Ali Bozorg
- Biotechnology Department, College of Science, University of Tehran, Tehran, Iran
| | - Amin Azimi
- Biotechnology Department, College of Science, University of Tehran, Tehran, Iran
| | - Homa Zamani
- Department of Cell Therapy and Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Panahi HA, Bolhassani A, Javadi G, Noormohammadi Z. A comprehensive in silico analysis for identification of therapeutic epitopes in HPV16, 18, 31 and 45 oncoproteins. PLoS One 2018; 13:e0205933. [PMID: 30356257 PMCID: PMC6200245 DOI: 10.1371/journal.pone.0205933] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/28/2018] [Accepted: 09/11/2018] [Indexed: 11/25/2022] Open
Abstract
Human papillomaviruses (HPVs) are a group of circular double-stranded DNA viruses, showing severe tropism to mucosal tissues. A subset of HPVs, especially HPV16 and 18, are the primary etiological cause for several epithelial cell malignancies, causing about 5.2% of all cancers worldwide. Due to the high prevalence and mortality, HPV-associated cancers have remained as a significant health problem in human society, making an urgent need to develop an effective therapeutic vaccine against them. Achieving this goal is primarily dependent on the identification of efficient tumor-associated epitopes, inducing a robust cell-mediated immune response. Previous information has shown that E5, E6, and E7 early proteins are responsible for the induction and maintenance of HPV-associated cancers. Therefore, the prediction of major histocompatibility complex (MHC) class I T cell epitopes of HPV16, 18, 31 and 45 oncoproteins was targeted in this study. For this purpose, a two-step plan was designed to identify the most probable CD8+ T cell epitopes. In the first step, MHC-I and II binding, MHC-I processing, MHC-I population coverage and MHC-I immunogenicity prediction analyses, and in the second step, MHC-I and II protein-peptide docking, epitope conservation, and cross-reactivity with host antigens’ analyses were carried out successively by different tools. Finally, we introduced five probable CD8+ T cell epitopes for each oncoprotein of the HPV genotypes (60 epitopes in total), which obtained better scores by an integrated approach. These predicted epitopes are valuable candidates for in vitro or in vivo therapeutic vaccine studies against the HPV-associated cancers. Additionally, this two-step plan that each step includes several analyses to find appropriate epitopes provides a rational basis for DNA- or peptide-based vaccine development.
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Affiliation(s)
- Heidar Ali Panahi
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
- * E-mail: ,
| | - Gholamreza Javadi
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Zahra Noormohammadi
- Department of Biology, School of Basic Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran
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Cancer Vaccine Immunotherapy with RNA-Loaded Liposomes. Int J Mol Sci 2018; 19:ijms19102890. [PMID: 30249040 PMCID: PMC6213933 DOI: 10.3390/ijms19102890] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/08/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 12/11/2022] Open
Abstract
Cancer vaccines may be harnessed to incite immunity against poorly immunogenic tumors, however they have failed in therapeutic settings. Poor antigenicity coupled with systemic and intratumoral immune suppression have been significant drawbacks. RNA encoding for tumor associated or specific epitopes can serve as a more immunogenic and expeditious trigger of anti-tumor immunity. RNA stimulates innate immunity through toll like receptor stimulation producing type I interferon, and it mediates potent adaptive responses. Since RNA is inherently unstable, delivery systems have been developed to protect and deliver it to intended targets in vivo. In this review, we discuss liposomes as RNA delivery vehicles and their role as cancer vaccines.
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Overexpression of a virus-like particle influenza vaccine in Eri silkworm pupae, using Autographa californica nuclear polyhedrosis virus and host-range expansion. Arch Virol 2018; 163:2787-2797. [PMID: 30027487 DOI: 10.1007/s00705-018-3941-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/04/2018] [Accepted: 06/28/2018] [Indexed: 12/26/2022]
Abstract
Ecological investigations of silkworms have revealed that Eri silkworms (Samia cynthia ricini) possess useful morphological and ecological characteristics for virus-like particle (VLP) production, namely non-seasonal breeding, longer lengths, and heavier weights than Bombyx mori silkworms. Furthermore, when vector DNA from Bombyx mori nuclear polyhedrosis virus (BmNPV), which is unable to replicate in Sf9 cells from Eri silkworms, was replaced with the Autographa californica nuclear polyhedrosis virus (AcNPV) vector, three improved AcNPV influenza virus recombinants capable of replication in Sf9 cells were obtained. Although VLP antigens produced previously in silkworms were not evaluated individually, the present recombinant Fukushima (FkH5) and Anhui (AnH7) VLP antigens were detected in tissue fluids and fat bodies of Eri silkworms. Here, we aimed to determine the function of the AcNPV vector and P143 gene by expressing recombinants in Sf9 cells and eri silkworm pupae. The FkH5 recombinant produced high yields of haemagglutinin (HA)-positive VLPs, showing a mean HA titre of 1.2 million. Similarly, high production of H7 HA VLPs was observed in the fat bodies of eri silkworm pupae. Antigenic analysis and electron microscopy examination of Eri-silkworm-produced H5 HA VLPs showed characteristic antigenicity and morphology similar to those of the influenza virus. Although FkH5 recombinants possessing the AcNPV vector did not replicate in Bm-N cells, the introduction of the helicase p143 gene from BmNPV resulted in their production in Bm-N and Sf9 cells.
