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BMC Medicine Aug 2022RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the...
BACKGROUND
RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody function is limited, especially among children. Antibodies that promote opsonic phagocytosis and other cellular functions appear to be important contributors to RTS,S immunity.
METHODS
We studied a phase IIb trial of RTS,S/AS02 conducted in young children in malaria-endemic regions of Mozambique. We evaluated the induction of antibodies targeting the circumsporozoite protein (CSP, vaccine antigen) that interact with Fcγ-receptors (FcRγs) and promote phagocytosis (neutrophils, monocytes, THP-1 cells), antibody-dependent respiratory burst (ADRB) by neutrophils, and natural killer (NK) cell activity, as well as the temporal kinetics of responses over 5 years of follow-up (ClinicalTrials.gov registry number NCT00197041).
RESULTS
RTS,S vaccination induced CSP-specific IgG with FcγRIIa and FcγRIII binding activity and promoted phagocytosis by neutrophils, THP-1 monocytes, and primary human monocytes, neutrophil ADRB activity, and NK cell activation. Responses were highly heterogenous among children, and the magnitude of neutrophil phagocytosis by antibodies was relatively modest, which may reflect modest vaccine efficacy. Induction of functional antibodies was lower among children with higher malaria exposure. Functional antibody magnitude and the functional activity of antibodies largely declined within a year post-vaccination, and decay were highest in the first 6 months, consistent with the decline in vaccine efficacy over that time. Decay rates varied for different antibody parameters and decay was slower for neutrophil phagocytosis. Biostatistical modelling suggested IgG1 and IgG3 contribute in promoting FcγR binding and phagocytosis, and IgG targeting the NANP-repeat and C-terminal regions CSP were similarly important for functional activities.
CONCLUSIONS
Results provide new insights to understand the modest and time-limited efficacy of RTS,S in children and the induction of antibody functional activities. Improving the induction and maintenance of antibodies that promote phagocytosis and cellular functions, and combating the negative effect of malaria exposure on vaccine responses are potential strategies for improving RTS,S efficacy and longevity.
Topics: Antibodies, Protozoan; Child; Child, Preschool; Humans; Immunoglobulin G; Malaria; Malaria Vaccines; Malaria, Falciparum; Plasmodium falciparum; Protozoan Proteins; Vaccination
PubMed: 36002841
DOI: 10.1186/s12916-022-02466-2 -
Trends in Parasitology Jun 2020Despite ongoing efforts, a highly effective vaccine against Plasmodium falciparum remains elusive. Vaccines targeting the pre-erythrocytic stages of the P. falciparum... (Review)
Review
Despite ongoing efforts, a highly effective vaccine against Plasmodium falciparum remains elusive. Vaccines targeting the pre-erythrocytic stages of the P. falciparum life cycle are the most advanced to date, affording moderate levels of efficacy in field trials. However, the discovery that the members of the merozoite PfRH5-PfCyRPA-PfRipr (RCR) complex are capable of inducing strain-transcendent neutralizing antibodies has renewed enthusiasm for the possibility of preventing disease by targeting the parasite during the blood stage of infection. With Phase I/II clinical trials now underway using first-generation vaccines against PfRH5, and more on the horizon for PfCyRPA and PfRipr, this review explores the rationale and future potential of the RCR complex as a P. falciparum vaccine target.
Topics: Antibodies, Neutralizing; Antigens, Protozoan; Carrier Proteins; Clinical Trials as Topic; Malaria; Malaria Vaccines; Plasmodium falciparum; Protozoan Proteins
PubMed: 32359873
DOI: 10.1016/j.pt.2020.04.003 -
Seminars in Immunopathology Jun 2020Malaria is an old scourge of humankind and has a large negative impact on the economic development of affected communities. Recent success in malaria control and... (Review)
Review
Malaria is an old scourge of humankind and has a large negative impact on the economic development of affected communities. Recent success in malaria control and reduction of mortality seems to have stalled emphasizing that our current intervention tools need to be complemented by malaria vaccines. Different populations of unconventional T cells such as mucosal-associated invariant T (MAIT) cells, invariant natural killer T (iNKT) cells and γδ T cells are gaining attention in the field of malaria immunology. Significant advances in our basic understanding of unconventional T cell biology in rodent malaria models have been made, however, their roles in humans during malaria are less clear. Unconventional T cells are abundant in skin, gut and liver tissues, and long-lasting expansions and functional alterations were observed upon malaria infection in malaria naïve and malaria pre-exposed volunteers. Here, we review the current understanding of involvement of unconventional T cells in anti-Plasmodium falciparum immunity and highlight potential future research avenues.
