RESUMEN
BACKGROUNDS: Malaria, a preventive and treatable disease, is still responsible for annual deaths reported in most tropical regions, principally in sub-Saharan Africa. Subunit recombinant transmission-blocking vaccines (TBVs) have been proposed as promising vaccines to succeed in malaria elimination and eradication. Here, a provisional study was designed to assess the immunogenicity and functional activity of alanyl aminopeptidase N (APN1) of Anopheles stephensi, as a TBV candidate, administered with MPL, CpG, and QS21 adjuvants in the murine model. METHODOLOGY/PRINCIPAL FINDINGS: The mouse groups were immunized with recombinant APN1 (rAPN1) alone or formulated with CpG, MPL, QS-21, or a combination of adjuvants (CMQ), and the elicited immune responses were evaluated after the third immunization. The standard membrane feeding assay (SMFA) measured the functional activity of antibodies against bacterial-expressed APN1 protein in adjuvanted vaccine groups on transmission of P. falciparum (NF54) to An. stephensi mosquitoes. Evaluation of mice vaccinated with rAPN1 formulated with distinct adjuvants manifested a significant increase in the high-avidity level of anti-APN1 IgG and IgG subclasses; however, rAPN1 induced the highest level of high-avidity anti-APN1 IgG1, IgG2a, and IgG2b antibodies in the immunized vaccine group 5 (APN1/CMQ). In addition, vaccine group 5 (receiving APN1/CMQ), had still the highest level of anti-APN1 IgG antibodies relative to other immunized groups after six months, on day 180. The SMFA data indicates a trend towards higher transmission-reducing activity in groups 2 and 5, which received the antigen formulated with CpG or a combination of three adjuvants. CONCLUSIONS/SIGNIFICANCE: The results have shown the capability of admixture to stimulate high-affinity and long-lasting antibodies against the target antigen to hinder Plasmodium parasite development in the mid-gut of An. stephensi. The attained results authenticated APN1/CMQ and APN1/CpG as a potent APN1-based TBV formulation which will be helpful in designing a vaccine in the future.
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Adyuvantes Inmunológicos , Anopheles , Antígenos CD13 , Vacunas contra la Malaria , Saponinas , Animales , Anopheles/parasitología , Anopheles/inmunología , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Ratones , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Saponinas/farmacología , Saponinas/administración & dosificación , Antígenos CD13/inmunología , Antígenos CD13/metabolismo , Femenino , Plasmodium falciparum/inmunología , Malaria/prevención & control , Malaria/transmisión , Malaria/inmunología , Malaria/parasitología , Oligodesoxirribonucleótidos/farmacología , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/inmunología , Ratones Endogámicos BALB C , Malaria Falciparum/prevención & control , Malaria Falciparum/transmisión , Malaria Falciparum/inmunología , Malaria Falciparum/parasitologíaRESUMEN
The sequestration of Plasmodium falciparum-infected erythrocytes to the host endothelium is central to the pathogenesis of malaria. The sequestration is mediated by the parasite´s diverse Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) variants, which bind select human receptors on the endothelium. Severe malaria is associated with PfEMP1 binding human endothelial protein C receptor (EPCR) via their CIDRα1 domains. Antibodies binding and inhibiting across the sequence diverse CIDRα1 domains are likely important in acquired immunity against severe malaria. In this study, we explored if immunization with AP205 bacteriophage capsid-virus-like particles (cVLPs) presenting a mosaic of diverse CIDRα1 protein variants would stimulate broadly reactive and inhibitory antibody responses in mice. Three different mosaic cVLP vaccines each composed of five CIDRα1 protein variants with varying degrees of sequence conservation of residues at and near the EPCR binding site, were tested. All mosaic cVLP vaccines induced functional antibodies comparable to those induced by matched cocktails of cVLPs decorated with the single CIDRα1 variant. No broadly reactive responses were observed. However, the vaccines did induce some cross-reactivity and inhibition within the CIDRα1 subclasses included in the vaccines, demonstrating potential use of the cVLP vaccine platform for the design of multivalent vaccines.
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Receptor de Proteína C Endotelial , Proteínas Protozoarias , Vacunas de Partículas Similares a Virus , Animales , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/genética , Ratones , Vacunas de Partículas Similares a Virus/inmunología , Vacunas de Partículas Similares a Virus/administración & dosificación , Humanos , Receptor de Proteína C Endotelial/inmunología , Receptor de Proteína C Endotelial/metabolismo , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Plasmodium falciparum/inmunología , Anticuerpos Antiprotozoarios/inmunología , Femenino , Dominios Proteicos , Unión Proteica , Ratones Endogámicos BALB C , Receptores de Superficie Celular/inmunología , Malaria Falciparum/prevención & control , Malaria Falciparum/inmunología , Malaria Falciparum/parasitologíaRESUMEN
Introduction: in areas with intense perennial malaria transmission, limited data is available on the impact of environmental conditions especially rainfall on naturally acquired immunity against promising malaria vaccine candidates. For this reason, we have compared IgG antibody responses specific to Plasmodium spp. derived MSP3 and UB05 vaccine candidates, in plasma of children living in two areas of Cameroon differing in rainfall conditions. Methods: data about children less than 5 years old was collected during the years 2017 and 2018. Next malaria asymptomatic P. falciparum (Pf) infected children were selected following malaria test confirmation. MSP3 and UB05 specific IgG antibody responses were measured in participant´s plasma using enzyme-linked immunosorbent assay (ELISA). Results: interestingly, IgG antibody responses specific to UB05 were significantly higher (p<0.0001) in Pf-negative children when compared to their asymptomatic Pf-infected counterparts living in monomodal rainfall areas. In contrast, a significantly higher (p<0.0001) IgG response to MSP3 was observed instead in asymptomatic Pf-infected children in the same population. In addition, IgG responses specific to UB05 remained significantly higher in bimodal when compared to monomodal rainfall areas irrespective of children´s Pf infection status (p<0.0055 for Pf-positive and p<0.0001 for negative children). On the contrary, IgG antibody responses specific to MSP3 were significantly higher in bimodal relative to monomodal rainfall areas (P<0.0001) just for Pf-negative children. Conclusion: thus IgG antibody responses specific to UBO5 are a better correlate of naturally acquired immunity against malaria in Pf-negative Cameroonian children especially in monomodal rainfall areas.