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Hitzeroth II, Chabeda A, Whitehead MP, Graf M, Rybicki EP. Optimizing a Human Papillomavirus Type 16 L1-Based Chimaeric Gene for Expression in Plants. Front Bioeng Biotechnol 2018; 6:101. [PMID: 30062095 PMCID: PMC6054922 DOI: 10.3389/fbioe.2018.00101] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/30/2018] [Accepted: 06/26/2018] [Indexed: 12/28/2022] Open
Abstract
Human papillomaviruses (HPVs) are the causative agents of cervical cancer, the fourth most prevalent cancer in women worldwide. The major capsid protein L1 self-assembles into virus-like particles (VLPs), even in the absence of the minor L2 protein: such VLPs have successfully been used as prophylactic vaccines. There remains a need, however, to develop cheaper vaccines that protect against a wider range of HPV types. The use of all or parts of the L2 minor capsid protein can potentially address this issue, as it has sequence regions conserved across several HPV types, which can elicit a wider spectrum of cross-neutralizing antibodies. Production of HPV VLPs in plants is a viable option to reduce costs; the use of a L1/L2 chimera which has previously elicited a cross-protective immune response is an option to broaden cross-protection. The objective of this study was to investigate the effect of codon optimization and of increasing the G+C content of synthetic L1/L2 genes on protein expression in plants. Additionally, we replaced varying portions of the 5' region of the L1 gene with the wild type (wt) viral sequence to determine the effect of several negative regulatory elements on expression. We showed that GC-rich genes resulted in a 10-fold increase of mRNA levels and 3-fold higher accumulation of proteins. However, the highest increase of expression was achieved with a high GC-content human codon-optimized gene, which resulted in a 100-fold increase in mRNA levels and 8- to 9-fold increase in protein levels. Changing the 5' end of the L1 gene back to its wt sequence decreased mRNA and protein expression. Our results suggest that the negative elements in the 5' end of L1 are inadvertently destroyed by changing the codon usage, which enhances protein expression.
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Affiliation(s)
- Inga I Hitzeroth
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch, South Africa
| | - Aleyo Chabeda
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch, South Africa
| | - Mark P Whitehead
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch, South Africa
| | - Marcus Graf
- Thermo Fisher Scientific GENEART GmbH, Regensburg, Germany
| | - Edward P Rybicki
- Biopharming Research Unit, Department of Molecular and Cell Biology, University of Cape Town, Rondebosch, South Africa.,Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory, South Africa
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Ying Q, Ma T, Cheng L, Zhang X, Truax AD, Ma R, Liu Z, Lei Y, Zhang L, Ye W, Zhang F, Xu Z, Shang L, Liu R, Wang F, Wu X. Construction and immunological characterization of CD40L or GM-CSF incorporated Hantaan virus like particle. Oncotarget 2018; 7:63488-63503. [PMID: 27542281 PMCID: PMC5325379 DOI: 10.18632/oncotarget.11329] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/28/2016] [Accepted: 07/10/2016] [Indexed: 12/22/2022] Open
Abstract
Infection of Hantaan virus (HTNV) usually causes hemorrhagic fever with renal syndrome (HFRS). China has the worst epidemic incidence of HFRS as well as high fatality. Inactivated whole virus has been used for HFRS vaccination, however there are still problems such as safety concerns. CD40 ligand (CD40L) and granulocyte macrophage colony-stimulating factor (GM-CSF) are well-known immune stimulating molecules that can enhance antigen presenting, lymphocytes activation and maturation, incorporation of CD40L and GM-CSF to the surface of virus like particles (VLPs) can greatly improve the vaccination effect. We constructed eukaryotic vectors expressing HTNV M segment and S segment, as well as vectors expressing HTNV M segment with CD40L or GM-CSF, our results showed successful production of CD40L or GM-CSF incorporated HTNV VLPs. In vitro stimulation with CD40L or GM-CSF anchored HTNV VLP showed enhanced activation of macrophages and DCs. CD40L/GM-CSF incorporated VLP can induce higher level of HTNV specific antibody and neutralizing antibody in mice. Immunized mice splenocytes showed higher ability of secreting IFN-γ and IL-2, as well as enhancing CTL activity. These results suggest CD40L/GM-CSF incorporated VLP can serve as prospective vaccine candidate.
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Affiliation(s)
- Qikang Ying
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Tiejun Ma
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Linfeng Cheng
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Xiaoxiao Zhang
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Agnieszka D Truax
- The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA
| | - Ruixue Ma
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Ziyu Liu
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Yingfeng Lei
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Liang Zhang
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Wei Ye
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Fanglin Zhang
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Zhikai Xu
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Lei Shang
- Department of Statistics, Fourth Military Medical University, Xi'an, 710032, China
| | - Rongrong Liu
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Fang Wang
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
| | - Xingan Wu
- Department of Microbiology, School of Basic Medicine, Fourth Military Medical University, Xi'an, 710032, China
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Kamada M, Inui H, Kagawa T, Mineda A, Tamura T, Fujioka T, Motoki T, Hirai H, Ishii E, Irahara M. What information can change the attitude of teachers toward the human papillomavirus vaccine? J Obstet Gynaecol Res 2018; 44:778-787. [PMID: 29442400 DOI: 10.1111/jog.13584] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/17/2017] [Accepted: 12/18/2017] [Indexed: 12/22/2022]
Abstract
AIM We conducted a self-administered survey on the perception of teachers toward human papillomavirus (HPV) vaccine to determine the ways to increase their willingness to encourage its use. METHODS Answers were obtained both prior to and after having the teachers read five brief information articles: (i) cervical cancer knowledge, (ii) vaccine knowledge, (iii) result of a survey in Nagoya, (iv) news report of the World Health Organization statement and (v) articles written by Dr Muranaka, a journalist. RESULTS Most of the respondents (180/247) did not know about the natural history of cervical cancer. Only 36% knew that HPV is the cause of cervical cancer, although 63% knew that HPV vaccine would prevent cervical cancer. Few respondents had knowledge regarding adverse events following immunization and the survey results from Nagoya. Among those who were initially negative for the HPV vaccine, only 43% revealed that they fully understood its safety and only 29% reversed their opinion to recommend vaccination to their daughters and/or students, even after reading our informational material. The most useful information for changing their attitudes was to increase their understanding of vaccines and informing them about Nagoya city survey results. They mostly wanted a proof of the preventive effects of the vaccine on cervical cancer in Japan. CONCLUSION Gynecologists and pediatricians must proactively communicate accurate scientific information to the government and the media to spread awareness among people in Japan. Also, we must try to demonstrate the capabilities of this vaccine to prevent cervical cancer and/or its precancerous lesions.
