Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B With Chimpanzee Adenovirus 63 and Modified Vaccinia Ankara Vectored Vaccines Expressing ME-TRAP

Malaria remains one of the leading causes of mortality globally [1], and there is urgent need for a vaccine. The majority of deaths are in children <5 years old, with this age group accounting for approximately 306 000 deaths in 2015. The enormous economic and social consequences of malaria have been well documented [2]. Efforts to develop effective vaccines are complicated by the complex immunology of malaria parasite infection, and no reliable natural model of complete immunity exists. Despite this, a small number of candidate vaccines have shown partial efficacy against experimental and natural human infection, with the current leading vaccine being the recombinant protein in adjuvant, RTS,S/AS01. RTS,S targets circumsporozoite protein (CS), which is expressed by the Plasmodium falciparum sporozoite at the preerythrocytic stage and was the first subunit vaccine to show high rates of sterile efficacy, typically 50%, in controlled human malaria infection (CHMI) studies [3]. In a large African phase 3 trial, this vaccine had an efficacy against clinical malaria of 55.8% (97.5% confidence interval [CI], 50.6%–60.4%) in children aged 5–17 months and 31.3% (23.6%–38.3%) in infants aged 6–12 weeks over the first year after vaccination [4, 5]. Vaccine efficacy wanes over time but can be enhanced by a fourth dose [6]. Analysis of the immunological correlates of efficacy of this vaccine suggest that vaccine-induced antibodies targeting CS are the most important mediators of RTS,S-induced protection against malaria [3], although no antibody level threshold has been shown to be predictive of efficacy. The rate at which anti-CS antibodies wane is similar to the rate at which efficacy declines [7, 8], suggesting that anti-CS antibodies may also be associated with the duration of protection. A number of factors, including age at vaccination, human immunodeficiency virus status, and high baseline anti-CS antibody titers influence anti-CS antibody titers after vaccination with RTS,S [9]. The preerythrocytic stage of P. falciparum infection presents an attractive target for an efficacious human vaccine because sufficient reduction in the number of viable merozoites reaching the blood from the liver will prevent parasitization of red blood cells and initiation of the symptomatic blood stage of infection. Anti-CS antibodies can target sporozoites for destruction prior to hepatocyte invasion. Because sporozoites travel from the skin to liver within minutes, it may be difficult for a vaccine to achieve complete protection against P. falciparum based solely on antibodies to sporozoites. The liver stage of infection provides a longer window of opportunity for cell-mediated immunity to recognize and destroy infected hepatocytes. Chimpanzee adenovirus 63 (ChAd63) with a multiepitope string fused to thrombospondin-related adhesion protein (ME-TRAP) insert and modified vaccinia virus Ankara (MVA) with the ME-TRAP insert are viral-vectored vaccines, and when they are administered in a prime-boost sequence at an 8-week interval, they are a leading candidate vaccine strategy targeting the liver stage of infection [10]. The ChAd63 and MVA viral vectors deliver the recombinant ME-TRAP insert, which generates a potent cellular immune response against the liver-stage P. falciparum antigen, TRAP, of greater magnitude than the cellular response induced by RTS,S/AS01. This strategy showed durable partial efficacy in 2 phase 2a sporozoite challenge trials in the United Kingdom [11, 12], using the 3D7 parasite as a challenge strain. The viral vector–encoded P. falciparum TRAP allele is from the heterologous T9/96 strain, and induced T-cell responses correlate with efficacy [11]. Therefore, these are effectively heterologous strain CHMI studies. Interestingly, a higher level of efficacy of 67% (95% CI, 33%–83%) against P. falciparum infections detected by polymerase chain reaction (PCR) was observed in a phase 2b trial in Kenyan adults [13]. Again, T cells to TRAP peptides correlated with vaccine efficacy, but the short duration of malaria transmission and follow-up at this trial site precluded analysis of the durability of vaccine-induced protection [13]. This heterologous prime-boost strategy showed potent cellular immunogenicity in adults in the United Kingdom [11], as well as adults and infants in malaria-endemic areas [13–15] (Ewer et al, unpublished data) and has an excellent track record of safety and tolerability in these populations. Analysis of the potential utility of combining antisporozoite and anti–liver-stage vaccines have suggested a likely additive or synergistic effect [16], in keeping with findings from preclinical studies [17, 18]. In this phase 1/2a, open-labeled, CHMI study, we assessed the safety, immunogenicity, and efficacy of a vaccine schedule combining these 2 distinct candidate vaccine types in a staggered immunization regimen: one that induces very high titer antibodies to CS, using RTS,S/AS01B, and another that induces potent T-cell responses to TRAP, using viral vectors.