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Anticuerpos Antiprotozoarios , Antígenos de Protozoos , Ensayo de Inmunoadsorción Enzimática , Inmunoglobulina G , Malaria Falciparum , Plasmodium falciparum , Proteínas Protozoarias , Humanos , Camerún , Malaria Falciparum/inmunología , Malaria Falciparum/epidemiología , Inmunoglobulina G/sangre , Preescolar , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunología , Antígenos de Protozoos/inmunología , Anticuerpos Antiprotozoarios/sangre , Lactante , Femenino , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/inmunología , Masculino , Lluvia , Proteínas Recombinantes/inmunologíaRESUMEN
INTRODUCTION: The use of novel adjuvants in human vaccines continues to expand as their contribution to preventing disease in challenging populations and caused by complex pathogens is increasingly understood. AS01 is a family of liposome-based vaccine Adjuvant Systems containing two immunostimulants: 3-O-desacyl-4'-monophosphoryl lipid A and the saponin QS-21. AS01-containing vaccines have been approved and administered to millions of individuals worldwide. AREAS COVERED: Here, we report advances in our understanding of the mode of action of AS01 that contributed to the development of efficacious vaccines preventing disease due to malaria, herpes zoster, and respiratory syncytial virus. AS01 induces early innate immune activation that induces T cell-mediated and antibody-mediated responses with optimized functional characteristics and induction of immune memory. AS01-containing vaccines appear relatively impervious to baseline immune status translating into high efficacy across populations. Currently licensed AS01-containing vaccines have shown acceptable safety profiles in clinical trials and post-marketing settings. EXPERT OPINION: Initial expectations that adjuvantation with AS01 could support effective vaccine responses and contribute to disease control have been realized. Investigation of the utility of AS01 in vaccines to prevent other challenging diseases, such as tuberculosis, is ongoing, together with efforts to fully define its mechanisms of action in different vaccine settings.
Adjuvants are added to vaccines to increase the immune response produced after vaccination. Adjuvant Systems contain two or more molecules that stimulate the immune system. AS01 is an Adjuvant System that contains two components, MPL and QS-21, that stimulate the immune system. AS01 is included in three approved vaccines: a malaria vaccine for children, a herpes zoster vaccine for older adults, and a respiratory syncytial virus vaccine also for older adults. Vaccines containing AS01 have been extensively evaluated in clinical trials and administered to millions of individuals during market use. These vaccines are effective in preventing disease and have acceptable safety in different age groups. Experiments have been done to investigate how AS01 works in vaccines to produce an efficient immune response that helps to protect against the disease being targeted. A key effect of AS01 is to encourage specific immune cells to produce chemicals that stimulate the immune system. We now know that this effect is due to co-operation between MPL and QS-21. Experiments have shown that AS01 induces a sophisticated immune 'gene signature' in blood within 24 h after vaccination, and people who developed this 'gene signature' had a stronger response to vaccination. AS01 seems to be able to stimulate the immune system of most people even if they are older or have a weakened immune system. This means that AS01 could be included in other vaccines against other challenging diseases, such as tuberculosis, or could be used in the treatment of some disease, such as chronic hepatitis B.
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Adyuvantes Inmunológicos , Adyuvantes de Vacunas , Saponinas , Humanos , Saponinas/inmunología , Saponinas/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Lípido A/análogos & derivados , Lípido A/inmunología , Lípido A/farmacología , Animales , Inmunidad Innata/efectos de los fármacos , Vacunas contra Virus Sincitial Respiratorio/inmunología , Liposomas , Malaria/prevención & control , Malaria/inmunología , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Combinación de MedicamentosRESUMEN
Malaria is a global disease affecting a large portion of the world's population. Although vaccines have recently become available, their efficacies are suboptimal. We generated virus-like particles (VLPs) that expressed either apical membrane antigen 1 (AMA1) or microneme-associated antigen (MIC) of Plasmodium berghei and compared their efficacy in BALB/c mice. We found that immune sera acquired from AMA1 VLP- or MIC VLP-immunized mice specifically interacted with the antigen of choice and the whole P. berghei lysate antigen, indicating that the antibodies were highly parasite-specific. Both VLP vaccines significantly enhanced germinal center B cell frequencies in the inguinal lymph nodes of mice compared with the control, but only the mice that received MIC VLPs showed significantly enhanced CD4+ T cell responses in the blood following P. berghei challenge infection. AMA1 and MIC VLPs significantly suppressed TNF-α and interleukin-10 production but had a negligible effect on interferon-γ. Both VLPs prevented excessive parasitemia buildup in immunized mice, although parasite burden reduction induced by MIC VLPs was slightly more effective than that induced by AMA1. Both VLPs were equally effective at preventing body weight loss. Our findings demonstrated that the MIC VLP was an effective inducer of protection against murine experimental malaria and should be the focus of further development.
