Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals
Susanne H Hodgson, Katie J Ewer, Carly M Bliss, Nick J Edwards, Thomas Rampling, Nicholas A Anagnostou, Eoghan de Barra, Tom Havelock, Georgina Bowyer, Ian D Poulton, Simone de Cassan, Rhea Longley, Joseph J Illingworth, Alexander D Douglas, Pooja B Mange, Katharine A Collins, Rachel Roberts, Stephen Gerry, Eleanor Berrie, Sarah Moyle, Stefano Colloca, Riccardo Cortese, Robert E Sinden, Sarah C Gilbert, Philip Bejon, Alison M Lawrie, Alfredo Nicosia, Saul N Faust, Adrian V S Hill, Susanne H Hodgson, Katie J Ewer, Carly M Bliss, Nick J Edwards, Thomas Rampling, Nicholas A Anagnostou, Eoghan de Barra, Tom Havelock, Georgina Bowyer, Ian D Poulton, Simone de Cassan, Rhea Longley, Joseph J Illingworth, Alexander D Douglas, Pooja B Mange, Katharine A Collins, Rachel Roberts, Stephen Gerry, Eleanor Berrie, Sarah Moyle, Stefano Colloca, Riccardo Cortese, Robert E Sinden, Sarah C Gilbert, Philip Bejon, Alison M Lawrie, Alfredo Nicosia, Saul N Faust, Adrian V S Hill
Abstract
Background: Circumsporozoite protein (CS) is the antigenic target for RTS,S, the most advanced malaria vaccine to date. Heterologous prime-boost with the viral vectors simian adenovirus 63 (ChAd63)-modified vaccinia virus Ankara (MVA) is the most potent inducer of T-cells in humans, demonstrating significant efficacy when expressing the preerythrocytic antigen insert multiple epitope-thrombospondin-related adhesion protein (ME-TRAP). We hypothesized that ChAd63-MVA containing CS may result in a significant clinical protective efficacy.
Methods: We conducted an open-label, 2-site, partially randomized Plasmodium falciparum sporozoite controlled human malaria infection (CHMI) study to compare the clinical efficacy of ChAd63-MVA CS with ChAd63-MVA ME-TRAP.
Results: One of 15 vaccinees (7%) receiving ChAd63-MVA CS and 2 of 15 (13%) receiving ChAd63-MVA ME-TRAP achieved sterile protection after CHMI. Three of 15 vaccinees (20%) receiving ChAd63-MVA CS and 5 of 15 (33%) receiving ChAd63-MVA ME-TRAP demonstrated a delay in time to treatment, compared with unvaccinated controls. In quantitative polymerase chain reaction analyses, ChAd63-MVA CS was estimated to reduce the liver parasite burden by 69%-79%, compared with 79%-84% for ChAd63-MVA ME-TRAP.
Conclusions: ChAd63-MVA CS does reduce the liver parasite burden, but ChAd63-MVA ME-TRAP remains the most promising antigenic insert for a vectored liver-stage vaccine. Detailed analyses of parasite kinetics may allow detection of smaller but biologically important differences in vaccine efficacy that can influence future vaccine development.
Clinical trials registration: NCT01623557.
Keywords: CHMI; CS; ChAd63; ME-TRAP; MVA; P. falciparum; malaria; vaccine.
© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.
Figures
![Figure 1.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4354983/bin/jiu57901.jpg)
![Figure 2.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4354983/bin/jiu57902.jpg)
![Figure 3.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4354983/bin/jiu57903.jpg)
![Figure 4.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4354983/bin/jiu57904.jpg)
![Figure 5.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4354983/bin/jiu57905.jpg)
![Figure 6.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4354983/bin/jiu57906.jpg)
![Figure 7.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4354983/bin/jiu57907.jpg)
References
- White NJ, Pukrittayakamee S, Hien TT, et al. Malaria. Lancet. 2014;383:723–35.
- WHO World Malaria Report. 2013.
- Agnandji ST, Lell B, Fernandes JF, et al. A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med. 2012;367:2284–95.
- Olotu A, Fegan G, Wambua J, et al. Four-year efficacy of RTS,S/AS01E and its interaction with malaria exposure. N Engl J Med. 2013;368:1111–20.
- Bejon P, White MT, Olotu A, et al. Efficacy of RTS,S malaria vaccines: individual-participant pooled analysis of phase 2 data. Lancet Infect Dis. 2013;13:319–27.
- Agnandji ST, Fendel R, Mestre M, et al. Induction of Plasmodium falciparum-specific CD4+ T cells and memory B cells in Gabonese children vaccinated with RTS,S/AS01(E) and RTS,S/AS02(D) PLoS One. 2011;6:e18559.
- Foquet L, Hermsen CC, van Gemert GJ, et al. Vaccine-induced monoclonal antibodies targeting circumsporozoite protein prevent Plasmodium falciparum infection. J Clin Invest. 2014;124:140–4.
- Ndungu FM, Mwacharo J, Kimani D, et al. A statistical interaction between circumsporozoite protein-specific T cell and antibody responses and risk of clinical malaria episodes following vaccination with RTS,S/AS01E. PLoS One. 2012;7:e52870.
- Birkett AJ, Moorthy VS, Loucq C, Chitnis CE, Kaslow DC. Malaria vaccine R&D in the Decade of Vaccines: breakthroughs, challenges and opportunities. Vaccine. 2013;31(suppl 2):B233–43.
- WHO. Malaria Vaccine Technology Roadmap. 2013.
- Sedegah M, Hollingdale MR, Farooq F, et al. Sterile immunity to malaria after DNA prime/adenovirus boost immunization is associated with effector memory CD8+T cells targeting AMA1 class I epitopes. PLoS One. 2014;9:e106241.
