Abstract
BackgroundTraditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question.MethodologyWe conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4+/CD8+ phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro.ConclusionsChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection.Trial RegistrationClinicalTrials.gov NCT01095055
Highlights
An effective vaccine against the blood-stage of Plasmodium falciparum infection could significantly contribute to any future strategy for reducing malaria morbidity and mortality, limiting transmission and aiding disease eradication [1]
chimpanzee adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection
Despite these extensive efforts to date, no candidate blood-stage vaccine has been developed that has demonstrated statistically significant efficacy with regard to clinical outcome in a pre-specified primary endpoint analysis in a Phase IIa/b clinical trial designed to assess vaccine efficacy [3,8]. The majority of such blood-stage vaccine candidates have traditionally focused on recombinant protein-inadjuvant formulations with the aim of inducing growth inhibitory antibody responses against merozoite antigens involved in the erythrocyte invasion process [3]
Summary
An effective vaccine against the blood-stage of Plasmodium falciparum infection could significantly contribute to any future strategy for reducing malaria morbidity and mortality, limiting transmission and aiding disease eradication [1]. Significant strainspecific efficacy was recently reported in a pre-specified secondary analysis of a Phase IIb trial of a mono-valent 3D7 strain apical membrane antigen 1 (AMA1) protein vaccine [6] Of note, this vaccine showed an encouraging signal in a prior Phase IIa controlled human malaria infection study [7]. This vaccine showed an encouraging signal in a prior Phase IIa controlled human malaria infection study [7] Despite these extensive efforts to date, no candidate blood-stage vaccine has been developed that has demonstrated statistically significant efficacy with regard to clinical outcome in a pre-specified primary endpoint analysis in a Phase IIa/b clinical trial designed to assess vaccine efficacy [3,8].
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