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Zhang S, Zeng Y, Cui L, Zhang Y, Chen T, Xue W, Wang H, Liu H, Zhang Y, Chen L, Zhou L, Xiong Y, Zheng Q, Yu H, Cheng T, Zhang J, Gu Y, Li T, Xia N, Li S. Immunogenicity and cellular response of a herpes zoster virus gEgI fusion protein adjuvanted with CpG-emulsion in mice. J Nanobiotechnology 2025; 23:395. [PMID: 40448056 DOI: 10.1186/s12951-025-03423-w] [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] [Scholar Register] [Received: 12/24/2024] [Accepted: 04/30/2025] [Indexed: 06/02/2025] Open
Abstract
Herpes zoster (HZ), commonly known as shingles, arises from the reactivation of the latent varicella-zoster virus (VZV) when VZV-specific cellular immunity declines below a critical threshold necessary for viral suppression. The current leading vaccine, Shingrix, which incorporates the adjuvant AS01B with glycoprotein E (gE), has significantly contributed to HZ prevention but raises concerns regarding safety and accessibility. Addressing the need for safer and more accessible HZ vaccinations, we developed a vaccine comprising a fusion protein of glycoprotein E and I (gEgI), connected via a linker, targeting abundant B cell and CD4 T cell epitopes. Our study assessed the immunogenicity of the gE alone and the gEgI fusion protein in adult mice, revealing that gEgI prompts a more potent and comprehensive T cell response compared to gE alone. Furthermore, we introduced a composite adjuvant, an emulsion-type adjuvant combined with CpG1018 (XUA09C), which was shown to enhance both humoral and cellular immune responses beyond the capabilities of XUA09 with CpG alone. Comparative analyses demonstrated that the XUA09C-adjuvanted gEgI vaccine induces comparable antibody responses and significantly superior T cell responses relative to Shingrix in both adult, VZV-primed, and aged mice. Single-cell RNA sequencing highlighted that gEgI/XUA09C more effectively promotes early immune activation, B and T cell proliferation, and memory T cell augmentation compared to Shingrix. These findings position the XUA09C-adjuvanted gEgI as a promising candidate for further development in HZ vaccine strategies, potentially better serving the needs of the immunocompromised population.
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Affiliation(s)
- Sibo Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Yarong Zeng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Lingyan Cui
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Yiwen Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Tingting Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Wenhui Xue
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Hong Wang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Hongjing Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Yuyun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Lin Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Lizhi Zhou
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Yueting Xiong
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Qingbing Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Hai Yu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Tong Cheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Jun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China
| | - Ying Gu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China.
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China.
| | - Tingting Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China.
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China.
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China.
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China.
| | - Shaowei Li
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health, School of Life Sciences, Xiamen University, Xiamen, 361102, China.
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, Collaborative Innovation Center of Biologic Products, National Innovation Platform for Industry-Education Integration in Vaccine Research, Xiamen University, Xiamen, 361102, China.
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Zheng X, Yang R, Zhao Y, Zhang Y, Yuan G, Li W, Xiao Z, Dong X, Ma M, Guo Y, Wang W, Zhao X, Yang H, Qiu S, Peng Z, Liu A, Yu S, Zhang Y. Alum/CpG adjuvant promotes immunogenicity of inactivated SARS-CoV-2 Omicron vaccine through enhanced humoral and cellular immunity. Virology 2024; 594:110050. [PMID: 38479071 DOI: 10.1016/j.virol.2024.110050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 02/29/2024] [Accepted: 03/06/2024] [Indexed: 04/09/2024]
Abstract
The SARS-CoV-2 Omicron variant, which was classified as a variant of concern (VOC) by the World Health Organization on 26 November 2021, has attracted worldwide attention for its high transmissibility and immune evasion ability. The existing COVID-19 vaccine has been shown to be less effective in preventing Omicron variant infection and symptomatic infection, which brings new challenges to vaccine development and application. Here, we evaluated the immunogenicity and safety of an Omicron variant COVID-19 inactivated vaccine containing aluminum and CpG adjuvants in a variety of animal models. The results showed that the vaccine candidate could induce high levels of neutralizing antibodies against the Omicron variant virus and binding antibodies, and significantly promoted cellular immune response. Meanwhile, the vaccine candidate was safe. Therefore, it provided more foundation for the development of aluminum and CpG as a combination adjuvant in human vaccines.
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Affiliation(s)
- Xiaotong Zheng
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Rong Yang
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Yuxiu Zhao
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Yadan Zhang
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Guangying Yuan
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Weidong Li
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Zhuangzhuang Xiao
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Xiaofei Dong
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Meng Ma
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Yancen Guo
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Wei Wang
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Xue Zhao
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Hongqiang Yang
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Shaoting Qiu
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Zheng Peng
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Ankang Liu
- Beijing Institute of Biological Products Company Limited, Beijing, China
| | - Shouzhi Yu
- Beijing Institute of Biological Products Company Limited, Beijing, China.
| | - Yuntao Zhang
- Beijing Institute of Biological Products Company Limited, Beijing, China; China National Biotec Group Company Limited, Beijing, China.
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Zhang Y, Yang R, Yuan G, Li W, Cui Z, Xiao Z, Dong X, Yang H, Liu X, Zhang L, Hou Y, Liu M, Liu S, Hao Y, Zhang Y, Zheng X. Enhancing Inactivated Yellow Fever 17D Vaccine-Induced Immune Responses in Balb/C Mice Using Alum/CpG. Vaccines (Basel) 2023; 11:1744. [PMID: 38140149 PMCID: PMC10747526 DOI: 10.3390/vaccines11121744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 11/17/2023] [Accepted: 11/20/2023] [Indexed: 12/24/2023] Open
Abstract
There are some concerns about the safety of live attenuated yellow fever vaccines (YF-live), particularly viscerotropic adverse events, which have a high mortality rate. The cellular production of the vaccine will not cause these adverse effects and has the potential to extend applicability to those who have allergic reactions, immunosuppression, and age. In this study, inactivated yellow fever (YF) was prepared and adsorbed with Alum/CpG. The cellular and humoral immunities were investigated in a mouse model. The results showed that Alum/CpG (20 μg/mL) could significantly increase the binding and neutralizing activities of the antibodies against YF. Moreover, the antibody level at day 28 after one dose was similar to that of the attenuated vaccine, but significantly higher after two doses. At the same time, Alum/CpG significantly increased the levels of IFN-γ and IL-4 cytokines.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Yuntao Zhang
- Beijing Institute of Biological Products Company Limited, Beijing 100170, China; (Y.Z.); (R.Y.); (G.Y.); (W.L.); (Z.C.); (Z.X.); (X.D.); (H.Y.); (X.L.); (L.Z.); (Y.H.); (M.L.); (S.L.); (Y.H.)
| | - Xiaotong Zheng
- Beijing Institute of Biological Products Company Limited, Beijing 100170, China; (Y.Z.); (R.Y.); (G.Y.); (W.L.); (Z.C.); (Z.X.); (X.D.); (H.Y.); (X.L.); (L.Z.); (Y.H.); (M.L.); (S.L.); (Y.H.)
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Zhao T, Cai Y, Jiang Y, He X, Wei Y, Yu Y, Tian X. Vaccine adjuvants: mechanisms and platforms. Signal Transduct Target Ther 2023; 8:283. [PMID: 37468460 PMCID: PMC10356842 DOI: 10.1038/s41392-023-01557-7] [Citation(s) in RCA: 283] [Impact Index Per Article: 141.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/19/2023] [Accepted: 06/27/2023] [Indexed: 07/21/2023] Open
Abstract
Adjuvants are indispensable components of vaccines. Despite being widely used in vaccines, their action mechanisms are not yet clear. With a greater understanding of the mechanisms by which the innate immune response controls the antigen-specific response, the adjuvants' action mechanisms are beginning to be elucidated. Adjuvants can be categorized as immunostimulants and delivery systems. Immunostimulants are danger signal molecules that lead to the maturation and activation of antigen-presenting cells (APCs) by targeting Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs) to promote the production of antigen signals and co-stimulatory signals, which in turn enhance the adaptive immune responses. On the other hand, delivery systems are carrier materials that facilitate antigen presentation by prolonging the bioavailability of the loaded antigens, as well as targeting antigens to lymph nodes or APCs. The adjuvants' action mechanisms are systematically summarized at the beginning of this review. This is followed by an introduction of the mechanisms, properties, and progress of classical vaccine adjuvants. Furthermore, since some of the adjuvants under investigation exhibit greater immune activation potency than classical adjuvants, which could compensate for the deficiencies of classical adjuvants, a summary of the adjuvant platforms under investigation is subsequently presented. Notably, we highlight the different action mechanisms and immunological properties of these adjuvant platforms, which will provide a wide range of options for the rational design of different vaccines. On this basis, this review points out the development prospects of vaccine adjuvants and the problems that should be paid attention to in the future.
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Affiliation(s)
- Tingmei Zhao
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yulong Cai
- Division of Biliary Tract Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Yujie Jiang
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Xuemei He
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
| | - Yifan Yu
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China
- Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaohe Tian
- Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, 610041, Sichuan, People's Republic of China.
- Department of Radiology and Huaxi MR Research Center (HMRRC), Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, China.
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Losada C, Samaha H, Scherer EM, Kazzi B, Khalil L, Ofotokun I, Rouphael N. Efficacy and Durability of Immune Response after Receipt of HPV Vaccines in People Living with HIV. Vaccines (Basel) 2023; 11:1067. [PMID: 37376456 DOI: 10.3390/vaccines11061067] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 05/24/2023] [Accepted: 05/31/2023] [Indexed: 06/29/2023] Open
Abstract
People living with HIV (PLH) experience higher rates of HPV infection as well as an increased risk of HPV-related disease, including malignancies. Although they are considered a high-priority group for HPV vaccination, there are limited data regarding the long-term immunogenicity and efficacy of HPV vaccines in this population. Seroconversion rates and geometric mean titers elicited by vaccination are lower in PLH compared to immunocompetent participants, especially in individuals with CD4 counts below 200 cells/mm3 and a detectable viral load. The significance of these differences is still unclear, as a correlate of protection has not been identified. Few studies have focused on demonstrating vaccine efficacy in PLH, with variable results depending on the age at vaccination and baseline seropositivity. Although waning humoral immunity for HPV seems to be more rapid in this population, there is evidence that suggests that seropositivity lasts at least 2-4 years following vaccination. Further research is needed to determine the differences between vaccine formulations and the impact of administrating additional doses on durability of immune protection.