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Antígenos de Protozoos , Vacunas contra la Malaria , Proteínas de la Membrana , Plasmodium berghei , Proteínas Protozoarias , Vacunas de Partículas Similares a Virus , Animales , Femenino , Ratones , Anticuerpos Antiprotozoarios/inmunología , Anticuerpos Antiprotozoarios/sangre , Antígenos de Protozoos/inmunología , Linfocitos B/inmunología , Linfocitos B/metabolismo , Linfocitos T CD4-Positivos/inmunología , Malaria/prevención & control , Malaria/inmunología , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Proteínas de la Membrana/inmunología , Ratones Endogámicos BALB C , Parasitemia/inmunología , Parasitemia/prevención & control , Plasmodium berghei/inmunología , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/genética , Vacunas de Partículas Similares a Virus/inmunología , Vacunas de Partículas Similares a Virus/administración & dosificaciónRESUMEN
Reticulocyte-binding protein homologue 5 (RH5), a leading blood-stage Plasmodium falciparum malaria vaccine target, interacts with cysteine-rich protective antigen (CyRPA) and RH5-interacting protein (RIPR) to form an essential heterotrimeric "RCR-complex". We investigate whether RCR-complex vaccination can improve upon RH5 alone. Using monoclonal antibodies (mAbs) we show that parasite growth-inhibitory epitopes on each antigen are surface-exposed on the RCR-complex and that mAb pairs targeting different antigens can function additively or synergistically. However, immunisation of female rats with the RCR-complex fails to outperform RH5 alone due to immuno-dominance of RIPR coupled with inferior potency of anti-RIPR polyclonal IgG. We identify that all growth-inhibitory antibody epitopes of RIPR cluster within the C-terminal EGF-like domains and that a fusion of these domains to CyRPA, called "R78C", combined with RH5, improves the level of in vitro parasite growth inhibition compared to RH5 alone. These preclinical data justify the advancement of the RH5.1 + R78C/Matrix-M™ vaccine candidate to Phase 1 clinical trial.
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Anticuerpos Monoclonales , Anticuerpos Antiprotozoarios , Antígenos de Protozoos , Vacunas contra la Malaria , Malaria Falciparum , Plasmodium falciparum , Proteínas Protozoarias , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Animales , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunología , Femenino , Malaria Falciparum/prevención & control , Malaria Falciparum/inmunología , Malaria Falciparum/parasitología , Antígenos de Protozoos/inmunología , Ratas , Anticuerpos Antiprotozoarios/inmunología , Anticuerpos Monoclonales/inmunología , Humanos , Epítopos/inmunología , Proteínas Portadoras/inmunología , Proteínas Portadoras/metabolismoRESUMEN
BACKGROUND: Malaria transmission-blocking vaccines (TBVs) aim to inhibit malaria parasite development in mosquitoes and prevent further transmission to the human host. The putative-secreted ookinete protein 25 (PSOP25), highly conserved in Plasmodium spp., is a promising TBV target. Here, we investigated PvPSOP25 from P. vivax as a TBV candidate using transgenic murine parasite P. berghei and clinical P. vivax isolates. METHODS AND FINDINGS: A transgenic P. berghei line expressing PvPSOP25 (TrPvPSOP25Pb) was generated. Full-length PvPSOP25 was expressed in the yeast Pichia pastoris and used to immunize mice to obtain anti-rPvPSOP25 sera. The transmission-blocking activity of the anti-rPvPSOP25 sera was evaluated through in vitro assays and mosquito-feeding experiments. The antisera generated by immunization with rPvPSOP25 specifically recognized the native PvPSOP25 antigen expressed in TrPvPSOP25Pb ookinetes. In vitro assays showed that the immune sera significantly inhibited exflagellation and ookinete formation of the TrPvPSOP25Pb parasite. Mosquitoes feeding on mice infected with the transgenic parasite and passively transferred with the anti-rPvPSOP25 sera showed a 70.7% reduction in oocyst density compared to the control group. In a direct membrane feeding assay conducted with five clinical P. vivax isolates, the mouse anti-rPvPSOP25 antibodies significantly reduced the oocyst density while showing a negligible influence on mosquito infection prevalence. CONCLUSIONS: This study supported the feasibility of transgenic murine malaria parasites expressing P. vivax antigens as a useful tool for evaluating P. vivax TBV candidates. Meanwhile, the moderate transmission-reducing activity of the generated anti-rPvPSOP25 sera necessitates further research to optimize its efficacy.