Topics: Humans; Malaria; Malaria Vaccines; Malaria, Falciparum; Mucosal-Associated Invariant T Cells; Plasmodium falciparum
PubMed: 32076813
DOI: 10.1007/s00281-020-00791-3 -
Current Opinion in Microbiology Dec 2020Malaria continues to pose a severe threat to over half of the world's population each year. With no long-term, effective vaccine available and a growing resistance to... (Review)
Review
Malaria continues to pose a severe threat to over half of the world's population each year. With no long-term, effective vaccine available and a growing resistance to antimalarials, there is a need for innovative methods of Plasmodium treatment. Recent evidence has pointed to a role of the composition of the gut microbiota in the severity of Plasmodium infection in both animal models and human studies. Further evidence has shown that the gut microbiota influences the adaptive immune response of the host, the arm of the immune system necessary for Plasmodium clearance, sustained Plasmodium immunity, and vaccine efficacy. Together, this illustrates the future potential of gut microbiota modulation as a novel method of preventing severe malaria.
Topics: Adaptive Immunity; Animals; Bacteria; Gastrointestinal Microbiome; Humans; Immunity; Malaria; Malaria Vaccines; Plasmodium
PubMed: 33007644
DOI: 10.1016/j.mib.2020.08.006 -
Frontiers in Cellular and Infection... 2019
Topics: Antiprotozoal Agents; Host-Parasite Interactions; Humans; Malaria; Plasmodium; Protozoan Infections; Protozoan Vaccines; Trypanosoma; Trypanosomiasis
PubMed: 31448246
DOI: 10.3389/fcimb.2019.00293 -
Frontiers in Immunology 2021In areas where transmission is endemic, clinical immunity against malaria is progressively acquired during childhood and adults are usually protected against the severe... (Review)
Review
In areas where transmission is endemic, clinical immunity against malaria is progressively acquired during childhood and adults are usually protected against the severe clinical consequences of the disease. Nevertheless, pregnant women, notably during their first pregnancies, are susceptible to placental malaria and the associated serious clinical outcomes. Placental malaria is characterized by the massive accumulation of infected erythrocytes and monocytes in the placental intervillous spaces leading to maternal anaemia, hypertension, stillbirth and low birth weight due to premature delivery, and foetal growth retardation. Remarkably, the prevalence of placental malaria sharply decreases with successive pregnancies. This protection is associated with the development of antibodies directed towards the surface of -infected erythrocytes from placental origin. Placental sequestration is mediated by the interaction between VAR2CSA, a member of the erythrocyte membrane protein 1 family expressed on the infected erythrocytes surface, and the placental receptor chondroitin sulfate A. VAR2CSA stands today as the leading candidate for a placental malaria vaccine. We recently reported the safety and immunogenicity of two VAR2CSA-derived placental malaria vaccines (PRIMVAC and PAMVAC), spanning the chondroitin sulfate A-binding region of VAR2CSA, in both malaria-naïve and -exposed non-pregnant women in two distinct Phase I clinical trials (ClinicalTrials.gov, NCT02658253 and NCT02647489). This review discusses recent advances in placental malaria vaccine development, with a focus on the recent clinical data, and discusses the next clinical steps to undertake in order to better comprehend vaccine-induced immunity and accelerate vaccine development.
Topics: Animals; Antigens, Protozoan; Drug Development; Female; Host-Parasite Interactions; Humans; Immunization; Immunogenicity, Vaccine; Malaria Vaccines; Malaria, Falciparum; Placenta; Pregnancy; Pregnancy Complications, Parasitic; Treatment Outcome
PubMed: 33717176
DOI: 10.3389/fimmu.2021.634508 -
Expert Review of Vaccines Feb 2021Transmission-blocking vaccines (TBV) prevent community spread of malaria by targeting mosquito sexual stage parasites, a life-cycle bottleneck, and will be used in... (Review)
Review
INTRODUCTION
Transmission-blocking vaccines (TBV) prevent community spread of malaria by targeting mosquito sexual stage parasites, a life-cycle bottleneck, and will be used in elimination programs. TBV rely on herd immunity to reduce mosquito infections and thereby new infections in both vaccine recipients and non-recipients, but do not provide protection once an individual receives an infectious mosquito bite which complicates clinical development.
AREAS COVERED
Here, we describe the concept and biology behind TBV, and we provide an update on clinical development of the leading vaccine candidate antigens. Search terms 'malaria vaccine,' 'sexual stages,' 'transmission blocking vaccine,' 'VIMT' and 'SSM-VIMT' were used for PubMed queries to identify relevant literature.
EXPERT OPINION
Candidates targeting zygote surface antigen Pfs25, and its orthologue Pvs25, induced functional activity in humans that reduced mosquito infection in surrogate assays, but require increased durability to be useful in the field. Candidates targeting gamete surface antigens Pfs230 and Pfs48/45, respectively, are in or nearing clinical trials. Nanoparticle platforms and adjuvants are being explored to enhance immunogenicity. Efficacy trials require special considerations, such as cluster-randomized designs to measure herd immunity that reduces human and mosquito infection rates, while addressing human and mosquito movements as confounding factors.