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Affiliation(s)
- Cecilia Losada
- The Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University, Decatur, GA 30030, USA
| | - Hady Samaha
- The Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University, Decatur, GA 30030, USA
| | - Erin M Scherer
- The Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University, Decatur, GA 30030, USA
| | - Bahaa Kazzi
- The Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University, Decatur, GA 30030, USA
| | - Lana Khalil
- The Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University, Decatur, GA 30030, USA
| | - Ighovwerha Ofotokun
- Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, GA 30322, USA
| | - Nadine Rouphael
- The Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University, Decatur, GA 30030, USA
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De Vito A, Colpani A, Trunfio M, Fiore V, Moi G, Fois M, Leoni N, Ruiu S, Babudieri S, Calcagno A, Madeddu G. Living with HIV and Getting Vaccinated: A Narrative Review. Vaccines (Basel) 2023; 11:896. [PMID: 37243000 PMCID: PMC10220625 DOI: 10.3390/vaccines11050896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 04/21/2023] [Accepted: 04/23/2023] [Indexed: 05/28/2023] Open
Abstract
After 40 years of its appearance, human immunodeficiency virus (HIV) infection remains a leading public health challenge worldwide. Since the introduction of antiretroviral treatment (ART), HIV infection has become a chronic condition, and people living with HIV could have life expectancies close to those of the general population. People with HIV often have an increased risk of infection or experience more severe morbidity following exposure to vaccine-preventable diseases. Nowadays, several vaccines are available against bacteria and viruses. However, national and international vaccination guidelines for people with HIV are heterogeneous, and not every vaccine is included. For these reasons, we aimed to perform a narrative review about the vaccinations available for adults living with HIV, reporting the most updated studies performed for each vaccine among this population. We performed a comprehensive literature search through electronic databases (Pubmed-MEDLINE and Embase) and search engines (Google Scholar). We included English peer-reviewed publications (articles and reviews) on HIV and vaccination. Despite widespread use and guideline recommendations, few vaccine trials have been conducted in people with HIV. In addition, not all vaccines are recommended for people with HIV, especially for those with low CD4 cells count. Clinicians should carefully collect the history of vaccinations and patients' acceptance and preferences and regularly check the presence of antibodies for vaccine-preventable pathogens.
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Affiliation(s)
- Andrea De Vito
- Unit of Infectious Diseases, Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.M.)
| | - Agnese Colpani
- Unit of Infectious Diseases, Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.M.)
| | - Mattia Trunfio
- Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, 10149 Torino, Italy
| | - Vito Fiore
- Unit of Infectious Diseases, Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.M.)
| | - Giulia Moi
- Unit of Infectious Diseases, Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.M.)
| | - Marco Fois
- Unit of Infectious Diseases, Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.M.)
| | - Nicola Leoni
- Unit of Infectious Diseases, Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.M.)
| | - Stefano Ruiu
- Unit of Infectious Diseases, Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.M.)
| | - Sergio Babudieri
- Unit of Infectious Diseases, Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.M.)
| | - Andrea Calcagno
- Unit of Infectious Diseases, Department of Medical Sciences, University of Turin, 10149 Torino, Italy
| | - Giordano Madeddu
- Unit of Infectious Diseases, Department of Medicine, Surgery, and Pharmacy, University of Sassari, 07100 Sassari, Italy; (A.C.); (G.M.)
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Ren H, Li H, Cao L, Wang Z, Zhou Y, Guo J, Zhang Y, Liu H, Xu W. Intranasal immunization with HRSV prefusion F protein and CpG adjuvant elicits robust protective effects in mice. Vaccine 2022; 40:6830-6838. [PMID: 36253219 DOI: 10.1016/j.vaccine.2022.09.071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/09/2022] [Accepted: 09/23/2022] [Indexed: 11/06/2022]
Abstract
Human respiratory syncytial virus (HRSV) is a leading cause of lower respiratory tract infections in elderly individuals and young children/infants and can cause bronchiolitis and even death. There is no licensed HRSV vaccine. An ideal vaccine should induce high titers of neutralizing antibodies and a Th1-biased immune response. In this study, we used EXPI293 cells to express the fusion (F) protein with a prefusion conformation (PrF) and compared the safety and efficacy of intranasal immunization with PrF in combination with two mucosal adjuvants (CpG ODN and liposomes) in mice. After two intranasal administrations, mice in the PrF + CpG group produced high titers of neutralizing antibodies (4961) and a Th1-biased immune response compared with the PrF + Lipo group. The lung viral load of mice in the PrF + CpG group was significantly reduced (3.5 log) compared with that in the adjuvant control group, and the survival rate was 100 %, while the survival rate of mice in the PrF + Lipo group was only 67 %. At the same time, this immunization strategy reduced the pathological damage to the lungs in mice. In conclusion, the combination of PrF and CpG adjuvant is immunogenic, elicits a Th1 type immune response, and completely protects mice from a lethal HRSV challenge. It is worthy of further evaluation as an HRSV vaccine in clinical trials. Clinical trial registration. This study was not related to human participation or experimentation.
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Affiliation(s)
- Hu Ren
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Hai Li
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Lei Cao
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Zhan Wang
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yangzi Zhou
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jinyuan Guo
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yan Zhang
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Hongtu Liu
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China; Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.
| | - Wenbo Xu
- NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China; Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, Hubei, China.
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8
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Liu D, An C, Bai Y, Li K, Liu J, Wang Q, He Q, Song Z, Zhang J, Song L, Cui B, Mao Q, Jiang W, Liang Z. A Novel Single-Stranded RNA-Based Adjuvant Improves the Immunogenicity of the SARS-CoV-2 Recombinant Protein Vaccine. Viruses 2022; 14:v14091854. [PMID: 36146661 PMCID: PMC9504790 DOI: 10.3390/v14091854] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/19/2022] [Accepted: 08/20/2022] [Indexed: 11/17/2022] Open
Abstract
The research and development (R&D) of novel adjuvants is an effective measure for improving the immunogenicity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recombinant protein vaccine. Toward this end, we designed a novel single-stranded RNA-based adjuvant, L2, from the SARS-CoV-2 prototype genome. L2 could initiate retinoic acid-inducible gene-I signaling pathways to effectively activate the innate immunity. ZF2001, an aluminum hydroxide (Al) adjuvanted SARS-CoV-2 recombinant receptor binding domain (RBD) subunit vaccine with emergency use authorization in China, was used for comparison. L2, with adjuvant compatibility with RBD, elevated the antibody response to a level more than that achieved with Al, CpG 7909, or poly(I:C) as adjuvants in mice. L2 plus Al with composite adjuvant compatibility with RBD markedly improved the immunogenicity of ZF2001; in particular, neutralizing antibody titers increased by about 44-fold for Omicron, and the combination also induced higher levels of antibodies than CpG 7909/poly(I:C) plus Al in mice. Moreover, L2 and L2 plus Al effectively improved the Th1 immune response, rather than the Th2 immune response. Taken together, L2, used as an adjuvant, enhanced the immune response of the SARS-CoV-2 recombinant RBD protein vaccine in mice. These findings should provide a basis for the R&D of novel RNA-based adjuvants.
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Affiliation(s)
- Dong Liu
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
- Changchun Institute of Biological Products Co., Ltd., Changchun 130062, China
| | - Chaoqiang An
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
- Beijing Minhai Biotechnology Co., Ltd., Beijing 102629, China
| | - Yu Bai
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
| | - Kelei Li
- Beijing Minhai Biotechnology Co., Ltd., Beijing 102629, China
| | - Jianyang Liu
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
| | - Qian Wang
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
| | - Qian He
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
| | - Ziyang Song
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
| | - Jialu Zhang
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
| | - Lifang Song
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
| | - Bopei Cui
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
| | - Qunying Mao
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
| | - Wei Jiang
- Changchun Institute of Biological Products Co., Ltd., Changchun 130062, China
- Correspondence: (W.J.); (Z.L.)
| | - Zhenglun Liang
- Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing 102600, China
- Correspondence: (W.J.); (Z.L.)
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9
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Jain A, Mittal S, Tripathi LP, Nussinov R, Ahmad S. Host-pathogen protein-nucleic acid interactions: A comprehensive review. Comput Struct Biotechnol J 2022; 20:4415-4436. [PMID: 36051878 PMCID: PMC9420432 DOI: 10.1016/j.csbj.2022.08.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 08/01/2022] [Accepted: 08/01/2022] [Indexed: 12/02/2022] Open
Abstract
Recognition of pathogen-derived nucleic acids by host cells is an effective host strategy to detect pathogenic invasion and trigger immune responses. In the context of pathogen-specific pharmacology, there is a growing interest in mapping the interactions between pathogen-derived nucleic acids and host proteins. Insight into the principles of the structural and immunological mechanisms underlying such interactions and their roles in host defense is necessary to guide therapeutic intervention. Here, we discuss the newest advances in studies of molecular interactions involving pathogen nucleic acids and host factors, including their drug design, molecular structure and specific patterns. We observed that two groups of nucleic acid recognizing molecules, Toll-like receptors (TLRs) and the cytoplasmic retinoic acid-inducible gene (RIG)-I-like receptors (RLRs) form the backbone of host responses to pathogen nucleic acids, with additional support provided by absent in melanoma 2 (AIM2) and DNA-dependent activator of Interferons (IFNs)-regulatory factors (DAI) like cytosolic activity. We review the structural, immunological, and other biological aspects of these representative groups of molecules, especially in terms of their target specificity and affinity and challenges in leveraging host-pathogen protein-nucleic acid interactions (HP-PNI) in drug discovery.
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Affiliation(s)
- Anuja Jain
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
| | - Shikha Mittal
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan, Himachal Pradesh, 173234, India
| | - Lokesh P. Tripathi
- National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, Japan
- Riken Center for Integrative Medical Sciences, Tsurumi, Yokohama, Kanagawa, Japan
| | - Ruth Nussinov
- Computational Structural Biology Section, Basic Science Program, Frederick National, Laboratory for Cancer Research, Frederick, MD 21702, USA
- Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Israel
| | - Shandar Ahmad
- School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi 110067, India
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10
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Yang JX, Tseng JC, Yu GY, Luo Y, Huang CYF, Hong YR, Chuang TH. Recent Advances in the Development of Toll-like Receptor Agonist-Based Vaccine Adjuvants for Infectious Diseases. Pharmaceutics 2022; 14:pharmaceutics14020423. [PMID: 35214155 PMCID: PMC8878135 DOI: 10.3390/pharmaceutics14020423] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 02/11/2022] [Accepted: 02/14/2022] [Indexed: 02/06/2023] Open
Abstract
Vaccines are powerful tools for controlling microbial infections and preventing epidemic diseases. Efficient inactive, subunit, or viral-like particle vaccines usually rely on a safe and potent adjuvant to boost the immune response to the antigen. After a slow start, over the last decade there has been increased developments on adjuvants for human vaccines. The development of adjuvants has paralleled our increased understanding of the molecular mechanisms for the pattern recognition receptor (PRR)-mediated activation of immune responses. Toll-like receptors (TLRs) are a group of PRRs that recognize microbial pathogens to initiate a host’s response to infection. Activation of TLRs triggers potent and immediate innate immune responses, which leads to subsequent adaptive immune responses. Therefore, these TLRs are ideal targets for the development of effective adjuvants. To date, TLR agonists such as monophosphoryl lipid A (MPL) and CpG-1018 have been formulated in licensed vaccines for their adjuvant activity, and other TLR agonists are being developed for this purpose. The COVID-19 pandemic has also accelerated clinical research of vaccines containing TLR agonist-based adjuvants. In this paper, we reviewed the agonists for TLR activation and the molecular mechanisms associated with the adjuvants’ effects on TLR activation, emphasizing recent advances in the development of TLR agonist-based vaccine adjuvants for infectious diseases.