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Vacunas contra la Malaria , Malaria Vivax , Plasmodium berghei , Plasmodium vivax , Proteínas Protozoarias , Animales , Ratones , Plasmodium vivax/genética , Plasmodium vivax/inmunología , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Plasmodium berghei/genética , Plasmodium berghei/inmunología , Proteínas Protozoarias/genética , Proteínas Protozoarias/inmunología , Humanos , Malaria Vivax/transmisión , Malaria Vivax/parasitología , Malaria Vivax/prevención & control , Malaria Vivax/inmunología , Femenino , Antígenos de Protozoos/genética , Antígenos de Protozoos/inmunología , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Malaria/transmisión , Malaria/prevención & control , Malaria/parasitología , Malaria/inmunología , Ratones Endogámicos BALB CRESUMEN
INTRODUCTION: Malaria continues to remain a major global health problem with nearly a quarter of a billion clinical cases and more than 600,000 deaths in 2022. There has been significant progress toward vaccine development, however, poor efficacy of approved vaccines requiring multiple immunizing doses emphasizes the need for continued efforts toward improved vaccines. Progress to date, nonetheless, has provided impetus for malaria elimination. AREAS COVERED: In this review we will focus on diverse immune mechanisms targeting gametocytes in the human host and gametocyte-mediated malaria transmission via the mosquito vector. EXPERT OPINION: To march toward the goal of malaria elimination it will be critical to target the process of malaria transmission by mosquitoes, mediated exclusively by the sexual stages, i.e. male, and female gametocytes, ingested from infected vertebrate host. Studies over several decades have established antigens in the parasite sexual stages developing in the mosquito midgut as attractive targets for the development of transmission blocking vaccines (TBVs). Immune clearance of gametocytes in the vertebrate host can synergize with TBVs and directly aid in maintaining effective transmission reducing immune potential.
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Vacunas contra la Malaria , Malaria , Mosquitos Vectores , Desarrollo de Vacunas , Humanos , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Animales , Malaria/prevención & control , Malaria/transmisión , Malaria/inmunología , Malaria/parasitología , Mosquitos Vectores/parasitología , Mosquitos Vectores/inmunología , Plasmodium/inmunologíaRESUMEN
BACKGROUND: The World Health Organization novel malaria vaccine for at-risk children has the potential to greatly reduce the current malaria burden in sub-Saharan Africa. However, most studies have reported contradictory findings regarding community willingness for the vaccine, which could easily undermine the expected benefits of the vaccine. This study aims to ascertain the current state of community readiness and acceptance for the implementation of a novel malaria vaccine (RTS,S/ASO1) among at-risk children in sub-Saharan Africa, based on available evidence. METHODS: This study will follow the Preferred Reporting Items for Systematic Reviews and Meta-analyses protocol (PRISMA-P) guidelines. Relevant studies will be comprehensively searched from PubMed, ScienceDirect, Web of Science, Google Scholar, and African journals online, in accordance with the Cochrane search guidelines. Two independent reviewers will screen titles, abstracts and full texts of eligible studies based on some specified eligibility criteria. When it is feasible to conduct a meta-analysis, a random effects model will be employed to estimate the common effect due to anticipated high heterogeneity of the data. The effect measure for readiness or acceptance will be reported as a pooled proportion with corresponding 95% confidence interval. Additionally, odds ratios with 95% confidence interval will be estimated to assess factors associated with readiness. These will be presented on a forest plot. DISSEMINATION PLANS: The findings of the study will be peer-reviewed and published in a scientific journal. Conference presentations will also be made to the different stakeholders in the malaria vaccination campaigns. SYSTEMATIC REVIEW REGISTRATION: The protocol has been registered with PROSPERO Registration Number: CRD42023480528.
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Vacunas contra la Malaria , Revisiones Sistemáticas como Asunto , África del Sur del Sahara , Vacunas contra la Malaria/administración & dosificación , Humanos , Malaria/prevención & control , Niño , Preescolar , Aceptación de la Atención de Salud/estadística & datos numéricos , Aceptación de la Atención de Salud/psicologíaRESUMEN
Malaria remains an endemic public health concern in Africa, significantly contributing to morbidity and mortality rates. The inadequacies of traditional prevention measures, like integrated vector management and antimalarial drugs, have spurred efforts to strengthen the development and deployment of malaria vaccines. In addition to existing interventions like insecticide-treated bed nets and artemisinin-based combination therapies, malaria vaccine introduction and implementation in Africa could drastically reduce the disease burden and hasten steps toward malaria elimination. The malaria vaccine rollout is imminent as optimistic results from final clinical trials are anticipated. Thus, determining potential hurdles to malaria vaccine delivery and uptake in malaria-endemic regions of sub-Saharan Africa will enhance decisions and policymakers' preparedness to facilitate efficient and equitable vaccine delivery. A multisectoral approach is recommended to increase funding and resources, active community engagement and participation, and the involvement of healthcare providers.
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Vacunas contra la Malaria , Malaria , Humanos , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/uso terapéutico , Malaria/prevención & control , África/epidemiología , Vacunación , África del Sur del Sahara/epidemiologíaRESUMEN
The Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) is the World Health Organization's key standing advisory body to conduct an independent review of research, particularly of transmission and economic modeling analyses that estimate the impact and value of vaccines. From 26th February-1st March 2024, at its first of two semi-annual meetings, IVIR-AC provided feedback and recommendations across four sessions; this report summarizes the proceedings and recommendations from that meeting. Session topics included modeling of the impact and cost-effectiveness of the R21/Matrix-M malaria vaccine, meta-analysis of economic evaluations of vaccines, a global analysis estimating the impact of vaccination over the last 50 years, and modeling the impact of different RTS,S malaria vaccine dose schedules in seasonal settings.
