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Sallam M, Al-Khatib AO, Al-Mahzoum KS, Abdelaziz DH, Sallam M. Current Developments in Malaria Vaccination: A Concise Review on Implementation, Challenges, and Future Directions. Clin Pharmacol 2025; 17:29-47. [PMID: 40191019 PMCID: PMC11971972 DOI: 10.2147/cpaa.s513282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/25/2025] [Indexed: 04/09/2025] Open
Abstract
Introduction Malaria remains a persistent challenge in global health, disproportionately affecting populations in endemic regions (eg, sub-Saharan Africa). Despite decades of international collaborative efforts, malaria continues to claim hundreds of thousands of lives each year, with young children and pregnant women enduring the heaviest burden. This concise review aimed to provide an up-to-date assessment of malaria vaccines progress, challenges, and future directions. Methods A PubMed/MEDLINE search (2015-2024) was conducted to identify studies on malaria vaccine development, implementation barriers, efficacy, and vaccination hesitancy. Clinical trials, reviews, and global health reports were included based on relevance to the review aims. No strict inclusion criteria were applied, and selection was guided by key review themes and policy relevance. Results The introduction of pre-erythrocytic malaria vaccines (RTS,S/AS01 and R21/Matrix-M), represents an important milestone in malaria control efforts with promising results from the erythrocytic vaccine RH5.1/Matrix-M in recent clinical trials. However, the approval of these vaccines is accompanied by significant challenges such as the limited efficacy, the complexity of multi-dose regimens, and numerous barriers to widespread implementation in resource-limited settings. The review identified the complex challenges to broad malaria vaccination coverage, including logistical barriers, healthcare infrastructure effect, financial limitations, malaria vaccine hesitancy, among other obstacles in malaria-endemic regions. Promising developments in malaria vaccination, such as next-generation candidates (eg, mRNA-based vaccines), hold the potential to offer improved efficacy, longer-lasting protection, and greater scalability. There is a critical need to integrate malaria vaccination efforts with established malaria control interventions (eg, insecticide-treated bed nets, vector control strategies, and anti-malarial drugs). Conclusion Achieving sustained control of malaria morbidity and mortality will require strong global collaboration, sufficient funding, and continuous efforts to address inequities in access and delivery of malaria control measures including the malaria vaccines.
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Affiliation(s)
- Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, The University of Jordan, Amman, Jordan
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman, Jordan
- Department of Translational Medicine, Faculty of Medicine, Lund University, Malmö, Sweden
| | - Arwa Omar Al-Khatib
- Faculty of Pharmacy, Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan
| | | | - Doaa H Abdelaziz
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Baha University, Al-Baha, Saudi Arabia
- Department of Clinical Pharmacy, the National Hepatology and Tropical Medicine Research Institute, Cairo, Egypt
| | - Mohammed Sallam
- Department of Pharmacy, Mediclinic Parkview Hospital, Mediclinic Middle East, Dubai, United Arab Emirates
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Zainal KH, Hasyim AA, Yamamoto Y, Mizuno T, Sato Y, Rasyid SH, Niikura M, Abe YI, Iyori M, Mizukami H, Shida H, Yoshida S. A Head-to-Head Comparative Study of the Replication-Competent Vaccinia Virus and AAV1-Based Malaria Vaccine versus RTS,S/AS01 in Murine Models. Vaccines (Basel) 2024; 12:1155. [PMID: 39460322 PMCID: PMC11512279 DOI: 10.3390/vaccines12101155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: We developed a multistage Plasmodium falciparum vaccine using a heterologous prime-boost immunization strategy. This involved priming with a highly attenuated, replication-competent vaccinia virus strain LC16m8Δ (m8Δ) and boosting with adeno-associated virus type 1 (AAV1). This approach demonstrated 100% efficacy in both protection and transmission-blocking in a murine model. In this study, we compared our LC16m8∆/AAV1 vaccine, which harbors a gene encoding Pfs25-PfCSP fusion protein, to RTS,S/AS01 (RTS,S) in terms of immune responses, protective efficacy, and transmission-blocking activity (TBA) in murine models. Methods: Mice were immunized following prime-boost vaccine regimens m8∆/AAV1 or RTS,S and challenged with transgenic Plasmodium berghei parasites. Immune responses were assessed via ELISA, and TB efficacy was evaluated using direct feeding assays. Results: m8∆/AAV1 provided complete protection (100%) in BALB/c mice and moderate (40%) protection in C57BL/6 mice, similar to RTS,S. Unlike RTS,S's narrow focus (repeat region), m8∆/AAV1 triggered antibodies for all PfCSP regions (N-terminus, repeat, and C-terminus) with balanced Th1/Th2 ratios. Regarding transmission blockade, serum from m8∆/AAV1-vaccinated BALB/c mice achieved substantial transmission-reducing activity (TRA = 83.02%) and TB activity (TBA = 38.98%)-attributes not observed with RTS,S. Furthermore, m8∆/AAV1 demonstrated durable TB efficacy (94.31% TRA and 63.79% TBA) 100 days post-immunization. Conclusions: These results highlight m8∆/AAV1's dual action in preventing sporozoite invasion and onward transmission, a significant advantage over RTS,S. Consequently, m8∆/AAV1 represents an alternative and a promising vaccine candidate that can enhance malaria control and elimination strategies.
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Affiliation(s)
- Kartika Hardianti Zainal
- Laboratory of Vaccinology and Applied Immunology, School of Pharmacy, Kanazawa University, Kanazawa 920-1192, Japan; (K.H.Z.); (A.A.H.); (Y.Y.); (T.M.); (Y.S.); (S.H.R.); (Y.-i.A.)
| | - Ammar Abdurrahman Hasyim
- Laboratory of Vaccinology and Applied Immunology, School of Pharmacy, Kanazawa University, Kanazawa 920-1192, Japan; (K.H.Z.); (A.A.H.); (Y.Y.); (T.M.); (Y.S.); (S.H.R.); (Y.-i.A.)
- Department of Parasitology, Faculty of Medicine, Universitas Indonesia, Jakarta 10430, Indonesia
| | - Yutaro Yamamoto
- Laboratory of Vaccinology and Applied Immunology, School of Pharmacy, Kanazawa University, Kanazawa 920-1192, Japan; (K.H.Z.); (A.A.H.); (Y.Y.); (T.M.); (Y.S.); (S.H.R.); (Y.-i.A.)
| | - Tetsushi Mizuno
- Laboratory of Vaccinology and Applied Immunology, School of Pharmacy, Kanazawa University, Kanazawa 920-1192, Japan; (K.H.Z.); (A.A.H.); (Y.Y.); (T.M.); (Y.S.); (S.H.R.); (Y.-i.A.)
- Department of Global Infectious Diseases, Graduate School of Medical Sciences, Kanazawa University, Kanazawa 920-0934, Japan
| | - Yuna Sato
- Laboratory of Vaccinology and Applied Immunology, School of Pharmacy, Kanazawa University, Kanazawa 920-1192, Japan; (K.H.Z.); (A.A.H.); (Y.Y.); (T.M.); (Y.S.); (S.H.R.); (Y.-i.A.)
| | - Sani Hadiyan Rasyid
- Laboratory of Vaccinology and Applied Immunology, School of Pharmacy, Kanazawa University, Kanazawa 920-1192, Japan; (K.H.Z.); (A.A.H.); (Y.Y.); (T.M.); (Y.S.); (S.H.R.); (Y.-i.A.)
| | - Mamoru Niikura
- School of Life and Environmental Science, Azabu University, Sagamihara 252-5201, Japan;
| | - Yu-ichi Abe
- Laboratory of Vaccinology and Applied Immunology, School of Pharmacy, Kanazawa University, Kanazawa 920-1192, Japan; (K.H.Z.); (A.A.H.); (Y.Y.); (T.M.); (Y.S.); (S.H.R.); (Y.-i.A.)
| | - Mitsuhiro Iyori
- Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo 202-8585, Japan;
| | - Hiroaki Mizukami
- Division of Gene Therapy, Jichi Medical University, Shimotsuke 329-0498, Japan;
| | - Hisatoshi Shida
- Laboratory of Primate Model, Research Center for Infectious Diseases, Institute for Frontier Life and Medical Science, Kyoto University, Kyoto 606-8507, Japan;
| | - Shigeto Yoshida
- Laboratory of Vaccinology and Applied Immunology, School of Pharmacy, Kanazawa University, Kanazawa 920-1192, Japan; (K.H.Z.); (A.A.H.); (Y.Y.); (T.M.); (Y.S.); (S.H.R.); (Y.-i.A.)
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Ciubotariu II, Broyles BK, Xie S, Thimmapuram J, Mwenda MC, Mambwe B, Mulube C, Matoba J, Schue JL, Moss WJ, Bridges DJ, He Q, Carpi G. Diversity and selection analyses identify transmission-blocking antigens as the optimal vaccine candidates in Plasmodium falciparum. EBioMedicine 2024; 106:105227. [PMID: 39018754 PMCID: PMC11663769 DOI: 10.1016/j.ebiom.2024.105227] [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: 04/18/2024] [Revised: 06/18/2024] [Accepted: 06/18/2024] [Indexed: 07/19/2024] Open
Abstract
BACKGROUND A highly effective vaccine for malaria remains an elusive target, at least in part due to the under-appreciated natural parasite variation. This study aimed to investigate genetic and structural variation, and immune selection of leading malaria vaccine candidates across the Plasmodium falciparum's life cycle. METHODS We analysed 325 P. falciparum whole genome sequences from Zambia, in addition to 791 genomes from five other African countries available in the MalariaGEN Pf3k Database. Ten vaccine antigens spanning three life-history stages were examined for genetic and structural variations, using population genetics measures, haplotype network analysis, and 3D structure selection analysis. FINDINGS Among the ten antigens analysed, only three in the transmission-blocking vaccine category display P. falciparum 3D7 as the dominant haplotype. The antigens AMA1, CSP, MSP119 and CelTOS, are much more diverse than the other antigens, and their epitope regions are under moderate to strong balancing selection. In contrast, Rh5, a blood stage antigen, displays low diversity yet slightly stronger immune selection in the merozoite-blocking epitope region. Except for CelTOS, the transmission-blocking antigens Pfs25, Pfs48/45, Pfs230, Pfs47, and Pfs28 exhibit minimal diversity and no immune selection in epitopes that induce strain-transcending antibodies, suggesting potential effectiveness of 3D7-based vaccines in blocking transmission. INTERPRETATION These findings offer valuable insights into the selection of optimal vaccine candidates against P. falciparum. Based on our results, we recommend prioritising conserved merozoite antigens and transmission-blocking antigens. Combining these antigens in multi-stage approaches may be particularly promising for malaria vaccine development initiatives. FUNDING Purdue Department of Biological Sciences; Puskas Memorial Fellowship; National Institute of Allergy and Infectious Diseases (U19AI089680).
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Affiliation(s)
- Ilinca I Ciubotariu
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
| | - Bradley K Broyles
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA
| | - Shaojun Xie
- Bioinformatics Core, Purdue University, West Lafayette, IN, USA
| | | | - Mulenga C Mwenda
- PATH-Malaria Control and Elimination Partnership in Africa (MACEPA), National Malaria Elimination Centre, Lusaka, Zambia
| | - Brenda Mambwe
- PATH-Malaria Control and Elimination Partnership in Africa (MACEPA), National Malaria Elimination Centre, Lusaka, Zambia
| | - Conceptor Mulube
- PATH-Malaria Control and Elimination Partnership in Africa (MACEPA), National Malaria Elimination Centre, Lusaka, Zambia
| | | | - Jessica L Schue
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - William J Moss
- The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | | | - Qixin He
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
| | - Giovanna Carpi
- Department of Biological Sciences, Purdue University, West Lafayette, IN, USA; Purdue Institute of Inflammation, Immunology and Infectious Disease, West Lafayette, IN, USA.
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Abuelazm MT, Elzeftawy MA, Kamal MA, Badr H, Gamal M, Aboulgheit M, Abdelazeem B, Abd-Elsalam S, Abouzid M. Protective efficacy and safety of radiation-attenuated and chemo-attenuated Plasmodium Falciparum sporozoite vaccines against controlled and natural malaria infection: a systematic review and meta-analysis of randomized controlled trials. Infection 2024; 52:707-722. [PMID: 38319556 DOI: 10.1007/s15010-024-02174-4] [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: 08/28/2023] [Accepted: 01/01/2024] [Indexed: 02/07/2024]
Abstract
BACKGROUND AND OBJECTIVE Despite the significant burden of Plasmodium falciparum (Pf) malaria and the licensure of two vaccines for use in infants and young children that are partially effective in preventing clinical malaria caused by Pf, a highly effective vaccine against Pf infection is still lacking. Live attenuated vaccines using Pf sporozoites as the immunogen (PfSPZ Vaccines) hold promise for addressing this gap. Here we review the safety and efficacy of two of the most promising PfSPZ approaches: PfSPZ Vaccine (radiation attenuated PfSPZ) and PfSPZ-CVac (chemo-attenuated PfSPZ). METHODS We conducted a systematic review and meta-analysis by searching PubMed, EMBASE, SCOPUS, CENTRAL, and WOS until 22nd December 2021. We included randomized controlled trials (RCTs) of these two vaccine approaches that measured protection against parasitaemia following controlled human malaria infection (CHMI) in malaria-naive and malaria-exposed adults or following exposure to naturally transmitted Pf malaria in African adults and children (primary outcome) and that also measured the incidence of solicited and unsolicited adverse events as indicators of safety and tolerability after vaccination (secondary outcome). We included randomized controlled trials (RCTs) that measured the detected parasitaemia after vaccination (primary outcome) and the incidence of various solicited and unsolicited adverse events (secondary outcome). The quality of the included RCTs using the Cochrane ROB 1 tool and the quality of evidence using the GRADE system were evaluated. We pooled dichotomous data using the risk ratio (RR) for development of parasitemia in vaccinees relative to controls as a measure of vaccine efficacy (VE), including the corresponding confidence interval (CI). This study was registered with PROSPERO (CRD42022308057). RESULTS We included 19 RCTs. Pooled RR favoured PfSPZ Vaccine (RR: 0.65 with 95% CI [0.53, 0.79], P = 0.0001) and PfSPZ-table (RR: 0.42 with 95% CI [0.27, 0.67], P = 0.0002) for preventing parasitaemia, relative to normal saline placebo. Pooled RR showed no difference between PfSPZ Vaccine and the control in the occurrence of any solicited adverse event (RR: 1.00 with 95% CI [0.82, 1.23], P = 0.98), any local solicited adverse events (RR: 0.73 with 95% CI [0.49, 1.08], P = 0.11), any systemic solicited adverse events (RR: 0.94 with 95% CI [0.75, 1.17], P = 0.58), and any unsolicited adverse event (RR: 0.93 with 95% CI [0.78, 1.10], P = 0.37). CONCLUSION PfSPZ and PfSPZ-CVacs showed comparable efficacy. Therefore, they can introduce a promising strategy for malaria prophylaxis, but more large-scale field trials are required to sustain efficacy and yield clinically applicable findings.
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Affiliation(s)
| | | | | | - Helmy Badr
- Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | | | - Basel Abdelazeem
- Department of Cardiology, West Virginia University, Morgantown, WV, USA
| | | | - Mohamed Abouzid
- Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Rokietnicka 3, 60-806, Poznan, Poland.
- Doctoral School, Poznan University of Medical Sciences, Poznan, Poland.
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Ciubotariu II, Broyles BK, Xie S, Thimmapuram J, Mwenda MC, Mambwe B, Mulube C, Matoba J, Schue JL, Moss WJ, Bridges DJ, He Q, Carpi G. Diversity and selection analyses identify transmission-blocking antigens as the optimal vaccine candidates in Plasmodium falciparum. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.05.11.24307175. [PMID: 38766239 PMCID: PMC11100930 DOI: 10.1101/2024.05.11.24307175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
Background A highly effective vaccine for malaria remains an elusive target, at least in part due to the under-appreciated natural parasite variation. This study aimed to investigate genetic and structural variation, and immune selection of leading malaria vaccine candidates across the Plasmodium falciparum's life cycle. Methods We analyzed 325 P. falciparum whole genome sequences from Zambia, in addition to 791 genomes from five other African countries available in the MalariaGEN Pf3k Rdatabase. Ten vaccine antigens spanning three life-history stages were examined for genetic and structural variations, using population genetics measures, haplotype network analysis, and 3D structure selection analysis. Findings Among the ten antigens analyzed, only three in the transmission-blocking vaccine category display P. falciparum 3D7 as the dominant haplotype. The antigens AMA1, CSP, MSP119 and CelTOS, are much more diverse than the other antigens, and their epitope regions are under moderate to strong balancing selection. In contrast, Rh5, a blood stage antigen, displays low diversity yet slightly stronger immune selection in the merozoite-blocking epitope region. Except for CelTOS, the transmission-blocking antigens Pfs25, Pfs48/45, Pfs230, Pfs47, and Pfs28 exhibit minimal diversity and no immune selection in epitopes that induce strain-transcending antibodies, suggesting potential effectiveness of 3D7-based vaccines in blocking transmission. Interpretations These findings offer valuable insights into the selection of optimal vaccine candidates against P. falciparum. Based on our results, we recommend prioritizing conserved merozoite antigens and transmission-blocking antigens. Combining these antigens in multi-stage approaches may be particularly promising for malaria vaccine development initiatives. Funding Purdue Department of Biological Sciences; Puskas Memorial Fellowship; National Institute of Allergy and Infectious Diseases (U19AI089680).
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Affiliation(s)
- Ilinca I. Ciubotariu
- Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA
| | - Bradley K. Broyles
- Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA
| | - Shaojun Xie
- Bioinformatics Core, Purdue University, West Lafayette, Indiana, USA
| | | | - Mulenga C. Mwenda
- PATH-Malaria Control and Elimination Partnership in Africa (MACEPA), National Malaria Elimination Centre, Lusaka, Zambia
| | - Brenda Mambwe
- PATH-Malaria Control and Elimination Partnership in Africa (MACEPA), National Malaria Elimination Centre, Lusaka, Zambia
| | - Conceptor Mulube
- PATH-Malaria Control and Elimination Partnership in Africa (MACEPA), National Malaria Elimination Centre, Lusaka, Zambia
| | | | - Jessica L. Schue
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - William J. Moss
- The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | | | - Qixin He
- Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA
| | - Giovanna Carpi
- Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA
- Purdue Institute of Inflammation, Immunology and Infectious Disease, West Lafayette, Indiana, USA
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Hayashi CTH, Cao Y, Zavala F, Simonyan H, Young CN, Kumar N. Antibodies elicited by Plasmodium falciparum circumsporozoite proteins lacking sequentially deleted C-terminal amino acids reveal mouse strain and epitopes specific differences. Vaccine 2023; 41:6824-6833. [PMID: 37827967 PMCID: PMC11004087 DOI: 10.1016/j.vaccine.2023.10.009] [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: 09/07/2023] [Revised: 10/03/2023] [Accepted: 10/04/2023] [Indexed: 10/14/2023]
Abstract
Malaria affects ∼ ¼ billion people globally and requires the development of additional tools to aid in elimination efforts. The recently approved RTS,S/AS01 vaccine represents a positive step, however, the moderate efficacy necessitates the development of more efficacious vaccines. PfCSP is a key target antigen for pre-erythrocytic vaccines aimed at preventing Plasmodium falciparum malaria infections. Epitopes within the central repeat region and at the junction of the repeat and N-terminal domain are well documented as major protective B cell epitopes. On the other hand, a majority of antibodies against the epitopes in the C-terminal domain, have been shown to be non-protective against sporozoite challenge. The C-terminal domain, however, contains CD4+ and CD8+ T cell epitopes previously shown to be important for regulating immune responses. The present study was designed to further explore the immunomodulatory potential of the C-terminal domain using DNA vaccines encoding PfCSP with sequential C-terminal truncations following known T cell epitopes. Five DNA vaccines encoding different truncations of PfCSP within the C-terminal domain were administered via intramuscular route and in vivo electroporation for effective immunogenicity. Protection in mice was evaluated by challenge with transgenic P. berghei expressing PfCSP. In Balb/c mice, antibody responses and protective efficacy were both affected progressively with sequential deletion of C-terminal amino acid residues. Similar studies in C57Bl/6 mice revealed that immunizations with plasmids encoding truncated PfCSP showed partial protection from sporozoite challenge with no significant differences in antibody titers observed compared to full-length PfCSP DNA immunized mice. Further analysis revealed murine strain-specific differences in the recognition of specific epitopes.
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MESH Headings
- Animals
- Protozoan Proteins/immunology
- Protozoan Proteins/genetics
- Malaria Vaccines/immunology
- Malaria Vaccines/administration & dosage
- Malaria Vaccines/genetics
- Mice
- Plasmodium falciparum/immunology
- Plasmodium falciparum/genetics
- Antibodies, Protozoan/immunology
- Vaccines, DNA/immunology
- Vaccines, DNA/genetics
- Vaccines, DNA/administration & dosage
- Epitopes, T-Lymphocyte/immunology
- Epitopes, T-Lymphocyte/genetics
- Malaria, Falciparum/prevention & control
- Malaria, Falciparum/immunology
- Mice, Inbred BALB C
- Female
- Epitopes, B-Lymphocyte/immunology
- Epitopes, B-Lymphocyte/genetics
- Epitopes/immunology
- Epitopes/genetics
- Sporozoites/immunology
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Affiliation(s)
- Clifford T H Hayashi
- Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington DC 20052, USA
| | - Yi Cao
- Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington DC 20052, USA
| | - Fidel Zavala
- Johns Hopkins Malaria Research Institute, Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21215, USA
| | - Hayk Simonyan
- Department of Pharmacology and Physiology, School of Medicine and Health Sciences, George Washington University, Washington DC 20052, USA
| | - Colin N Young
- Department of Pharmacology and Physiology, School of Medicine and Health Sciences, George Washington University, Washington DC 20052, USA
| | - Nirbhay Kumar
- Department of Global Health, Milken Institute School of Public Health, George Washington University, Washington DC 20052, USA.
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Nicholas J, De SL, Thawornpan P, Brashear AM, Kolli SK, Subramani PA, Barnes SJ, Cui L, Chootong P, Ntumngia FB, Adams JH. Preliminary characterization of Plasmodium vivax sporozoite antigens as pre-erythrocytic vaccine candidates. PLoS Negl Trop Dis 2023; 17:e0011598. [PMID: 37703302 PMCID: PMC10519608 DOI: 10.1371/journal.pntd.0011598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 09/25/2023] [Accepted: 08/15/2023] [Indexed: 09/15/2023] Open
Abstract
Plasmodium vivax pre-erythrocytic (PE) vaccine research has lagged far behind efforts to develop Plasmodium falciparum vaccines. There is a critical gap in our knowledge of PE antigen targets that can induce functionally inhibitory neutralizing antibody responses. To overcome this gap and guide the selection of potential PE vaccine candidates, we considered key characteristics such as surface exposure, essentiality to infectivity and liver stage development, expression as recombinant proteins, and functional immunogenicity. Selected P. vivax sporozoite antigens were surface sporozoite protein 3 (SSP3), sporozoite microneme protein essential for cell traversal (SPECT1), sporozoite surface protein essential for liver-stage development (SPELD), and M2 domain of MAEBL. Sequence analysis revealed little variation occurred in putative B-cell and T-cell epitopes of the PE candidates. Each antigen was tested for expression as refolded recombinant proteins using an established bacterial expression platform and only SPELD failed. The successfully expressed antigens were immunogenic in vaccinated laboratory mice and were positively reactive with serum antibodies of P. vivax-exposed residents living in an endemic region in Thailand. Vaccine immune antisera were tested for reactivity to native sporozoite proteins and for their potential vaccine efficacy using an in vitro inhibition of liver stage development assay in primary human hepatocytes quantified on day 6 post-infection by high content imaging analysis. The anti-PE sera produced significant inhibition of P. vivax sporozoite invasion and liver stage development. This report provides an initial characterization of potential new PE candidates for a future P. vivax vaccine.
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Affiliation(s)
- Justin Nicholas
- Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, United States of America
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
| | - Sai Lata De
- Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, United States of America
| | - Pongsakorn Thawornpan
- Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand
| | - Awtum M. Brashear
- Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, United States of America
- Division of Infectious Diseases, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
| | - Surendra Kumar Kolli
- Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, United States of America
| | - Pradeep Annamalai Subramani
- Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, United States of America
| | - Samantha J. Barnes
- Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, United States of America
| | - Liwang Cui
- Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, United States of America
- Division of Infectious Diseases, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida, United States of America
| | - Patchanee Chootong
- Department of Clinical Microbiology and Applied Technology, Faculty of Medical Technology, Mahidol University, Bangkok, Thailand
| | - Francis Babila Ntumngia
- Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, United States of America
| | - John H. Adams
- Center for Global Health and Interdisciplinary Research, College of Public Health, University of South Florida, Tampa, Florida, United States of America
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Mariano RMDS, Gonçalves AAM, de Oliveira DS, Ribeiro HS, Pereira DFS, Santos IS, Lair DF, da Silva AV, Galdino AS, Chávez-Fumagalli MA, da Silveira-Lemos D, Dutra WO, Giunchetti RC. A Review of Major Patents on Potential Malaria Vaccine Targets. Pathogens 2023; 12:pathogens12020247. [PMID: 36839519 PMCID: PMC9959516 DOI: 10.3390/pathogens12020247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/30/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Malaria is a parasitic infection that is a great public health concern and is responsible for high mortality rates worldwide. Different strategies have been employed to improve disease control, demonstrating the ineffectiveness of controlling vectors, and parasite resistance to antimalarial drugs requires the development of an effective preventive vaccine. There are countless challenges to the development of such a vaccine directly related to the parasite's complex life cycle. After more than four decades of basic research and clinical trials, the World Health Organization (WHO) has recommended the pre-erythrocytic Plasmodium falciparum (RTS, S) malaria vaccine for widespread use among children living in malaria-endemic areas. However, there is a consensus that major improvements are needed to develop a vaccine with a greater epidemiological impact in endemic areas. This review discusses novel strategies for malaria vaccine design taking the target stages within the parasite cycle into account. The design of the multi-component vaccine shows considerable potential, especially as it involves transmission-blocking vaccines (TBVs) that eliminate the parasite's replication towards sporozoite stage parasites during a blood meal of female anopheline mosquitoes. Significant improvements have been made but additional efforts to achieve an efficient vaccine are required to improve control measures. Different strategies have been employed, thus demonstrating the ineffectiveness in controlling vectors, and parasite resistance to antimalarial drugs requires the development of a preventive vaccine. Despite having a vaccine in an advanced stage of development, such as the RTS, S malaria vaccine, the search for an effective vaccine against malaria is far from over. This review discusses novel strategies for malaria vaccine design taking into account the target stages within the parasite's life cycle.
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Affiliation(s)
- Reysla Maria da Silveira Mariano
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Ana Alice Maia Gonçalves
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Diana Souza de Oliveira
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Helen Silva Ribeiro
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Diogo Fonseca Soares Pereira
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Ingrid Soares Santos
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Daniel Ferreira Lair
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Augusto Ventura da Silva
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Alexsandro Sobreira Galdino
- Laboratory of Biotechnology of Microorganisms, Federal University of São João Del-Rei, Divinópolis CEP 35501-296, MG, Brazil
| | - Miguel Angel Chávez-Fumagalli
- Computational Biology and Chemistry Research Group, Vicerrectorado de Investigación, Universidad Católica de Santa María, Urb. San José S/N, Arequipa 04000, Peru
| | - Denise da Silveira-Lemos
- Campus Jaraguá, University José of Rosário Vellano, UNIFENAS, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Walderez Ornelas Dutra
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
| | - Rodolfo Cordeiro Giunchetti
- Laboratory of Biology of Cell Interactions, Department of Morphology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte CEP 31270-901, MG, Brazil
- Correspondence: or ; Tel.: +55-31-3409-3003
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Waghela IN, Mallory KL, Taylor JA, Schneider CG, Savransky T, Janse CJ, Lin PJC, Tam YK, Weissman D, Angov E. Exploring in vitro expression and immune potency in mice using mRNA encoding the Plasmodium falciparum malaria antigen, CelTOS. Front Immunol 2022; 13:1026052. [PMID: 36591298 PMCID: PMC9798330 DOI: 10.3389/fimmu.2022.1026052] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 11/18/2022] [Indexed: 12/23/2022] Open
Abstract
The secreted malarial protein, Cell-Traversal protein for Ookinetes and Sporozoites (CelTOS), is highly conserved among Plasmodium species, and plays a role in the invasion of mosquito midgut cells and hepatocytes in the vertebrate host. CelTOS was identified as a potential protective antigen based on a proteomic analysis, which showed that CelTOS stimulated significant effector T cells producing IFN-γ in peripheral blood mononuclear cells (PBMCs) from radiation attenuated sporozoite-immunized, malaria-naïve human subjects. In a rodent malaria model, recombinant full-length CelTOS protein/adjuvant combinations induced sterile protection, and in several studies, functional antibodies were produced that had hepatocyte invasion inhibition and transmission-blocking activities. Despite some encouraging results, vaccine approaches using CelTOS will require improvement before it can be considered as an effective vaccine candidate. Here, we report on the use of mRNA vaccine technology to induce humoral and cell-mediated immune responses using this antigen. Several pfceltos encoding mRNA transcripts were assessed for the impact on protein translation levels in vitro. Protein coding sequences included those to evaluate the effects of signal sequence, N-glycosylation on translation, and of nucleoside substitutions. Using in vitro transfection experiments as a pre-screen, we assessed the quality of the expressed CelTOS target relative to the homogeneity, cellular localization, and durability of expression levels. Optimized mRNA transcripts, which demonstrated highest protein expression levels in vitro were selected for encapsulation in lipid nanoparticles (LNP) and used to immunize mice to assess for both humoral and cellular cytokine responses. Our findings indicate that mRNA transcripts encoding pfceltos while potent for inducing antigen-specific cellular cytokine responses in mice, were less able to mount PfCelTOS-specific antibody responses using a two-dose regimen. An additional booster dose was needed to overcome low seroconversion rates in mice. With respect to antibody fine specificities, N-glycosylation site mutated immunogens yielded lower immune responses, particularly to the N-terminus of the molecule. While it remains unclear the impact on CelTOS antigen as immunogen, this study highlights the need to optimize antigen design for vaccine development.