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Affiliation(s)
- Masaharu Kamada
- Department of Obstetrics and Gynecology, Shikoku-chuo, Japan
| | - Hiroaki Inui
- Department of Obstetrics and Gynecology, Shikoku-chuo, Japan
| | - Tomohiro Kagawa
- Department of Obstetrics and Gynecology, Shikoku-chuo, Japan
| | - Ayuka Mineda
- Department of Obstetrics and Gynecology, Shikoku-chuo, Japan
| | - Takao Tamura
- Department of Obstetrics and Gynecology, Shikoku-chuo, Japan
| | - Tomohito Fujioka
- Department of Pediatrics, Shikoku Central Hospital of the Mutual Aid Association of Public School Teachers, Shikoku-chuo, Japan
| | - Takahiro Motoki
- Department of Pediatrics, Shikoku Central Hospital of the Mutual Aid Association of Public School Teachers, Shikoku-chuo, Japan
| | - Hiroki Hirai
- Department of Pediatrics, Shikoku Central Hospital of the Mutual Aid Association of Public School Teachers, Shikoku-chuo, Japan
| | - Eiichi Ishii
- Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan
| | - Minoru Irahara
- Department of Obstetrics and Gynecology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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Ramondetta L. Response to Harper and De Mars, HPV vaccines: A review of the first decade. Gynecol Oncol Rep 2017; 22:113-114. [PMID: 29296654 PMCID: PMC5741802 DOI: 10.1016/j.gore.2017.10.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 09/20/2017] [Accepted: 10/02/2017] [Indexed: 12/26/2022] Open
Affiliation(s)
- Lois Ramondetta
- Gynecologic Oncology, UT MD Anderson Cancer Center, Lyndon Baines Johnson Hospital, Harris Health System, Houston, TX, USA
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Li J, Chen S, Ge J, Lu F, Ren S, Zhao Z, Pu X, Chen X, Sun J, Gu Y. A novel therapeutic vaccine composed of a rearranged human papillomavirus type 16 E6/E7 fusion protein and Fms-like tyrosine kinase-3 ligand induces CD8 + T cell responses and antitumor effect. Vaccine 2017; 35:6459-6467. [PMID: 29029939 DOI: 10.1016/j.vaccine.2017.09.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/21/2017] [Revised: 07/26/2017] [Accepted: 09/03/2017] [Indexed: 01/15/2023]
Abstract
The development of cervical cancer is mainly caused by infection with high risk genotypes of human papillomavirus, particularly type 16 (HPV16), which accounts for more than 50% of cervical cancer. The two early viral oncogenes, E6 and E7, are continuously expressed in cervical cancer cells and are necessary to maintain the malignant cellular phenotype, thus providing ideal targets for immunotherapy of cervical cancer. In this study, a novel vaccine strategy was developed based on a rationally shuffled HPV16 E6/E7 fusion protein, the addition of Fms-like tyrosine kinase-3 ligand (Flt3L) or the N domain of calreticulin (NCRT), and the usage of a CpG adjuvant. Four recombinant proteins were constructed: m16E6E7 (mutant E6/E7 fusion protein), rm16E6E7 (rearranged mutant HPV16 E6/E7 fusion protein), Flt3L-RM16 (Flt3L fused to rm16E6E7), and NCRT-RM16 (NCRT fused to rm16E6E7). Our results suggest that Flt3L-RM16 was the most potent of these proteins in terms of inducing E6- and E7-specific CD8+ T cell responses. Additionally, Flt3L-RM16 significantly induced regression of established E6/E7-expressing TC-1 tumors. Higher doses of Flt3L-RM16 trended toward higher levels of antitumor activity, but these differences did not reach statistical significance. In summary, this study found that Flt3L-RM16 fusion protein is a promising therapeutic vaccine for immunotherapy of HPV16-associated cervical cancer.
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Affiliation(s)
- Jianqiang Li
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Si Chen
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Jun Ge
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Feng Lu
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Sulin Ren
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Zhiqiang Zhao
- Suzhou Yuankang Bio-pharmaceutical Co., Ltd., Suzhou, China.
| | - Xiuying Pu
- Suzhou Yuankang Bio-pharmaceutical Co., Ltd., Suzhou, China.
| | - Xiaoxiao Chen
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Jiaojiao Sun
- Jiangsu Theravac Bio-pharmaceutical CO., Ltd, Nanjing, China.
| | - Yueqing Gu
- China Pharmaceutical University, Nanjing, China.
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35
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Kidd LC, Chaing S, Chipollini J, Giuliano AR, Spiess PE, Sharma P. Relationship between human papillomavirus and penile cancer-implications for prevention and treatment. Transl Androl Urol 2017; 6:791-802. [PMID: 29184775 PMCID: PMC5673821 DOI: 10.21037/tau.2017.06.27] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/16/2017] [Accepted: 06/22/2017] [Indexed: 11/06/2022] Open
Abstract
Penile cancer is a rare disease in the United States, but rates are increasing, causing concern. Several risk factors have been associated with the disease, including human papillomavirus (HPV) infection. Knowledge of HPV pathogenesis has led to the development of a vaccine, which has proven instrumental in reducing the incidence of female HPV-related cancers, but results in men have yet to be elucidated. Fortunately, rates of vaccination are up-trending in both males and females in the past several years. In addition, targeted therapies are the focus of several ongoing research efforts. Some of these therapeutics are currently in use, while several are in trials. With continued patient education and research, both treatment and prevention of HPV-related pre-malignant lesions and penile cancer will likely diminish.