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Comités Consultivos , Vacunas contra la Malaria , Organización Mundial de la Salud , Humanos , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/inmunología , Análisis Costo-Beneficio , Vacunación/métodos , Malaria/prevención & control , Inmunización/métodosRESUMEN
Vaccination of malaria-naive volunteers with a high dose of Plasmodium falciparum sporozoites chemoattenuated by chloroquine (CQ) (PfSPZ-CVac [CQ]) has previously demonstrated full protection against controlled human malaria infection (CHMI). However, lower doses of PfSPZ-CVac [CQ] resulted in incomplete protection. This provides the opportunity to understand the immune mechanisms needed for better vaccine-induced protection by comparing individuals who were protected with those not protected. Using mass cytometry, we characterized immune cell composition and responses of malaria-naive European volunteers who received either lower doses of PfSPZ-CVac [CQ], resulting in 50% protection irrespective of the dose, or a placebo vaccination, with everyone becoming infected following CHMI. Clusters of CD4+ and γδ T cells associated with protection were identified, consistent with their known role in malaria immunity. Additionally, EMRA CD8+ T cells and CD56+CD8+ T cell clusters were associated with protection. In a cohort from a malaria-endemic area in Gabon, these CD8+ T cell clusters were also associated with parasitemia control in individuals with lifelong exposure to malaria. Upon stimulation with P. falciparum-infected erythrocytes, CD4+, γδ, and EMRA CD8+ T cells produced IFN-γ and/or TNF, indicating their ability to mediate responses that eliminate malaria parasites.
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Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Vacunas contra la Malaria , Malaria Falciparum , Plasmodium falciparum , Esporozoítos , Adolescente , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Antimaláricos/uso terapéutico , Antimaláricos/administración & dosificación , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Cloroquina/uso terapéutico , Cloroquina/farmacología , Europa (Continente) , Pueblo Europeo , Gabón , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Malaria Falciparum/inmunología , Malaria Falciparum/prevención & control , Parasitemia/inmunología , Plasmodium falciparum/inmunología , Esporozoítos/inmunología , Vacunación/métodos , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Pueblo CentroafricanoRESUMEN
Among Plasmodium spp. responsible for human malaria, Plasmodium vivax ranks as the second most prevalent and has the widest geographical range; however, vaccine development has lagged behind that of Plasmodium falciparum, the deadliest Plasmodium species. Recently, we developed a multistage vaccine for P. falciparum based on a heterologous prime-boost immunization regimen utilizing the attenuated vaccinia virus strain LC16m8Δ (m8Δ)-prime and adeno-associated virus type 1 (AAV1)-boost, and demonstrated 100% protection and more than 95% transmission-blocking (TB) activity in the mouse model. In this study, we report the feasibility and versatility of this vaccine platform as a P. vivax multistage vaccine, which can provide 100% sterile protection against sporozoite challenge and >95% TB efficacy in the mouse model. Our vaccine comprises m8Δ and AAV1 viral vectors, both harboring the gene encoding two P. vivax circumsporozoite (PvCSP) protein alleles (VK210; PvCSP-Sal and VK247; -PNG) and P25 (Pvs25) expressed as a Pvs25-PvCSP fusion protein. For protective efficacy, the heterologous m8Δ-prime/AAV1-boost immunization regimen showed 100% (short-term; Day 28) and 60% (long-term; Day 242) protection against PvCSP VK210 transgenic Plasmodium berghei sporozoites. For TB efficacy, mouse sera immunized with the vaccine formulation showed >75% TB activity and >95% transmission reduction activity by a direct membrane feeding assay using P. vivax isolates in blood from an infected patient from the Brazilian Amazon region. These findings provide proof-of-concept that the m8Δ/AAV1 vaccine platform is sufficiently versatile for P. vivax vaccine development. Future studies are needed to evaluate the safety, immunogenicity, vaccine efficacy, and synergistic effects on protection and transmission blockade in a non-human primate model for Phase I trials.
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Dependovirus , Vectores Genéticos , Vacunas contra la Malaria , Malaria Vivax , Plasmodium vivax , Animales , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Plasmodium vivax/inmunología , Plasmodium vivax/genética , Malaria Vivax/prevención & control , Malaria Vivax/transmisión , Malaria Vivax/inmunología , Ratones , Dependovirus/genética , Dependovirus/inmunología , Femenino , Proteínas Protozoarias/inmunología , Proteínas Protozoarias/genética , Anticuerpos Antiprotozoarios/inmunología , Anticuerpos Antiprotozoarios/sangre , Modelos Animales de Enfermedad , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Humanos , Ratones Endogámicos BALB C , Inmunización Secundaria , Eficacia de las VacunasRESUMEN
BACKGROUND: The newly developed malaria vaccine called "R21/Matrix-M malaria vaccine" showed a high safety and efficacy level, and Ghana is the first country to approve this new vaccine. The present study aimed to evaluate the rate of vaccine hesitancy (VH) towards the newly developed malaria vaccine among parents who currently have children who are not eligible for the vaccine but may be eligible in the near future. Additionally, the study aimed to identify the factors that could potentially influence VH. METHODS: A cross-sectional survey using both online-based questionnaires and face-to-face interviews was conducted in Ghana from June to August 2023. The survey specifically targeted parents of ineligible children for vaccination, including those aged less than 5 months or between 3 and 12 years. The Parent Attitudes about Childhood Vaccination (PACV) scale was used to assess parental VH. RESULTS: A total of 765 people participated in this study. Their median age was 36.0 years with an interquartile range of 31.0-41.0 years, 67.7% were females, 41.8% completed their tertiary education, 63.3% were married, 81.6% worked in non-healthcare sectors, and 59.7% reported that their monthly income was insufficient. About one-third (34.5%) of the parents were hesitant to give their children the R21/Matrix-M malaria vaccine. The following predictors were associated with VH: working in the healthcare sector (adjusted odds ratio (AOR) = 0.50; 95% confidence interval (CI) 0.30-0.80; p = 0.005), having the other parent working in the healthcare sector (AOR = 0.54; 95% CI 0.30-0.94; p = 0.034), and not taking scheduled routine vaccinations (AOR = 1.90; 95% CI 1.27-2.84; p = 0.002). CONCLUSIONS: Addressing VH is crucial for optimizing R21/Matrix-M vaccine coverage in Ghana's malaria control strategy. By tackling VH issues, Ghana can effectively safeguard children's health in malaria-prone areas.
