Clinical assessment of a recombinant simian adenovirus ChAd63: a potent new vaccine vector
Geraldine A O'Hara, Christopher J A Duncan, Katie J Ewer, Katharine A Collins, Sean C Elias, Fenella D Halstead, Anna L Goodman, Nick J Edwards, Arturo Reyes-Sandoval, Prudence Bird, Rosalind Rowland, Susanne H Sheehy, Ian D Poulton, Claire Hutchings, Stephen Todryk, Laura Andrews, Antonella Folgori, Eleanor Berrie, Sarah Moyle, Alfredo Nicosia, Stefano Colloca, Riccardo Cortese, Loredana Siani, Alison M Lawrie, Sarah C Gilbert, Adrian V S Hill, Geraldine A O'Hara, Christopher J A Duncan, Katie J Ewer, Katharine A Collins, Sean C Elias, Fenella D Halstead, Anna L Goodman, Nick J Edwards, Arturo Reyes-Sandoval, Prudence Bird, Rosalind Rowland, Susanne H Sheehy, Ian D Poulton, Claire Hutchings, Stephen Todryk, Laura Andrews, Antonella Folgori, Eleanor Berrie, Sarah Moyle, Alfredo Nicosia, Stefano Colloca, Riccardo Cortese, Loredana Siani, Alison M Lawrie, Sarah C Gilbert, Adrian V S Hill
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 × 10(10) 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.
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References
- Crompton PD, Pierce SK, Miller LH. Advances and challenges in malaria vaccine development. J Clin Invest. 2010;120:4168–78.
- Nussenzweig RS, Vanderberg J, Most H, Orton C. Protective immunity produced by the injection of X-irradiated sporozoites of Plasmodium berghei. Nature. 1967;216:160–2.
- Khusmith S, Sedegah M, Hoffman SL. Complete protection against Plasmodium yoelii by adoptive transfer of a CD8+ cytotoxic T-cell clone recognizing sporozoite surface protein 2. Infect Immun. 1994;62:2979–83.
- Romero P, Maryanski JL, Corradin G, Nussenzweig RS, Nussenzweig V, Zavala F. Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature. 1989;341:323–6.
- Reyes-Sandoval A, Wyllie DH, Bauza K, et al. CD8+ T effector memory cells protect against liver-stage malaria. J Immunol. 2011;187:1347–57.
- Schmidt NW, Butler NS, Badovinac VP, Harty JT. Extreme CD8 T cell requirements for anti-malarial liver-stage immunity following immunization with radiation attenuated sporozoites. PLoS Pathog. 2010;6:e1000998.
- Hill AV, Reyes-Sandoval A, O’Hara G, et al. Prime-boost vectored malaria vaccines: progress and prospects. Hum Vaccin. 2010;6:78–83.
- Plebanski M, Gilbert SC, Schneider J, et al. Protection from Plasmodium berghei infection by priming and boosting T cells to a single class I-restricted epitope with recombinant carriers suitable for human use. Eur J Immunol. 1998;28:4345–55.
- Rollier CS, Reyes-Sandoval A, Cottingham MG, Ewer K, Hill AV. Viral vectors as vaccine platforms: deployment in sight. Curr Opin Immunol. 2011;23:377–82.
- Webster DP, Dunachie S, McConkey S, et al. Safety of recombinant fowlpox strain FP9 and modified vaccinia virus Ankara vaccines against liver-stage P. falciparum malaria in non-immune volunteers. Vaccine. 2006;24:3026–34.
- Bejon P, Andrews L, Andersen RF, et al. Calculation of liver-to-blood inocula, parasite growth rates, and preerythrocytic vaccine efficacy, from serial quantitative polymerase chain reaction studies of volunteers challenged with malaria sporozoites. J Infect Dis. 2005;191:619–26.
- Buchbinder SP, Mehrotra DV, Duerr A, et al. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial. Lancet. 2008;372:1881–93.
- Tatsis N, Ertl HC. Adenoviruses as vaccine vectors. Mol Ther. 2004;10:616–29.
- Dudareva M, Andrews L, Gilbert SC, et al. Prevalence of serum neutralizing antibodies against chimpanzee adenovirus 63 and human adenovirus 5 in Kenyan children, in the context of vaccine vector efficacy. Vaccine. 2009;27:3501–4.
- Reyes-Sandoval A, Sridhar S, Berthoud T, et al. Single-dose immunogenicity and protective efficacy of simian adenoviral vectors against Plasmodium berghei. Eur J Immunol. 2008;38:732–41.
- Capone S, Reyes-Sandoval A, Naddeo M, et al. Immune responses against a liver-stage malaria antigen induced by simian adenoviral vector AdCh63 and MVA prime-boost immunization in non-human primates. Vaccine. 2010;29:256–65.
- Bejon P, Ogada E, Mwangi T, et al. Extended follow-up following a phase 2b randomized trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya. PLoS One. 2007;2:e707.
- Dunachie SJ, Walther M, Epstein JE, et al. A DNA prime-modified vaccinia virus Ankara boost vaccine encoding thrombospondin-related adhesion protein but not circumsporozoite protein partially protects healthy malaria-naive adults against Plasmodium falciparum sporozoite challenge. Infect Immun. 2006;74:5933–42.
- Keating SM, Bejon P, Berthoud T, et al. Durable human memory T cells quantifiable by cultured enzyme-linked immunospot assays are induced by heterologous prime boost immunization and correlate with protection against malaria. J Immunol. 2005;175:5675–80.
- Ledgerwood JE, Costner P, Desai N, et al. A replication defective recombinant Ad5 vaccine expressing Ebola virus GP is safe and immunogenic in healthy adults. Vaccine. 2010;29:304–13.
- Peiperl L, Morgan C, Moodie Z, et al. Safety and immunogenicity of a replication-defective adenovirus type 5 HIV vaccine in Ad5-seronegative persons: a randomized clinical trial (HVTN 054) PLoS One. 2010;5:e13579.
- Webster D, Dunachie S, McConkey S, et al. Safety of recombinant fowlpox strain 9 and modified vaccinia virus Ankara vaccines against liver-stage P. falciparum malaria non-immune volunteers. Vaccine. 2005:3026–34.
- Moorthy VS, Imoukhuede EB, Milligan P, et al. A randomised, double-blind, controlled vaccine efficacy trial of DNA/MVA ME-TRAP against malaria infection in Gambian adults. PLoS Med. 2004;1:e33.
- Bejon P, Mwacharo J, Kai O, et al. A phase 2b randomised trial of the candidate malaria vaccines FP9 ME-TRAP and MVA ME-TRAP among children in Kenya. PLoS Clin Trials. 2006;1:e29.
- Webster DP, Dunachie S, Vuola JM, et al. Enhanced T cell-mediated protection against malaria in human challenges by using the recombinant poxviruses FP9 and modified vaccinia virus Ankara. Proc Natl Acad Sci USA. 2005;102:4836–41.
- Asmuth DM, Brown EL, DiNubile MJ, et al. Comparative cell-mediated immunogenicity of DNA/DNA, DNA/adenovirus type 5 (Ad5), or Ad5/Ad5 HIV-1 clade B gag vaccine prime-boost regimens. J Infect Dis. 2010;201:132–41.
Source: PubMed