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Affiliation(s)
- Laura C. Kidd
- Department of Urology, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Sharon Chaing
- Department of Urology, University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Juan Chipollini
- Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Anna R. Giuliano
- Center for Infection Research in Cancer (CIRC), Moffitt Cancer Center, Tampa, FL, USA
| | - Philippe E. Spiess
- Department of Genitourinary Oncology, Moffitt Cancer Center, Tampa, FL, USA
| | - Pranav Sharma
- Department of Urology, Texas Tech University Health Sciences Center, Lubbock, TX, USA
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36
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Genotipificación del virus del papiloma humano en un grupo de mujeres mexicanas atendidas en un hospital de alta especialidad: las infecciones múltiples y su potencial trascendencia en el esquema actual de vacunación. Med Clin (Barc) 2017; 149:287-292. [DOI: 10.1016/j.medcli.2017.02.021] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/28/2016] [Revised: 02/04/2017] [Accepted: 02/09/2017] [Indexed: 11/22/2022]
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37
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Holanda RA, Muñoz JE, Dias LS, Silva LBR, Santos JRA, Pagliari S, Vieira ÉLM, Paixão TA, Taborda CP, Santos DA, Bruña-Romero O. Recombinant vaccines of a CD4+ T-cell epitope promote efficient control of Paracoccidioides brasiliensis burden by restraining primary organ infection. PLoS Negl Trop Dis 2017; 11:e0005927. [PMID: 28938005 PMCID: PMC5627964 DOI: 10.1371/journal.pntd.0005927] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/08/2017] [Revised: 10/04/2017] [Accepted: 09/02/2017] [Indexed: 11/19/2022] Open
Abstract
Paracoccidioidomycosis (PCM) is an infectious disease endemic to South America, caused by the thermally dimorphic fungi Paracoccidioides. Currently, there is no effective human vaccine that can be used in prophylactic or therapeutic regimes. We tested the hypothesis that the immunogenicity of the immunodominant CD4+ T-cell epitope (P10) of Paracoccidioides brasiliensis gp43 antigen might be significantly enhanced by using a hepatitis B virus-derived particle (VLP) as an antigen carrier. This chimera was administered to mice as a (His)6-purified protein (rPbT) or a replication-deficient human type 5 adenoviral vector (rAdPbT) in an immunoprophylaxis assay. The highly virulent Pb18 yeast strain was used to challenge our vaccine candidates. Fungal challenge evoked robust P10-specific memory CD4+ T cells secreting protective Th-1 cytokines in most groups of immunized mice. Furthermore, the highest level of fungal burden control was achieved when rAdPbT was inoculated in a homologous prime-boost regimen, with 10-fold less CFU recovering than in non-vaccinated mice. Systemic Pb18 spreading was only prevented when rAdPbT was previously inoculated. In summary, we present here VLP/P10 formulations as vaccine candidates against PCM, some of which have demonstrated for the first time their ability to prevent progression of this pernicious fungal disease, which represents a significant social burden in developing countries.
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MESH Headings
- Animals
- Antigens, Fungal/immunology
- CD4-Positive T-Lymphocytes/immunology
- Cytokines/immunology
- Cytokines/metabolism
- Epitopes, T-Lymphocyte/genetics
- Epitopes, T-Lymphocyte/immunology
- Fungal Proteins/immunology
- Fungal Vaccines/administration & dosage
- Fungal Vaccines/immunology
- Glycoproteins/immunology
- Hepatitis B virus/genetics
- Immunization
- Immunodominant Epitopes/immunology
- Immunogenicity, Vaccine
- Immunologic Memory
- Liver/microbiology
- Lung/microbiology
- Mice, Inbred BALB C
- Paracoccidioides/growth & development
- Paracoccidioides/immunology
- Paracoccidioidomycosis/immunology
- Paracoccidioidomycosis/microbiology
- Paracoccidioidomycosis/prevention & control
- Spleen/microbiology
- Th1 Cells/immunology
- Vaccines, Synthetic/administration & dosage
- Vaccines, Synthetic/genetics
- Vaccines, Synthetic/immunology
- Vaccines, Virus-Like Particle/administration & dosage
- Vaccines, Virus-Like Particle/genetics
- Vaccines, Virus-Like Particle/immunology
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Affiliation(s)
- Rodrigo Assunção Holanda
- Departamento de Microbiologia, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
- Laboratório de Biologia Parasitária, Universidade CEUMA, Maranhão, Brazil
- * E-mail:
| | - Julián Esteban Muñoz
- Departamento de Microbiologia, Universidade de São Paulo, São Paulo, Brazil
- Escuela de Medicina y Ciencias de la Salud, Universidad del Rosario, Bogotá, Colombia
| | - Lucas Santos Dias
- Departamento de Microbiologia, Universidade de São Paulo, São Paulo, Brazil
| | | | - Julliana Ribeiro Alves Santos
- Departamento de Microbiologia, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
- Laboratório de Microbiologia Ambiental, Universidade CEUMA, Maranhão, Brazil
| | - Sthefany Pagliari
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Santa Catarina, Brazil
| | | | - Tatiane Alves Paixão
- Departamento de Patologia Geral, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
| | | | - Daniel Assis Santos
- Departamento de Microbiologia, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
| | - Oscar Bruña-Romero
- Departamento de Microbiologia, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
- Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina, Santa Catarina, Brazil
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38
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Cai L, Yu R, Hao X, Ding X. Folate Receptor-targeted Bioflavonoid Genistein-loaded Chitosan Nanoparticles for Enhanced Anticancer Effect in Cervical Cancers. NANOSCALE RESEARCH LETTERS 2017; 12:509. [PMID: 28853026 PMCID: PMC5574823 DOI: 10.1186/s11671-017-2253-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 05/26/2017] [Accepted: 07/27/2017] [Indexed: 05/23/2023]
Abstract
In this study, novel folic acid-conjugated chitosan nanoparticle was formulated for specific delivery of bioflavonoid, Genistein (GEN), to the cervical cancer cells. The prepared GEN-loaded chitosan nanoparticles (GCN) and folic acid-conjugated GCN (FGCN) showed smaller size with a controlled drug release profile. FGCN exhibited enhanced internalization potential in HeLa cells than that of GCN. The specific internalization of FGCN was mainly due to the affinity of folic acid (FA) with FRs-α which is present in large numbers in HeLa cells. The results revealed that FGCN has a specific affinity towards HeLa cells that will contribute to the better treatment. Folic acid-tagged nanoformulations exhibited a superior cytotoxic effect compared to that of non-targeted formulations. Consistently, IC50 value of GEN decreased from 33.8 to 14.6 μg/ml when treated with FGCN after 24 h incubation. The apoptosis studies indicated that the FGCN nanoparticles were then either GCN or free GEN in terms of anticancer activity. Overall, results revealed that folate conjugation to the delivery system might have great effect on the survival of cervical cancers that will be beneficial for overall cancer treatment.