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Vacunas contra la Malaria , Padres , Humanos , Ghana , Estudios Transversales , Femenino , Masculino , Vacunas contra la Malaria/administración & dosificación , Adulto , Padres/psicología , Preescolar , Niño , Vacilación a la Vacunación/estadística & datos numéricos , Vacilación a la Vacunación/psicología , Lactante , Encuestas y Cuestionarios , Vacunación/estadística & datos numéricos , Vacunación/psicología , Malaria/prevención & control , Persona de Mediana EdadRESUMEN
A malaria vaccine represents an essential complementary tool to curb the stagnation, or even increase, in malaria cases observed over the last decade due to the emergence of resistance to insecticides impregnated on mosquito nets, wars and internal conflicts, as well as global warming. In October 2021, WHO recommended the use of the RTS,S/ASO1 vaccine for children aged 5-17 months in areas of moderate to high transmission. In October 2023, a second vaccine received WHO approval for deployment in the same population, following demonstration of around 70 % efficacy in protecting young children against malaria for one year. Given their partial efficacy, however, these vaccines are not generally recommended for travelers to endemic countries.
Un vaccin contre le paludisme représente une mesure complémentaire essentielle pour juguler la stagnation, voire l'augmentation des cas de paludisme observée durant cette dernière décade en raison de l'émergence de la résistance aux insecticides imprégnés sur les moustiquaires, des guerres et conflits internes ainsi que du réchauffement climatique. En octobre 2021, l'OMS a recommandé l'emploi du vaccin RTS,S/ASO1 pour les enfants de 5 à 17 mois dans les zones de transmission modérée à forte. En octobre 2023, un second vaccin a reçu l'aval de l'OMS pour son déploiement dans la même population, suite à la démonstration d'une efficacité d'environ 70 % pour protéger les jeunes enfants contre le paludisme pendant une année. Vu leur efficacité partielle, ces vaccins ne sont cependant généralement pas recommandés pour les voyageurs se rendant dans les pays d'endémie.
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Vacunas contra la Malaria , Malaria , Humanos , Vacunas contra la Malaria/administración & dosificación , Malaria/prevención & control , Organización Mundial de la Salud , Lactante , Erradicación de la Enfermedad/métodos , Erradicación de la Enfermedad/organización & administraciónRESUMEN
In October 2021, the WHO recommended the world's first malaria vaccine-RTS,S/AS01-to prevent malaria in children living in areas with moderate-to-high transmission in sub-Saharan Africa (SSA). A second malaria vaccine, R21/Matrix-M, was recommended for use in October 2023 and added to the WHO list of prequalified vaccines in December 2023. This study analysis assessed the country status of implementation and delivery strategies for RTS,S/AS01 by searching websites for national malaria policies, guidelines and related documents. Direct contact with individuals working in malaria programmes was made to obtain documents not publicly available. 10 countries had documents with information relating to malaria vaccine implementation, 7 referencing RTS,S/AS01 and 3 (Burkina Faso, Kenya and Nigeria) referencing RTS,S/AS01 and R21/Matrix-M. Five other countries reported plans for malaria vaccine roll-out without specifying which vaccine. Ghana, Kenya and Malawi, which piloted RTS,S/AS01, have now integrated the vaccine into routine immunisation services. Cameroon and Burkina Faso are the first countries outside the pilot countries to incorporate the vaccine into national immunisation services. Uganda plans a phased RTS,S/AS01 introduction, while Guinea plans to first pilot RTS,S/AS01 in five districts. The RTS,S/AS01 schedule varied by country, with the first dose administered at 5 or 6 months in all countries but the fourth dose at either 18, 22 or 24 months. SSA countries have shown widespread interest in rolling out the malaria vaccine, the Global Alliance for Vaccines and Immunization having approved financial support for 20 of 30 countries which applied as of March 2024. Limited availability of RTS,S/AS01 means that some approved countries will not receive the required doses. Vaccine availability and equity must be addressed even as R21/Matrix-M becomes available.
