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, Katie J Ewer, Georgina Bowyer, Carly M Bliss, Nick J Edwards, Danny Wright, Ruth O Payne, Navin Venkatraman, Eoghan de Barra, Claudia M Snudden, Ian D Poulton, Hans de Graaf, Priya Sukhtankar, Rachel Roberts, Karen Ivinson, Rich Weltzin, Bebi-Yassin Rajkumar, Ulrike Wille-Reece, Cynthia K Lee, Christian F Ockenhouse, Robert E Sinden, Stephen Gerry, Alison M Lawrie, Johan Vekemans, Danielle Morelle, Marc Lievens, Ripley W Ballou, Graham S Cooke, Saul N Faust, Sarah Gilbert, Adrian V S Hill, Tommy Rampling, Katie J Ewer, Georgina Bowyer, Carly M Bliss, Nick J Edwards, Danny Wright, Ruth O Payne, Navin Venkatraman, Eoghan de Barra, Claudia M Snudden, Ian D Poulton, Hans de Graaf, Priya Sukhtankar, Rachel Roberts, Karen Ivinson, Rich Weltzin, Bebi-Yassin Rajkumar, Ulrike Wille-Reece, Cynthia K Lee, Christian F Ockenhouse, Robert E Sinden, Stephen Gerry, Alison M Lawrie, Johan Vekemans, Danielle Morelle, Marc Lievens, Ripley W Ballou, Graham S Cooke, Saul N Faust, Sarah Gilbert, Adrian V S Hill

Abstract

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 vaccinia 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: ChAd63; ME-TRAP; P. falciparum; RTS,S; malaria; vaccine.

© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Flow of study design and volunteer recruitment. Twenty-seven subjects were excluded because of inclusion/exclusion criteria. Three subjects withdrew consent after screening but before enrollment. Two subjects were deemed eligible as control subjects but only after group 3 enrollment was complete. They were kept as backup subjects in case of last-minute withdrawals from group 3 but never underwent controlled human malaria infection (CHMI). Seventeen subjects expressed a preference as to which vaccine group to be allocated to and were assigned accordingly. Twenty subjects expressed no preference for vaccine group allocation, and were therefore randomized to group by the study statistician. Abbreviations: ChAd63, chimpanzee adenovirus serotype 63; ME-TRAP, multiple-epitope thrombospondin-related adhesion protein; MVA, modified vaccinia virus Ankara.
Figure 2.
Figure 2.
Efficacy of RTS,S/AS01B plus chimpanzee adenovirus 63 and modified vaccinia virus Ankara–vectored vaccine (ChAd63-MVA) expressing a multiepitope string fused to thrombospondin-related adhesion protein (ME-TRAP) and RTS,S/AS01B alone following Plasmodium falciparum 3D7 sporozoite challenge. A, Kaplan–Meier survival analysis of the time to treatment following initial controlled human malaria infection (CHMI). Mean time to diagnosis (± standard deviation [SD]) was 12.2±0.7 days for unvaccinated controls. Seventeen of 17 subjects (100%) in group 1 and 14 of 16 subjects (87.5%) in group 2 had no diagnosis by day 21 or received a diagnosis after the control mean time + 2 SD. B, Kaplan–Meier survival analysis of the time to the first sample with >20 parasites/mL detected by quantitative polymerase chain reaction (qPCR). Mean time to end point (±SD) was 7.4±0.7 days for unvaccinated controls. Sixteen of 17 subjects (94.1%) in group 1 and 15 of 16 subjects (93.8%) in group 2 did not reach this end point or did so after the control mean time + 2 SD. C, Kaplan–Meier survival analysis of the time to the first sample with >500 parasites/mL detected by qPCR. Mean time to end point (±SD) was 9.8±0.8 days for unvaccinated controls. Seventeen of 17 subjects (100%) in group 1 and 15 of 16 subjects (93.8%) in group 2 did not reach this end point or did so after the control mean time + 2 SD. D, Kaplan–Meier survival analysis of the time to treatment following repeat CHMI in protected subjects. Significance testing was performed by the log-rank test.
Figure 3.
Figure 3.
Antibody responses to vaccination, measured by enzyme-linked immunosorbent assay (ELISA). A, Anti-thrombospondin adhesion protein (TRAP) immunoglobulin G (IgG) antibody responses after vaccination with RTS,S/AS01B plus chimpanzee adenovirus 63 and modified vaccinia virus Ankara–vectored vaccine (ChAd63-MVA) expressing a multiepitope string fused to TRAP (ME-TRAP; group 1 subjects only). Lines represent group medians. B, Anti–circumsporozoite protein (CS) IgG antibody responses after vaccination with RTS,S/AS01B plus ChAd63-MVA ME-TRAP (group 1; blue) or RTS,S alone (group 2; black). Line represents group median. C, Comparison of anti-CS IgG antibody responses between group 1 (blue) and group 2 (black) as measured on the day before controlled human malaria infection (CHMI). P > .999, by the Mann–Whitney test. Comparison of anti-CS IgG antibody responses in volunteers who were or were not sterilely protected. Lines represent geometric means. D, Correlation between anti-CS IgG titers on the day before challenge and parasite density on day 7 after challenge. Spearman r = −0.4; P = .018. E, Avidity of total IgG against the NANP repeat region of circumsporozoite protein. Significant increase in avidity between day 28 and the day before challenge in protected but not nonprotected volunteers. P = .001, by the Wilcoxon matched pairs test. Avidity of total IgG remained significantly higher at time of the second CHMI (RC-1) than at day 28. P = .002, Mann–Whitney test. Lines represent geometric mean. Abbreviations: C+, elapsed time after CHMI, in days; C-1, day before CHMI; PCR, polymerase chain reaction; RC-1, day before second CHMI.
Figure 4.
Figure 4.
Antigen-specific T-cell responses to vaccination, measured by interferon γ (IFN-γ) enzyme-linked immunospot assay (ELISPOT). A, Median T-cell responses to multiepitope string fused to thrombospondin-related adhesion protein (ME-TRAP). B, Median T-cell responses to circumsporozoite protein (CS) peptide pools are shown for group 1 (RTS,S/AS01 and ME-TRAP; blue line) and group 2 (RTS,S/AS01; black line). Abbreviations: ChAd63, chimpanzee adenovirus 63; MVA, modified vaccinia virus Ankara; PBMC, peripheral blood mononuclear cell; SFC, spot-forming cell.
Figure 5.
Figure 5.
T-cell responses determined by flow cytometry on cryopreserved peripheral blood mononuclear cells before and after vaccination for circumsporozoite protein (CS) and hepatitis B virus surface antigen (HBsAg). Polypositivity indicates number of cells per million expressing ≥2 of the following markers: CD154 (CD40 ligand), interferon γ (IFN-γ), interleukin 2 (IL-2), and tumor necrosis factor α (TNF-α). A and B, Number of CS-specific polypositive CD4+ or CD8+ T cells per million in groups 1 and 2, respectively. C, Comparison of CD4+ polypositive T cells at peak time point after vaccination (day 42) and the day before controlled human malaria infection (CHMI) for groups 1 (G1) and 2 (G2). D, Correlation between peak CS-specific CD4+ polypositive frequency and anti-CS IgG level on the day before challenge (r = 0.4; P = .03, by the Spearman test). E and F, Number of HBsAg-specific polypositive CD4+ or CD8+ T cells per million in groups 1 and 2, respectively. Abbreviations: C+, elapsed time after CHMI, in days; C-1, day before CHMI; IgG, immunoglobulin G.
Figure 6.
Figure 6.
Intracellular cytokine staining of peripheral blood mononuclear cells (PBMCs) 1 day before controlled human malaria infection (CHMI; 27 days after the final RTS,S vaccination and 13 days after vaccination with modified vaccinia virus Ankara [MVA] expressing a multiepitope string fused to thrombospondin-related adhesion protein [ME-TRAP]), showing the CD107a expression frequency and the frequencies of cytokine-secreting cells as a percentage of the frequency of parent CD4+ and CD8+ T cells. Geometric mean of each response is shown in response to stimulation with TRAP T9/96 peptides (homologous to vaccine insert) by group 1 (A), TRAP 3D7 peptides (homologous to CHMI challenge strain) by group 1 (B), and circumsporozoite (CS) peptides by groups 1 and 2 (C). D, Ex vivo interferon γ enzyme-linked immunospot (ELISPOT)–determined responses of group 1 and 2 volunteers to CS peptides split into 3 peptide pools and a combined pool, with background subtracted. Dotted line shows the median background ELISPOT response, setting the positive response threshold. Data are for 17 individuals in group 1 and 16 in group 2. Data points represent individual volunteers. Abbreviations: IFN-γ, interferon γ; IL-2, interleukin 2; SFC, spot-forming cell; TNF-α, tumor necrosis factor α.

