ChAd63-MVA–vectored Blood-stage Malaria Vaccines Targeting MSP1 and AMA1: Assessment of Efficacy Against Mosquito Bite Challenge in Humans

Abstract

The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets.

Assessment of Immune Interference, Antagonism, and Diversion following Human Immunization with Biallelic Blood-Stage Malaria Viral-Vectored Vaccines and Controlled Malaria Infection

“…Following malaria sporozoite infection, blood-stage merozoites are predicted to rupture out of the liver and enter the blood on days 6.5-7 postchallenge (dC+6.5 and dC+7). Median time to patent parasitemia was 10.8 d for both MSP1-and AMA1-vaccinated volunteers compared with 9.7 for the controls (26). Whereas PBMC samples assayed up to 150 d postchallenge (dC+150) showed some small but significant differences between the 3D7 and FVO allele-specific responses, there was no significant boosting of 3D7 AMA1-specific T cell responses.…”

“…1) (26). In all cases, the two Ags were separately delivered by a heterologous prime-boost immunization regimen consisting of a priming i.m.…”

“…with MVA vector (doses, 1.25-5 3 10 8 PFU) recombinant for the same Ag. All necessary regulatory and ethical approvals were granted as previously described (24)(25)(26), and the trials were registered with ClinicalTrials.gov. All volunteers gave written informed consent prior to participation, and the studies were conducted according to the principles of the Declaration of Helsinki and in accordance with Good Clinical Practice.…”

“…We explored this effect in the The Journal of Immunologycontext of a CHMI study, whereby immunized volunteers were experimentally exposed to five mosquito bites harboring infectious 3D7 clone P. falciparum sporozoites (26,44). All of the volunteers immunized with the MSP1 or AMA1 vaccines alone developed blood-stage malaria infection and were treated at the time of patency as diagnosed by thin blood film microscopy (26).…”

“…1). This regimen was shown to be safe and immunogenic for both Ab and T cell responses in healthy adult human volunteers and, when the vectors for both Ags were coadministered, sterilizing efficacy was observed in one of nine individuals against controlled human malaria infection (CHMI) with vaccine homologous P. falciparum 3D7 strain sporozoites (26).…”