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Affiliation(s)
- Ishita N. Waghela
- Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States,Parsons Corporation, Centreville, VA, United States
| | - Katherine L. Mallory
- Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States,Parsons Corporation, Centreville, VA, United States
| | - Justin A. Taylor
- Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States,The Geneva Foundation, Tacoma, WA, United States
| | - Cosette G. Schneider
- Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States,Oak Ridge Institute for Science and Education, Oak Ridge, TN, United States
| | - Tatyana Savransky
- Entomology Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States,General Dynamics Information Technology, Falls Church, VA, United States
| | - Chris J. Janse
- Parasitology, Center of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands
| | | | - Ying K. Tam
- Acuitas Therapeutics Inc., Vancouver, BC, Canada
| | - Drew Weissman
- Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Evelina Angov
- Malaria Biologics Branch, Walter Reed Army Institute of Research, Silver Spring, MD, United States,*Correspondence: Evelina Angov,
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10
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Kamil M, Deveci G, Kina UY, Kappe SHI, Aly ASI. Subcutaneous Immunization with Unaltered Axenic Malaria Parasite Liver Stages Induces Sterile Protection against Infectious Sporozoite Challenge. Vaccines (Basel) 2022; 10:1884. [PMID: 36366392 PMCID: PMC9695791 DOI: 10.3390/vaccines10111884] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/03/2022] [Accepted: 08/08/2022] [Indexed: 05/09/2025] Open
Abstract
Host cell-free, axenic development of liver stages (LS) of the malaria parasite has been demonstrated. Here we explored axenic liver stages as a novel live whole parasite malaria vaccine platform, which is unaltered and not prone to human-error, compared to the immunization with live-attenuated sporozoites that must be done intravenously. We show that in contrast to live sporozoites, axenic LS are not infectious to the immunized host. Subcutaneous immunizations of mice with Plasmodium yoelii axenic LS, developed from wild-type (WT) sporozoites or WT sporozoites expressing enhanced-GFP, conferred sterile protection against P. yoelii infectious sporozoite challenge. Thus, axenic liver stages of P. falciparum and P. vivax might constitute an attractive alternative to live sporozoite immunization.
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Affiliation(s)
- Mohd Kamil
- Aly Lab., Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey
| | - Gozde Deveci
- Aly Lab., Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey
- Department of Biotechnology, Institute of Health Sciences, Bezmialem Vakif University, Istanbul 34093, Turkey
| | - Umit Y. Kina
- Aly Lab., Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey
- Department of Biotechnology, Institute of Health Sciences, Bezmialem Vakif University, Istanbul 34093, Turkey
| | - Stefan H. I. Kappe
- Center for Global Infectious Disease Research, Seattle Children’s Research Institute, 307 Westlake Avenue N. Suite 500, Seattle, WA 98109, USA
| | - Ahmed S. I. Aly
- Aly Lab., Beykoz Institute of Life Sciences and Biotechnology, Bezmialem Vakif University, Istanbul 34820, Turkey
- School of Science and Engineering, Al Akhawayn University, Ifrane 53000, Morocco
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11
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Computational Clues of Immunogenic Hotspots in Plasmodium falciparum Erythrocytic Stage Vaccine Candidate Antigens: In Silico Approach. BIOMED RESEARCH INTERNATIONAL 2022; 2022:5886687. [PMID: 36277884 PMCID: PMC9584662 DOI: 10.1155/2022/5886687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 09/27/2022] [Indexed: 11/30/2022]
Abstract
Malaria is the most pernicious parasitic infection, and Plasmodium falciparum is the most virulent species with substantial morbidity and mortality worldwide. The present in silico investigation was performed to reveal the biophysical characteristics and immunogenic epitopes of the 14 blood-stage proteins of the P. falciparum using comprehensive immunoinformatics approaches. For this aim, various web servers were employed to predict subcellular localization, antigenicity, allergenicity, solubility, physicochemical properties, posttranslational modification sites (PTMs), the presence of signal peptide, and transmembrane domains. Moreover, structural analysis for secondary and 3D model predictions were performed for all and stable proteins, respectively. Finally, human helper T lymphocyte (HTL) epitopes were predicted using HLA reference set of IEDB server and screened in terms of antigenicity, allergenicity, and IFN-γ induction as well as population coverage. Also, a multiserver B-cell epitope prediction was done with subsequent screening for antigenicity, allergenicity, and solubility. Altogether, these proteins showed appropriate antigenicity, abundant PTMs, and many B-cell and HTL epitopes, which could be directed for future vaccination studies in the context of multiepitope vaccine design.
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12
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An In Silico Analysis of Malaria Pre-Erythrocytic-Stage Antigens Interpreting Worldwide Genetic Data to Suggest Vaccine Candidate Variants and Epitopes. Microorganisms 2022; 10:microorganisms10061090. [PMID: 35744609 PMCID: PMC9231253 DOI: 10.3390/microorganisms10061090] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/12/2022] [Accepted: 05/19/2022] [Indexed: 02/05/2023] Open
Abstract
Failure to account for genetic diversity of antigens during vaccine design may lead to vaccine escape. To evaluate the vaccine escape potential of antigens used in vaccines currently in development or clinical testing, we surveyed the genetic diversity, measured population differentiation, and performed in silico prediction and analysis of T-cell epitopes of ten such Plasmodium falciparum pre-erythrocytic-stage antigens using whole-genome sequence data from 1010 field isolates. Of these, 699 were collected in Africa (Burkina Faso, Cameroon, Guinea, Kenya, Malawi, Mali, and Tanzania), 69 in South America (Brazil, Colombia, French Guiana, and Peru), 59 in Oceania (Papua New Guinea), and 183 in Asia (Cambodia, Myanmar, and Thailand). Antigens surveyed include cell-traversal protein for ookinetes and sporozoites, circumsporozoite protein, liver-stage antigens 1 and 3, sporozoite surface proteins P36 and P52, sporozoite asparagine-rich protein-1, sporozoite microneme protein essential for cell traversal-2, and upregulated-in-infectious-sporozoite 3 and 4 proteins. The analyses showed that a limited number of these protein variants, when combined, would be representative of worldwide parasite populations. Moreover, predicted T-cell epitopes were identified that could be further explored for immunogenicity and protective efficacy. Findings can inform the rational design of a multivalent malaria vaccine.
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13
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Nava-Lausón C, Spencer LM, Sajo-Bohus L, Dávila J, Tellkamp MP. Evaluation of X-ray ionizing radiation on Plasmodium berghei invasion of erythrocytes. BIONATURA 2022. [DOI: 10.21931/rb/2022.07.01.19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Developing new strategies for designing effective vaccines has become a priority for parasitologists worldwide. There is high interest in designing a vaccine against malaria since it is considered one of the most prevalent infectious diseases in the tropics. We evaluated the effects of X-rays irradiation on the erythrocytic stage of Plasmodium berghei ANKA merozoites and schizonts using doses of ionizing radiation ranging between 10 and 300 Gy on parasitized red blood cells (PRBC) to study the attenuating effects of radiation on the merozoites. Parasitic activity diminution was observed starting at 50 Gy, and the dose for complete attenuation was established at 200 Gy, corresponding with a 100% survival rate of mice. In vivo invasion experiments and immunofluorescence assays (IFA) showed inhibition of merozoite invasion of the host red blood cells (RBC). Nonetheless, immunization with irradiated parasitized red blood cells (IPRBC) was ineffective in protective assays. We perform cytoadherence and inhibition of cytoadhesion assays on irradiated merozoites. The results showed that high irradiation doses caused an unspecific cellular adhesion phenomenon independent of the ICAM-1 and CD36 interaction, which was determined by Cytoadhesion assays.
Our results show that, even though X-ray irradiation is an effective method to induce complete parasite attenuation, it might affect the parasite's membrane surface structures triggering unspecific adhesion.
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Affiliation(s)
- Carina Nava-Lausón
- Cell Biology Department, Simón Bolívar University, Valle de Sartenejas, Caracas - Venezuela
| | - Lilian M. Spencer
- Cell Biology Department, Simón Bolívar University, Valle de Sartenejas, Caracas - Venezuela School of Biological Sciences and Engineering, Yachay Tech University, San Miguel de Urcuquí - Ecuador
| | - Laszlo Sajo-Bohus
- Physics Department, Simón Bolívar University, Valle de Sartenejas, Caracas - Venezuela
| | - Jesús Dávila
- Radiotherapy Service Gurve, La Trinidad. Caracas, Venezuela
| | - Markus P. Tellkamp
- School of Biological Sciences and Engineering, Yachay Tech University, San Miguel de Urcuquí - Ecuador
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14
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Chemoprophylaxis under sporozoites-lumefantrine (CPS-LMF) immunization induce protective immune responses against Plasmodium yoelii sporozoites infection in mice. 3 Biotech 2021; 11:465. [PMID: 34745816 DOI: 10.1007/s13205-021-03022-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 10/06/2021] [Indexed: 01/16/2023] Open
Abstract
Malaria represents one of the major life-threatening diseases that poses a huge socio-economic impact, worldwide. Chemoprophylaxis vaccination using a relatively low number of wild-type infectious sporozoites represents an attractive and effective vaccine strategy against malaria. However, the role of immune responses to pre-erythrocytic versus blood-stage parasites in protection against different antimalarial drugs remains unclear. Here, in the present study, we explored the immune responses against the repetitive inoculation of live Plasmodium yoelii (P. yoelii) sporozoites in an experimental Swiss mouse model under antimalarial drug lumefantrine chemoprophylaxis (CPS-LMF). We monitored the liver stage parasitic load, pro/anti-inflammatory cytokines expression, and erythrocytic stage patency, following repetitive cycles of sporozoites inoculations. It was found that repetitive sporozoites inoculation under CPS-LMF results in delayed blood-stage infection during the fourth sporozoites challenge, while sterile protection was produced in mice following the fifth cycle of sporozoites challenge. Intriguingly, we observed a significant up-regulation of pro-inflammatory cytokines (IFN-γ, TNF-α and IL-12) and iNOS response and down-regulation of anti-inflammatory cytokines (IL-4, IL-10 and TGF-β) in the liver HMNC (hepatic mononuclear cells) and spleen cells after 4th and 5th cycle of sporozoites challenge in the CPS-LMF mice. Meanwhile, we also noticed that the liver stage parasites load under CPS-LMF immunization has gradually reduced after 2nd, 3rd, 4th and 5th sporozoites challenge. Overall, our study suggests that chemoprophylaxis vaccination under LMF drug cover develops strong immune responses and confer superior long-lasting protection against P. yoelii sporozoites. Furthermore, this vaccination strategy can be used to study the protective and stage-specific immunity against new protective antigens. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s13205-021-03022-0.
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15
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Sahu T, Gehrke EJ, Flores-Garcia Y, Mlambo G, Romano JD, Coppens I. Chemoprophylaxis vaccination with a Plasmodium liver stage autophagy mutant affords enhanced and long-lasting protection. NPJ Vaccines 2021; 6:98. [PMID: 34376691 PMCID: PMC8355287 DOI: 10.1038/s41541-021-00360-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 07/06/2021] [Indexed: 11/09/2022] Open
Abstract
Genetically attenuated sporozoite vaccines can elicit long-lasting protection against malaria but pose risks of breakthrough infection. Chemoprophylaxis vaccination (CVac) has proven to be the most effective vaccine strategy against malaria. Here, we demonstrate that a liver stage-specific autophagy mutant of Plasmodium berghei (ATG8 overexpressor), when used as a live vaccine under a CVac regimen, provides superior long-lasting protection, in both inbred and outbred mice, as compared to WT-CVac. Uniquely, the protection elicited by this mutant is predominantly dependent on a CD8+ T-cell response through an IFN-γ-independent mechanism and is associated with a stable population of antigen-experienced CD8+ T cells. Jointly, our findings support the exploitation of liver-stage mutants as vaccines under a CVac protocol. This vaccination strategy is also a powerful model to study the mechanisms of protective immunity and discover new protective antigens.
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Affiliation(s)
- Tejram Sahu
- Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
| | - Ella J Gehrke
- Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Yevel Flores-Garcia
- Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Godfree Mlambo
- Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Julia D Romano
- Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA
| | - Isabelle Coppens
- Department of Molecular Microbiology and Immunology, Johns Hopkins Malaria Research Institute, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
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16
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Gunnarsson S, Prabakaran S. In silico identification of novel open reading frames in Plasmodium falciparum oocyte and salivary gland sporozoites using proteogenomics framework. Malar J 2021; 20:71. [PMID: 33546698 PMCID: PMC7866754 DOI: 10.1186/s12936-021-03598-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 01/16/2021] [Indexed: 11/25/2022] Open
Abstract
Background Plasmodium falciparum causes the deadliest form of malaria, which remains one of the most prevalent infectious diseases. Unfortunately, the only licensed vaccine showed limited protection and resistance to anti-malarial drug is increasing, which can be largely attributed to the biological complexity of the parasite’s life cycle. The progression from one developmental stage to another in P. falciparum involves drastic changes in gene expressions, where its infectivity to human hosts varies greatly depending on the stage. Approaches to identify candidate genes that are responsible for the development of infectivity to human hosts typically involve differential gene expression analysis between stages. However, the detection may be limited to annotated proteins and open reading frames (ORFs) predicted using restrictive criteria. Methods The above problem is particularly relevant for P. falciparum; whose genome annotation is relatively incomplete given its clinical significance. In this work, systems proteogenomics approach was used to address this challenge, as it allows computational detection of unannotated, novel Open Reading Frames (nORFs), which are neglected by conventional analyses. Two pairs of transcriptome/proteome were obtained from a previous study where one was collected in the mosquito-infectious oocyst sporozoite stage, and the other in the salivary gland sporozoite stage with human infectivity. They were then re-analysed using the proteogenomics framework to identify nORFs in each stage. Results Translational products of nORFs that map to antisense, intergenic, intronic, 3′ UTR and 5′ UTR regions, as well as alternative reading frames of canonical proteins were detected. Some of these nORFs also showed differential expression between the two life cycle stages studied. Their regulatory roles were explored through further bioinformatics analyses including the expression regulation on the parent reference genes, in silico structure prediction, and gene ontology term enrichment analysis. Conclusion The identification of nORFs in P. falciparum sporozoites highlights the biological complexity of the parasite. Although the analyses are solely computational, these results provide a starting point for further experimental validation of the existence and functional roles of these nORFs,
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Affiliation(s)
- Sophie Gunnarsson
- Department of Genetics, University of Cambridge, Downing Site, Cambridge, CB2 3EH, UK
| | - Sudhakaran Prabakaran
- Department of Genetics, University of Cambridge, Downing Site, Cambridge, CB2 3EH, UK.
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17
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Diversify and Conquer: The Vaccine Escapism of Plasmodium falciparum. Microorganisms 2020; 8:microorganisms8111748. [PMID: 33171746 PMCID: PMC7694999 DOI: 10.3390/microorganisms8111748] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 11/02/2020] [Accepted: 11/05/2020] [Indexed: 12/14/2022] Open
Abstract
Over the last century, a great deal of effort and resources have been poured into the development of vaccines to protect against malaria, particularly targeting the most widely spread and deadly species of the human-infecting parasites: Plasmodium falciparum. Many of the known proteins the parasite uses to invade human cells have been tested as vaccine candidates. However, precisely because of the importance and immune visibility of these proteins, they tend to be very diverse, and in many cases redundant, which limits their efficacy in vaccine development. With the advent of genomics and constantly improving sequencing technologies, an increasingly clear picture is emerging of the vast genomic diversity of parasites from different geographic areas. This diversity is distributed throughout the genome and includes most of the vaccine candidates tested so far, playing an important role in the low efficacy achieved. Genomics is a powerful tool to search for genes that comply with the most desirable attributes of vaccine targets, allowing us to evaluate function, immunogenicity and also diversity in the worldwide parasite populations. Even predicting how this diversity might evolve and spread in the future becomes possible, and can inform novel vaccine efforts.
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18
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Scaria PV, Chen BB, Rowe CG, Alani N, Muratova OV, Barnafo EK, Lambert LE, Zaidi IU, Lees A, Rausch KM, Narum DL, Duffy PE. Comparison of carrier proteins to conjugate malaria transmission blocking vaccine antigens, Pfs25 and Pfs230. Vaccine 2020; 38:5480-5489. [PMID: 32600913 PMCID: PMC11127250 DOI: 10.1016/j.vaccine.2020.06.018] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 06/03/2020] [Accepted: 06/05/2020] [Indexed: 12/18/2022]
Abstract
Malaria transmission blocking vaccines (TBV) target the sexual stage of the parasite and have been pursued as a stand-alone vaccine or for combination with pre-erythrocytic or blood stage vaccines. Our efforts to develop TBV focus primarily on two antigens, Pfs25 and Pfs230. Chemical conjugation of these poorly immunogenic antigens to carrier proteins enhances their immunogenicity, and conjugates of these antigens to Exoprotein A (EPA) are currently under evaluation in clinical trials. Nonetheless, more potent carriers may augment the immunogenicity of these antigens for a more efficacious vaccine; here, we evaluate a series of proteins to identify such a carrier. Pfs25 and Pfs230 were chemically conjugated to 4 different carriers [tetanus toxoid (TT), a recombinant fragment of tetanus toxin heavy chain (rTThc), recombinant CRM197 produced in Pseudomonas fluorescens (CRM197) or in E. coli (EcoCRM®)] and compared to EPA conjugates in mouse immunogenicity studies. Conjugates of each antigen formulated in Alhydrogel® elicited similar antibody titers but showed differences in functional activity. At a 0.5 µg dose, Pfs230 conjugated to TT, CRM197 and EcoCRM® showed significantly higher functional activity compared to EPA. When formulated with the more potent adjuvant GLA-LSQ, all 4 alternate conjugates induced higher antibody titers as well as increased functional activity compared to the EPA conjugate. IgG subclass analysis of Pfs230 conjugates showed no carrier-dependent differences in the IgG profile. While Alhydrogel® formulations induced a Th2 dominant immune response, GLA-LSQ formulations induced a mixed Th1/Th2 response.
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Affiliation(s)
- Puthupparampil V Scaria
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Beth B Chen
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Christopher G Rowe
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Nada Alani
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Olga V Muratova
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Emma K Barnafo
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Lynn E Lambert
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Irfan U Zaidi
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | | | - Kelly M Rausch
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David L Narum
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Patrick E Duffy
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
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19
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Bhardwaj P, Bhatia E, Sharma S, Ahamad N, Banerjee R. Advancements in prophylactic and therapeutic nanovaccines. Acta Biomater 2020; 108:1-21. [PMID: 32268235 PMCID: PMC7163188 DOI: 10.1016/j.actbio.2020.03.020] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 03/13/2020] [Accepted: 03/17/2020] [Indexed: 02/07/2023]
Abstract
Vaccines activate suitable immune responses to fight against diseases but can possess limitations such as compromised efficacy and immunogenic responses, poor stability, and requirement of adherence to multiple doses. ‘Nanovaccines’ have been explored to elicit a strong immune response with the advantages of nano-sized range, high antigen loading, enhanced immunogenicity, controlled antigen presentation, more retention in lymph nodes and promote patient compliance by a lower frequency of dosing. Various types of nanoparticles with diverse pathogenic or foreign antigens can help to overcome immunotolerance and alleviate the need of booster doses as required with conventional vaccines. Nanovaccines have the potential to induce both cell-mediated and antibody-mediated immunity and can render long-lasting immunogenic memory. With such properties, nanovaccines have shown high potential for the prevention of infectious diseases such as acquired immunodeficiency syndrome (AIDS), malaria, tuberculosis, influenza, and cancer. Their therapeutic potential has also been explored in the treatment of cancer. The various kinds of nanomaterials used for vaccine development and their effects on immune system activation have been discussed with special relevance to their implications in various pathological conditions. Statement of Significance Interaction of nanoparticles with the immune system has opened multiple avenues to combat a variety of infectious and non-infectious pathological conditions. Limitations of conventional vaccines have paved the path for nanomedicine associated benefits with a hope of producing effective nanovaccines. This review highlights the role of different types of nanovaccines and the role of nanoparticles in modulating the immune response of vaccines. The applications of nanovaccines in infectious and non-infectious diseases like malaria, tuberculosis, AIDS, influenza, and cancers have been discussed. It will help the readers develop an understanding of mechanisms of immune activation by nanovaccines and design appropriate strategies for novel nanovaccines.
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20
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Bettencourt P. Current Challenges in the Identification of Pre-Erythrocytic Malaria Vaccine Candidate Antigens. Front Immunol 2020; 11:190. [PMID: 32153565 PMCID: PMC7046804 DOI: 10.3389/fimmu.2020.00190] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Accepted: 01/24/2020] [Indexed: 12/27/2022] Open
Abstract
Plasmodium spp.-infected mosquitos inject sporozoites into the skin of a mammalian host during a blood meal. These enter the host's circulatory system and establish an infection in the liver. After a silent metamorphosis, merozoites invade the blood leading to the symptomatic and transmissible stages of malaria. The silent pre-erythrocytic malaria stage represents a bottleneck in the disease which is ideal to block progression to clinical malaria, through chemotherapeutic and immunoprophylactic interventions. RTS,S/AS01, the only malaria vaccine close to licensure, although with poor efficacy, blocks the sporozoite invasion mainly through the action of antibodies against the CSP protein, a major component of the pellicle of the sporozoite. Strikingly, sterile protection against malaria can be obtained through immunization with radiation-attenuated sporozoites, genetically attenuated sporozoites or through chemoprophylaxis with infectious sporozoites in animals and humans, but the deployability of sporozoite-based live vaccines pose tremendous challenges. The protection induced by sporozoites occurs in the pre-erythrocytic stages and is mediated mainly by antibodies against the sporozoite and CD8+ T cells against peptides presented by MHC class I molecules in infected hepatocytes. Thus, the identification of malaria antigens expressed in the sporozoite and liver-stage may provide new vaccine candidates to be included, alone or in combination, as recombinant protein-based, virus-like particles or sub-unit virally-vectored vaccines. Here I review the efforts being made to identify Plasmodium falciparum antigens expressed during liver-stage with focus on the development of parasite, hepatocyte, mouse models, and resulting rate of infection in order to identify new vaccine candidates and to improve the efficacy of the current vaccines. Finally, I propose new approaches for the identification of liver-stage antigens based on immunopeptidomics.
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21
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Preclinical Development and Assessment of Viral Vectors Expressing a Fusion Antigen of Plasmodium falciparum LSA1 and LSAP2 for Efficacy against Liver-Stage Malaria. Infect Immun 2020; 88:IAI.00573-19. [PMID: 31740525 PMCID: PMC6977128 DOI: 10.1128/iai.00573-19] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 11/14/2019] [Indexed: 12/14/2022] Open
Abstract
Despite promising progress in malaria vaccine development in recent years, an efficacious subunit vaccine against Plasmodium falciparum remains to be licensed and deployed. Cell-mediated protection from liver-stage malaria relies on a sufficient number of antigen-specific T cells reaching the liver during the time that parasites are present. A single vaccine expressing two antigens could potentially increase both the size and breadth of the antigen-specific response while halving vaccine production costs. Despite promising progress in malaria vaccine development in recent years, an efficacious subunit vaccine against Plasmodium falciparum remains to be licensed and deployed. Cell-mediated protection from liver-stage malaria relies on a sufficient number of antigen-specific T cells reaching the liver during the time that parasites are present. A single vaccine expressing two antigens could potentially increase both the size and breadth of the antigen-specific response while halving vaccine production costs. In this study, we investigated combining two liver-stage antigens, P. falciparum LSA1 (PfLSA1) and PfLSAP2, and investigated the induction of protective efficacy by coadministration of single-antigen vectors or vaccination with dual-antigen vectors, using simian adenovirus and modified vaccinia virus Ankara vectors. The efficacy of these vaccines was assessed in mouse malaria challenge models using chimeric P. berghei parasites expressing the relevant P. falciparum antigens and challenging mice at the peak of the T cell response. Vaccination with a combination of the single-antigen vectors expressing PfLSA1 or PfLSAP2 was shown to improve protective efficacy compared to vaccination with each single-antigen vector alone. Vaccination with dual-antigen vectors expressing both PfLSA1 and PfLSAP2 resulted in responses to both antigens, particularly in outbred mice, and most importantly, the efficacy was equivalent to that of vaccination with a mixture of single-antigen vectors. Based on these promising data, dual-antigen vectors expressing PfLSA1 and PfLSAP2 will now proceed to manufacturing and clinical assessment under good manufacturing practice (GMP) guidelines.
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22
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Goh YS, McGuire D, Rénia L. Vaccination With Sporozoites: Models and Correlates of Protection. Front Immunol 2019; 10:1227. [PMID: 31231377 PMCID: PMC6560154 DOI: 10.3389/fimmu.2019.01227] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 05/14/2019] [Indexed: 12/14/2022] Open
Abstract
Despite continuous efforts, the century-old goal of eradicating malaria still remains. Multiple control interventions need to be in place simultaneously to achieve this goal. In addition to effective control measures, drug therapies and insecticides, vaccines are critical to reduce mortality and morbidity. Hence, there are numerous studies investigating various malaria vaccine candidates. Most of the malaria vaccine candidates are subunit vaccines. However, they have shown limited efficacy in Phase II and III studies. To date, only whole parasite formulations have been shown to induce sterile immunity in human. In this article, we review and discuss the recent developments in vaccination with sporozoites and the mechanisms of protection involved.
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Affiliation(s)
- Yun Shan Goh
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Biopolis, Singapore, Singapore
| | - Daniel McGuire
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Biopolis, Singapore, Singapore.,School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
| | - Laurent Rénia
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (ASTAR), Biopolis, Singapore, Singapore.,School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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23
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Amelia F, Iyori M, Emran TB, Yamamoto DS, Genshi K, Otsuka H, Onoue Y, Yusuf Y, Islam A, Yoshida S. Down-selecting circumsporozoite protein-based malaria vaccine: A comparison of malaria sporozoite challenge model. Parasite Immunol 2019; 41:e12624. [PMID: 30883819 DOI: 10.1111/pim.12624] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 02/28/2019] [Accepted: 03/08/2019] [Indexed: 12/18/2022]
Abstract
Plasmodium falciparum circumsporozoite protein (PfCSP) is the main target antigen in development of pre-erythrocytic malaria vaccines. To evaluate PfCSP vaccines in animal models, challenge by intravenous sporozoite injection is preferentially used. However, in clinical trials, vaccinated human volunteers are exposed to the bites of malaria-infected mosquitoes. In this study, we down-selected Escherichia coli-produced full-length PfCSP (PfCSP-F) and its three truncated PfCSPs based on their abilities to elicit immune response and protection in mice against two challenge models. We showed that immunization with three doses of PfCSP-F elicited high anti-PfCSP antibody titres and 100% protection against the bites of infected mosquitoes. Meanwhile, three-dose truncated PfCSP induced 60%-70% protection after immunization with each truncated PfCSP. Heterologous prime-boost immunization regimen with adenovirus-PfCSP-F and R32LR greatly induced complete protection against intravenous sporozoite injection. Our results suggest that Abs to both anti-repeat and anti-nonrepeat regions induced by PfCSP-F are required to confer complete protection against challenge by the bites of infected mosquitoes, whereas anti-repeat Abs play an important role in protection against intravenous sporozoite injection. Our findings provide a potential clinical application that PfCSP-F vaccine induces potent Abs capable of neutralizing sporozoites in the dermis inoculated by infected mosquitoes and subsequently sporozoites in the blood circulation.
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Affiliation(s)
- Fitri Amelia
- Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
- Department of Chemistry, Universitas Negeri Padang, Padang, Indonesia
| | - Mitsuhiro Iyori
- Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
| | - Talha Bin Emran
- Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
| | - Daisuke S Yamamoto
- Division of Medical Zoology, Department of Infection and Immunity, Jichi Medical University, Shimotsuke, Japan
| | - Kento Genshi
- Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
| | - Hiromu Otsuka
- Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
| | - Yutaro Onoue
- Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
| | - Yenni Yusuf
- Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
| | - Ashekul Islam
- Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
| | - Shigeto Yoshida
- Laboratory of Vaccinology and Applied Immunology, Kanazawa University School of Pharmacy, Kanazawa, Japan
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24
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Tan J, Piccoli L, Lanzavecchia A. The Antibody Response to Plasmodium falciparum: Cues for Vaccine Design and the Discovery of Receptor-Based Antibodies. Annu Rev Immunol 2018; 37:225-246. [PMID: 30566366 DOI: 10.1146/annurev-immunol-042617-053301] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Plasmodium falciparum remains a serious public health problem and a continuous challenge for the immune system due to the complexity and diversity of the pathogen. Recent advances from several laboratories in the characterization of the antibody response to the parasite have led to the identification of critical targets for protection and revealed a new mechanism of diversification based on the insertion of host receptors into immunoglobulin genes, leading to the production of receptor-based antibodies. These advances have opened new possibilities for vaccine design and passive antibody therapies to provide sterilizing immunity and control blood-stage parasites.