References

    1. World Health Organization (WHO). World malaria report 2015. Geneva, Switzerland: WHO, 2015.
    1. Okiro EA, Hay SI, Gikandi PW et al. . The decline in paediatric malaria admissions on the coast of Kenya. Malar J 2007; 6:151.
    1. 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.
    1. Rts SCTP, Agnandji ST, Lell B et al. . A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants. N Engl J Med 2012; 367:2284–95.
    1. Agnandji ST, Lell B, Soulanoudjingar SS et al. . First results of phase 3 trial of RTS,S/AS01 malaria vaccine in African children. N Engl J Med 2011; 365:1863–75.
    1. Rts SCTP. Efficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial. Lancet 2015; 386:31–45.
    1. White MT, Bejon P, Olotu A et al. . A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine. BMC Med 2014; 12:117.
    1. 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.
    1. White MT, Verity R, Griffin JT et al. . Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial. Lancet Infect Dis 2015; 15:1450–8.
    1. 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.
    1. 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.
    1. Hodgson SH, Ewer KJ, Bliss CM et al. . Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals. J Infect Dis 2015; 211:1076–86.
    1. Ogwang C, Kimani D, Edwards NJ et al. . Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults. Sci Transl Med 2015; 7:286re5.
    1. Ogwang C, Afolabi M, Kimani D et al. . Safety and immunogenicity of heterologous prime-boost immunisation with Plasmodium falciparum malaria candidate vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in healthy Gambian and Kenyan adults. PLoS One 2013; 8:e57726.
    1. Kimani D, Jagne YJ, Cox M et al. . Translating the immunogenicity of prime-boost immunization with ChAd63 and MVA ME-TRAP from malaria naive to malaria-endemic populations. Mol Ther 2014; 22:1992–2003.
    1. Walker AS, Lourenco J, Hill AV, Gupta S. Modeling combinations of pre-erythrocytic Plasmodium falciparum malaria vaccines. Am J Trop Med Hyg 2015; 93:1254–9.
    1. Hutchings CL, Birkett AJ, Moore AC, Hill AV. Combination of protein and viral vaccines induces potent cellular and humoral immune responses and enhanced protection from murine malaria challenge. Infect Immun 2007; 75:5819–26.
    1. Bauza K, Atcheson E, Malinauskas T, Blagborough AM, Reyes-Sandoval A. Tailoring a combination pre-erythrocytic malaria vaccine. Infect Immun 2016; 84:622–34.
    1. 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.
    1. Stoute JA, Slaoui M, Heppner DG et al. . A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria. RTS,S Malaria Vaccine Evaluation Group. N Engl J Med 1997; 336:86–91.
    1. Lalvani A, Moris P, Voss G et al. . Potent induction of focused Th1-type cellular and humoral immune responses by RTS,S/SBAS2, a recombinant Plasmodium falciparum malaria vaccine. J Infect Dis 1999; 180:1656–64.
    1. Seder RA, Chang LJ, Enama ME et al. . Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science 2013; 341:1359–65.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe