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Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B with Chimpanzee Adenovirus 63 and Modif

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Safety and High Level Efficacy of the Combination Malaria Vaccine Regimen of RTS,S/AS01B with Chimpanzee Adenovirus 63 and Modif The Journal of Infectious Diseases MAJOR ARTICLE 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 Tommy Rampling,1 Katie J. Ewer,1 Georgina Bowyer,1 Carly M. Bliss,1 Nick J. Edwards,1 Danny Wright,1 Ruth O. Payne,1 Navin Venkatraman,1 Eoghan de Barra,6 Claudia M. Snudden,1 Ian D. Poulton,1 Hans de Graaf,5 Priya Sukhtankar,5 Rachel Roberts,1 Karen Ivinson,7 Rich Weltzin,7 Bebi-Yassin Rajkumar,7 Ulrike Wille-Reece,7 Cynthia K. Lee,7 Christian F. Ockenhouse,7 Robert E. Sinden,3 Stephen Gerry,2 Alison M. Lawrie,1 8 8 8 8 4 5 1 1 Johan Vekemans, Danielle Morelle, Marc Lievens, Ripley W. Ballou, Graham S. Cooke, Saul N. Faust, Sarah Gilbert, and Adrian V. S. Hill Downloaded from https://academic.oup.com/jid/article/214/5/772/2238110 by guest on 06 January 2021 1The Jenner Institute, 2Centre for Statistics in Medicine, University of Oxford, 3Department of Life Sciences, 4Infectious Diseases Section, Faculty of Medicine, Department of Medicine, Imperial College London, and 5NIHR Wellcome Trust Clinical Research Facility, University of Southampton and University Hospital Southampton NHS Foundation Trust, United Kingdom; 6Royal College of Surgeons in Ireland, Dublin; 7PATH Malaria Vaccine Initiative, Seattle, Washington; and 8GSK Vaccines, Rixensart, Belgium Background. The need for a highly efficacious vaccine against Plasmodium falciparum remains pressing. In this controlled human malaria infection (CHMI) study, we assessed the safety, efficacy and immunogenicity of a schedule combining 2 distinct vaccine types in a staggered immunization regimen: one inducing high-titer antibodies to circumsporozoite protein (RTS,S/ AS01B) and the other inducing potent T-cell responses to thrombospondin-related adhesion protein (TRAP) by using a viral vector. Method. Thirty-seven healthy malaria-naive adults were vaccinated with either a chimpanzee adenovirus 63 and modified vac- – cinia virus Ankara vectored vaccine expressing a multiepitope string fused to TRAP and 3 doses of RTS,S/AS01B (group 1; n = 20) or 3 doses of RTS,S/AS01B alone (group 2; n = 17). CHMI was delivered by mosquito bites to 33 vaccinated subjects at week 12 after the first vaccination and to 6 unvaccinated controls. Results. No suspected unexpected serious adverse reactions or severe adverse events related to vaccination were reported. Protective vaccine efficacy was observed in 14 of 17 subjects (82.4%) in group 1 and 12 of 16 subjects (75%) in group 2. All control subjects received a diagnosis of blood-stage malaria parasite infection. Both vaccination regimens were immunogenic. Fourteen protected subjects underwent repeat CHMI 6 months after initial CHMI; 7 of 8 (87.5%) in group 1 and 5 of 6 (83.3%) in group 2 remained protected. Conclusions. The high level of sterile efficacy observed in this trial is encouraging for further evaluation of combination approaches using these vaccine types. Clinical Trials Registration. NCT01883609. Keywords. malaria; P. falciparum; vaccine; RTS,S; ChAd63; ME-TRAP. Malaria remains one of the leading causes of mortality globally partial efficacy against experimental and natural human infec- [1], and there is urgent need for a vaccine. The majority of tion, with the current leading vaccine being the recombinant deaths are in children <5 years old, with this age group account- protein in adjuvant, RTS,S/AS01. RTS,S targets circumsporo- ing for approximately 306 000 deaths in 2015. The enormous zoite protein (CS), which is expressed by the Plasmodium falcip- economic and social consequences of malaria have been well arum sporozoite at the preerythrocytic stage and was the first documented [2]. Efforts to develop effective vaccines are com- subunit vaccine to show high rates of sterile efficacy, typically plicated by the complex immunology of malaria parasite infec- 50%, in controlled human malaria infection (CHMI) studies tion, and no reliable natural model of complete immunity exists. [3]. In a large African phase 3 trial, this vaccine had an efficacy Despite this, a small number of candidate vaccines have shown 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 Received 7 April 2016; accepted 6 June 2016; published online 15 June 2016. fi Correspondence: T. Rampling, Nuffield Department of Medicine, University of Oxford, Centre after vaccination [4, 5]. Vaccine ef cacy wanes over time but for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Old Road, Headington, Ox- can be enhanced by a fourth dose [6]. Analysis of the immuno- ford, UK ([email protected]). logical correlates of efficacy of this vaccine suggest that vaccine- The Journal of Infectious Diseases® 2016;214:772–81 © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of induced antibodies targeting CS are the most important medi- America. This is