Clinical Assessment of a Recombinant Simian Adenovirus ChAd63: A Potent New Vaccine Vector

Abstract

Background. Vaccine development in human Plasmodium falciparum malaria has been hampered by the exceptionally high levels of CD8+ T cells required for efficacy. Use of potently immunogenic human adenoviruses as vaccine vectors could overcome this problem, but these are limited by preexisting immunity to human adenoviruses.Methods. From 2007 to 2010, we undertook a phase I dose and route finding study of a new malaria vaccine, a replication-incompetent chimpanzee adenovirus 63 (ChAd63) encoding the preerythrocytic insert multiple epitope thrombospondin-related adhesion protein (ME-TRAP; n = 54 vaccinees) administered alone (n = 28) or with a modified vaccinia virus Ankara (MVA) ME-TRAP booster immunization 8 weeks later (n = 26). We observed an excellent safety profile. High levels of TRAP antigen–specific CD8+ and CD4+ T cells, as detected by interferon γ enzyme-linked immunospot assay and flow cytometry, were induced by intramuscular ChAd63 ME-TRAP immunization at doses of 5 × 1010 viral particles and above. Subsequent administration of MVA ME-TRAP boosted responses to exceptionally high levels, and responses were maintained for up to 30 months postvaccination.Conclusions. The ChAd63 chimpanzee adenovirus vector appears safe and highly immunogenic, providing a viable alternative to human adenoviruses as vaccine vectors for human use.Clinical Trials Registration. NCT00890019.

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

“…No data on cellular responses to this antigen have been reported following natural P. falciparum infection; however, given that vaccination elicited peptide-restimulated responses spanning the entire RH5 sequence, the RH5_FL molecule does not appear to lack T cell epitopes. The kinetics and magnitude of the response were also similar to those previously reported following human vaccination with the same vectors encoding P. falciparum or P. vivax antigens (36)(37)(38)(39)43). Similarly, studies using chimpanzee adenovirus vectors followed by MVA boost (44,46,58) have routinely shown that a mixed antigen-specific CD4 + /CD8 + T cell response is induced in humans.…”

“…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).…”

Construction and Evaluation of Novel Rhesus Monkey Adenovirus Vaccine Vectors

“…ecombinant adenoviruses (Ads) are currently being explored as candidate vaccine vectors for multiple pathogens (1)(2)(3)(4)(5)(6), as a result of their safety profile, manufacturability, and ability to induce broad and strong immune responses (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Multiple human and chimpanzee adenovirus vectors have been developed to date (8,9,(11)(12)(13).…”

Pre-Erythrocytic Vaccine Candidates in Malaria

“…The recent addition of a chimpanzee adenovirus 63 (Ch"d63) for priming has provided encouraging results (see Table ). "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].…”