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Vacunas contra la Malaria , Organización Mundial de la Salud , Humanos , Vacunas contra la Malaria/administración & dosificación , África del Sur del Sahara , Malaria/prevención & control , Programas de Inmunización , Política de SaludRESUMEN
BACKGROUND: The RTS,S/AS01E malaria vaccine (RTS,S) was introduced by national immunisation programmes in Ghana, Kenya, and Malawi in 2019 in large-scale pilot schemes. We aimed to address questions about feasibility and impact, and to assess safety signals that had been observed in the phase 3 trial that included an excess of meningitis and cerebral malaria cases in RTS,S recipients, and the possibility of an excess of deaths among girls who received RTS,S than in controls, to inform decisions about wider use. METHODS: In this prospective evaluation, 158 geographical clusters (66 districts in Ghana; 46 sub-counties in Kenya; and 46 groups of immunisation clinic catchment areas in Malawi) were randomly assigned to early or delayed introduction of RTS,S, with three doses to be administered between the ages of 5 months and 9 months and a fourth dose at the age of approximately 2 years. Primary outcomes of the evaluation, planned over 4 years, were mortality from all causes except injury (impact), hospital admission with severe malaria (impact), hospital admission with meningitis or cerebral malaria (safety), deaths in girls compared with boys (safety), and vaccination coverage (feasibility). Mortality was monitored in children aged 1-59 months throughout the pilot areas. Surveillance for meningitis and severe malaria was established in eight sentinel hospitals in Ghana, six in Kenya, and four in Malawi. Vaccine uptake was measured in surveys of children aged 12-23 months about 18 months after vaccine introduction. We estimated that sufficient data would have accrued after 24 months to evaluate each of the safety signals and the impact on severe malaria in a pooled analysis of the data from the three countries. We estimated incidence rate ratios (IRRs) by comparing the ratio of the number of events in children age-eligible to have received at least one dose of the vaccine (for safety outcomes), or age-eligible to have received three doses (for impact outcomes), to that in non-eligible age groups in implementation areas with the equivalent ratio in comparison areas. To establish whether there was evidence of a difference between girls and boys in the vaccine's impact on mortality, the female-to-male mortality ratio in age groups eligible to receive the vaccine (relative to the ratio in non-eligible children) was compared between implementation and comparison areas. Preliminary findings contributed to WHO's recommendation in 2021 for widespread use of RTS,S in areas of moderate-to-high malaria transmission. FINDINGS: By April 30, 2021, 652â673 children had received at least one dose of RTS,S and 494â745 children had received three doses. Coverage of the first dose was 76% in Ghana, 79% in Kenya, and 73% in Malawi, and coverage of the third dose was 66% in Ghana, 62% in Kenya, and 62% in Malawi. 26â285 children aged 1-59 months were admitted to sentinel hospitals and 13â198 deaths were reported through mortality surveillance. Among children eligible to have received at least one dose of RTS,S, there was no evidence of an excess of meningitis or cerebral malaria cases in implementation areas compared with comparison areas (hospital admission with meningitis: IRR 0·63 [95% CI 0·22-1·79]; hospital admission with cerebral malaria: IRR 1·03 [95% CI 0·61-1·74]). The impact of RTS,S introduction on mortality was similar for girls and boys (relative mortality ratio 1·03 [95% CI 0·88-1·21]). Among children eligible for three vaccine doses, RTS,S introduction was associated with a 32% reduction (95% CI 5-51%) in hospital admission with severe malaria, and a 9% reduction (95% CI 0-18%) in all-cause mortality (excluding injury). INTERPRETATION: In the first 2 years of implementation of RTS,S, the three primary doses were effectively deployed through national immunisation programmes. There was no evidence of the safety signals that had been observed in the phase 3 trial, and introduction of the vaccine was associated with substantial reductions in hospital admission with severe malaria. Evaluation continues to assess the impact of four doses of RTS,S. FUNDING: Gavi, the Vaccine Alliance; the Global Fund to Fight AIDS, Tuberculosis and Malaria; and Unitaid.
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Estudios de Factibilidad , Programas de Inmunización , Vacunas contra la Malaria , Malaria Cerebral , Humanos , Ghana/epidemiología , Malaui/epidemiología , Lactante , Femenino , Kenia/epidemiología , Vacunas contra la Malaria/administración & dosificación , Vacunas contra la Malaria/efectos adversos , Masculino , Preescolar , Malaria Cerebral/epidemiología , Malaria Cerebral/mortalidad , Estudios Prospectivos , Malaria Falciparum/prevención & control , Malaria Falciparum/epidemiología , Meningitis/epidemiología , Meningitis/prevención & controlRESUMEN
BACKGROUND: The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibodies that block parasite development in the mosquito and mosquitoes becoming infectious. The Pfs48/45 protein is a leading Plasmodium falciparum transmission-blocking vaccine candidate. The R0.6C fusion protein, consisting of Pfs48/45 domain 3 (6C) and the N-terminal region of P. falciparum glutamate-rich protein (R0), has previously been produced in Lactococcus lactis and elicited functional antibodies in rodents. Here, we assess the safety and transmission-reducing efficacy of R0.6C adsorbed to aluminium hydroxide with and without Matrix-M™ adjuvant in humans. METHODS: In this first-in-human, open-label clinical trial, malaria-naïve adults, aged 18-55 years, were recruited at the Radboudumc in Nijmegen, the Netherlands. Participants received four intramuscular vaccinations on days 0, 28, 56 and 168 with either 30 µg or 100 µg of R0.6C and were randomised for the allocation of one of the two different adjuvant combinations: aluminium hydroxide alone, or aluminium hydroxide combined with Matrix-M1™ adjuvant. Adverse events were recorded from inclusion until 84 days after the fourth vaccination. Anti-R0.6C and anti-6C IgG titres were measured by enzyme-linked immunosorbent assay. Transmission-reducing activity of participants' serum and purified vaccine-specific immunoglobulin G was assessed by standard membrane feeding assays using laboratory-reared Anopheles stephensi mosquitoes and cultured P. falciparum gametocytes. RESULTS: Thirty-one participants completed four vaccinations and were included in the analysis. Administration of all doses was safe and well-tolerated, with one related grade 3 adverse event (transient fever) and no serious adverse events occurring. Anti-R0.6C and anti-6C IgG titres were similar between the 30 and 100 µg R0.6C arms, but higher in Matrix-M1™ arms. Neat participant sera did not induce significant transmission-reducing activity in mosquito feeding experiments, but concentrated vaccine-specific IgGs purified from sera collected two weeks after the fourth vaccination achieved up to 99% transmission-reducing activity. CONCLUSIONS: R0.6C/aluminium hydroxide with or without Matrix-M1™ is safe, immunogenic and induces functional Pfs48/45-specific transmission-blocking antibodies, albeit at insufficient serum concentrations to result in transmission reduction by neat serum. Future work should focus on identifying alternative vaccine formulations or regimens that enhance functional antibody responses. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov under identifier NCT04862416.