Topics: Animals; Antibodies, Protozoan; Antigens, Surface; Humans; Immunity, Herd; Malaria Vaccines; Malaria, Falciparum; Malaria, Vivax; Mosquito Control; Mosquito Vectors; Plasmodium falciparum; Plasmodium vivax
PubMed: 33478283
DOI: 10.1080/14760584.2021.1878028 -
Nature Communications Nov 2023Clinical immunity against Plasmodium falciparum infection develops in residents of malaria endemic regions, manifesting in reduced clinical symptoms during infection and...
Clinical immunity against Plasmodium falciparum infection develops in residents of malaria endemic regions, manifesting in reduced clinical symptoms during infection and in protection against severe disease but the mechanisms are not fully understood. Here, we compare the cellular and humoral immune response of clinically immune (0-1 episode over 18 months) and susceptible (at least 3 episodes) during a mild episode of Pf malaria infection in a malaria endemic region of Malawi, by analysing peripheral blood samples using high dimensional mass cytometry (CyTOF), spectral flow cytometry and single-cell transcriptomic analyses. In the clinically immune, we find increased proportions of circulating follicular helper T cells and classical monocytes, while the humoral immune response shows characteristic age-related differences in the protected. Presence of memory CD4 T cell clones with a strong cytolytic ZEB2 T helper 1 effector signature, sharing identical T cell receptor clonotypes and recognizing the Pf-derived circumsporozoite protein (CSP) antigen are found in the blood of the Pf-infected participants gaining protection. Moreover, in clinically protected participants, ZEB2 memory CD4 T cells express lower level of inhibitory and chemotactic receptors. We thus propose that clonally expanded ZEB2 CSP-specific cytolytic memory CD4 Th1 cells may contribute to clinical immunity against the sporozoite and liver-stage Pf malaria.
Topics: Humans; Plasmodium falciparum; Malaria, Falciparum; Malaria; Th1 Cells; Protozoan Proteins; Clone Cells; Malaria Vaccines
PubMed: 38001069
DOI: 10.1038/s41467-023-43376-y -
Nature Communications Sep 2023Apical membrane antigen 1 (AMA1) is a key malaria vaccine candidate and target of neutralizing antibodies. AMA1 binds to a loop in rhoptry neck protein 2 (RON2L) to form...
Apical membrane antigen 1 (AMA1) is a key malaria vaccine candidate and target of neutralizing antibodies. AMA1 binds to a loop in rhoptry neck protein 2 (RON2L) to form the moving junction during parasite invasion of host cells, and this complex is conserved among apicomplexan parasites. AMA1-RON2L complex immunization achieves higher growth inhibitory activity than AMA1 alone and protects mice against Plasmodium yoelii challenge. Here, three single-component AMA1-RON2L immunogens were designed that retain the structure of the two-component AMA1-RON2L complex: one structure-based design (SBD1) and two insertion fusions. All immunogens elicited high antibody titers with potent growth inhibitory activity, yet these antibodies did not block RON2L binding to AMA1. The SBD1 immunogen induced significantly more potent strain-transcending neutralizing antibody responses against diverse strains of Plasmodium falciparum than AMA1 or AMA1-RON2L complex vaccination. This indicates that SBD1 directs neutralizing antibody responses to strain-transcending epitopes in AMA1 that are independent of RON2L binding. This work underscores the importance of neutralization mechanisms that are distinct from RON2 blockade. The stable single-component SBD1 immunogen elicits potent strain-transcending protection that may drive the development of next-generation vaccines for improved malaria and apicomplexan parasite control.
Topics: Animals; Mice; Malaria Vaccines; Antibodies, Neutralizing; Cell Membrane; Epitopes; Immunization
PubMed: 37660103
DOI: 10.1038/s41467-023-40878-7 -
Infection and Immunity Apr 2020Efficient delivery of antigenic cargo to trigger protective immune responses is critical to the success of vaccination. Genetically engineered microorganisms, including... (Review)
Review
Efficient delivery of antigenic cargo to trigger protective immune responses is critical to the success of vaccination. Genetically engineered microorganisms, including virus, bacteria, and protozoa, can be modified to carry and deliver heterologous antigens to the host immune system. The biological vectors can induce a broad range of immune responses and enhance heterologous antigen-specific immunological outcomes. The protozoan genus is widespread in domestic animals, causing serious coccidiosis. parasites with strong immunogenicity are potent coccidiosis vaccine candidates and offer a valuable model of live vaccines against infectious diseases in animals. parasites can also function as a vaccine vector. Herein, we review recent advances in design and application of recombinant as a vaccine vector, which has been a topic of ongoing research in our laboratory. By recapitulating the establishment of an transfection platform and its application, it will help lay the foundation for the future development of effective parasite-based vaccine delivery vectors and beyond.
Topics: Animals; Antigens, Protozoan; Coccidiosis; Eimeria; Humans; Microorganisms, Genetically-Modified; Protozoan Vaccines; Vaccination; Vaccines, Attenuated; Vaccines, Synthetic
PubMed: 32094255
DOI: 10.1128/IAI.00861-19