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Affiliation(s)
- Jing-Xing Yang
- Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; (J.-X.Y.); (J.-C.T.)
| | - Jen-Chih Tseng
- Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; (J.-X.Y.); (J.-C.T.)
| | - Guann-Yi Yu
- National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli 35053, Taiwan;
| | - Yunping Luo
- Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, China;
| | - Chi-Ying F. Huang
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
| | - Yi-Ren Hong
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Tsung-Hsien Chuang
- Immunology Research Center, National Health Research Institutes, Miaoli 35053, Taiwan; (J.-X.Y.); (J.-C.T.)
- Department of Life Sciences, National Central University, Taoyuan City 32001, Taiwan
- Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: ; Tel.: +886-37-246166 (ext. 37611)
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11
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Rapaka RR, Cross AS, McArthur MA. Using Adjuvants to Drive T Cell Responses for Next-Generation Infectious Disease Vaccines. Vaccines (Basel) 2021; 9:vaccines9080820. [PMID: 34451945 PMCID: PMC8402546 DOI: 10.3390/vaccines9080820] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 07/16/2021] [Accepted: 07/20/2021] [Indexed: 12/12/2022] Open
Abstract
Using adjuvants to drive features of T cell responses to vaccine antigens is an important technological challenge in the design of new and improved vaccines against infections. Properties such as T helper cell function, T cell memory, and CD8+ T cell cytotoxicity may play critical roles in optimal and long-lived immunity through vaccination. Directly manipulating specific immune activation or antigen delivery pathways with adjuvants may selectively augment desired T cell responses in vaccination and may improve the effectiveness and durability of vaccine responses in humans. In this review we outline recently studied adjuvants in their potential for antigen presenting cell and T cell programming during vaccination, with an emphasis on what has been observed in studies in humans as available.
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12
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Abstract
The world of vaccines has changed tremendously since the time of Louis Pasteur. In the present day, it is regarded as vaccinology, a discipline which includes not only the knowledge of vaccine production, strategies for its delivery and influence on the clinical course of disease and the response of the host immune system but also regulatory, ethical, economic and ecological aspects of their use. A hundred years after Pasteur created the first vaccine, there was another scientific breakthrough of great importance in this field, i. e. Sanger sequencing. Progress in genome sequencing and other molecular techniques over the intervening 40 years has been enormous. High-throughput sequencing (HTS) platforms and bioinformatics tools are becoming widely available, falling in cost, and results are achieved very quickly. They enable the construction of modern vaccines, as well as the assessment of their safety, effectiveness and impact on the host organism and the environment. These techniques can also provide a tool for quality control of vaccines. Unprecedented possibilities are opened up by the HTS technique, but limiting factors on its implementation have to be contended with such as lack of reference materials and problems with method optimisation or validation. In the face of the current COVID-19 pandemic, a significant role is allotted to this sequencing technique while an effective vaccine against the disease caused by SARS-CoV-2 is sough.
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13
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Abstract
CpG Oligonucleotides (ODN) are immunomodulatory synthetic oligonucleotides specifically designed to stimulate Toll-like receptor 9. TLR9 is expressed on human plasmacytoid dendritic cells and B cells and triggers an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. This chapter reviews recent progress in understanding the mechanism of action of CpG ODN and provides an overview of human clinical trial results using CpG ODN to improve vaccines for the prevention/treatment of cancer, allergy, and infectious disease.
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Affiliation(s)
| | | | - Dennis M Klinman
- National Cancer Institute, NIH, Frederick, MD, USA.
- Leitman Klinman Consulting, Potomac, MD, USA.
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14
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Galluzzi L, Vacchelli E, Eggermont A, Fridman WH, Galon J, Sautès-Fridman C, Tartour E, Zitvogel L, Kroemer G. Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology 2021; 1:699-716. [PMID: 22934262 PMCID: PMC3429574 DOI: 10.4161/onci.20696] [Citation(s) in RCA: 170] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications.
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Affiliation(s)
- Lorenzo Galluzzi
- Université Paris Descartes/Paris V; Sorbonne Paris Cité; Paris, France ; Institut Gustave Roussy; Villejuif, France
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15
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Abstract
The usage of combination antiretroviral therapy in people with HIV (PWH) has incited profound improvement in morbidity and mortality. Yet, PWH may not experience full restoration of immune function which can manifest with non-AIDS comorbidities that frequently associate with residual inflammation and can imperil quality of life or longevity. In this review, we discuss the pathogenesis underlying chronic inflammation and residual immune dysfunction in PWH, as well as potential therapeutic interventions to ameliorate them and prevent incidence or progression of non-AIDS comorbidities. Current evidence advocates that early diagnosis and prompt initiation of therapy at high CD4 counts may represent the best available approach for an improved immune recovery in PWH.
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Affiliation(s)
- Catherine W Cai
- HIV Pathogenesis Section, Laboratory of Immunoregulation, NIAID, NIH, United States
| | - Irini Sereti
- HIV Pathogenesis Section, Laboratory of Immunoregulation, NIAID, NIH, United States.
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16
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Lee JH, Hong S, Im JH, Lee JS, Baek JH, Kwon HY. Systematic review and meta-analysis of immune response of double dose of hepatitis B vaccination in HIV-infected patients. Vaccine 2020; 38:3995-4000. [PMID: 32334887 DOI: 10.1016/j.vaccine.2020.04.022] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 03/24/2020] [Accepted: 04/07/2020] [Indexed: 12/30/2022]
Abstract
INTRODUCTION The prevalence of co-infection of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) is high and increases risk of hepatitis B chronicity and mortality. Despite guidelines for HIV-infected patients to be immunized against HBV, the immunogenicity of the HBV vaccination in HIV-infected patients is lower than that in the HIV-seronegative population. METHOD In this study, we performed a systematic review of the literature and meta-analysis of randomized clinical trials to investigate the response rate to an increased dose of HBV vaccination in HIV-infected patients. A fixed-effects model, with heterogeneity and sensitivity analyses, was used. We identified nine studies involving 970 HIV-positive vaccine recipients. RESULTS The study results were divided into two groups, depending on the time when antibody against hepatitis surface antigen was measured. Results showed a significant increase in response rates among patients who received a double dose of the vaccine versus the standard dose in both subgroups; the pooled odds ratio (OR) was 1.76 (95% confidence interval [CI]: 1.36-2.29) and 2.28 (95% CI: 1.73-3.01) for the rate that was measured 4-6 weeks and >12 months after completion of vaccination, respectively. The total OR was 1.99 (95% CI: 1.64-2.41). No heterogeneity was found. DISCUSSION Our meta-analysis shows that a double dose of the HBV vaccine may significantly improve the immune response in HIV-infected patients. Higher immunogenicity was observed, when it was measured 4-6 weeks and >12 months after completion of the vaccination.
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Affiliation(s)
- Jung-Hwan Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea.
| | - Seri Hong
- National Cancer Control Institute, National Cancer Center, Goyang, Republic of Korea.
| | - Jae Hyoung Im
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea.
| | - Jin-Soo Lee
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea.
| | - Ji Hyeon Baek
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea.
| | - Hea Yoon Kwon
- Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea.
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17
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Farooq PD, Sherman KE. Hepatitis B Vaccination and Waning Hepatitis B Immunity in Persons Living with HIV. Curr HIV/AIDS Rep 2020; 16:395-403. [PMID: 31468298 DOI: 10.1007/s11904-019-00461-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
PURPOSE OF REVIEW Persons with HIV are at a higher risk for acquiring HBV (hepatitis B virus) than the general population due to shared modes of transmission and are significantly more likely to develop and die from sequelae of chronic HBV infection. Early vaccination is key to achieving HBV protective immunity, but response rates are still much lower than in the general population, ranging from 35 to 70%. Individuals with HIV also experience more rapidly waning immunity than those without HIV. Strategies to augment initial response and improve long-term immunity in individuals with HIV include alterations in dose, frequency, and the use of immune adjuvants. RECENT FINDINGS Recent studies have focused on the use of different vaccine formulations, the use of vaccine adjuvants, increased number and strength of vaccine dosages, increased dose frequency, alternative routes of administration, dual vaccinations, and the use of booster vaccines. Although no consensus has been reached on the use of certain vaccination regimens, three and four double-dose vaccine schedules via the intramuscular route have demonstrated higher initial response rates. Early vaccination when CD4 cell counts are greater than 350/mm3 with low viral loads has been shown to improve initial response, along with completion of immunization series. Adjuvants such as TLR4 and TLR9 agonists appear to improve response to HBV vaccination, but further research is needed in individuals with HIV. Persons with HIV have significant lower initial and long-term seroresponse rates after HBV vaccination than immunocompetent individuals. Recent and ongoing studies continue to evaluate multiple strategies to improve these rates within a uniquely susceptible population.
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Affiliation(s)
- Priya D Farooq
- Division of Digestive Diseases, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0595, USA
| | - Kenneth E Sherman
- Division of Digestive Diseases, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH, 45267-0595, USA.
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18
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Yang F, Kosten TR. Psychopharmacology: neuroimmune signaling in psychiatric disease-developing vaccines against abused drugs using toll-like receptor agonists. Psychopharmacology (Berl) 2019; 236:2899-2907. [PMID: 30726515 DOI: 10.1007/s00213-019-5176-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 01/16/2019] [Indexed: 01/05/2023]
Abstract
RATIONALE Since substance use disorders have few or no effective pharmacotherapies, researchers have developed vaccines as immune-therapies against nicotine, cocaine, methamphetamine, and opioids including fentanyl. OBJECTIVES We focus on enhancing antibody (AB) production through stimulation of toll-like receptor-5 (TLR5) during active vaccination. The stimulating adjuvant is Entolimod, a novel protein derivative of flagellin. We review the molecular and cellular mechanisms underlying Entolimod's actions on TLR5. RESULTS Entolimod shows excellent efficacy for increasing AB levels to levels well beyond those produced by anti-addiction vaccines alone in animal models and humans. These ABs also significantly block the behavioral effects of the targeted drug of abuse. The TLR5 stimulation involves a wide range of immune cell types such as dendritic, antigen presenting, T and B cells. Entolimod binding to TLR5 initiates an intracellular signaling cascade that stimulates cytokine production of tumor necrosis factor and two interleukins (IL-6 and IL-12). While cytokine release can be catastrophic in cytokine storm, Entolimod produces a modulated release with few side effects even at doses 30 times greater than doses needed in these vaccine studies. Entolimod has markedly increased AB responses to all of our anti-addiction vaccines in rodent models, and in normal humans. CONCLUSIONS Entolimod and TLR5 stimulation has broad application to vaccines and potentially to other psychiatric disorders like depression, which has critical inflammatory contributions that Entolimod could reduce.
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Affiliation(s)
- Fang Yang
- Department of Psychiatry, Baylor College of Medicine, 1977 Butler Blvd, Suite E4.207, Houston, TX, 77030, USA
| | - Thomas R Kosten
- Department of Psychiatry, Baylor College of Medicine, 1977 Butler Blvd, Suite E4.207, Houston, TX, 77030, USA.