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Affiliation(s)
- Joshua Tan
- Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland; .,Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom.,Current affiliation: National Institute of Allergy and Infectious Diseases, Rockville, Maryland 20852, USA
| | - Luca Piccoli
- Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland;
| | - Antonio Lanzavecchia
- Institute for Research in Biomedicine, Università della Svizzera italiana, 6500 Bellinzona, Switzerland; .,VIR Biotechnology, San Francisco, California 94158, USA
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25
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Halbroth BR, Sebastian S, Poyntz HC, Bregu M, Cottingham MG, Hill AVS, Spencer AJ. Development of a Molecular Adjuvant to Enhance Antigen-Specific CD8 + T Cell Responses. Sci Rep 2018; 8:15020. [PMID: 30301933 PMCID: PMC6177389 DOI: 10.1038/s41598-018-33375-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 09/27/2018] [Indexed: 12/26/2022] Open
Abstract
Despite promising progress in malaria vaccine development, an efficacious subunit vaccine against P. falciparum remains to be licensed and deployed. This study aimed to improve on the immunogenicity of the leading liver-stage vaccine candidate (ChAd63-MVA ME-TRAP), known to confer protection by eliciting high levels of antigen-specific CD8+ T cells. We previously showed fusion of ME-TRAP to the human MHC class II invariant chain (Ii) could enhance CD8+ T cell responses in non-human primates, but did not progress to clinical testing due to potential risk of auto-immunity by vaccination of humans with a self-antigen. Initial immunogenicity analyses of ME-TRAP fused to subdomains of the Ii showed that the Ii transmembrane domain alone can enhance CD8+ T cell responses. Subsequently, truncated Ii sequences with low homology to human Ii were developed and shown to enhance CD8+ T cell responses. By systematically mutating the TM domain sequence, multimerization of the Ii chain was shown to be important for immune enhancement. We subsequently identified several proteins from a variety of microbial pathogens with similar characteristics, that also enhance the CD8+ T cell response and could therefore be used in viral vector vaccines when potent cell mediated immunity is required.
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Affiliation(s)
- Benedict R Halbroth
- The Jenner Institute, University of Oxford, ORCRB, Roosevelt Drive, Oxford, United Kingdom.
| | - Sarah Sebastian
- The Jenner Institute, University of Oxford, ORCRB, Roosevelt Drive, Oxford, United Kingdom
| | - Hazel C Poyntz
- The Jenner Institute, University of Oxford, ORCRB, Roosevelt Drive, Oxford, United Kingdom
| | - Migena Bregu
- The Jenner Institute, University of Oxford, ORCRB, Roosevelt Drive, Oxford, United Kingdom
| | - Matthew G Cottingham
- The Jenner Institute, University of Oxford, ORCRB, Roosevelt Drive, Oxford, United Kingdom
| | - Adrian V S Hill
- The Jenner Institute, University of Oxford, ORCRB, Roosevelt Drive, Oxford, United Kingdom
| | - Alexandra J Spencer
- The Jenner Institute, University of Oxford, ORCRB, Roosevelt Drive, Oxford, United Kingdom.
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26
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Marin-Mogollon C, van Pul FJA, Miyazaki S, Imai T, Ramesar J, Salman AM, Winkel BMF, Othman AS, Kroeze H, Chevalley-Maurel S, Reyes-Sandoval A, Roestenberg M, Franke-Fayard B, Janse CJ, Khan SM. Chimeric Plasmodium falciparum parasites expressing Plasmodium vivax circumsporozoite protein fail to produce salivary gland sporozoites. Malar J 2018; 17:288. [PMID: 30092798 PMCID: PMC6085629 DOI: 10.1186/s12936-018-2431-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Accepted: 07/28/2018] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Rodent malaria parasites where the gene encoding circumsporozoite protein (CSP) has been replaced with csp genes from the human malaria parasites, Plasmodium falciparum or Plasmodium vivax, are used as pre-clinical tools to evaluate CSP vaccines in vivo. These chimeric rodent parasites produce sporozoites in Anopheles stephensi mosquitoes that are capable of infecting rodent and human hepatocytes. The availability of chimeric P. falciparum parasites where the pfcsp gene has been replaced by the pvcsp would open up possibilities to test P. vivax CSP vaccines in small scale clinical trials using controlled human malaria infection studies. METHODS Using CRISPR/Cas9 gene editing two chimeric P. falciparum parasites, were generated, where the pfcsp gene has been replaced by either one of the two major pvcsp alleles, VK210 or VK247. In addition, a P. falciparum parasite line that lacks CSP expression was also generated. These parasite lines have been analysed for sporozoite production in An. stephensi mosquitoes. RESULTS The two chimeric Pf-PvCSP lines exhibit normal asexual and sexual blood stage development in vitro and produce sporozoite-containing oocysts in An. stephensi mosquitoes. Expression of the corresponding PvCSP was confirmed in oocyst-derived Pf-PvCSP sporozoites. However, most oocysts degenerate before sporozoite formation and sporozoites were not found in either the mosquito haemocoel or salivary glands. Unlike the chimeric Pf-PvCSP parasites, oocysts of P. falciparum parasites lacking CSP expression do not produce sporozoites. CONCLUSIONS Chimeric P. falciparum parasites expressing P. vivax circumsporozoite protein fail to produce salivary gland sporozoites. Combined, these studies show that while PvCSP can partially complement the function of PfCSP, species-specific features of CSP govern full sporozoite maturation and development in the two human malaria parasites.
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Affiliation(s)
- Catherin Marin-Mogollon
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Fiona J A van Pul
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Shinya Miyazaki
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Takashi Imai
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
- Department of Infectious Diseases and Host Defense, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8510, Japan
| | - Jai Ramesar
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Ahmed M Salman
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Welcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Beatrice M F Winkel
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Ahmad Syibli Othman
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
- Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Terengganu, Malaysia
| | - Hans Kroeze
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Severine Chevalley-Maurel
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Arturo Reyes-Sandoval
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Welcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Meta Roestenberg
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Blandine Franke-Fayard
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Chris J Janse
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Shahid M Khan
- Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.
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27
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Roth A, Maher SP, Conway AJ, Ubalee R, Chaumeau V, Andolina C, Kaba SA, Vantaux A, Bakowski MA, Thomson-Luque R, Adapa SR, Singh N, Barnes SJ, Cooper CA, Rouillier M, McNamara CW, Mikolajczak SA, Sather N, Witkowski B, Campo B, Kappe SHI, Lanar DE, Nosten F, Davidson S, Jiang RHY, Kyle DE, Adams JH. A comprehensive model for assessment of liver stage therapies targeting Plasmodium vivax and Plasmodium falciparum. Nat Commun 2018; 9:1837. [PMID: 29743474 PMCID: PMC5943321 DOI: 10.1038/s41467-018-04221-9] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 04/10/2018] [Indexed: 12/26/2022] Open
Abstract
Malaria liver stages represent an ideal therapeutic target with a bottleneck in parasite load and reduced clinical symptoms; however, current in vitro pre-erythrocytic (PE) models for Plasmodium vivax and P. falciparum lack the efficiency necessary for rapid identification and effective evaluation of new vaccines and drugs, especially targeting late liver-stage development and hypnozoites. Herein we report the development of a 384-well plate culture system using commercially available materials, including cryopreserved primary human hepatocytes. Hepatocyte physiology is maintained for at least 30 days and supports development of P. vivax hypnozoites and complete maturation of P. vivax and P. falciparum schizonts. Our multimodal analysis in antimalarial therapeutic research identifies important PE inhibition mechanisms: immune antibodies against sporozoite surface proteins functionally inhibit liver stage development and ion homeostasis is essential for schizont and hypnozoite viability. This model can be implemented in laboratories in disease-endemic areas to accelerate vaccine and drug discovery research.
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Affiliation(s)
- Alison Roth
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA
| | - Steven P Maher
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA
- Center for Tropical and Emerging Global Diseases, University of Georgia, 500 DW Brooks Dr. Suite 370, Athens, GA, 30602, USA
| | - Amy J Conway
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA
| | - Ratawan Ubalee
- Department of Entomology, Armed Forces Research Institute of Medical Sciences (AFRIMS), 315/6 Rajvithi Rd, Bangkok, 10400, Thailand
| | - Victor Chaumeau
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Shoklo Malaria Research Unit, Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, 68/30 Bantung Rd, Mae Sot, Tak, 63110, Thailand
| | - Chiara Andolina
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Shoklo Malaria Research Unit, Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, 68/30 Bantung Rd, Mae Sot, Tak, 63110, Thailand
| | - Stephen A Kaba
- Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA
| | - Amélie Vantaux
- Malaria Molecular Epidemiology Unit, Institut Pasteur du Cambodge, 5 Boulevard Monivong-PO Box 983, Phnom Penh, 12 201, Cambodia
| | - Malina A Bakowski
- California Institute for Biomedical Research (Calibr), 11119N. Torrey Pines Rd, Suite 100, La Jolla, CA, 92037, USA
| | - Richard Thomson-Luque
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA
| | - Swamy Rakesh Adapa
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA
| | - Naresh Singh
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA
| | - Samantha J Barnes
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA
| | - Caitlin A Cooper
- Center for Tropical and Emerging Global Diseases, University of Georgia, 500 DW Brooks Dr. Suite 370, Athens, GA, 30602, USA
| | - Mélanie Rouillier
- Medicines for Malaria Venture, Pré-Bois Rd 20, Meyrin, 1215, Switzerland
| | - Case W McNamara
- California Institute for Biomedical Research (Calibr), 11119N. Torrey Pines Rd, Suite 100, La Jolla, CA, 92037, USA
| | - Sebastian A Mikolajczak
- Center for Infectious Disease Research, 307 Westlake Ave N Suite 500, Seattle, WA, 98109, USA
| | - Noah Sather
- Center for Infectious Disease Research, 307 Westlake Ave N Suite 500, Seattle, WA, 98109, USA
| | - Benoît Witkowski
- California Institute for Biomedical Research (Calibr), 11119N. Torrey Pines Rd, Suite 100, La Jolla, CA, 92037, USA
| | - Brice Campo
- Medicines for Malaria Venture, Pré-Bois Rd 20, Meyrin, 1215, Switzerland
| | - Stefan H I Kappe
- Center for Infectious Disease Research, 307 Westlake Ave N Suite 500, Seattle, WA, 98109, USA
| | - David E Lanar
- Malaria Vaccine Branch, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Silver Spring, MD, 20910, USA
| | - François Nosten
- Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Shoklo Malaria Research Unit, Mahidol Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, 68/30 Bantung Rd, Mae Sot, Tak, 63110, Thailand
| | - Silas Davidson
- Department of Entomology, Armed Forces Research Institute of Medical Sciences (AFRIMS), 315/6 Rajvithi Rd, Bangkok, 10400, Thailand
| | - Rays H Y Jiang
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA
| | - Dennis E Kyle
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA
- Center for Tropical and Emerging Global Diseases, University of Georgia, 500 DW Brooks Dr. Suite 370, Athens, GA, 30602, USA
| | - John H Adams
- Department of Global Health, College of Public Health, Center for Global Health and Infectious Diseases Research, University of South Florida, 3720 Spectrum Blvd 404, Tampa, FL, 33612, USA.
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28
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Protein-protein conjugate nanoparticles for malaria antigen delivery and enhanced immunogenicity. PLoS One 2017; 12:e0190312. [PMID: 29281708 PMCID: PMC5744994 DOI: 10.1371/journal.pone.0190312] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 12/12/2017] [Indexed: 12/19/2022] Open
Abstract
Chemical conjugation of polysaccharide to carrier proteins has been a successful strategy to generate potent vaccines against bacterial pathogens. We developed a similar approach for poorly immunogenic malaria protein antigens. Our lead candidates in clinical trials are the malaria transmission blocking vaccine antigens, Pfs25 and Pfs230D1, individually conjugated to the carrier protein Exoprotein A (EPA) through thioether chemistry. These conjugates form nanoparticles that show enhanced immunogenicity compared to unconjugated antigens. In this study, we examined the broad applicability of this technology as a vaccine development platform, by comparing the immunogenicity of conjugates prepared by four different chemistries using different malaria antigens (PfCSP, Pfs25 and Pfs230D1), and carriers such as EPA, TT and CRM197. Several conjugates were synthesized using thioether, amide, ADH and glutaraldehyde chemistries, characterized for average molecular weight and molecular weight distribution, and evaluated in mice for humoral immunogenicity. Conjugates made with the different chemistries, or with different carriers, showed no significant difference in immunogenicity towards the conjugated antigens. Since particle size can influence immunogenicity, we tested conjugates with different average size in the range of 16–73 nm diameter, and observed greater immunogenicity of smaller particles, with significant differences between 16 and 73 nm particles. These results demonstrate the multiple options with respect to carriers and chemistries that are available for protein-protein conjugate vaccine development.
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Salman AM, Montoya-Díaz E, West H, Lall A, Atcheson E, Lopez-Camacho C, Ramesar J, Bauza K, Collins KA, Brod F, Reis F, Pappas L, González-Cerón L, Janse CJ, Hill AVS, Khan SM, Reyes-Sandoval A. Rational development of a protective P. vivax vaccine evaluated with transgenic rodent parasite challenge models. Sci Rep 2017; 7:46482. [PMID: 28417968 PMCID: PMC5394459 DOI: 10.1038/srep46482] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 03/15/2017] [Indexed: 01/05/2023] Open
Abstract
Development of a protective and broadly-acting vaccine against the most widely distributed human malaria parasite, Plasmodium vivax, will be a major step towards malaria elimination. However, a P. vivax vaccine has remained elusive by the scarcity of pre-clinical models to test protective efficacy and support further clinical trials. In this study, we report the development of a highly protective CSP-based P. vivax vaccine, a virus-like particle (VLP) known as Rv21, able to provide 100% sterile protection against a stringent sporozoite challenge in rodent models to malaria, where IgG2a antibodies were associated with protection in absence of detectable PvCSP-specific T cell responses. Additionally, we generated two novel transgenic rodent P. berghei parasite lines, where the P. berghei csp gene coding sequence has been replaced with either full-length P. vivax VK210 or the allelic VK247 csp that additionally express GFP-Luciferase. Efficacy of Rv21 surpassed viral-vectored vaccination using ChAd63 and MVA. We show for the first time that a chimeric VK210/247 antigen can elicit high level cross-protection against parasites expressing either CSP allele, which provide accessible and affordable models suitable to support the development of P. vivax vaccines candidates. Rv21 is progressing to GMP production and has entered a path towards clinical evaluation.
