Adenovirus 5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part A: Safety and Immunogenicity in Seronegative Adults

Abstract

BackgroundModels of immunity to malaria indicate the importance of CD8+ T cell responses for targeting intrahepatic stages and antibodies for targeting sporozoite and blood stages. We designed a multistage adenovirus 5 (Ad5)-vectored Plasmodium falciparum malaria vaccine, aiming to induce both types of responses in humans, that was tested for safety and immunogenicity in a Phase 1 dose escalation trial in Ad5-seronegative volunteers.Methodology/Principal FindingsThe NMRC-M3V-Ad-PfCA vaccine combines two adenovectors encoding circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1). Group 1 (n = 6) healthy volunteers received one intramuscular injection of 2×10∧10 particle units (1×10∧10 each construct) and Group 2 (n = 6) a five-fold higher dose. Transient, mild to moderate adverse events were more pronounced with the higher dose. ELISpot responses to CSP and AMA1 peaked at 1 month, were higher in the low dose (geomean CSP = 422, AMA1 = 862 spot forming cells/million) than in the high dose (CSP = 154, p = 0.049, AMA1 = 423, p = 0.045) group and were still positive at 12 months in a number of volunteers. ELISpot depletion assays identified dependence on CD4+ or on both CD4+ and CD8+ T cells, with few responses dependent only on CD8+ T cells. Intracellular cytokine staining detected stronger CD8+ than CD4+ T cell IFN-γ responses (CSP p = 0.0001, AMA1 p = 0.003), but similar frequencies of multifunctional CD4+ and CD8+ T cells secreting two or more of IFN-γ, TNF-α or IL-2. Median fluorescence intensities were 7–10 fold higher in triple than single secreting cells. Antibody responses were low but trended higher in the high dose group and did not inhibit growth of cultured P. falciparum blood stage parasites.SignificanceAs found in other trials, adenovectored vaccines appeared safe and well-tolerated at doses up to 1×10∧11 particle units. This is the first demonstration in humans of a malaria vaccine eliciting strong CD8+ T cell IFN-γ responses.Trial Registration ClinicalTrials.gov NCT00392015

Immunogenicity of a Prime-Boost Vaccine Containing the Circumsporozoite Proteins of Plasmodium vivax in Rodents

“…The results obtained with the mouse model have fueled a number of human trials with plasmid DNA, recombinant viruses, and, more recently, radiation-attenuated sporozoites as vaccine formulations. Unfortunately, in spite of the enthusiasm generated by the mouse model, T cell-based vaccines against preerythrocytic stages of malaria have provided sterile immunity against infection with P. falciparum to only a few vaccinated individuals to date (39)(40)(41)(42)(43)(44). The precise reason for this failure is not clear.…”

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

“…This heterologous prime-boost approach has shown antibody induction against difficult-to-express malaria antigens in numerous animal models, including nonhuman primates (32,34,35). These vectors, delivering antigens from P. falciparum, have now been shown to be safe and immunogenic for T cell and antibodies in healthy European and American adult volunteers (36)(37)(38)(39)(40), as well as African adults, children, and infants (41,42). More recently, similar adenovirus-poxvirus vectored vaccine technologies have been used to immunize humans against numerous other pathogens including P. vivax malaria (43), Ebola virus (44), hepatitis C virus (HCV) (45), respiratory syncytial virus (RSV) (46) and HIV-1 (47).…”

Immunization with Apical Membrane Antigen 1 Confers Sterile Infection-Blocking Immunity against Plasmodium Sporozoite Challenge in a Rodent Model

“…Most recently, a two-component adenovirus-vectored vaccine consisting of one adenovector encoding the P. falciparum CSP protein and one encoding AMA-1 induced moderate T cell IFN-␥ responses against both antigens but only low antibody responses, with no growthinhibitory activity. However, the protective efficacy of the combination or of the AMA-1 component alone was not assessed (50).…”