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19
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Vanpouille-Box C, Hoffmann JA, Galluzzi L. Pharmacological modulation of nucleic acid sensors - therapeutic potential and persisting obstacles. Nat Rev Drug Discov 2019; 18:845-867. [PMID: 31554927 DOI: 10.1038/s41573-019-0043-2] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2019] [Indexed: 02/08/2023]
Abstract
Nucleic acid sensors, primarily TLR and RLR family members, as well as cGAS-STING signalling, play a critical role in the preservation of cellular and organismal homeostasis. Accordingly, deregulated nucleic acid sensing contributes to the origin of a diverse range of disorders, including infectious diseases, as well as cardiovascular, autoimmune and neoplastic conditions. Accumulating evidence indicates that normalizing aberrant nucleic acid sensing can mediate robust therapeutic effects. However, targeting nucleic acid sensors with pharmacological agents, such as STING agonists, presents multiple obstacles, including drug-, target-, disease- and host-related issues. Here, we discuss preclinical and clinical data supporting the potential of this therapeutic paradigm and highlight key limitations and possible strategies to overcome them.
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Affiliation(s)
- Claire Vanpouille-Box
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.,Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | - Jules A Hoffmann
- University of Strasbourg Institute for Advanced Studies, Strasbourg, France.,CNRS UPR 9022, Institute for Molecular and Cellular Biology, Strasbourg, France.,Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA. .,Sandra and Edward Meyer Cancer Center, New York, NY, USA. .,Department of Dermatology, Yale School of Medicine, New Haven, CT, USA. .,Université Paris Descartes, Paris, France.
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20
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Ma Z, Zhang E, Gao S, Xiong Y, Lu M. Toward a Functional Cure for Hepatitis B: The Rationale and Challenges for Therapeutic Targeting of the B Cell Immune Response. Front Immunol 2019; 10:2308. [PMID: 31608073 PMCID: PMC6769125 DOI: 10.3389/fimmu.2019.02308] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 09/12/2019] [Indexed: 12/13/2022] Open
Abstract
The central role of the cellular immune response in the control and clearance of the hepatitis B virus (HBV) infection has been well-established. The contribution of humoral immunity, including B cell and antibody responses against HBV, has been investigated for a long time but has attracted increasing attention again in recent years. The anti-HBs antibody was first recognized as a marker of protective immunity after the acute resolution of the HBV infection (or vaccination) and is now defined as a biomarker for the functional cure of chronic hepatitis B (CHB). In this way, therapies targeting HBV-specific B cells and the induction of an anti-HBs antibody response are essential elements of a rational strategy to terminate chronic HBV infection. However, a high load of HBsAg in the blood, which has been proposed to induce antigen-specific immune tolerance, represents a major obstacle to curing CHB. Long-term antiviral treatment by nucleoside analogs, by targeting viral translation by siRNA, by inhibiting HBsAg release via nucleic acid polymers, or by neutralizing HBsAg via specific antibodies could potentially reduce the HBsAg load in CHB patients. A combined strategy including a reduction of the HBsAg load via the above treatments and the therapeutic targeting of B cells by vaccination may induce the appearance of anti-HBs antibodies and lead to a functional cure of CHB.
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Affiliation(s)
- Zhiyong Ma
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ejuan Zhang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Shicheng Gao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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21
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Lacey CJ. HPV vaccination in HIV infection. ACTA ACUST UNITED AC 2019; 8:100174. [PMID: 31252073 PMCID: PMC6603434 DOI: 10.1016/j.pvr.2019.100174] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/23/2019] [Accepted: 06/24/2019] [Indexed: 02/07/2023]
Abstract
Persons with HIV are at increased risk of HPV infection, HPV disease, and HPV-related cancers compared to HIV negative persons. In persons with HIV, immune responses to vaccination are often sub-optimal, and while these improve with ART, they often remain lower and decline more rapidly than in HIV-negative individuals. Although the evidence base to support the immunogenicity of HPV vaccines in HIV + ve persons is reasonable, the evidence base to support the efficacy of HPV vaccines in HIV + ve individuals is inconsistent. There is one study in HIV + ve men who have sex with men (MSM) which showed no effect, and two other studies, one in HIV + ve women and one in HIV + ve adolescents that showed reduced effectiveness. All these effectiveness studies used Gardasil 4 (G4). Two studies in HIV + ve persons have shown superior immunogenicity of Cervarix (which uses a TLR4 agonist adjuvant) compared to G4. Studies of Hepatitis B vaccines in HIV + ve persons have shown that either (i) increased number of doses (ii) increased vaccine dose, or (iii) TLR agonist adjuvanted vaccines, all produce increased immunogenicity compared to standard vaccine regimes. Therefore, questions remain as to optimal HPV vaccine regimes in HIV and further clinical trials with different HPV vaccine regimes are needed.
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22
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El Chaer F, El Sahly HM. Vaccination in the Adult Patient Infected with HIV: A Review of Vaccine Efficacy and Immunogenicity. Am J Med 2019; 132:437-446. [PMID: 30611828 DOI: 10.1016/j.amjmed.2018.12.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/11/2018] [Accepted: 12/17/2018] [Indexed: 12/20/2022]
Abstract
Patients infected with HIV remain at increased risk of mortality and morbidity from diseases that are preventable with vaccines partly due to the persisting immunopathology that results in impaired responses to vaccination despite virologic suppression. Because data on clinical effectiveness in patients who are immunocompromised remain limited, undervaccination of individuals with HIV poses a major concern. Multiple societies have published recommendations on vaccination in individuals infected with HIV. Many of these recommendations are based on extrapolation of data from clinical trials that usually exclude patients with HIV, although there is a growing body of data from patients infected with HIV as well. In this review, we describe the available literature on vaccine response in the adult patient with HIV as measured by immunogenicity or vaccine efficacy.
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Affiliation(s)
- Firas El Chaer
- Department of Medicine, University of Maryland School of Medicine, Baltimore; University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore
| | - Hana M El Sahly
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Tx.
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23
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Sharma RK, Sehgal S, Sachdeva N, Kumar R, Gupta A. Direct Engagement of TLR9 Ligand with T Helper Cells Leads to Cell Proliferation & Up-regulation of Cytokines. Immunol Invest 2019; 48:79-95. [PMID: 30239236 DOI: 10.1080/08820139.2018.1515223] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Abstract
PURPOSE Toll like receptor (TLR) engagement is primarily a function of the innate immune cells. The purpose of the study was to assess direct uptake of ODN 2216 in T helper cells and effects on cell proliferation and cytokine expression. METHODS We isolated CD4+ CD25- T helper cells by magnetic sorting and studied the uptake of ODN 2216 using flow cytometry and confocal microscopy. We then studied the effect of ODN 2216 engagement on cell proliferation and cytokine expression using flow cytometry and gene expression of TLR9 signaling genes using real time RT-PCR. RESULTS We made a chance observation that purified T helper cells from healthy individuals consistently bind to the TLR9 ligand ODN 2216. In PBMCs, on the other hand, 98% of monocytes preferentially bound to ODN 2216 FITC, indicating that they competed with the lymphocytes. We confirmed intracellular localization of ODN 2216 FITC as well as intracellular expression of TLR9 in Thelper cells. Furthermore, ODN 2216 FITC was also co-localized with the lysosomal membrane associated protein 1. The uptake of TLR9 ligand culminated in cellular proliferation, up-regulation of cytokines and increased mRNA expression of TLR9 and IRF7 in T helper cells, in the absence of antigen presenting cells. ODN 2216 uptake was inhibited by promethazine as well as by TLR9 antagonist. CONCLUSIONS Our results show a direct engagement of TLR9 ligand in T helper cells and suggest involvement of TLR9 signalling in CD4+T cells, which may envisage novel targets for TLR inhibitors.
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Affiliation(s)
- Ravi Kumar Sharma
- a Advanced Eye Center , Post graduate Institute of Medical Education and Research , Chandigarh , India
| | - Shobha Sehgal
- b Department of Immunopathology , Post Graduate Institute of Medical Education and Research , Chandigarh , India
| | - Naresh Sachdeva
- c Department of Endocrinology , Post Graduate Institute of Medical Education and Research , Chandigarh , India
| | - Rajendra Kumar
- d Department of Biological Sciences , Indian Institute of Science Education and Research , Mohali , Punjab , India
| | - Amod Gupta
- a Advanced Eye Center , Post graduate Institute of Medical Education and Research , Chandigarh , India
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24
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Ma Z, Cao Q, Xiong Y, Zhang E, Lu M. Interaction between Hepatitis B Virus and Toll-Like Receptors: Current Status and Potential Therapeutic Use for Chronic Hepatitis B. Vaccines (Basel) 2018; 6:vaccines6010006. [PMID: 29337856 PMCID: PMC5874647 DOI: 10.3390/vaccines6010006] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2017] [Revised: 01/06/2018] [Accepted: 01/11/2018] [Indexed: 02/06/2023] Open
Abstract
Immune defense against infection with the hepatitis B virus (HBV) is complex and involves both host innate and adaptive immune systems. It is well accepted that the development of sufficient HBV-specific T cell and B cell responses are required for controlling an HBV infection. However, the contribution of innate immunity to removing HBV has been explored in recent years. Toll-like receptors (TLRs) are recognized as the first line of antiviral immunity because they initiate intracellular signaling pathways to induce antiviral mediators such as interferons (IFNs) and other cytokines. Recent studies show that the activation of TLR-mediated signaling pathways results in a suppression of HBV replication in vitro and in vivo. However, HBV has also evolved strategies to counter TLR responses including the suppression of TLR expression and the blockage of downstream signaling pathways. Antiviral treatment in chronic HBV-infected patients leads to an upregulation of TLR expression and the restoration of its innate antiviral functions. Thus, TLR activation may serve as an additional immunotherapeutic option for treating chronic HBV infection in combination with antiviral treatment.
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Affiliation(s)
- Zhiyong Ma
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Qian Cao
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Yong Xiong
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
| | - Ejuan Zhang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany.
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Abstract
OBJECTIVE To characterize the effect of the HIV-1 infection and antiretroviral treatment (ART) in the human memory B (MEB)-cell compartment. DESIGN A cross-sectional study was designed to analyze MEB cells of HIV-1 ART treated and ART-naive study participants, and uninfected individuals. METHODS Frequency and absolute counts of MEB cell subsets in blood were determined by multicolor flow cytometry. Spontaneous cell death and B-cell proliferative capacity was evaluated in vitro by cell culture and flow cytometry. Splenic function was determined by pitted erythrocytes quantification in HIV-1 ART-treated study participants. RESULTS HIV-1 ART-treated individuals did not show functional hyposplenism despite the lack of recovery IgMIgDCD27 marginal zone-like B cells. Moreover, two germinal center-dependent MEB cells subsets were also dysregulated in HIV-1 individuals: IgMIgDCD27 (IgM only) cells were increased, whereas the switched subset (IgMIgD) was reduced in viremic individuals. Althought ART restored the numbers of these populations; the switched MEB cells were enriched in CD27 cells, which showed the highest susceptibility to spontaneous cell death ex vivo. In addition, B cells from viremic individuals showed a poor response to B-cell receptor and toll-like receptor 9 stimulation that was circumvented when both stimuli were used simultaneously. CONCLUSION B cells from HIV-1 study participants show a poor stimulation capacity, that may be bypassed by the proper combination of stimuli, and a dysregulated MEB cell pool that suggest an affectation of the germinal center reaction, only partially normalized by ART. Interestingly, hyposplenism does not explain the lack of recovery of the marginal zone-like B cells in ART-treated HIV-1 individuals.