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Affiliation(s)
- Limei Cai
- Department of Gynaecology and Obstetrics, Ruian People’s Hospital, Ruian, Zhejiang 325200 China
| | - Rufen Yu
- Department of Gynaecology and Obstetrics, Ruian People’s Hospital, Ruian, Zhejiang 325200 China
| | - Xi Hao
- Department of Gynaecology and Obstetrics, Ruian People’s Hospital, Ruian, Zhejiang 325200 China
| | - Xiangcui Ding
- Department of Gynaecology and Obstetrics, Ruian People’s Hospital, Ruian, Zhejiang 325200 China
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39
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Mishra P, Dey RK. Development of docetaxel-loaded PEG–PLA nanoparticles using surfactant-free method for controlled release studies. INT J POLYM MATER PO 2017. [DOI: 10.1080/00914037.2017.1354193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/02/2023]
Affiliation(s)
- Prajna Mishra
- Centre for Applied Chemistry, Central University of Jharkhand, Ranchi, India
| | - Ratan Kumar Dey
- Centre for Applied Chemistry, Central University of Jharkhand, Ranchi, India
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41
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Gu Y, Wei M, Wang D, Li Z, Xie M, Pan H, Wu T, Zhang J, Li S, Xia N. Characterization of an Escherichia coli-derived human papillomavirus type 16 and 18 bivalent vaccine. Vaccine 2017; 35:4637-4645. [PMID: 28736197 DOI: 10.1016/j.vaccine.2017.06.084] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/18/2017] [Revised: 06/23/2017] [Accepted: 06/24/2017] [Indexed: 12/26/2022]
Abstract
Human papillomavirus (HPV) types 16 and 18 account for approximately 70% of cervical cancer worldwide. Neutralizing HPV prophylactic vaccines offer significant benefit, as they block HPV infection and prevent subsequent disease. However, the three licensed HPV vaccines that cover these two genotypes were produced in eukaryotic cells, which is expensive, particularly for low-income countries where HPV is highest. Here, we report a new HPV16 and -18 bivalent candidate vaccine produced from Escherichia coli. We used two strategies of N-terminal truncation of HPV L1 proteins and soluble non-fusion expression to generate HPV16 and HPV18 L1-only virus-like particles (VLPs) in a scalable process. Through comprehensive characterization of the bivalent candidate vaccine, we confirm lot consistency in a pilot scale-up of 30L, 100L and 500L. Using cryo-EM 3D reconstruction, we found that HPV16 and -18VLPs present in a T=7 icosahedral arrangement, similar in shape and size to that of the native virions. This HPV16/18 bivalent vaccine shares comparable immunogenicity with the licensed vaccines. Overall, we show that the production of a HPV16/18 bivalent vaccine from an E. coli expression system is robust and scalable, with potentially good accessibility worldwide as a population-based immunization strategy.
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Affiliation(s)
- Ying Gu
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Life Sciences, Xiamen University, Xiamen 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Minxi Wei
- Xiamen Innovax Biotech Company, Ltd, Xiamen, Fujian 361022, China
| | - Daning Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zhihai Li
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Minghui Xie
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Life Sciences, Xiamen University, Xiamen 361102, China
| | - Huirong Pan
- Xiamen Innovax Biotech Company, Ltd, Xiamen, Fujian 361022, China
| | - Ting Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jun Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Shaowei Li
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Life Sciences, Xiamen University, Xiamen 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Ningshao Xia
- National Institute of Diagnostics and Vaccine Development in Infectious Disease, School of Life Sciences, Xiamen University, Xiamen 361102, China; State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
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Spontaneous and Vaccine-Induced Clearance of Mus Musculus Papillomavirus 1 Infection. J Virol 2017; 91:JVI.00699-17. [PMID: 28515303 PMCID: PMC5512245 DOI: 10.1128/jvi.00699-17] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/25/2017] [Accepted: 05/07/2017] [Indexed: 12/24/2022] Open
Abstract
Mus musculus papillomavirus 1 (MmuPV1/MusPV1) induces persistent papillomas in immunodeficient mice but not in common laboratory strains. To facilitate the study of immune control, we sought an outbred and immunocompetent laboratory mouse strain in which persistent papillomas could be established. We found that challenge of SKH1 mice (Crl:SKH1-Hrhr) with MmuPV1 by scarification on their tail resulted in three clinical outcomes: (i) persistent (>2-month) papillomas (∼20%); (ii) transient papillomas that spontaneously regress, typically within 2 months (∼15%); and (iii) no visible papillomas and viral clearance (∼65%). SKH1 mice with persistent papillomas were treated by using a candidate preventive/therapeutic naked-DNA vaccine that expresses human calreticulin (hCRT) fused in frame to MmuPV1 E6 (mE6) and mE7 early proteins and residues 11 to 200 of the late protein L2 (hCRTmE6/mE7/mL2). Three intramuscular DNA vaccinations were delivered biweekly via in vivo electroporation, and both humoral and CD8 T cell responses were mapped and measured. Previously persistent papillomas disappeared within 2 months after the final vaccination. Coincident virologic clearance was confirmed by in situ hybridization and a failure of disease to recur after CD3 T cell depletion. Vaccination induced strong mE6 and mE7 CD8+ T cell responses in all mice, although they were significantly weaker in mice that initially presented with persistent warts than in those that spontaneously cleared their infection. A human papillomavirus 16 (HPV16)-targeted version of the DNA vaccine also induced L2 antibodies and protected mice from vaginal challenge with an HPV16 pseudovirus. Thus, MmuPV1 challenge of SKH1 mice is a promising model of spontaneous and immunotherapy-directed clearances of HPV-related disease.IMPORTANCE High-risk-type human papillomaviruses (hrHPVs) cause 5% of all cancer cases worldwide, notably cervical, anogenital, and oropharyngeal cancers. Since preventative HPV vaccines have not been widely used in many countries and do not impact existing infections, there is considerable interest in the development of therapeutic vaccines to address existing disease and infections. The strict tropism of HPV requires the use of animal papillomavirus models for therapeutic vaccine development. However, MmuPV1 failed to grow in common laboratory strains of mice with an intact immune system. We show that MmuPV1 challenge of the outbred immunocompetent SKH1 strain produces both transient and persistent papillomas and that vaccination of the mice with a DNA expressing an MmuPV1 E6E7L2 fusion with calreticulin can rapidly clear persistent papillomas. Furthermore, an HPV16-targeted version of the DNA can protect against vaginal challenge with HPV16, suggesting the promise of this approach to both prevent and treat papillomavirus-related disease.
