Evaluation of the Efficacy of ChAd63-MVA Vectored Vaccines Expressing Circumsporozoite Protein and ME-TRAP Against Controlled Human Malaria Infection in Malaria-Naive Individuals

Abstract

Background. Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors simian adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the preerythrocytic antigen insert multiple epitope–thrombospondin-related adhesion protein (ME-TRAP). We hypothesized that ChAd63-MVA containing CS may result in a significant clinical protective efficacy.Methods. We conducted an open-label, 2-site, partially randomized Plasmodium falciparum sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP.Results. One of 15 vaccinees (7%) receiving ChAd63-MVA CS and 2 of 15 (13%) receiving ChAd63-MVA ME-TRAP achieved sterile protection after CHMI. Three of 15 vaccinees (20%) receiving ChAd63-MVA CS and 5 of 15 (33%) receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment, compared with unvaccinated controls. In quantitative polymerase chain reaction analyses, ChAd63-MVA CS was estimated to reduce the liver parasite burden by 69%–79%, compared with 79%–84% for ChAd63-MVA ME-TRAP.Conclusions. ChAd63-MVA CS does reduce the liver parasite burden, but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller but biologically important differences in vaccine efficacy that can influence future vaccine development.Clinical Trials Registration. NCT01623557.

Recent Developments in Malaria Vaccinology

“…More recent studies have assessed the efficacy of ChAd63-MVA vaccines encoding other candidate antigens in Phase I/IIa studies. The same vectors encoding CSP again showed lower efficacy than ME-TRAP, confirming the previous results observed with the FP9-MVA platform (Hodgson et al, 2015) and the US Navy's HAdV5 studies. ChAd63-MVA encoding the blood-stage antigens MSP1 and AMA1 were also tested by mosquito-bite CHMI, given evidence from pre-clinical mouse models that CD8 þ T cells against blood-stage antigens could reduce liver-stage parasite burden, due to the expression of these targets by the late liver-stage exo-erythrocytic forms (Draper et al, 2009) and evidence that AMA1 is expressed by sporozoites .…”

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

“…In line with such an effect of preexisting antisporozoite immunity would be the observation that those Tanzanian volunteers with a longer prepatancy by qPCR also had higher baseline antibody titers against the sporozoite antigen CSP. However, the first detection by qPCR in both the Dutch and Tanzanians after intradermal PfSPZ injection was uncharacteristically late compared to that for infection by mosquito bite routinely conducted in The Netherlands and elsewhere (11,16,18,19,23,24,35). This is likely due to less efficient liver-stage infection by this route and hence a low initial blood-stage load that reaches the qPCR detection limit only later.…”

“…CHMI trials have so far been performed in countries were malaria is not endemic in previously unexposed individuals (11,(16)(17)(18)(19). A logical next step is to study the potential differences in the acquisition, maintenance, or recall of immune responses in individuals from different transmission settings and genetic backgrounds (20,21).…”

Pre-Erythrocytic Vaccine Candidates in Malaria

“…"dCh63 priming elicits both CD + and CD8+ T cells at much higher levels than DN" or FP9 priming [211], and also results in a much higher proportion of IFN-γ-secreting monofunctional CD8+ T cells that were correlated to sterile protection [212]. This combination has provided protection from infection in malarianaive volunteers comparable to the immunity provided by CSP using the same delivery platform [212,213]. Further, ME-TR"P using the Ch"d63/MV" regimen elicited a strong immune response and provided signiicant protection in "fricans who had prior exposure to malaria [ 3,21 ].…”