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Affiliation(s)
- Ahmed M Salman
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK.,Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, (LUMC, L4-Q), Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Eduardo Montoya-Díaz
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Heather West
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Amar Lall
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Erwan Atcheson
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Cesar Lopez-Camacho
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Jai Ramesar
- Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, (LUMC, L4-Q), Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Karolis Bauza
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Katharine A Collins
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Florian Brod
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Fernando Reis
- Universidade Federal de Minas Gerais, Belo Horizonte - MG - Brasil
| | - Leontios Pappas
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Lilia González-Cerón
- Centro Regional de Investigación en Salud Pública, Instituto Nacional de Salud Pública, 4ta Avenida Norte y Calle 19 Poniente, Tapachula, Chiapas, CP 30740, Mexico
| | - Chris J Janse
- Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, (LUMC, L4-Q), Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Adrian V S Hill
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
| | - Shahid M Khan
- Leiden Malaria Research Group, Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, (LUMC, L4-Q), Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Arturo Reyes-Sandoval
- The Jenner Institute, Nuffield Department of Medicine, University of Oxford, The Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford, OX3 7BN, UK
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Evaluation of Plasmodium vivax Cell-Traversal Protein for Ookinetes and Sporozoites as a Preerythrocytic P. vivax Vaccine. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2017; 24:CVI.00501-16. [PMID: 28179403 PMCID: PMC5382829 DOI: 10.1128/cvi.00501-16] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/31/2017] [Indexed: 01/08/2023]
Abstract
Four different vaccine platforms, each targeting the human malaria parasite Plasmodium vivax cell-traversal protein for ookinetes and sporozoites (PvCelTOS), were generated and assessed for protective efficacy. These platforms consisted of a recombinant chimpanzee adenoviral vector 63 (ChAd63) expressing PvCelTOS (Ad), a recombinant modified vaccinia virus Ankara expressing PvCelTOS (MVA), PvCelTOS conjugated to bacteriophage Qβ virus-like particles (VLPs), and a recombinant PvCelTOS protein expressed in eukaryotic HEK293T cells (protein). Inbred BALB/c mice and outbred CD-1 mice were immunized using the following prime-boost regimens: Ad-MVA, Ad-VLPs, and Ad-protein. Protective efficacy against sporozoite challenge was assessed after immunization using a novel chimeric rodent Plasmodium berghei parasite (Pb-PvCelTOS). This chimeric parasite expresses P. vivax CelTOS in place of the endogenous P. berghei CelTOS and produces fully infectious sporozoites. A single Ad immunization in BALB/c and CD-1 mice induced anti-PvCelTOS antibodies which were boosted efficiently using MVA, VLP, or protein immunization. PvCelTOS-specific gamma interferon- and tumor necrosis factor alpha-producing CD8+ T cells were induced at high frequencies by all prime-boost regimens in BALB/c mice but not in CD-1 mice; in CD-1 mice, they were only marginally increased after boosting with MVA. Despite the induction of anti-PvCelTOS antibodies and PvCelTOS-specific CD8+ T-cell responses, only low levels of protective efficacy against challenge with Pb-PvCelTOS sporozoites were obtained using any immunization strategy. In BALB/c mice, no immunization regimens provided significant protection against a Pb-PvCelTOS chimeric sporozoite challenge. In CD-1 mice, modest protective efficacy against challenge with chimeric P. berghei sporozoites expressing either PvCelTOS or P. falciparum CelTOS was observed using the Ad-protein vaccination regimen.
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31
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López C, Yepes-Pérez Y, Hincapié-Escobar N, Díaz-Arévalo D, Patarroyo MA. What Is Known about the Immune Response Induced by Plasmodium vivax Malaria Vaccine Candidates? Front Immunol 2017; 8:126. [PMID: 28243235 PMCID: PMC5304258 DOI: 10.3389/fimmu.2017.00126] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Accepted: 01/25/2017] [Indexed: 12/15/2022] Open
Abstract
Malaria caused by Plasmodium vivax continues being one of the most important infectious diseases around the world; P. vivax is the second most prevalent species and has the greatest geographic distribution. Developing an effective antimalarial vaccine is considered a relevant control strategy in the search for means of preventing the disease. Studying parasite-expressed proteins, which are essential in host cell invasion, has led to identifying the regions recognized by individuals who are naturally exposed to infection. Furthermore, immunogenicity studies have revealed that such regions can trigger a robust immune response that can inhibit sporozoite (hepatic stage) or merozoite (erythrocyte stage) invasion of a host cell and induce protection. This review provides a synthesis of the most important studies to date concerning the antigenicity and immunogenicity of both synthetic peptide and recombinant protein candidates for a vaccine against malaria produced by P. vivax.
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Affiliation(s)
- Carolina López
- Molecular Biology and Immunology Department, Fundación Instituto de Immunología de Colombia (FIDIC), Bogotá, Colombia; PhD Programme in Biomedical and Biological Sciences, Universidad del Rosario, Bogotá, Colombia
| | - Yoelis Yepes-Pérez
- Molecular Biology and Immunology Department, Fundación Instituto de Immunología de Colombia (FIDIC), Bogotá, Colombia; MSc Programme in Microbiology, Universidad Nacional de Colombia, Bogotá, Colombia
| | - Natalia Hincapié-Escobar
- Molecular Biology and Immunology Department, Fundación Instituto de Immunología de Colombia (FIDIC) , Bogotá , Colombia
| | - Diana Díaz-Arévalo
- Molecular Biology and Immunology Department, Fundación Instituto de Immunología de Colombia (FIDIC), Bogotá, Colombia; Universidad de Ciencias Aplicadas y Ambientales (UDCA), Bogotá, Colombia
| | - Manuel A Patarroyo
- Molecular Biology and Immunology Department, Fundación Instituto de Immunología de Colombia (FIDIC), Bogotá, Colombia; Basic Sciences Department, School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
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32
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Parmar R, Patel H, Yadav N, Patidar M, Tyagi RK, Dalai SK. Route of administration of attenuated sporozoites is instrumental in rendering immunity against Plasmodia infection. Vaccine 2016; 34:3229-3234. [PMID: 27160038 DOI: 10.1016/j.vaccine.2016.04.095] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 04/19/2016] [Accepted: 04/28/2016] [Indexed: 02/07/2023]
Abstract
Whole sporozoite vaccine (WSV) approach has been shown to induce efficient CD8(+) T cell response, critical for developing of long-lasting sterile protection against Plasmodium. Although WSV was initiated over four decades ago, we still do not fully understand about the absolute requirements for the generation of liver-stage specific CD8(+) T memory cells. For more than a decade intravenous (IV) route of immunization has been shown to be protective in pre-clinical studies. However, the intradermal (ID) route is preferred over IV route by many researchers as it is perceived to mimic the natural route of parasite delivery through mosquito bite. Various clinical studies have shown that ID route provokes poor protective responses compared to those seen with IV route of administration. The present study highlights the importance of circumsporozoite (CS) protein in preventing sporozoite entry to the hepatocytes, which however, it is not necessarily sufficient to ensure sterile protection. Instead, this article favors the idea that liver-stage development is a prime requirement for generation of antigen specific CD8(+) T cells and suggests the conditions favored by IV inoculation of sporozoite.
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Affiliation(s)
- Rajesh Parmar
- Institute of Science, Nirma University, Ahmedabad, Gujarat, India
| | - Hardik Patel
- Institute of Science, Nirma University, Ahmedabad, Gujarat, India
| | - Naveen Yadav
- Institute of Science, Nirma University, Ahmedabad, Gujarat, India
| | - Manoj Patidar
- Institute of Science, Nirma University, Ahmedabad, Gujarat, India
| | - Rajeev K Tyagi
- Institute of Science, Nirma University, Ahmedabad, Gujarat, India
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33
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Repetitive live sporozoites inoculation under arteether chemoprophylaxis confers protection against subsequent sporozoite challenge in rodent malaria model. Acta Trop 2016; 158:130-138. [PMID: 26925772 DOI: 10.1016/j.actatropica.2016.02.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 02/14/2016] [Accepted: 02/22/2016] [Indexed: 01/06/2023]
Abstract
Inoculation with live sporozoites under prophylactic antimalarial cover (CPS-immunization) represents an alternate approach to develop sterile, reproducible, and long-term protection against malaria. Here, we have employed arteether (ART), a semi synthetic derivative of artemisinin to explore its potential as a chemoprophylaxis candidate in CPS approach and systematically compared the protective potential of arteether with mefloquine, azithromycin and primaquine. Blood stage patency and quantitative RT-PCR of liver stage parasite load were monitored as primary key end-points for protection against malaria challenge infection. For this purpose, sequential exposures of Plasmodium yoelii sporozoites under prophylactic treatment with arteether (ART), mefloquine (MFQ), azithromycin (AZ) or primaquine (PQ) was conducted in experimental Swiss mice. Our results show that during the first three sequential exposures (1st, 2nd and 3rd challenge) no marked difference in the blood stage patency was observed between control and CPS-ART group. However, delayed patency was recorded following 4th sporozoite challenge and mice enjoyed sterile protection after 5th sporozoite challenge. A similar response was observed in CPS-MFQ group, whereas earlier protection was recorded in CPS-AZ group i.e., after 4th sprozoite challenge. However, mice under PQ cover did not show any protection/delay in patency even after five sequential sporozoite inoculations, possibly due to inhibition of liver stage development. Furthermore, protection acquired by CPS-immunization is stage-specific as the protected mice remained susceptible to challenge with blood stage parasites. In short, the present study demonstrates that sporozoite administration under ART, MFQ or AZ treatment confers strong protection against subsequent sporozoite infection and the acquired response is dependent on the presence of liver stage parasites.
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34
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Swearingen KE, Lindner SE, Shi L, Shears MJ, Harupa A, Hopp CS, Vaughan AM, Springer TA, Moritz RL, Kappe SHI, Sinnis P. Interrogating the Plasmodium Sporozoite Surface: Identification of Surface-Exposed Proteins and Demonstration of Glycosylation on CSP and TRAP by Mass Spectrometry-Based Proteomics. PLoS Pathog 2016; 12:e1005606. [PMID: 27128092 PMCID: PMC4851412 DOI: 10.1371/journal.ppat.1005606] [Citation(s) in RCA: 141] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Accepted: 04/08/2016] [Indexed: 12/22/2022] Open
Abstract
Malaria parasite infection is initiated by the mosquito-transmitted sporozoite stage, a highly motile invasive cell that targets hepatocytes in the liver for infection. A promising approach to developing a malaria vaccine is the use of proteins located on the sporozoite surface as antigens to elicit humoral immune responses that prevent the establishment of infection. Very little of the P. falciparum genome has been considered as potential vaccine targets, and candidate vaccines have been almost exclusively based on single antigens, generating the need for novel target identification. The most advanced malaria vaccine to date, RTS,S, a subunit vaccine consisting of a portion of the major surface protein circumsporozoite protein (CSP), conferred limited protection in Phase III trials, falling short of community-established vaccine efficacy goals. In striking contrast to the limited protection seen in current vaccine trials, sterilizing immunity can be achieved by immunization with radiation-attenuated sporozoites, suggesting that more potent protection may be achievable with a multivalent protein vaccine. Here, we provide the most comprehensive analysis to date of proteins located on the surface of or secreted by Plasmodium falciparum salivary gland sporozoites. We used chemical labeling to isolate surface-exposed proteins on sporozoites and identified these proteins by mass spectrometry. We validated several of these targets and also provide evidence that components of the inner membrane complex are in fact surface-exposed and accessible to antibodies in live sporozoites. Finally, our mass spectrometry data provide the first direct evidence that the Plasmodium surface proteins CSP and TRAP are glycosylated in sporozoites, a finding that could impact the selection of vaccine antigens. Malaria remains one of the most important infectious diseases in the world, responsible for an estimated 500 million new cases and 600,000 deaths annually. The etiologic agents of the disease are protozoan parasites of the genus Plasmodium that have a complex cycle between mosquito and mammalian hosts. Though all clinical symptoms are attributable to the blood stages, it is only by attacking the transmission stages that we can make an impact on the economic and health burdens of malaria. Infection is initiated when mosquitoes inoculate sporozoites into the skin as they probe for blood. Sporozoites must locate blood vessels and enter the circulation to reach the liver where they invade and grow in hepatocytes. The inoculum is low and these early stages of infection are asymptomatic. Though the small amounts of material available for study has made large scale -omics studies difficult, killing the parasite at this stage would prevent infection and block downstream transmission to mosquitoes, thus preventing spread of disease. Here we use state-of-the-art biochemistry tools to identify the proteins on the sporozoite surface and find that two of the most studied proteins, CSP and TRAP, have post-translational modifications. These studies will aid investigations into the novel biology of sporozoites and importantly, significantly expand the pool of potential vaccine candidates.
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Affiliation(s)
| | - Scott E. Lindner
- Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, Seattle, Washington, United States of America
- Center for Malaria Research, Pennsylvania State University, University Park, Pennsylvania, United States of America
| | - Lirong Shi
- Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Melanie J. Shears
- Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Anke Harupa
- Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, Seattle, Washington, United States of America
| | - Christine S. Hopp
- Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Ashley M. Vaughan
- Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, Seattle, Washington, United States of America
| | | | - Robert L. Moritz
- Institute for Systems Biology, Seattle, Washington, United States of America
- * E-mail: (RLM); (SHIK); (PS)
| | - Stefan H. I. Kappe
- Center for Infectious Disease Research, formerly Seattle Biomedical Research Institute, Seattle, Washington, United States of America
- * E-mail: (RLM); (SHIK); (PS)
| | - Photini Sinnis
- Johns Hopkins Malaria Research Institute and Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
- * E-mail: (RLM); (SHIK); (PS)
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Stone BC, Kas A, Billman ZP, Fuller DH, Fuller JT, Shendure J, Murphy SC. Complex Minigene Library Vaccination for Discovery of Pre-Erythrocytic Plasmodium T Cell Antigens. PLoS One 2016; 11:e0153449. [PMID: 27070430 PMCID: PMC4829254 DOI: 10.1371/journal.pone.0153449] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 03/30/2016] [Indexed: 01/15/2023] Open
Abstract
Development of a subunit vaccine targeting liver-stage Plasmodium parasites requires the identification of antigens capable of inducing protective T cell responses. However, traditional methods of antigen identification are incapable of evaluating T cell responses against large numbers of proteins expressed by these parasites. This bottleneck has limited development of subunit vaccines against Plasmodium and other complex intracellular pathogens. To address this bottleneck, we are developing a synthetic minigene technology for multi-antigen DNA vaccines. In an initial test of this approach, pools of long (150 bp) antigen-encoding oligonucleotides were synthesized and recombined into vectors by ligation-independent cloning to produce two DNA minigene library vaccines. Each vaccine encoded peptides derived from 36 (vaccine 1) and 53 (vaccine 2) secreted or transmembrane pre-erythrocytic P. yoelii proteins. BALB/cj mice were vaccinated three times with a single vaccine by biolistic particle delivery (gene gun) and screened for interferon-γ-producing T cell responses by ELISPOT. Library vaccination induced responses against four novel antigens. Naïve mice exposed to radiation-attenuated sporozoites mounted a response against only one of the four novel targets (PyMDH, malate dehydrogenase). The response to PyMDH could not be recalled by additional homologous sporozoite immunizations but could be partially recalled by heterologous cross-species sporozoite exposure. Vaccination against the dominant PyMDH epitope by DNA priming and recombinant Listeria boosting did not protect against sporozoite challenge. Improvements in library design and delivery, combined with methods promoting an increase in screening sensitivity, may enable complex minigene screening to serve as a high-throughput system for discovery of novel T cell antigens.