an Open Access article distributed under the terms of the Creative Commons ators of RTS,S-induced protection against malaria [3], although Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly no antibody level threshold has been shown to be predictive of cited. DOI: 10.1093/infdis/jiw244 efficacy. The rate at which anti-CS antibodies wane is similar to 772 • JID 2016:214 (1 September) • Rampling et al the rate at which efficacy declines [7, 8], suggesting that anti-CS combining these 2 distinct candidate vaccine types in a stag- antibodies may also be associated with the duration of protec- gered immunization regimen: one that induces very high titer tion. A number of factors, including age at vaccination, human antibodies to CS, using RTS,S/AS01B, and another that induces immunodeficiency virus status, and high baseline anti-CS anti- potent T-cell responses to TRAP, using viral vectors. body titers influence anti-CS antibody titers after vaccination METHODS with RTS,S [9]. The preerythrocytic stage of P. falciparum infection presents Participants an attractive target for an efficacious human vaccine because Recruitment and vaccination was conducted at 3 United King- sufficient reduction in the number of viable merozoites reaching dom sites, in Oxford, Southampton and London. The CHMI the blood from the liver will prevent parasitization of red blood procedure was performed as previously described [19] at Impe- cells and initiation of the symptomatic blood stage of infection. rial College, London, using 5 infectious bites from Anopheles Anti-CS antibodies can target sporozoites for destruction prior stephensi mosquitoes infected with P. falciparum strain 3D7. to hepatocyte invasion. Because sporozoites travel from the skin All subjects were infected with a single batch of mosquitoes at to liver within minutes, it may be difficult for a vaccine to the initial CHMI and with a second single batch at the repeat Downloaded from https://academic.oup.com/jid/article/214/5/772/2238110 by guest on 06 January 2021 achieve complete protection against P. falciparum based solely CHMI. Infected mosquitoes were supplied by the Depart- on antibodies to sporozoites. The liver stage of infection pro- ment of Entomology, Walter Reed Army Institute of Research vides a longer window of opportunity for cell-mediated immu- (Washington D.C.). Healthy, malaria-naive males and nonpreg- nity to recognize and destroy infected hepatocytes. Chimpanzee nant females aged 18–45 years were invited to participate in the adenovirus 63 (ChAd63) with a multiepitope string fused study. All volunteers gave written informed consent prior to to thrombospondin-related adhesion protein (ME-TRAP) participation, and the study was conducted according to the insert and modified vaccinia virus Ankara (MVA) with the principles of the Declaration of Helsinki and in accordance ME-TRAP insert are viral-vectored vaccines, and when they with good clinical practice (GCP). are administered in a prime-boost sequence at an 8-week inter- Ethical and Regulatory Approval val, they are a leading candidate vaccine strategy targeting the Necessary approvals for the study were granted by the United liver stage of infection [10]. The ChAd63 and MVAviral vectors Kingdom National Research Ethics Service, Committee South deliver the recombinant ME-TRAP insert, which generates Central–Oxford A (reference 13/SC/0208), the Western Institu- a potent cellular immune responseagainsttheliver-stage tion Review Board (reference 20130698), and the United King- P. falciparum antigen, TRAP, of greater magnitude than the cel- dom Medicines and Healthcare Products Regulatory Agency lular response induced by RTS,S/AS01. This strategy showed (reference 21584/0317/001-0001). The trial was registered durable partial efficacy in 2 phase 2a sporozoite challenge trials with ClinicalTrials.gov (reference NCT01883609). The Local in the United Kingdom [11, 12], using the 3D7 parasite as a Safety Committee provided safety oversight, and GCP compli- challenge strain. The viral vector–encoded P. falciparum ance was independently monitored externally by the Clinical TRAP allele is from the heterologous T9/96 strain, and induced Trials and Research Governance Team of the University of T-cell responses correlate with efficacy [11]. Therefore, these are Oxford. effectively heterologous strain CHMI studies. Interestingly, a higher level of efficacy of 67% (95% CI, 33%–83%) against P. Study Design falciparum infections detected by polymerase chain reaction This phase 2a, open-labeled, partially randomized challenge (PCR) was observed in a phase 2b trial in Kenyan adults [13]. trial consisted of 4 cohorts. Allocation to study group occurred Again, T cells to TRAP peptides correlated with vaccine efficacy, at screening and was based on subject preference. Any subjects but the short duration of malaria transmission and follow-up at without a preference were randomly assigned to vaccine group 1 this trial site precluded analysis of the durability of vaccine- or vaccine group 2.
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