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26
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Catherine FX, Piroth L. Hepatitis B virus vaccination in HIV-infected people: A review. Hum Vaccin Immunother 2017; 13:1-10. [PMID: 28267387 PMCID: PMC5489285 DOI: 10.1080/21645515.2016.1277844] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 12/16/2016] [Accepted: 12/24/2016] [Indexed: 12/21/2022] Open
Abstract
HBV immunization is highly recommended in people infected with HIV. However, the classical schedule used in the general population has been shown to be insufficient in people living with HIV. This review summarizes the main studies dealing with HBV vaccination in people living with HIV, depending on their baseline status (in particular, never vaccinated, already vaccinated, or with an isolated anti-HBc serological profile). It shows that reinforced 40µg intramuscular HBV vaccination schedules are now frequently recommended, either initially in people never vaccinated, or in the lack of an anamnestic response in other situations. Adjuvants cannot be currently recommended. Anti-HBs titers have to be checked 1 to 2 months following the last vaccine dose, and annually thereafter a booster is necessary if antiHBs titers decrease below 10 mIU/mL. In patients with a CD4 cell count <200/µL, guidelines recommend starting the vaccination regimen as soon as possible after HAART has been started.
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27
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Spanou E, Kalisperati P, Pateras IS, Papalampros A, Barbouti A, Tzioufas AG, Kotsinas A, Sougioultzis S. Genetic Variability as a Regulator of TLR4 and NOD Signaling in Response to Bacterial Driven DNA Damage Response (DDR) and Inflammation: Focus on the Gastrointestinal (GI) Tract. Front Genet 2017; 8:65. [PMID: 28611823 PMCID: PMC5447025 DOI: 10.3389/fgene.2017.00065] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 05/09/2017] [Indexed: 12/13/2022] Open
Abstract
The fundamental role of human Toll-like receptors (TLRs) and NOD-like receptors (NLRs), the two most studied pathogen recognition receptors (PRRs), is the protection against pathogens and excessive tissue injury. Recent evidence supports the association between TLR/NLR gene mutations and susceptibility to inflammatory, autoimmune, and malignant diseases. PRRs also interfere with several cellular processes, such as cell growth, apoptosis, cell proliferation, differentiation, autophagy, angiogenesis, cell motility and migration, and DNA repair mechanisms. We briefly review the impact of TLR4 and NOD1/NOD2 and their genetic variability in the process of inflammation, tumorigenesis and DNA repair, focusing in the gastrointestinal tract. We also review the available data on new therapeutic strategies utilizing TLR/NLR agonists and antagonists for cancer, allergic diseases, viral infections and vaccine development against both infectious diseases and cancer.
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Affiliation(s)
- Evagelia Spanou
- Gastroenterology Division, Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| | - Polyxeni Kalisperati
- Gastroenterology Division, Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| | - Ioannis S. Pateras
- Department of Histology and Embryology, University of AthensAthens, Greece
| | - Alexandros Papalampros
- 1st Department of Surgery, “Laikon” General Hospital, University of AthensAthens, Greece
| | - Alexandra Barbouti
- Department of Anatomy-Histology-Embryology, University of IoanninaIoannina, Greece
| | - Athanasios G. Tzioufas
- Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
| | | | - Stavros Sougioultzis
- Gastroenterology Division, Department of Pathophysiology, “Laikon” General Hospital, University of AthensAthens, Greece
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Abdoli A, Radmehr N, Bolhassani A, Eidi A, Mehrbod P, Motevalli F, Kianmehr Z, Chiani M, Mahdavi M, Yazdani S, Ardestani MS, Kandi MR, Aghasadeghi MR. Conjugated anionic PEG-citrate G2 dendrimer with multi-epitopic HIV-1 vaccine candidate enhance the cellular immune responses in mice. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2017; 45:1762-1768. [PMID: 28278580 DOI: 10.1080/21691401.2017.1290642] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Multi-epitope vaccines might cause immunity against multiple antigenic targets. Four immunodominant epitopes of HIV-1 genome were used to construct a polytope vaccine, formulated by dendrimer. Two regimens of polytopes mixture with dendrimer were utilized to immunize BALB/c mice. Adjuvants were also used to boost immune responses. The conjugated polytope could arouse significant cellular immune responses (P < 0.05) and Th1 response showed higher intensity compared to Th2 (P < 0.05). Our study depicted that conjugated dendrimer with multi-epitopic rHIVtop4 would efficiently induce cell-mediated immune responses and might be considered as promising delivery system for vaccines formulation.
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Affiliation(s)
- Asghar Abdoli
- a Hepatitis and AIDS Department , Pasteur Institute of Iran , Tehran , Iran
| | - Nina Radmehr
- b Faculty of Basic Sciences , Science and Research Branch, Islamic Azad University , Tehran , Iran
| | - Azam Bolhassani
- a Hepatitis and AIDS Department , Pasteur Institute of Iran , Tehran , Iran
| | - Akram Eidi
- b Faculty of Basic Sciences , Science and Research Branch, Islamic Azad University , Tehran , Iran
| | - Parvaneh Mehrbod
- c Influenza and Other Respiratory Viruses Department , Pasteur Institute of Iran , Tehran , Iran
| | - Fatemeh Motevalli
- a Hepatitis and AIDS Department , Pasteur Institute of Iran , Tehran , Iran
| | - Zahra Kianmehr
- d Immunoregulation Research Centre , Shahed University , Tehran , Iran
| | - Mohsen Chiani
- e Department of Pilot Biotechnology , Pasteur Institute of Iran , Tehran , Iran
| | - Mehdi Mahdavi
- f Department of Immunology , Pasteur Institute of Iran , Tehran , Iran
| | - Shaghayegh Yazdani
- g Department of Virology, School of Public Health , Tehran University of Medical Sciences , Tehran , Iran
| | - Mehdi Shafiee Ardestani
- h Department of Radiopharmacy, Faculty of Pharmacy , Tehran University of Medical Sciences , Tehran , Iran
| | - Mohammad Reza Kandi
- i Department of Life Science Engineering, Faculty of New Sciences and Technologies , University of Tehran
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Lau YF, Tang LH, Chien Lye D, Ooi EE, Leo YS. Serological response to trivalent inactivated influenza vaccine in HIV-infected adults in Singapore. Hum Vaccin Immunother 2017; 13:551-560. [PMID: 28277090 DOI: 10.1080/21645515.2016.1246636] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
A cohort of 81 HIV-infected participants received seasonal trivalent inactivated influenza vaccine (TIV) and their humoral responses were monitored using hemagglutination inhibition (HAI) assay and enzyme-linked immunosorbent assay (ELISA). Three weeks after the vaccination, the percentage of the cohort that had an HAI titer of >1:40 was 35% (for H1N1), 43% (for H3N2) and 19% (for influenza B). An increase in HAI titer can be achieved by an increase in magnitude of the antibody responses, which can be measured by an increase in ELISA titer; as well as a quality improvement of the antibody responses through increased avidity to the virus. For some individuals, an increase in avidity alone is sufficient to reach the sero-protective titer. Notably, a number of volunteers showed an increase in ELISA titer without a rise in HAI titer. A total of 24 participants (30%) did not show any significant increase in both HAI and ELISA tests after vaccination. Apart from a lower peripheral CD4+ T cell count, the non responders' peripheral blood mononuclear cells (PBMC) also had a higher IL-10 mRNA expression after TIV vaccination ex vivo. Cytokine profiling demonstrated that, apart from a weaker MCP-1 expression in the non-responder group, PBMC from both groups responded comparably to lipopolysaccharide (LPS) stimulation in vitro. Since only 3 participants developed sero-protective titers against all 3 subtypes after vaccination, our study highlights a need to enhance the immunogenicity of the subunit vaccine for this population, potentially through harnessing the innate immunity with an external adjuvant.
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Affiliation(s)
- Yuk-Fai Lau
- a Host-pathogen Interactions Laboratory, DMERI , DSO National Laboratories , The Republic of Singapore.,b Program in Emerging Infectious Diseases , Duke-NUS Medical School , The Republic of Singapore
| | - Lay-Hoon Tang
- a Host-pathogen Interactions Laboratory, DMERI , DSO National Laboratories , The Republic of Singapore
| | - David Chien Lye
- c Communicable Disease Centre , Tan Tock Seng Hospital , Singapore.,d Yong Loo Lin School of Medicine , National University of Singapore , Singapore
| | - Eng-Eong Ooi
- b Program in Emerging Infectious Diseases , Duke-NUS Medical School , The Republic of Singapore
| | - Yee-Sin Leo
- c Communicable Disease Centre , Tan Tock Seng Hospital , Singapore.,d Yong Loo Lin School of Medicine , National University of Singapore , Singapore.,e Saw Swee Hock School of Public Health , National University of Singapore , Singapore
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30
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Hervé PL, Descamps D, Deloizy C, Dhelft V, Laubreton D, Bouguyon E, Boukadiri A, Dubuquoy C, Larcher T, Benhamou PH, Eléouët JF, Bertho N, Mondoulet L, Riffault S. Non-invasive epicutaneous vaccine against Respiratory Syncytial Virus: Preclinical proof of concept. J Control Release 2016; 243:146-159. [DOI: 10.1016/j.jconrel.2016.10.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Revised: 10/03/2016] [Accepted: 10/04/2016] [Indexed: 11/29/2022]
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31
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Schüller S, Wisgrill L, Sadeghi K, Gindl E, Helmer H, Husslein P, Berger A, Spittler A, Förster-Waldl E. The TLR-specific adjuvants R-848 and CpG-B endorse the immunological reaction of neonatal antigen-presenting cells. Pediatr Res 2016; 80:311-8. [PMID: 27057737 DOI: 10.1038/pr.2016.71] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 02/02/2016] [Indexed: 01/18/2023]
Abstract
BACKGROUND Preterm neonates display an impaired vaccine response. Neonatal antigen-presenting cells (APCs) are less effective to induce an adaptive immune response and to promote the development of immunological memory. Efficient adjuvantal toll-like receptor (TLR)-triggering may overcome the neonatal immunological impairment. Accordingly, the aim of this study was to investigate the immunostimulatory action of R-848 and CpG-B on neonatal APCs. METHODS Surface marker and cytokine secretion of APCs were evaluated after incubation of cord blood and peripheral blood mononuclear cells with the indicated adjuvants and were analyzed using flow cytometry. RESULTS TLR-specific stimulation resulted in a significant induction of costimulatory molecules on neonatal APCs. Stimulation with R-848 resulted in significant higher secretion of TNFα, IL-6, IL-10, IL-12/IL-23p40, IL-12p70, and IFN-γ. Interestingly, CpG-B resulted in significant higher secretion of TNFα and IL-6. CONCLUSION In summary, the incubation of TLR-agonists induced activation and maturation of neonatal APCs. These data show that modern TLR-specific adjuvants achieve a direct effect and potent upregulation of activation and maturation markers and cytokines in preterm neonates. We thus conclude that agents triggering TLRs might possibly overcome neonatal lack of vaccine responses.