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Ma Y, Yang A, Peng S, Qiu J, Farmer E, Hung CF, Wu TC. Characterization of HPV18 E6-specific T cell responses and establishment of HPV18 E6-expressing tumor model. Vaccine 2017; 35:3850-3858. [PMID: 28599791 DOI: 10.1016/j.vaccine.2017.05.081] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/22/2017] [Revised: 05/02/2017] [Accepted: 05/26/2017] [Indexed: 02/02/2023]
Abstract
Human papillomavirus (HPV) has been identified as the primary etiologic factor of cervical cancer, and subsets of anogenital and oropharyngeal cancers. HPV18 is the second most prevalent high-risk HPV type after HPV16. Furthermore, HPV18 is responsible for approximately 12% of cervical squamous cell carcinoma and 37% of cervical adenocarcinoma cases worldwide. In this study, we aimed to characterize the HPV18-E6-specific epitope and establish an HPV18 animal tumor model to evaluate the E6-specific immune response induced by our DNA vaccine. We vaccinated naïve C57BL/6 mice with a prototype DNA vaccine, pcDNA3-HPV18-E6, via intramuscular injection followed by electroporation, and analyzed the E6-specific CD8+ T cell responses by flow cytometry using a reported T cell epitope. We then characterized the MHC restriction element for the characterized HPV18-E6 epitope. Additionally, we generated an HPV18-E6-expressing tumor cell line to study the antitumor effect mediated by E6-specific immunity. We observed a robust HPV18-E6aa67-75 peptide-specific CD8+ T cell response after vaccination with pcDNA3-HPV18-E6. Further characterization demonstrated that this epitope was mainly restricted by H-2Kb, but was also weakly presented by HLA-A∗0201, as previously reported. We observed that vaccination with pcDNA3-HPV18-E6 significantly inhibited the growth of HPV18-E6-expressing tumor cells, TC-1/HPV18-E6, in mice. An antibody depletion study demonstrated that both CD4+ and CD8+ T cells are necessary for the observed antitumor immunity. The characterization of HPV18-E6-specific T cell responses and the establishment of HPV18-E6-expressing tumor cell line provide infrastructures for further development of HPV18-E6 targeted immunotherapy.
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Affiliation(s)
- Ying Ma
- Department of Gynecology and Obstetrics, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong Province, China; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
| | - Andrew Yang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
| | - Shiwen Peng
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
| | - Jin Qiu
- Department of Obstetrics and Gynecology, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
| | - Emily Farmer
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
| | - Chien-Fu Hung
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
| | - T-C Wu
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, United States; Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
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Benard VB, Castle PE, Jenison SA, Hunt WC, Kim JJ, Cuzick J, Lee JH, Du R, Robertson M, Norville S, Wheeler CM. Population-Based Incidence Rates of Cervical Intraepithelial Neoplasia in the Human Papillomavirus Vaccine Era. JAMA Oncol 2017; 3:833-837. [PMID: 27685805 PMCID: PMC5765871 DOI: 10.1001/jamaoncol.2016.3609] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/14/2022]
Abstract
IMPORTANCE A substantial effect of human papillomavirus (HPV) vaccines on reducing HPV-related cervical disease is essential before modifying clinical practice guidelines in partially vaccinated populations. OBJECTIVE To determine the population-based cervical intraepithelial neoplasia (CIN) trends when adjusting for changes in cervical screening practices that overlapped with HPV vaccination implementation. DESIGN, SETTING, AND PARTICIPANTS The New Mexico HPV Pap Registry, which captures population-based estimates of both cervical screening prevalence and CIN, was used to compute CIN trends from January 1, 2007, to December 31, 2014. Under New Mexico Administrative Code, the New Mexico HPV Pap Registry, a statewide public health surveillance program, receives mandatory reporting of all cervical screening (cytologic and HPV testing) and any cervical, vulvar, and vaginal histopathological findings for all women residing in New Mexico irrespective of outcome. MAIN OUTCOME MEASURES Prespecified outcome measures included low-grade CIN (grade 1 [CIN1]) and high-grade CIN (grade 2 [CIN2] and grade 3 [CIN3]). RESULTS From 2007 to 2014, a total of 13 520 CIN1, 4296 CIN2, and 2823 CIN3 lesions were diagnosed among female individuals 15 to 29 years old. After adjustment for changes in cervical screening across the period, reductions in the CIN incidence per 100 000 women screened were significant for all grades of CIN among female individuals 15 to 19 years old, dropping from 3468.3 to 1590.6 for CIN1 (annual percentage change [APC], -9.0; 95% CI, -12.0 to -5.8; P < .001), from 896.4 to 414.9 for CIN2 (APC, -10.5; 95% CI, -18.8 to -1.2; P = .03), and from 240.2 to 0 for CIN3 (APC, -41.3; 95% CI, -65.7 to 0.3; P = .05). Reductions in the CIN2 incidence were also significant for women 20 to 24 years old, dropping from 1027.7 to 627.1 (APC, -6.3; 95% CI, -10.9 to -1.4; P = .02). CONCLUSIONS AND RELEVANCE Population-level decreases in CIN among cohorts partially vaccinated for HPV may be considered when clinical practice guidelines for cervical cancer screening are reassessed. Evidence is rapidly growing to suggest that further increases in raising the age to start screening are imminent, one step toward integrating screening and vaccination.