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Affiliation(s)
- Brad C. Stone
- Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, United States of America
- * E-mail: (BCS); (SCM)
| | - Arnold Kas
- Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, United States of America
| | - Zachary P. Billman
- Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, United States of America
| | - Deborah H. Fuller
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
| | - James T. Fuller
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
| | - Jay Shendure
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Sean C. Murphy
- Department of Laboratory Medicine, University of Washington, Seattle, Washington, United States of America
- Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, Washington, United States of America
- Department of Microbiology, University of Washington, Seattle, Washington, United States of America
- Seattle Malaria Clinical Trials Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
- Human Challenge Center, Center for Infectious Disease Research, Seattle, Washington, United States of America
- * E-mail: (BCS); (SCM)
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36
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Noulin F. Malaria modeling: In vitro stem cells vs in vivo models. World J Stem Cells 2016; 8:88-100. [PMID: 27022439 PMCID: PMC4807312 DOI: 10.4252/wjsc.v8.i3.88] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2015] [Revised: 12/07/2015] [Accepted: 01/29/2016] [Indexed: 02/06/2023] Open
Abstract
The recent development of stem cell research and the possibility of generating cells that can be stably and permanently modified in their genome open a broad horizon in the world of in vitro modeling. The malaria field is gaining new opportunities from this important breakthrough and novel tools were adapted and opened new frontiers for malaria research. In addition to the new in vitro systems, in recent years there were also significant advances in the development of new animal models that allows studying the entire cell cycle of human malaria. In this paper, we review the different protocols available to study human Plasmodium species either by using stem cell or alternative animal models.
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37
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Wilson KL, Xiang SD, Plebanski M. A Model to Study the Impact of Polymorphism Driven Liver-Stage Immune Evasion by Malaria Parasites, to Help Design Effective Cross-Reactive Vaccines. Front Microbiol 2016; 7:303. [PMID: 27014226 PMCID: PMC4786561 DOI: 10.3389/fmicb.2016.00303] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Accepted: 02/24/2016] [Indexed: 01/08/2023] Open
Abstract
Malaria parasites engage a multitude of strategies to evade the immune system of the host, including the generation of polymorphic T cell epitope sequences, termed altered peptide ligands (APLs). Herein we use an animal model to study how single amino acid changes in the sequence of the circumsporozoite protein (CSP), a major target antigen of pre-erythrocytic malaria vaccines, can lead to a reduction of cross reactivity by T cells. For the first time in any APL model, we further compare different inflammatory adjuvants (Montanide, Poly I:C), non-inflammatory adjuvants (nanoparticles), and peptide pulsed dendritic cells (DCs) for their potential capacity to induce broadly cross reactive immune responses. Results show that the capacity to induce a cross reactive response is primarily controlled by the T cell epitope sequence and cannot be modified by the use of different adjuvants. Moreover, we identify how specific amino acid changes lead to a one-way cross reactivity: where variant-x induced responses are re-elicited by variant-x and not variant-y, but variant-y induced responses can be re-elicited by variant-y and variant-x. We discuss the consequences of the existence of this one-way cross reactivity phenomenon for parasite immune evasion in the field, as well as the use of variant epitopes as a potential tool for optimized vaccine design.
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Affiliation(s)
- Kirsty L Wilson
- Vaccines and Infectious Diseases Laboratory, Department of Immunology and Pathology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University Melbourne, VIC, Australia
| | - Sue D Xiang
- Vaccines and Infectious Diseases Laboratory, Department of Immunology and Pathology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University Melbourne, VIC, Australia
| | - Magdalena Plebanski
- Vaccines and Infectious Diseases Laboratory, Department of Immunology and Pathology, Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University Melbourne, VIC, Australia
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38
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Gonçalves BP, Prevots DR, Kabyemela E, Fried M, Duffy PE. Preparing for future efficacy trials of severe malaria vaccines. Vaccine 2016; 34:1865-7. [PMID: 26923455 DOI: 10.1016/j.vaccine.2016.02.053] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 02/15/2016] [Accepted: 02/17/2016] [Indexed: 10/22/2022]
Abstract
Severe malaria is a major cause of mortality in children, but comprises only a small proportion of Plasmodium falciparum infections in naturally exposed populations. The evaluation of vaccines that prevent severe falciparum disease will require clinical trials whose primary efficacy endpoint will be severe malaria risk during follow-up. Here, we show that such trials are feasible with fewer than 1000 participants in areas with intense malaria transmission during the age interval when severe malaria incidence peaks.
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Affiliation(s)
- Bronner P Gonçalves
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States; Laboratory of Clinical Infectious Diseases-Epidemiology Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States
| | - D Rebecca Prevots
- Laboratory of Clinical Infectious Diseases-Epidemiology Unit, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States
| | - Edward Kabyemela
- MOMS Project, Seattle Biomedical Research Institute (currently Center for Infectious Disease Research), Seattle, WA, United States; Muheza Designated District Hospital, Muheza, Tanzania
| | - Michal Fried
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States; MOMS Project, Seattle Biomedical Research Institute (currently Center for Infectious Disease Research), Seattle, WA, United States; Muheza Designated District Hospital, Muheza, Tanzania
| | - Patrick E Duffy
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States; MOMS Project, Seattle Biomedical Research Institute (currently Center for Infectious Disease Research), Seattle, WA, United States; Muheza Designated District Hospital, Muheza, Tanzania.
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Abstract
In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of malaria. Progress during the last few years has been significant, and a first generation malaria candidate vaccine, RTS,S/AS01, is under review by the European Medicines Agency (EMA) for its quality, safety and efficacy under article 58, which allows the EMA to give a scientific opinion about products intended exclusively for markets outside of the European Union. However, much work is in progress to optimize malaria vaccines in regard to magnitude and durability of protective efficacy and the financing and practicality of delivery. Thus, we are hopeful that anti-malaria vaccines will soon be important tools in the battle against malaria.
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40
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Hoffman SL, Vekemans J, Richie TL, Duffy PE. The march toward malaria vaccines. Vaccine 2015; 33 Suppl 4:D13-23. [PMID: 26324116 DOI: 10.1016/j.vaccine.2015.07.091] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 07/25/2015] [Accepted: 07/27/2015] [Indexed: 01/14/2023]
Abstract
In 2013 there were an estimated 584,000 deaths and 198 million clinical illnesses due to malaria, the majority in sub-Saharan Africa. Vaccines would be the ideal addition to the existing armamentarium of anti-malaria tools. However, malaria is caused by parasites, and parasites are much more complex in terms of their biology than the viruses and bacteria for which we have vaccines, passing through multiple stages of development in the human host, each stage expressing hundreds of unique antigens. This complexity makes it more difficult to develop a vaccine for parasites than for viruses and bacteria, since an immune response targeting one stage may not offer protection against a later stage, because different antigens are the targets of protective immunity at different stages. Furthermore, depending on the life cycle stage and whether the parasite is extra- or intra-cellular, antibody and/or cellular immune responses provide protection. It is thus not surprising that there is no vaccine on the market for prevention of malaria, or any human parasitic infection. In fact, no vaccine for any disease with this breadth of targets and immune responses exists. In this limited review, we focus on four approaches to malaria vaccines, (1) a recombinant protein with adjuvant vaccine aimed at Plasmodium falciparum (Pf) pre-erythrocytic stages of the parasite cycle (RTS,S/AS01), (2) whole sporozoite vaccines aimed at Pf pre-erythrocytic stages (PfSPZ Vaccine and PfSPZ-CVac), (3) prime boost vaccines that include recombinant DNA, viruses and bacteria, and protein with adjuvant aimed primarily at Pf pre-erythrocytic, but also asexual erythrocytic stages, and (4) recombinant protein with adjuvant vaccines aimed at Pf and Plasmodium vivax sexual erythrocytic and mosquito stages. We recognize that we are not covering all approaches to malaria vaccine development, or most of the critically important work on development of vaccines against P. vivax, the second most important cause of malaria. Progress during the last few years has been significant, and a first generation malaria candidate vaccine, RTS,S/AS01, is under review by the European Medicines Agency (EMA) for its quality, safety and efficacy under article 58, which allows the EMA to give a scientific opinion about products intended exclusively for markets outside of the European Union. However, much work is in progress to optimize malaria vaccines in regard to magnitude and durability of protective efficacy and the financing and practicality of delivery. Thus, we are hopeful that anti-malaria vaccines will soon be important tools in the battle against malaria.
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Affiliation(s)
| | | | | | - Patrick E Duffy
- Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA
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41
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Dumoulin PC, Trop SA, Ma J, Zhang H, Sherman MA, Levitskaya J. Flow Cytometry Based Detection and Isolation of Plasmodium falciparum Liver Stages In Vitro. PLoS One 2015; 10:e0129623. [PMID: 26070149 PMCID: PMC4466555 DOI: 10.1371/journal.pone.0129623] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 05/11/2015] [Indexed: 11/19/2022] Open
Abstract
Malaria, the disease caused by Plasmodium parasites, remains a major global health burden. The liver stage of Plasmodium falciparum infection is a leading target for immunological and pharmacological interventions. Therefore, novel approaches providing specific detection and isolation of live P. falciparum exoerythrocytic forms (EEFs) are warranted. Utilizing a recently generated parasite strain expressing green fluorescent protein (GFP) we established a method which, allows for detection and isolation of developing live P. falciparum liver stages by flow cytometry. Using this technique we compared the susceptibility of five immortalized human hepatocyte cell lines and primary hepatocyte cultures from three donors to infection by P. falciparum sporozoites. Here, we show that EEFs can be detected and isolated from in vitro infected cultures of the HC-04 cell line and primary human hepatocytes. We confirmed the presence of developing parasites in sorted live human hepatocytes and characterized their morphology by fluorescence microscopy. Finally, we validated the practical applications of our approach by re-examining the importance of host ligand CD81 for hepatocyte infection by P. falciparum sporozoites in vitro and assessment of the inhibitory activity of anti-sporozoite antibodies. This methodology provides us with the tools to study both, the basic biology of the P. falciparum liver stage and the effects of host-derived factors on the development of P. falciparum EEFs.
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Affiliation(s)
- Peter C. Dumoulin
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, United States of America
| | - Stefanie A. Trop
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, United States of America
| | - Jinxia Ma
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, United States of America
| | - Hao Zhang
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, United States of America
| | - Matthew A. Sherman
- Triangle Research Labs, 6 Davis Drive, Durham, NC, 27709, United States of America
| | - Jelena Levitskaya
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, 21205, United States of America
- * E-mail:
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42
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Tan Z, Zhou T, Zheng H, Ding Y, Xu W. Malaria DNA vaccine gp96NTD-CSP elicits both CSP-specific antibody and CD8(+) T cell response. Parasitol Res 2015; 114:2333-2339. [PMID: 25786609 DOI: 10.1007/s00436-015-4429-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Accepted: 03/09/2015] [Indexed: 10/23/2022]
Abstract
It is ideal for the pre-erythrocytic stage subunit vaccine to induce both CSP-specific antibody and CD8(+) T cell response. Here, we designed a novel malaria DNA vaccine gp96NTD-CSP, which was constructed by fusing the full-length of CSP with the N-terminal domain of gp96 that deleted the endoplasmic reticulum-localized motif KDEL, and investigated its protective efficacy. We found that the fusion protein gp96NTD-CSP was mainly distributed on the surface of eukaryotic cells after transfection and could be sensed as a "danger signal" by the host immune system. Interestingly, both liver parasite burden and parasitemia in mice immunized with gp96NTD-CSP were significantly lower than those in the mice immunized either with gp96NTD, CSP, or gp96NTD-SYVPSAEQI, which was constructed by fusing the CSP-specific CD8(+) T cell epitope with the N-terminal domain of gp96 deleted with KDEL. Consistently, both the level of CSP-specific antibody and the frequency of IFN-γ secreted-CSP-specific CD8(+) T cells were much higher in mice immunized with gp96NTD-CSP than those in the mice immunized either with gp96NTD, CSP, or gp96NTD-SYVPSAEQI. Our results suggest that the malaria DNA vaccine gp96NTD-CSP could induce both humoral and cellular immune responses, which is attributed to the adjuvant effect of gp96NTD and full-length CSP.
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Affiliation(s)
- Zhangping Tan
- Department of Pathogenic Biology, The Third Military Medical University, Chongqing, 400038, People's Republic of China
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43
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Sack BK, Keitany GJ, Vaughan AM, Miller JL, Wang R, Kappe SHI. Mechanisms of stage-transcending protection following immunization of mice with late liver stage-arresting genetically attenuated malaria parasites. PLoS Pathog 2015; 11:e1004855. [PMID: 25974076 PMCID: PMC4431720 DOI: 10.1371/journal.ppat.1004855] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2014] [Accepted: 04/06/2015] [Indexed: 11/19/2022] Open
Abstract
Malaria, caused by Plasmodium parasite infection, continues to be one of the leading causes of worldwide morbidity and mortality. Development of an effective vaccine has been encumbered by the complex life cycle of the parasite that has distinct pre-erythrocytic and erythrocytic stages of infection in the mammalian host. Historically, malaria vaccine development efforts have targeted each stage in isolation. An ideal vaccine, however, would target multiple life cycle stages with multiple arms of the immune system and be capable of eliminating initial infection in the liver, the subsequent blood stage infection, and would prevent further parasite transmission. We have previously shown that immunization of mice with Plasmodium yoelii genetically attenuated parasites (GAP) that arrest late in liver stage development elicits stage-transcending protection against both a sporozoite challenge and a direct blood stage challenge. Here, we show that this immunization strategy engenders both T- and B-cell responses that are essential for stage-transcending protection, but the relative importance of each is determined by the host genetic background. Furthermore, potent anti-blood stage antibodies elicited after GAP immunization rely heavily on FC-mediated functions including complement fixation and FC receptor binding. These protective antibodies recognize the merozoite surface but do not appear to recognize the immunodominant merozoite surface protein-1. The antigen(s) targeted by stage-transcending immunity are present in both the late liver stages and blood stage parasites. The data clearly show that GAP-engendered protective immune responses can target shared antigens of pre-erythrocytic and erythrocytic parasite life cycle stages. As such, this model constitutes a powerful tool to identify novel, protective and stage-transcending T and B cell targets for incorporation into a multi-stage subunit vaccine.