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Affiliation(s)
- Simone Schüller
- Department of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria
| | - Lukas Wisgrill
- Department of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria
| | - Kambis Sadeghi
- Department of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria
| | - Erich Gindl
- Department of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria
| | - Hanns Helmer
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Peter Husslein
- Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria
| | - Angelika Berger
- Department of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria
| | - Andreas Spittler
- Department of Surgery, Research Labs & Core Facility Flow Cytometry, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Förster-Waldl
- Department of Paediatrics and Adolescent Medicine, Division of Neonatology, Paediatric Intensive Care & Neuropaediatrics, Medical University of Vienna, Vienna, Austria
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Pettengill MA, van Haren SD, Li N, Dowling DJ, Bergelson I, Jans J, Ferwerda G, Levy O. Distinct TLR-mediated cytokine production and immunoglobulin secretion in human newborn naïve B cells. Innate Immun 2016; 22:433-43. [PMID: 27252169 DOI: 10.1177/1753425916651985] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 04/27/2016] [Indexed: 11/15/2022] Open
Abstract
Neonatal innate immunity is distinct from that of adults, which may contribute to increased susceptibility to infection and limit vaccine responses. B cells play critical roles in protection from infection and detect PAMPs via TLRs, that, when co-activated with CD40, can drive B-cell proliferation and Ab production. We characterized the expression of TLRs in circulating B cells from newborns and adults, and evaluated TLR- and CD40-mediated naïve B-cell class-switch recombination (CSR) and cytokine production. Gene expression levels of most TLRs was similar between newborn and adult B cells, except that newborn naïve B cells expressed more TLR9 than adult naïve B cells. Neonatal naïve B cells demonstrated impaired TLR2- and TLR7- but enhanced TLR9-mediated cytokine production. Significantly fewer newborn naïve B cells underwent CSR to produce IgG, an impairment also noted with IL-21 stimulation. Additionally, co-stimulation via CD40 and TLRs induced greater cytokine production in adult B cells. Thus, while newborn naïve B cells demonstrate adult-level expression of TLRs and CD40, the responses to stimulation of these receptors are distinct. Relatively high expression of TLR9 and impaired CD40-mediated Ig secretion contributes to distinct innate and adaptive immunity of human newborns and may inform novel approaches to early-life immunization.
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Affiliation(s)
- Matthew A Pettengill
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA
| | - Simon D van Haren
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA
| | - Ning Li
- Department of Immunology and Rheumatology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - David J Dowling
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA
| | - Ilana Bergelson
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA
| | - Jop Jans
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gerben Ferwerda
- Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Ofer Levy
- Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA Precision Vaccines Program, Boston Children's Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA
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Weeratna RD, Chikh G, Zhang L, Fraser JD, Thorn JM, Merson JR, McCluskie MJ, Champion BR, Davis HL. Immunogenicity of a peptide-based anti-IgE conjugate vaccine in non-human primates. Immun Inflamm Dis 2016; 4:135-147. [PMID: 27957325 PMCID: PMC4879460 DOI: 10.1002/iid3.98] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 01/06/2016] [Accepted: 01/12/2016] [Indexed: 01/02/2023] Open
Abstract
The anti-human immunoglobulin E (IgE) monoclonal antibody, omalizumab (Xolair®, Genentech, South San Fransisco, CA), is effective in the treatment of poorly controlled moderate to severe allergic asthma and chronic idiopathic urticaria. It acts by specifically binding to the constant domain (Cϵ3) of free human IgE in the blood and interstitial fluid. Although efficacious, use of omalizumab is limited due to restrictions on patient weight and pre-existing IgE levels, and frequent dosing (q2-4 weeks). A vaccine inducing anti-IgE antibodies has the potential for similar clinical benefits with less frequent dosing and relatively lower cost of goods. We developed a vaccine containing two IgE peptide-conjugates targeting the Cϵ3 domain of human IgE. As part of preclinical evaluation of the vaccine to optimize formulation and dose prior to initiating clinical studies, we evaluated the vaccine in non-human primates, and demonstrate the induction of anti-peptide antibodies that can bind to conformationally intact human IgE and are capable, at least in some animals, of substantial lowering circulating IgE levels.
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Affiliation(s)
| | - Ghania Chikh
- Pfizer Vaccine ImmunotherapeuticsOttawa LaboratoriesOttawaOntarioCanada
| | - Lu Zhang
- Pfizer Vaccine ImmunotherapeuticsOttawa LaboratoriesOttawaOntarioCanada
| | | | | | - James R. Merson
- Pfizer Biotherapeutics Pharmaceutical SciencesSt. LouisMissouriUSA
| | | | | | - Heather L. Davis
- Pfizer Vaccine ImmunotherapeuticsOttawa LaboratoriesOttawaOntarioCanada
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Apostólico JDS, Boscardin SB, Yamamoto MM, de Oliveira-Filho JN, Kalil J, Cunha-Neto E, Rosa DS. HIV Envelope Trimer Specific Immune Response Is Influenced by Different Adjuvant Formulations and Heterologous Prime-Boost. PLoS One 2016; 11:e0145637. [PMID: 26727218 PMCID: PMC4699765 DOI: 10.1371/journal.pone.0145637] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 12/07/2015] [Indexed: 02/07/2023] Open
Abstract
The development of a preventive vaccine against human immunodeficiency virus (HIV-1) infection is the most efficient method to control the epidemic. The ultimate goal is to develop a vaccine able to induce specific neutralizing, non-neutralizing antibodies and cellular mediated immunity (CMI). Humoral and CMI responses can be directed to glycoproteins that are normally presented as a trimeric spike on the virus surface (gp140). Despite safer, subunit vaccines are normally less immunogenic/effective and need to be delivered together with an adjuvant. The choice of a suitable adjuvant can induce effective humoral and CMI that utterly lead to full protection against disease. In this report, we established a hierarchy of adjuvant potency on humoral and CMI when admixed with the recombinant HIV gp140 trimer. We show that vaccination with gp140 in the presence of different adjuvants can induce high-affinity antibodies, follicular helper T cells and germinal center B cells. The data show that poly (I:C) is the most potent adjuvant to induce specific CMI responses evidenced by IFN-γ production and CD4+/CD8+ T cell proliferation. Furthermore, we demonstrate that combining some adjuvants like MPL plus Alum and MPL plus MDP exert additive effects that impact on the magnitude and quality of humoral responses while mixing MDP with poly (I:C) or with R848 had no impact on total IgG titers but highly impact IgG subclass. In addition, heterologous DNA prime- protein boost yielded higher IgG titers when compare to DNA alone and improved the quality of humoral response when compare to protein immunization as evidenced by IgG1/IgG2a ratio. The results presented in this paper highlight the importance of selecting the correct adjuvant-antigen combination to potentiate desired cells for optimal stimulation.
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Affiliation(s)
- Juliana de Souza Apostólico
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP/EPM), São Paulo, Brazil
| | - Silvia Beatriz Boscardin
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Márcio Massao Yamamoto
- Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Jethe Nunes de Oliveira-Filho
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP/EPM), São Paulo, Brazil
| | - Jorge Kalil
- Heart Institute (InCor), University of São Paulo—School of Medicine, São Paulo, Brazil
- Institute for Investigation in Immunology—INCT, São Paulo, Brazil
| | - Edecio Cunha-Neto
- Heart Institute (InCor), University of São Paulo—School of Medicine, São Paulo, Brazil
- Institute for Investigation in Immunology—INCT, São Paulo, Brazil
- Laboratory of Clinical Immunology and Allergy—LIM60, University of São Paulo- School of Medicine, São Paulo, Brazil
| | - Daniela Santoro Rosa
- Department of Microbiology, Immunology and Parasitology, Federal University of São Paulo (UNIFESP/EPM), São Paulo, Brazil
- Institute for Investigation in Immunology—INCT, São Paulo, Brazil
- * E-mail:
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Cross AS, Greenberg N, Billington M, Zhang L, DeFilippi C, May RC, Bajwa KK. Phase 1 testing of detoxified LPS/group B meningococcal outer membrane protein vaccine with and without synthetic CPG 7909 adjuvant for the prevention and treatment of sepsis. Vaccine 2015; 33:6719-26. [PMID: 26514420 PMCID: PMC4679452 DOI: 10.1016/j.vaccine.2015.10.072] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 10/13/2015] [Accepted: 10/14/2015] [Indexed: 11/30/2022]
Abstract
BACKGROUND Gram-negative bacteria (GNB) are a leading cause of nosocomial infection and sepsis. Increasing multi-antibiotic resistance has left clinicians with fewer therapeutic options. Antibodies to GNB lipopolysaccharide (LPS, or endotoxin) have reduced morbidity and mortality as a result of infection and are not subject to the resistance mechanisms deployed by bacteria against antibiotics. In this phase 1 study, we administered a vaccine that elicits antibodies against a highly conserved portion of LPS with and without a CpG oligodeoxynucleotide (ODN) TLR9 agonist as adjuvant. METHODS A vaccine composed of the detoxified LPS (dLPS) from E. coli O111:B4 (J5 mutant) non-covalently complexed to group B meningococcal outer membrane protein (OMP). Twenty healthy adult subjects received three doses at 0, 29 and 59 days of antigen (10 μg dLPS) with or without CPG 7909 (250 or 500 μg). Subjects were evaluated for local and systemic adverse effects and laboratory findings. Anti-J5 LPS IgG and IgM antibody levels were measured by electrochemiluminesence. Due to premature study termination, not all subjects received all three doses. RESULTS All vaccine formulations were well-tolerated with no local or systemic events of greater than moderate severity. The vaccine alone group achieved a ≥ 4-fold "responder" response in IgG and IgM antibody in only one of 6 subjects. In contrast, the vaccine plus CPG 7909 groups appeared to have earlier and more sustained (to 180 days) responses, greater mean-fold increases, and a higher proportion of "responders" achieving ≥ 4-fold increases over baseline. CONCLUSIONS Although the study was halted before all enrolled subjects received all three doses, the J5dLPS/OMP vaccine, with or without CpG adjuvant, was safe and well-tolerated. The inclusion of CpG increased the number of subjects with a ≥ 4-fold antibody response, evident even after the second of three planned doses. A vaccine comprising J5dLPS/OMP antigen with CpG adjuvant merits further investigation. CLINICAL TRIALS REGISTRATION ClinicalTrials.gov Identifier: NCT01164514.