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Affiliation(s)
- Vicki B Benard
- Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Philip E Castle
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
| | - Steven A Jenison
- Division of Infectious Diseases, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque
| | - William C Hunt
- House of Prevention Epidemiology (HOPE), Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque
| | - Jane J Kim
- Department of Health Policy and Management, Center for Health Decision Science, Harvard T. H. Chan School of Public Health, Boston, Massachusetts
| | - Jack Cuzick
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, England
| | - Ji-Hyun Lee
- Division of Epidemiology, Biostatistics, and Preventive Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque
| | - Ruofei Du
- University of New Mexico Comprehensive Cancer Center, Albuquerque
| | - Michael Robertson
- House of Prevention Epidemiology (HOPE), Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque
| | - Scott Norville
- Division of Infectious Diseases, Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque
| | - Cosette M Wheeler
- House of Prevention Epidemiology (HOPE), Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque
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Baidya S, Das R, Kabir MG, Arifuzzaman M. Epitope design of L1 protein for vaccine production against Human Papilloma Virus types 16 and 18. Bioinformation 2017; 13:86-93. [PMID: 28584449 PMCID: PMC5450250 DOI: 10.6026/97320630013086] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/18/2017] [Revised: 03/22/2017] [Accepted: 03/23/2017] [Indexed: 02/07/2023] Open
Abstract
Cervical cancer accounts for about two-thirds of all cancer cases linked etiologically to Human Papilloma Virus (HPV). 15 oncogenic HPV types can cause cervical cancer, of which HPV16 and HPV18 combinedly account for about 70% of it. So, effective epitope design for the clinically relevant HPV types 16 and 18 would be of major medical benefit. Here, a comprehensive analysis is carried out to predict the epitopes against HPV types 16 and 18 through "reverse vaccinology" approach. We attempted to identify the evolutionarily conserved regions of major capsid protein (L1) as well as minor capsid protein (L2) of HPV and designed epitopes within these regions. In this study, we analyzed about 49 and 27 sequences of HPV L2 and L1 proteins respectively. Since we found that the intertype variability of L2 is higher than for L1 proteins, our analysis was emphasized on epitopes of L1 of HPV types 16 and 18. We had selected HLA-A*0201, DRB1*1501, DQB1*0602, DRB1*0401 and DQB1*0301 alleles for the prediction of T cell epitopes of L1 of HPV 16 and 18. Finally, we reported that predicted epitope sequences EEYDLQFIFQLCKITLTA, and RHGEEYDLQFIFQLCKITLTA of L1 protein of HPV 16, and LPDPNKF, PETQRLVWAC, PVPGQYDA, YNPETQRLVWAC, DTGYGAMD, PVPGQYDATK, KQDIPKVSAYQYRVFRV, RDNVSVDYKQTQLCI and YSRHVEEYDLQFIF of L1 protein of HPV 18 could be therapeutic tools for vaccine design against HPV.
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Affiliation(s)
- Sunanda Baidya
- Department of Biochemistry & Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Rasel Das
- Leibniz Institute for Surface Modification, Permoserstraße 15, 04318 Leipzig, Germany
| | - Md. Golam Kabir
- Department of Biochemistry & Molecular Biology, University of Chittagong, Chittagong 4331, Bangladesh
| | - Md. Arifuzzaman
- Department of Biochemistry and Biotechnology, University of Science and Technology Chittagong (USTC), Foy’s Lake, Chittagong 4202, Bangladesh
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Co-Administration of Anti-Angiogenic Peptide and DNA Vaccine in Cervical Cancer Tumor Model. INTERNATIONAL JOURNAL OF CANCER MANAGEMENT 2017. [DOI: 10.5812/ijcm.4723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/02/2023]
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Taking a Stab at Cancer; Oncolytic Virus-Mediated Anti-Cancer Vaccination Strategies. Biomedicines 2017; 5:biomedicines5010003. [PMID: 28536346 PMCID: PMC5423491 DOI: 10.3390/biomedicines5010003] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/27/2016] [Revised: 12/20/2016] [Accepted: 12/22/2016] [Indexed: 12/14/2022] Open
Abstract
Vaccines have classically been used for disease prevention. Modern clinical vaccines are continuously being developed for both traditional use as well as for new applications. Typically thought of in terms of infectious disease control, vaccination approaches can alternatively be adapted as a cancer therapy. Vaccines targeting cancer antigens can be used to induce anti-tumour immunity and have demonstrated therapeutic efficacy both pre-clinically and clinically. Various approaches now exist and further establish the tremendous potential and adaptability of anti-cancer vaccination. Classical strategies include ex vivo-loaded immune cells, RNA- or DNA-based vaccines and tumour cell lysates. Recent oncolytic virus development has resulted in a surge of novel viruses engineered to induce powerful tumour-specific immune responses. In addition to their use as cancer vaccines, oncolytic viruses have the added benefit of being directly cytolytic to cancer cells and thus promote antigen recognition within a highly immune-stimulating tumour microenvironment. While oncolytic viruses are perfectly equipped for efficient immunization, this complicates their use upon previous exposure. Indeed, the host's anti-viral counter-attacks often impair multiple-dosing regimens. In this review we will focus on the use of oncolytic viruses for anti-tumour vaccination. We will explore different strategies as well as ways to circumvent some of their limitations.