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Vacunas contra la Malaria , Malaria Falciparum , Glicoproteínas de Membrana , Plasmodium falciparum , Proteínas Protozoarias , Adolescente , Adulto , Animales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Adyuvantes Inmunológicos/administración & dosificación , Hidróxido de Aluminio/administración & dosificación , Anticuerpos Antiprotozoarios , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Malaria Falciparum/prevención & control , Malaria Falciparum/transmisión , Malaria Falciparum/inmunología , Países Bajos , Plasmodium falciparum/inmunología , Proteínas Protozoarias/inmunologíaRESUMEN
RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. To mitigate the risk of cerebral malaria (CM) among children under the age of 5, it is imperative to develop new vaccines. EVs are potential vaccine candidates as they obtain the ability of brain-targeted delivery and transfer plasmodium antigens and immunomodulators during infections. This study extracted EVs from BALB/c mice infected with Plasmodium yoelii 17XNL (P.y17XNL). C57BL/6J mice were intravenously immunized with EVs (EV-I.V. + CM group) or subcutaneously vaccinated with the combination of EVs and CpG ODN-1826 (EV + CPG ODN-S.C. + CM group) on days 0 and 20, followed by infection with Plasmodium berghei ANKA (P.bANKA) on day 20 post-second immunization. We monitored Parasitemia and survival rate. The integrity of the Blood-brain barrier (BBB) was examined using Evans blue staining.The levels of cytokines and adhesion molecules were evaluated using Luminex, RT-qPCR, and WB. Brain pathology was evaluated by hematoxylin and eosin and immunohistochemical staining. The serum levels of IgG, IgG1, and IgG2a were analyzed by enzyme-linked immunosorbent assay. Compared with those in the P.bANKA-infected group, parasitemia increased slowly, death was delayed (day 10 post-infection), and the survival rate reached 75 %-83.3 % in the EV-I.V. + ECM and EV + CPG ODN-S.C. + ECM groups. Meanwhile, compared with the EV + CPG ODN-S.C. + ECM group, although parasitemia was almost the same, the survival rate increased in the EV-I.V. + ECM group.Additionally, EVs immunization markedly downregulated inflammatory responses in the spleen and brain and ameliorated brain pathological changes, including BBB disruption and infected red blood cell (iRBC) sequestration. Furthermore, the EVs immunization group exhibited enhanced antibody responses (upregulation of IgG1 and IgG2a production) compared to the normal control group. EV immunization exerted protective effects, improving the integrity of the BBB, downregulating inflammation response of brain tissue, result in reduces the incidence of CM. The protective effects were determined by immunological pathways and brain targets elicited by EVs. Intravenous immunization exhibited better performance than subcutaneous immunization, which perhaps correlated with EVs, which can naturally cross BBB to play a better role in brain protection.
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Barrera Hematoencefálica , Eritrocitos , Vesículas Extracelulares , Malaria Cerebral , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Oligodesoxirribonucleótidos , Plasmodium berghei , Animales , Malaria Cerebral/inmunología , Malaria Cerebral/parasitología , Malaria Cerebral/prevención & control , Plasmodium berghei/inmunología , Vesículas Extracelulares/inmunología , Eritrocitos/parasitología , Eritrocitos/inmunología , Barrera Hematoencefálica/inmunología , Ratones , Oligodesoxirribonucleótidos/administración & dosificación , Vacunas contra la Malaria/inmunología , Vacunas contra la Malaria/administración & dosificación , Femenino , Encéfalo/parasitología , Encéfalo/inmunología , Encéfalo/patología , Citocinas/metabolismo , Citocinas/sangre , Plasmodium yoelii/inmunología , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Parasitemia/inmunología , Modelos Animales de Enfermedad , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunologíaRESUMEN
BACKGROUND: There are giant steps taken in the introduction of the novel malaria vaccine poised towards reducing mortality and morbidity associated with malaria. OBJECTIVES: This study aimed to determine the knowledge of malaria vaccine and factors militating against willingness to accept the vaccine among mothers presenting in nine hospitals in Enugu metropolis. METHODS: This was a cross-sectional study carried out among 491 mothers who presented with their children in nine hospitals in Enugu metropolis, South-East Nigeria. A pre-tested and interviewer-administered questionnaire was used in this study. RESULTS: A majority of the respondents, 72.1% were aware of malaria vaccine. A majority of the respondents, 83.1% were willing to receive malaria vaccine. Similarly, a majority of the mothers, 92.9%, were willing to vaccinate baby with the malaria vaccine, while 81.1% were willing to vaccinate self and baby with the malaria vaccine. The subjects who belong to the low socio-economic class were five times less likely to vaccinate self and baby with malaria vaccine when compared with those who were in the high socio-economic class (AOR = 0.2, 95% CI 0.1-0.5). Mothers who had good knowledge of malaria vaccination were 3.3 times more likely to vaccinate self and baby with malaria vaccine when compared with those who had poor knowledge of malaria vaccination (AOR = 3.3, 95% CI 1-6-6.8). CONCLUSION: Although the study documented a high vaccine acceptance among the mothers, there exists a poor knowledge of the malaria vaccine among them.