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Affiliation(s)
- Alan S Cross
- Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 1, Suite 480, Baltimore, MD 21201, United States.
| | - Nancy Greenberg
- Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 1, Suite 480, Baltimore, MD 21201, United States.
| | - Melissa Billington
- Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 1, Suite 480, Baltimore, MD 21201, United States.
| | - Lei Zhang
- Center for Vaccine Development, University of Maryland School of Medicine, 685 West Baltimore Street, HSF 1, Suite 480, Baltimore, MD 21201, United States.
| | - Christopher DeFilippi
- Division of Cardiovascular Medicine, Department of Medicine, University of Maryland School of Medicine, 22 South Greene Street, Baltimore, MD 21201, United States.
| | - Ryan C May
- The Emmes Corporation, 401 N. Washington Street, Rockville, MD 20850, United States.
| | - Kanwaldeep K Bajwa
- The Emmes Corporation, 401 N. Washington Street, Rockville, MD 20850, United States.
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Cho Y, Yu SJ, Cho EJ, Lee JH, Kim TM, Heo DS, Kim YJ, Yoon JH. High titers of anti-HBs prevent rituximab-related viral reactivation in resolved hepatitis B patient with non-Hodgkin's lymphoma. J Med Virol 2015; 88:1010-7. [PMID: 26531242 DOI: 10.1002/jmv.24423] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/02/2015] [Indexed: 12/23/2022]
Abstract
Rituximab, an anti-CD20 monoclonal antibody, is associated with an increased risk of hepatitis B virus (HBV) reactivation. This study aimed to determine the predictive factors for rituximab-related HBV reactivation in resolved hepatitis B patients, defined as HBsAg-negative, anti-HBc-positive, and undetectable HBV DNA. Among 840 consecutive patients with CD20-positive B-cell lymphoma who received rituximab-based chemotherapy from 2003 through 2014 at Seoul National University Hospital, 732 patients were excluded because either anti-HBc was not assessed or they were HBsAg-seropositive. This retrospective study included 108 resolved hepatitis B patients. During a median 33.5-month follow-up period, eight cases of HBV reactivation occurred only among the patients with low anti-HBs titers (<100 mIU/ml) at baseline and those who did not receive antiviral prophylaxis. Using multivariate analyses, antiviral prophylaxis and baseline anti-HBs titers were the protective factors for HBV reactivation (hazard ratio [HR], 0.90 and 0.95, respectively). Among those who did not receive antiviral prophylaxis, patients with high baseline anti-HBs (≥100 mIU/ml) experienced significantly lower risk of HBV reactivation (HR, 0.49; P = 0.006) than the patients with low baseline anti-HBs (<100 mIU/ml) whose cumulative HBV reactivation rates at 6 and 24 months after chemotherapy were 8.3% and 17.3%, respectively. High anti-HBs titer at baseline and antiviral prophylaxis prevented HBV reactivation, suggesting antiviral prophylaxis should be considered according to baseline anti-HBs titer. Meticulous follow-up for ALT and HBV DNA without antiviral prophylaxis might be possible for the patients with high baseline anti-HBs (≥100 mIU/ml).
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Affiliation(s)
- Yuri Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Ju Cho
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Tae Min Kim
- Department of Internal Medicine and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Dae Seog Heo
- Department of Internal Medicine and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Zhang E, Kosinska A, Lu M, Yan H, Roggendorf M. Current status of immunomodulatory therapy in chronic hepatitis B, fifty years after discovery of the virus: Search for the "magic bullet" to kill cccDNA. Antiviral Res 2015; 123:193-203. [PMID: 26476376 DOI: 10.1016/j.antiviral.2015.10.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 10/09/2015] [Accepted: 10/09/2015] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B (CHB) is currently treated with IFN-α and nucleos(t)ide analogues, which have many clinical benefits, but there is no ultimate cure. The major problem consists in the persistence of cccDNA in infected hepatocytes. Because no antiviral drug has been evaluated which significantly reduces copies of cccDNA, cytolytic and noncytolytic approaches are needed. Effective virus-specific T- and B-cell responses remain crucial in eliminating cccDNA-carrying hepatocytes and for the long-term control of HBV infection. Reduction of viremia by antiviral drugs provides a window for reconstitution of an HBV-specific immune response. Preclinical studies in mice and woodchucks have shown that immunostimulatory strategies, such as prime-boost vaccination and PD-1 blockade, can boost a weak virus-specific T cell response and lead to effective control of HBV infection. Based on data obtained in our preclinical studies, the combination of antiviral drugs and immunomodulators may control HBV viremia during a patient's drug-off period. In this article, we review current immune-modulatory approaches for the treatment of chronic hepatitis B and the elimination of cccDNA in preclinical models. This article forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis".
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Affiliation(s)
- Ejuan Zhang
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Anna Kosinska
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany
| | - Mengji Lu
- Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Huimin Yan
- Mucosal Immunity Research Group, State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei, China
| | - Michael Roggendorf
- Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany; Institute for Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
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O'Bryan TA, Rini EA, Okulicz J, Messner O, Ganesan A, Lalani T, Bavaro MF, O'Connell RJ, Agan BK, Landrum ML. HIV viraemia during hepatitis B vaccination shortens the duration of protective antibody levels. HIV Med 2015; 16:161-7. [PMID: 25586899 DOI: 10.1111/hiv.12189] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/02/2014] [Indexed: 01/15/2023]
Abstract
OBJECTIVES Individuals with HIV infection often have early waning of protective antibody following hepatitis B virus (HBV) vaccination. HIV viraemia at the time of vaccination may limit the durability of serum anti-HBV surface antibody (HBsAb) levels. We investigated the relationship of HIV plasma viral load (VL) and duration of HBsAb among vaccinees enrolled in the US Military HIV Natural History Study. METHODS We included in the study participants who had no history of prior HBV infection, who had received all HBV vaccine doses after HIV diagnosis, and who had demonstrated an initial vaccine response, defined as HBsAb ≥ 10 IU/L. Responders were retrospectively followed with serial HBV serology from the time of the last vaccine dose until the development of waning (HBsAb < 10 IU/L) or the last HBsAb measurement. Time to and risk for waning were evaluated with Kaplan-Meier survival methods and Cox proportional hazards models, respectively. RESULTS A total of 186 initial vaccine responders were identified. During 570 person-years of observation, HBsAb waned in 52 of 186 participants (28%). The cumulative proportion maintaining HBsAb ≥ 10 IU/L was 83% at 2 years and 56% at 5 years. Participants with an undetectable VL [hazard ratio (HR) 0.37; 95% confidence interval (CI) 0.18-0.76] or with detectable VL of ≤ 10 000 copies/mL (HR 0.46; 95% CI 0.21-1.00) had reduced risk of waning. Other factors including age, number of vaccine doses, CD4 count, and receipt of highly active antiretroviral therapy (HAART) were not significantly associated with risk of waning HBsAb. CONCLUSIONS Undetectable or low HIV VL at the time of HBV vaccination is associated with greater durability of vaccine response in patients with HIV infection.
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Affiliation(s)
- T A O'Bryan
- Infectious Disease Clinical Research Program, Uniformed Services University, Bethesda, MD, USA; San Antonio Military Medical Center, Fort Sam Houston, TX, USA
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Cooper C, Klein M, Walmsley S, Haase D, MacKinnon-Cameron D, Marty K, Li Y, Smith B, Halperin S, Law B, Scheifele D. High-Level Immunogenicity Is Achieved Vaccine With Adjuvanted Pandemic H1N12009and Improved With Booster Dosing in a Randomized Trial of HIV-Infected Adults. HIV CLINICAL TRIALS 2015. [DOI: 10.1310/hct1301-23] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Ma Z, Zhang E, Yang D, Lu M. Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses. Cell Mol Immunol 2014; 12:273-82. [PMID: 25418467 DOI: 10.1038/cmi.2014.112] [Citation(s) in RCA: 83] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 10/16/2014] [Accepted: 10/16/2014] [Indexed: 12/18/2022] Open
Abstract
It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus (HBV) infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons (IFNs) and pro-inflammatory cytokines. Experimental results from in vitro and in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T- and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.
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Affiliation(s)
- Zhiyong Ma
- 1] Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany [2] Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Ejuan Zhang
- Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China
| | - Dongliang Yang
- Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mengji Lu
- Institute of Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
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Sun HY, Sheng WH, Tsai MS, Lee KY, Chang SY, Hung CC. Hepatitis B virus coinfection in human immunodeficiency virus-infected patients: A review. World J Gastroenterol 2014; 20:14598-14614. [PMID: 25356024 PMCID: PMC4209527 DOI: 10.3748/wjg.v20.i40.14598] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2013] [Revised: 12/24/2013] [Accepted: 04/29/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a leading cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide. Due to the shared modes of transmission, coinfection with HBV and human immunodeficiency virus (HIV) is not uncommon. It is estimated that 10% of HIV-infected patients worldwide are coinfected with HBV. In areas where an HBV vaccination program is implemented, the HBV seroprevalence has declined significantly. In HIV/HBV-coinfected patients, HBV coinfection accelerates immunologic and clinical progression of HIV infection and increases the risk of hepatotoxicity when combination antiretroviral therapy (cART) is initiated, while HIV infection increases the risk of hepatitis events, cirrhosis, and end-stage liver disease related to chronic HBV infection. With the advances in antiviral therapy, concurrent, successful long-term suppression of HIV and HBV replication can be achieved in the cART era. To reduce the disease burden of HBV infection among HIV-infected patients, adoption of safe sex practices, avoidance of sharing needles and diluent, HBV vaccination and use of cART containing tenofovir disoproxil fumarate plus emtricitabine or lamivudine are the most effective approaches. However, due to HIV-related immunosuppression, using increased doses of HBV vaccine and novel approaches to HBV vaccination are needed to improve the immunogenicity of HBV vaccine among HIV-infected patients.
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42
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Okwen MP, Reid S, Njei B, Mbuagbaw L. Hepatitis B vaccination for reducing morbidity and mortality in persons with HIV infection. Cochrane Database Syst Rev 2014; 10:CD009886. [PMID: 25300375 PMCID: PMC4830339 DOI: 10.1002/14651858.cd009886.pub2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis B vaccine has been recommended for use in people living with HIV (PLHIV) mostly because of the similarities in routes of infection and their prevalence in the same geographic areas. PLHIV may not develop sero-protection after receiving standard hepatitis B vaccine due to their compromised immune status. OBJECTIVES To evaluate the efficacy of hepatitis B virus vaccine in PLHIV compared to placebo or no vaccine. SEARCH METHODS We searched 6 English language databases in July 2012, and updated the search in June 2013 and August 2014. We searched the grey literature, conference proceedings, specialised web sites, and contacted experts in the field. SELECTION CRITERIA Randomised controlled trials of hepatitis B vaccine compared to placebo or no vaccine, evaluating relevant outcomes of efficacy and safety. DATA COLLECTION AND ANALYSIS Two review authors independently sought and extracted data on study design, participants, hepatitis B infection, hepatitis B related morbidity and mortality, anti-HBs immunogenicity and adverse effects related to vaccines from published articles or through correspondence with authors. Data were analysed qualitatively. MAIN RESULTS One double-blind randomised controlled trial with 26 participants who were on antiretroviral therapy (ART), comparing hepatitis B vaccine to placebo conducted in Spain met our eligibility criteria and was included in this review. The study ran for three years and participants were followed up on a monthly basis. The study reported adequate humoral response to vaccine at 12 months and no local or systematic side effects in both intervention and control groups. This humoral response was lost when the participants stopped taking ART. The sample size of the study was small and the study was conducted in a high income setting unlike the areas of highest burden of hepatitis B and HIV co-infections. AUTHORS' CONCLUSIONS The evidence from this study is insufficient to support any recommendations regarding the use of hepatitis B vaccine in PLHIV. Neither does this evidence demonstrate that hepatitis B vaccine is unsafe in PLHIV. Further randomised controlled trials in high prevalence areas are required to generate evidence on the long term efficacy and safety of hepatitis B vaccine in PLHIV with and without ART. Different regimens and routes of administration should also be explored.