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Wang JY, Wang Y, Meng X. Chitosan Nanolayered Cisplatin-Loaded Lipid Nanoparticles for Enhanced Anticancer Efficacy in Cervical Cancer. NANOSCALE RESEARCH LETTERS 2016; 11:524. [PMID: 27888498 PMCID: PMC5124019 DOI: 10.1186/s11671-016-1698-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Received: 07/18/2016] [Accepted: 10/21/2016] [Indexed: 06/06/2023]
Abstract
In this study, cisplatin (CDDP)-loaded chitosan-coated solid lipid nanoparticles (SLN) was successfully formulated to treat HeLa cervical carcinoma. The formulation nanoparticles were nanosized and exhibited a controlled release of drug in physiological conditions. The blank nanoparticles exhibited an excellent biocompatibility profile indicating its suitability for cancer targeting. The incorporation of CDDP in SLN remarkably increased the cancer cell death as evident from the MTT assay. Importantly, CDDP-loaded chitosan-coated SLN (CChSLN) significantly (P < 0.05) decreased the viability of cancer cells even at low concentration. The higher cytotoxicity potential of CChSLN was attributed to the higher cellular uptake as well as the sustained drug release manner in comparison with CSLN. Consistent with the cytotoxicity assay, CChSLN showed the lowest IC50 value of 0.6125 μg/ml while CSLN presented 1.156 μg/ml. CChSLN showed a significantly higher apoptosis in cancer cells compared to that of CSLN and CDDP, which is attributed to the better internalization of nanocarriers and controlled release of anticancer drugs in the intracellular environment. Our findings suggest that this new formulation could be a promising alternative for the treatment of cervical cancers. These findings are encouraging us to continue our research, with a more extended investigation of cellular response in real time and in animal models.
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Affiliation(s)
- Jing-Yi Wang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chengdu Medical College, No.4, Erhuang Road, Chendong, 610051, Sichuan, People's Republic of China.
| | - Yu Wang
- Department of Health, NYS, Wadsworth, USA
| | - Xia Meng
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chengdu Medical College, No.4, Erhuang Road, Chendong, 610051, Sichuan, People's Republic of China
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Minimizing fucosylation in insect cell-derived glycoproteins reduces binding to IgE antibodies from the sera of patients with allergy. Biotechnol J 2016. [DOI: 10.1002/biot.201300061] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/15/2022]
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Elbarazi I, Raheel H, Cummings K, Loney T. A Content Analysis of Arabic and English Newspapers before, during, and after the Human Papillomavirus Vaccination Campaign in the United Arab Emirates. Front Public Health 2016; 4:176. [PMID: 27622185 PMCID: PMC5002875 DOI: 10.3389/fpubh.2016.00176] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/28/2016] [Accepted: 08/09/2016] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Cervical cancer is the fourth most common cancer among females in the United Arab Emirates (UAE) with an estimated incidence of 7.4 per 100,000 persons per year. In March 2008, the Health Authority of Abu Dhabi launched a free school-based campaign to provide all female Emirati students aged 15-17 years in the emirate of Abu Dhabi with the human papillomavirus vaccine (HPVV). Despite the proven efficacy of the HPVV in clinical trials, there has been limited research exploring the acceptance of this vaccine within a conservative Islamic society. The media plays a key role in changing beliefs and attitudes toward specific public health initiatives, such as vaccination programs. The primary aim of this study was to explore the content and communication style of the UAE newspapers (both Arabic and English) before, during, and after the HPV vaccination program. METHODS A systematic literature search was conducted on six national newspapers with the highest circulation figures in the UAE (Arabic: Al Ittihad, Al Khaleej, and Emarat El Youm; English: Khaleej Times, The National, and Gulf News) to retrieve articles related to cervical cancer prevention from January 2000 to May 2013. One bilingual researcher (Arabic-English) utilized content analysis to study the subject matter of communication in each article. RESULTS A total of 79 newspaper articles (N = 31 Arabic) were included in the study. Content analysis coding revealed five main themes: (i) "HPV Screening or Vaccination Programmes in the UAE" (N = 30); (ii) "Cervical Cancer Statistics in the UAE" (N = 22); (iii) "Aetiology of Cervical Cancer and HPVV Efficacy" (N = 12); (iv) "Cultural Sensitivity and Misconceptions Surrounding HPVV in School-Aged Females" (e.g., promoting promiscuity) (N = 8); and (v) "Cost-Effectiveness, Efficacy, and Safety" (N = 7). CONCLUSION The UAE media is playing an important role in raising public awareness about cervical cancer and specific governmental health initiatives such as the HPVV program. Governmental health authorities may want to consider collaborating with the UAE media to develop a communication strategy to reduce the fears and misconceptions surrounding HPVV. Improved parental and adolescent knowledge on the HPVV may lead to increased acceptance and uptake in the UAE society.
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Affiliation(s)
- Iffat Elbarazi
- Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University , Al Ain, Abu Dhabi , United Arab Emirates
| | - Hina Raheel
- Department of Obstetrics and Gynaecology, College of Medicine and Health Sciences, United Arab Emirates University , Al Ain, Abu Dhabi , United Arab Emirates
| | - Kim Cummings
- Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University , Al Ain, Abu Dhabi , United Arab Emirates
| | - Tom Loney
- Institute of Public Health, College of Medicine and Health Sciences, United Arab Emirates University , Al Ain, Abu Dhabi , United Arab Emirates
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