- Schwenk RJ, Richie TL. Protective immunity to pre-erythrocytic stage malaria. Trends Parasitol. 2011;27:306–14.
- Hoffman SL, Isenbarger D, Long GW, et al. Sporozoite vaccine induces genetically restricted T cell elimination of malaria from hepatocytes. Science. 1989;244:1078–81.
- 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, et al. Cloned cytotoxic T cells recognize an epitope in the circumsporozoite protein and protect against malaria. Nature. 1989;341:323–6.
- Weiss WR, Mellouk S, Houghten RA, et al. Cytotoxic T cells recognize a peptide from the circumsporozoite protein on malaria-infected hepatocytes. J Exp Med. 1990;171:763–73.
- Ewer KJ, O'Hara GA, Duncan CJ, et al. Protective CD8(+) T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation. Nat Commun. 2013;4:2836.
- Hill AV, Reyes-Sandoval A, O'Hara G, et al. Prime-boost vectored malaria vaccines: progress and prospects. Hum Vaccin. 2010;6:78–83.
- Chuang I, Sedegah M, Cicatelli S, et al. DNA prime/Adenovirus boost malaria vaccine encoding P. falciparum CSP and AMA1 induces sterile protection associated with cell-mediated immunity. PLoS One. 2013;8:e55571.
- Tamminga C, Sedegah M, Maiolatesi S, et al. Human adenovirus 5-vectored Plasmodium falciparum NMRC-M3V-Ad-PfCA vaccine encoding CSP and AMA1 is safe, well-tolerated and immunogenic but does not protect against controlled human malaria infection. Hum Vaccin Immunother. 2013;9:2165–77.
- Reyes-Sandoval A, Berthoud T, Alder N, et al. Prime-boost immunization with adenoviral and modified vaccinia virus Ankara vectors enhances the durability and polyfunctionality of protective malaria CD8+ T-cell responses. Infect Immun. 2010;78:145–53.
- Colloca S, Barnes E, Folgori A, et al. Vaccine vectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Sci Transl Med. 2012;4 115ra112.
- Sauerwein RW, Roestenberg M, Moorthy VS. Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat Rev Immunol. 2011;11:57–64.
- Thompson FM, Porter DW, Okitsu SL, et al. Evidence of blood stage efficacy with a virosomal malaria vaccine in a phase IIa clinical trial. PLoS One. 2008;3:e1493.
- O'Hara GA, Duncan CJ, Ewer KJ, et al. Clinical assessment of a recombinant simian adenovirus ChAd63: a potent new vaccine vector. J Infect Dis. 2012;205:772–81.
- 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.
- Walther M, Thompson FM, Dunachie S, et al. Safety, immunogenicity, and efficacy of prime-boost immunization with recombinant poxvirus FP9 and modified vaccinia virus Ankara encoding the full-length Plasmodium falciparum circumsporozoite protein. Infect Immun. 2006;74:2706–16.
- Imoukhuede EB, Berthoud T, Milligan P, et al. Safety and immunogenicity of the malaria candidate vaccines FP9 CS and MVA CS in adult Gambian men. Vaccine. 2006;24:6526–33.
- Bejon P, Peshu N, Gilbert SC, et al. Safety profile of the viral vectors of attenuated fowlpox strain FP9 and modified vaccinia virus Ankara recombinant for either of 2 preerythrocytic malaria antigens, ME-TRAP or the circumsporozoite protein, in children and adults in Kenya. Clin Infect Dis. 2006;42:1102–10.
- Bruna-Romero O, Rocha CD, Tsuji M, Gazzinelli RT. Enhanced protective immunity against malaria by vaccination with a recombinant adenovirus encoding the circumsporozoite protein of Plasmodium lacking the GPI-anchoring motif. Vaccine. 2004;22:3575–84.
- Coppi A, Pinzon-Ortiz C, Hutter C, Sinnis P. The Plasmodium circumsporozoite protein is proteolytically processed during cell invasion. J Exp Med. 2005;201:27–33.
- Singh AP, Buscaglia CA, Wang Q, et al. Plasmodium circumsporozoite protein promotes the development of the liver stages of the parasite. Cell. 2007;131:492–504.
- Cottingham MG, Carroll F, Morris SJ, et al. Preventing spontaneous genetic rearrangements in the transgene cassettes of adenovirus vectors. Biotechnol Bioeng. 2012;109:719–28.
- Epstein JE, Tewari K, Lyke KE, et al. Live attenuated malaria vaccine designed to protect through hepatic CD8(+) T cell immunity. Science. 2011;334:475–80.
- Sheehy SH, Duncan CJ, Elias SC, et al. ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans. Mol Ther. 2012;20:2355–68.
- 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.
- Sheehy SH, Duncan CJ, Elias SC, et al. Phase Ia clinical evaluation of the Plasmodium falciparum blood-stage antigen MSP1 in ChAd63 and MVA vaccine vectors. Mol Ther. 2011;19:2269–76.
- Sheehy SH, Duncan CJ, Elias SC, et al. Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors. PLoS One. 2012;7:e31208.
- Sedegah M, Kim Y, Ganeshan H, et al. Identification of minimal human MHC-restricted CD8+ T-cell epitopes within the Plasmodium falciparum circumsporozoite protein (CSP) Malar J. 2013;12:185.
- Epstein JE, Rao S, Williams F, et al. Safety and clinical outcome of experimental challenge of human volunteers with Plasmodium falciparum-infected mosquitoes: an update. J Infect Dis. 2007;196:145–54.
- Kester KE, Cummings JF, Ofori-Anyinam O, et al. Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: safety, efficacy, and immunologic associates of protection. J Infect Dis. 2009;200:337–46.
- 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 U S A. 2005;102:4836–41.
Source: PubMed