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Affiliation(s)
- Mbah P Okwen
- Centre for the Development of Best Practices in Health (CDBPH), Yaoundé Central Hospital, Yaoundé, Cameroon
| | - Savanna Reid
- Department of Epidemiology and Biostatistics, University of Nevada, Las Vegas, Henderson, Nevada, USA
| | - Basile Njei
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Lawrence Mbuagbaw
- Centre for the Development of Best Practices in Health (CDBPH), Yaoundé Central Hospital, Yaoundé, Cameroon
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Unleashing the potential of NOD- and Toll-like agonists as vaccine adjuvants. Proc Natl Acad Sci U S A 2014; 111:12294-9. [PMID: 25136133 DOI: 10.1073/pnas.1400478111] [Citation(s) in RCA: 229] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Innate immunity confers an immediate nonspecific mechanism of microbial recognition through germ line-encoded pattern recognition receptors (PRRs). Of these, Toll-like receptors (TLRs) and nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) have shaped our current understanding of innate regulation of adaptive immunity. It is now recognized that PRRs are paramount in instructing an appropriate adaptive immune response. Their ligands have been the focus of adjuvant research with the goal of generating modern vaccine combinations tailored to specific pathogens. In this review we will highlight the recent findings in the field of adjuvant research with a particular focus on the potential of TLR and NLR ligands as adjuvants and their influence on adaptive immune responses.
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Abstract
Vaccines are critical components for protecting HIV-infected adults from an increasing number of preventable diseases. However, missed opportunities for vaccination among HIV-infected persons persist, likely due to concerns regarding the safety and efficacy of vaccines, as well as the changing nature of vaccine guidelines. In addition, the optimal timing of vaccination among HIV-infected adults in regards to HIV stage and receipt of antiretroviral therapy remain important questions. This article provides a review of the current recommendations regarding vaccines among HIV-infected adults and a comprehensive summary of the evidence-based literature of the benefits and risks of vaccines among this vulnerable population.
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Affiliation(s)
- Nancy F. Crum-Cianflone
- Infectious Disease Clinic, Naval Medical Center San Diego, San Diego, California
- Department of Infectious Disease, Scripps Mercy Hospital, San Diego, California
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Scheiermann J, Klinman DM. Clinical evaluation of CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases and cancer. Vaccine 2014; 32:6377-89. [PMID: 24975812 DOI: 10.1016/j.vaccine.2014.06.065] [Citation(s) in RCA: 253] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Revised: 05/28/2014] [Accepted: 06/12/2014] [Indexed: 12/13/2022]
Abstract
Synthetic oligonucleotides (ODN) that express unmethylated "CpG motifs" trigger cells that express Toll-like receptor 9. In humans this includes plasmacytoid dendritic cells and B cells. CpG ODN induce an innate immune response characterized by the production of Th1 and pro-inflammatory cytokines. Their utility as vaccine adjuvants was evaluated in a number of clinical trials. Results indicate that CpG ODN improve antigen presentation and the generation of vaccine-specific cellular and humoral responses. This work provides an up-to-date overview of the utility of CpG ODN as adjuvants for vaccines targeting infectious agents and cancer.
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Affiliation(s)
- Julia Scheiermann
- Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick MD 21702, United States
| | - Dennis M Klinman
- Cancer and Inflammation Program, National Cancer Institute, NIH, Frederick MD 21702, United States.
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Mizusawa M, Perlman DC, Lucido D, Salomon N. Rapid loss of vaccine-acquired hepatitis B surface antibody after three doses of hepatitis B vaccination in HIV-infected persons. Int J STD AIDS 2014; 25:201-6. [PMID: 24216032 PMCID: PMC4442633 DOI: 10.1177/0956462413495820] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
HIV-infected individuals have poor responses to hepatitis B vaccine and may have decreased durability of post-vaccination immunity. Retrospective chart review was conducted for HIV-1 positive individuals aged ≥18 years who received hepatitis B vaccine at an urban HIV clinic. A total of 309 patients completed three doses and 178 had post-vaccine serology testing after the third dose. In multivariate analysis, time between the third dose and the first post-vaccine serology testing at 180-359 days (OR = 0.077, p = 0.049) and at ≥360 days (OR = 0.065, p = 0.019) were associated with poor vaccine responses. A significant decrease in seropositivity appeared as early as 180 days after the third vaccine dose, suggesting a rapid loss of vaccine-acquired hepatitis B surface antibody in HIV-infected persons. Our findings suggest that hepatitis B surface antibody should be tested at 6 to 12 months after completing primary vaccine series in order to detect early secondary vaccine failure.
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Garg R, Latimer L, Gerdts V, Potter A, van Drunen Littel-van den Hurk S. Vaccination with the RSV fusion protein formulated with a combination adjuvant induces long-lasting protective immunity. J Gen Virol 2014; 95:1043-1054. [PMID: 24572813 DOI: 10.1099/vir.0.062570-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Respiratory syncytial virus (RSV) is one of the primary causative agents of upper and lower respiratory tract infections in young children, in particular infants. Recently, we reported the protective efficacy of a RSV vaccine formulation consisting of a truncated version of the fusion (F) protein formulated with a Toll-like receptor (TLR) agonist and an immunostimulatory peptide in a carrier system (ΔF/TriAdj). To evaluate the duration of immunity induced by this vaccine candidate, we carried out long-term trials. The ΔF was formulated with triple adjuvant (TriAdj) containing either polyinosinic : polycytidylic acid (polyI : C) or cytosine-phosphate-guanosine oligodeoxynucleotides (CpG ODNs) and administered intranasally to mice. One year after the second vaccination all mice were challenged with RSV. Both ΔF/TriAdj formulations mediated the induction of high levels of IgG1, IgG2a and virus-neutralizing antibodies, and IgA in the lungs. Based on the numbers of IFN-γ- and IL-5-secreting cells in the spleen, the immune response was slightly T-helper cell type 1 (Th1)-biased. This was confirmed by the presence of F85-93-specific CD8(+) effector T cells in the lungs of both ΔF/TriAdj(polyI : C)- and ΔF/TriAdj(CpG)-immunized mice. Both ΔF/TriAdj formulations induced RSV-specific CD8(+) T cells. However, ΔF/TriAdj(polyI : C) generated significantly higher IgG affinity maturation and higher numbers of RSV-specific CD8(+) effector memory T cells in lungs and CD8(+) central memory T cells in spleen and lymph nodes than ΔF/TriAdj(CpG). After RSV challenge, no virus replication and no evidence of vaccine-induced pathology were detected in mice immunized with either of the ΔF/TriAdj formulations, demonstrating that the duration of immunity induced with these vaccines is at least one year.
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Affiliation(s)
- R Garg
- VIDO-Intervac, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada
| | - L Latimer
- VIDO-Intervac, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada
| | - V Gerdts
- VIDO-Intervac, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada
- Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada
| | - A Potter
- VIDO-Intervac, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada
- Veterinary Microbiology, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada
| | - S van Drunen Littel-van den Hurk
- VIDO-Intervac, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada
- Microbiology & Immunology, University of Saskatchewan, Saskatoon, SK, S7N 5E3, Canada
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48
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Kernéis S, Launay O, Turbelin C, Batteux F, Hanslik T, Boëlle PY. Long-term immune responses to vaccination in HIV-infected patients: a systematic review and meta-analysis. Clin Infect Dis 2014; 58:1130-9. [PMID: 24415637 DOI: 10.1093/cid/cit937] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Vaccine-induced antibodies may wane more quickly in persons living with human immunodeficiency virus (HIV) than in healthy individuals. We reviewed the literature on vaccines routinely recommended in HIV-infected patients to estimate how seroprotection decreases over time in those who initially responded to immunization. For each study retrieved from the literature, the decrease of seroprotection was modeled with a log binomial generalized linear model, and data were pooled in a meta-analysis to provide estimates of seroprotection 2 and 5 years after the last vaccine administration. Our analyses confirmed that the duration of seroprotection was shorter in HIV-infected patients and that with current guidelines, a substantial proportion of patients would have lost protective antibodies before a booster was proposed. We therefore discuss the implications for the monitoring of antibody levels and timing of revaccination in these patients.
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49
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Koff WC, Burton DR, Johnson PR, Walker BD, King CR, Nabel GJ, Ahmed R, Bhan MK, Plotkin SA. Accelerating next-generation vaccine development for global disease prevention. Science 2013; 340:1232910. [PMID: 23723240 DOI: 10.1126/science.1232910] [Citation(s) in RCA: 210] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Vaccines are among the greatest successes in the history of public health. However, past strategies for vaccine development are unlikely to succeed in the future against major global diseases such as AIDS, tuberculosis, and malaria. For such diseases, the correlates of protection are poorly defined and the pathogens evade immune detection and/or exhibit extensive genetic variability. Recent advances have heralded in a new era of vaccine discovery. However, translation of these advances into vaccines remains impeded by lack of understanding of key vaccinology principles in humans. We review these advances toward vaccine discovery and suggest that for accelerating successful vaccine development, new human immunology-based clinical research initiatives be implemented with the goal of elucidating and more effectively generating vaccine-induced protective immune responses.
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Affiliation(s)
- Wayne C Koff
- International AIDS Vaccine Initiative (IAVI), New York, NY 10004, USA.
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50
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Strategies to increase responsiveness to hepatitis B vaccination in adults with HIV-1. THE LANCET. INFECTIOUS DISEASES 2013; 12:966-76. [PMID: 23174382 DOI: 10.1016/s1473-3099(12)70243-8] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
HIV and hepatitis B virus co-infection leads to substantially increased morbidity and mortality compared with either infection alone. Immunisation with hepatitis B virus vaccine is the most effective way to prevent the infection in people with HIV; however, these patients have decreased vaccine responses and a short duration of protection compared with immunocompetent individuals. Control of HIV replication with highly active antiretroviral therapy and increased CD4 cell counts are associated with improved immune responses to hepatitis B vaccination. New vaccination strategies, such as increased vaccine dose, use of the intradermal route, and addition of adjuvants, could improve response rates in adults with HIV.
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