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Affiliation(s)
- Brandon K. Sack
- Seattle Biomedical Research Institute, Seattle, Washington, United States of America
| | - Gladys J. Keitany
- Department of Immunology, University of Washington, Seattle, Washington, United States of America
| | - Ashley M. Vaughan
- Seattle Biomedical Research Institute, Seattle, Washington, United States of America
| | - Jessica L. Miller
- Seattle Biomedical Research Institute, Seattle, Washington, United States of America
| | - Ruobing Wang
- Seattle Biomedical Research Institute, Seattle, Washington, United States of America
| | - Stefan H. I. Kappe
- Seattle Biomedical Research Institute, Seattle, Washington, United States of America
- Department of Global Health, University of Washington, Seattle, Washington, United States of America
- * E-mail:
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44
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Whitacre DC, Espinosa DA, Peters CJ, Jones JE, Tucker AE, Peterson DL, Zavala FP, Milich DR. P. falciparum and P. vivax Epitope-Focused VLPs Elicit Sterile Immunity to Blood Stage Infections. PLoS One 2015; 10:e0124856. [PMID: 25933001 PMCID: PMC4416889 DOI: 10.1371/journal.pone.0124856] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 03/17/2015] [Indexed: 01/09/2023] Open
Abstract
In order to design P. falciparum preerythrocytic vaccine candidates, a library of circumsporozoite (CS) T and B cell epitopes displayed on the woodchuck hepatitis virus core antigen (WHcAg) VLP platform was produced. To test the protective efficacy of the WHcAg-CS VLPs, hybrid CS P. berghei/P. falciparum (Pb/Pf) sporozoites were used to challenge immunized mice. VLPs carrying 1 or 2 different CS repeat B cell epitopes and 3 VLPs carrying different CS non-repeat B cell epitopes elicited high levels of anti-insert antibodies (Abs). Whereas, VLPs carrying CS repeat B cell epitopes conferred 98% protection of the liver against a 10,000 Pb/Pf sporozoite challenge, VLPs carrying the CS non-repeat B cell eptiopes were minimally-to-non-protective. One-to-three CS-specific CD4/CD8 T cell sites were also fused to VLPs, which primed CS-specific as well as WHcAg-specific T cells. However, a VLP carrying only the 3 T cell domains failed to protect against a sporozoite challenge, indicating a requirement for anti-CS repeat Abs. A VLP carrying 2 CS repeat B cell epitopes and 3 CS T cell sites in alum adjuvant elicited high titer anti-CS Abs (endpoint dilution titer >1x106) and provided 80–100% protection against blood stage malaria. Using a similar strategy, VLPs were constructed carrying P. vivax CS repeat B cell epitopes (WHc-Pv-78), which elicited high levels of anti-CS Abs and conferred 99% protection of the liver against a 10,000 Pb/Pv sporozoite challenge and elicited sterile immunity to blood stage infection. These results indicate that immunization with epitope-focused VLPs carrying selected B and T cell epitopes from the P. falciparum and P. vivax CS proteins can elicit sterile immunity against blood stage malaria. Hybrid WHcAg-CS VLPs could provide the basis for a bivalent P. falciparum/P. vivax malaria vaccine.
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MESH Headings
- Animals
- Antibodies, Protozoan/immunology
- CD4-Positive T-Lymphocytes/immunology
- Epitopes, B-Lymphocyte/chemistry
- Epitopes, B-Lymphocyte/immunology
- Epitopes, T-Lymphocyte/chemistry
- Epitopes, T-Lymphocyte/immunology
- Hepatitis B Virus, Woodchuck/immunology
- Immunity
- Immunization
- Life Cycle Stages
- Malaria, Falciparum/immunology
- Malaria, Falciparum/parasitology
- Malaria, Falciparum/prevention & control
- Malaria, Vivax/immunology
- Malaria, Vivax/parasitology
- Malaria, Vivax/prevention & control
- Mice, Inbred C57BL
- Plasmodium falciparum/immunology
- Plasmodium vivax/immunology
- Protozoan Proteins/immunology
- Rabbits
- Repetitive Sequences, Amino Acid
- Reproducibility of Results
- Virion/immunology
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Affiliation(s)
- David C. Whitacre
- Vaccine Research Institute of San Diego, San Diego, California, United States of America
- VLP Biotech, Inc., San Diego, California, United States of America
| | - Diego A. Espinosa
- Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Cory J. Peters
- Vaccine Research Institute of San Diego, San Diego, California, United States of America
- VLP Biotech, Inc., San Diego, California, United States of America
| | - Joyce E. Jones
- Vaccine Research Institute of San Diego, San Diego, California, United States of America
- VLP Biotech, Inc., San Diego, California, United States of America
| | - Amy E. Tucker
- VLP Biotech, Inc., San Diego, California, United States of America
| | - Darrell L. Peterson
- Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Fidel P. Zavala
- Department of Molecular Microbiology and Immunology, Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - David R. Milich
- Vaccine Research Institute of San Diego, San Diego, California, United States of America
- VLP Biotech, Inc., San Diego, California, United States of America
- * E-mail:
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45
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Joyner C, Barnwell JW, Galinski MR. No more monkeying around: primate malaria model systems are key to understanding Plasmodium vivax liver-stage biology, hypnozoites, and relapses. Front Microbiol 2015; 6:145. [PMID: 25859242 PMCID: PMC4374475 DOI: 10.3389/fmicb.2015.00145] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 02/07/2015] [Indexed: 01/17/2023] Open
Abstract
Plasmodium vivax is a human malaria parasite responsible for significant morbidity worldwide and potentially death. This parasite possesses formidable liver-stage biology that involves the formation of dormant parasites known as hypnozoites. Hypnozoites are capable of activating weeks, months, or years after a primary blood-stage infection causing relapsing bouts of illness. Elimination of this dormant parasitic reservoir will be critical for global malaria eradication. Although hypnozoites were first discovered in 1982, few advancements have been made to understand their composition and biology. Until recently, in vitro models did not exist to study these forms and studying them from human ex vivo samples was virtually impossible. Today, non-human primate (NHP) models and modern systems biology approaches are poised as tools to enable the in-depth study of P. vivax liver-stage biology, including hypnozoites and relapses. NHP liver-stage model systems for P. vivax and the related simian malaria species P. cynomolgi are discussed along with perspectives regarding metabolite biomarker discovery, putative roles of extracellular vesicles, and relapse immunobiology.
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Affiliation(s)
- Chester Joyner
- Malaria Host–Pathogen Interaction Center, Emory Vaccine Center, Yerkes National Primate Research Center, Emory UniversityAtlanta, GA, USA
| | - John W. Barnwell
- Malaria Host–Pathogen Interaction Center, Emory Vaccine Center, Yerkes National Primate Research Center, Emory UniversityAtlanta, GA, USA
- Malaria Branch, Division of Parasitic Diseases and Malaria, Centers for Disease Control and PreventionAtlanta, GA, USA
| | - Mary R. Galinski
- Malaria Host–Pathogen Interaction Center, Emory Vaccine Center, Yerkes National Primate Research Center, Emory UniversityAtlanta, GA, USA
- Division of Infectious Diseases, Department of Medicine, Emory UniversityAtlanta, GA, USA
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46
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Proietti C, Doolan DL. The case for a rational genome-based vaccine against malaria. Front Microbiol 2015; 5:741. [PMID: 25657640 PMCID: PMC4302942 DOI: 10.3389/fmicb.2014.00741] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2014] [Accepted: 12/06/2014] [Indexed: 12/22/2022] Open
Abstract
Historically, vaccines have been designed to mimic the immunity induced by natural exposure to the target pathogen, but this approach has not been effective for any parasitic pathogen of humans or complex pathogens that cause chronic disease in humans, such as Plasmodium. Despite intense efforts by many laboratories around the world on different aspects of Plasmodium spp. molecular and cell biology, epidemiology and immunology, progress towards the goal of an effective malaria vaccine has been disappointing. The premise of rational vaccine design is to induce the desired immune response against the key pathogen antigens or epitopes targeted by protective immune responses. We advocate that development of an optimally efficacious malaria vaccine will need to improve on nature, and that this can be accomplished by rational vaccine design facilitated by mining genomic, proteomic and transcriptomic datasets in the context of relevant biological function. In our opinion, modern genome-based rational vaccine design offers enormous potential above and beyond that of whole-organism vaccines approaches established over 200 years ago where immunity is likely suboptimal due to the many genetic and immunological host-parasite adaptations evolved to allow the Plasmodium parasite to coexist in the human host, and which are associated with logistic and regulatory hurdles for production and delivery.
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Affiliation(s)
- Carla Proietti
- Infectious Diseases Program, QIMR Berghofer Medical Research Institute Brisbane, QLD, Australia
| | - Denise L Doolan
- Infectious Diseases Program, QIMR Berghofer Medical Research Institute Brisbane, QLD, Australia
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47
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Crompton PD, Moebius J, Portugal S, Waisberg M, Hart G, Garver LS, Miller LH, Barillas-Mury C, Pierce SK. Malaria immunity in man and mosquito: insights into unsolved mysteries of a deadly infectious disease. Annu Rev Immunol 2014; 32:157-87. [PMID: 24655294 DOI: 10.1146/annurev-immunol-032713-120220] [Citation(s) in RCA: 225] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Malaria is a mosquito-borne disease caused by parasites of the obligate intracellular Apicomplexa phylum the most deadly of which, Plasmodium falciparum, prevails in Africa. Malaria imposes a huge health burden on the world's most vulnerable populations, claiming the lives of nearly one million children and pregnant women each year. Although there is keen interest in eradicating malaria, we do not yet have the necessary tools to meet this challenge, including an effective malaria vaccine and adequate vector control strategies. Here we review what is known about the mechanisms at play in immune resistance to malaria in both the human and mosquito hosts at each step in the parasite's complex life cycle with a view toward developing the tools that will contribute to the prevention of disease and death and, ultimately, to the goal of malaria eradication. In so doing, we hope to inspire immunologists to participate in defeating this devastating disease.
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48
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Dups JN, Pepper M, Cockburn IA. Antibody and B cell responses to Plasmodium sporozoites. Front Microbiol 2014; 5:625. [PMID: 25477870 PMCID: PMC4235289 DOI: 10.3389/fmicb.2014.00625] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2014] [Accepted: 11/03/2014] [Indexed: 11/18/2022] Open
Abstract
Antibodies are capable of blocking infection of the liver by Plasmodium sporozoites. Accordingly the induction of anti-sporozoite antibodies is a major aim of various vaccine approaches to malaria. In recent years our knowledge of the specificity and quantities of antibodies required for protection has been greatly expanded by clinical trials of various whole sporozoite and subunit vaccines. Moreover, the development of humanized mouse models and transgenic parasites have also aided our ability to assess the specificity of antibodies and their ability to block infection. Nonetheless, considerable gaps remain in our knowledge – in particular in understanding what antigens are recognized by infection blocking antibodies and in knowing how we can induce robust, long-lived antibody responses. Maintaining high levels of circulating antibodies is likely to be of primary importance, as antibodies must block infection in the short time it takes for sporozoites to reach the liver from the skin. It is clear that a better understanding of the development of protective B cell-mediated immunity will aid the development and refinement of malaria vaccines.
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Affiliation(s)
- Johanna N Dups
- Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University Canberra, ACT, Australia
| | - Marion Pepper
- Department of Immunology, School of Medicine, University of Washington Seattle, WA, USA
| | - Ian A Cockburn
- Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University Canberra, ACT, Australia
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49
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Bijker EM, Schats R, Obiero JM, Behet MC, van Gemert GJ, van de Vegte-Bolmer M, Graumans W, van Lieshout L, Bastiaens GJH, Teelen K, Hermsen CC, Scholzen A, Visser LG, Sauerwein RW. Sporozoite immunization of human volunteers under mefloquine prophylaxis is safe, immunogenic and protective: a double-blind randomized controlled clinical trial. PLoS One 2014; 9:e112910. [PMID: 25396417 PMCID: PMC4232459 DOI: 10.1371/journal.pone.0112910] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2014] [Accepted: 10/14/2014] [Indexed: 11/30/2022] Open
Abstract
Immunization of healthy volunteers with chloroquine ChemoProphylaxis and Sporozoites (CPS-CQ) efficiently and reproducibly induces dose-dependent and long-lasting protection against homologous Plasmodium falciparum challenge. Here, we studied whether chloroquine can be replaced by mefloquine, which is the only other licensed anti-malarial chemoprophylactic drug that does not affect pre-erythrocytic stages, exposure to which is considered essential for induction of protection by CPS immunization. In a double blind randomized controlled clinical trial, volunteers under either chloroquine prophylaxis (CPS-CQ, n = 5) or mefloquine prophylaxis (CPS-MQ, n = 10) received three sub-optimal CPS immunizations by bites from eight P. falciparum infected mosquitoes each, at monthly intervals. Four control volunteers received mefloquine prophylaxis and bites from uninfected mosquitoes. CPS-MQ immunization is safe and equally potent compared to CPS-CQ inducing protection in 7/10 (70%) versus 3/5 (60%) volunteers, respectively. Furthermore, specific antibody levels and cellular immune memory responses were comparable between both groups. We therefore conclude that mefloquine and chloroquine are equally effective in CPS-induced immune responses and protection. Trial registration: ClinicalTrials.gov NCT01422954.
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Affiliation(s)
- Else M. Bijker
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Remko Schats
- Leiden University Medical Center, Department of Infectious Diseases, PO Box 9600, 2300 RC Leiden, The Netherlands
| | - Joshua M. Obiero
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Marije C. Behet
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Geert-Jan van Gemert
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Marga van de Vegte-Bolmer
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Wouter Graumans
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Lisette van Lieshout
- Leiden University Medical Center, Department of Medical Microbiology, PO Box 9600, 2300 RC Leiden, The Netherlands
- Leiden University Medical Center, Department of Parasitology, PO Box 9600, 2300 RC Leiden, The Netherlands
| | - Guido J. H. Bastiaens
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Karina Teelen
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Cornelus C. Hermsen
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Anja Scholzen
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Leo G. Visser
- Leiden University Medical Center, Department of Infectious Diseases, PO Box 9600, 2300 RC Leiden, The Netherlands
| | - Robert W. Sauerwein
- Radboud university medical center, Department of Medical Microbiology, PO Box 9101, 6500 HB Nijmegen, The Netherlands
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Morrot A, Rodrigues MM. Tissue signatures influence the activation of intrahepatic CD8(+) T cells against malaria sporozoites. Front Microbiol 2014; 5:440. [PMID: 25202304 PMCID: PMC4141441 DOI: 10.3389/fmicb.2014.00440] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Accepted: 08/03/2014] [Indexed: 11/19/2022] Open
Abstract
Plasmodium sporozoites and liver stages express antigens that are targeted to the MHC-Class I antigen-processing pathway. After the introduction of Plasmodium sporozoites by Anopheles mosquitoes, bone marrow-derived dendritic cells in skin-draining lymph nodes are the first cells to cross-present parasite antigens and elicit specific CD8+ T cells. One of these antigens is the immunodominant circumsporozoite protein (CSP). The CD8+ T cell-mediated protective immune response against CSP is dependent on the interleukin loop involving IL-4 receptor expression on CD8+ cells and IL-4 secretion by CD4+ T cell helpers. In a few days, these CD8+ T cells re-circulate to secondary lymphoid organs and the liver. In the liver, the hepatic sinusoids are enriched with cells, such as dendritic, sinusoidal endothelial and Kupffer cells, that are able to cross-present MHC class I antigens to intrahepatic CD8+ T cells. Specific CD8+ T cells actively find infected hepatocytes and target intra-cellular parasites through mechanisms that are both interferon-γ-dependent and -independent. Immunity is mediated by CD8+ T effector or effector-memory cells and, when present in high numbers, these cells can provide sterilizing immunity. Human vaccination trials with recombinant formulations or attenuated sporozoites have yet to achieve the high numbers of specific effector T cells that are required for sterilizing immunity. In spite of the limited number of specific CD8+ T cells, attenuated sporozoites provided multiple times by the endovenous route provided a high degree of protective immunity. These observations highlight that CD8+ T cells may be useful for improving antibody-mediated protective immunity to pre-erythrocytic stages of malaria parasites.
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Affiliation(s)
- Alexandre Morrot
- Departamento de Imunologia, Instituro de Microbiologia, Universidade Federal do Rio de Janeiro Rio de Janeiro, Brazil
| | - Maurício M Rodrigues
- Departmento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de São Paulo-Escola Paulista de Medicina São Paulo, Brazil
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