Evaluation of the efficacy of ChAd63-MVA vectored vaccines expressing circumsporozoite protein and ME-TRAP against controlled human malaria infection in malaria-naive individuals - PubMed (original) (raw)

Clinical Trial

. 2015 Apr 1;211(7):1076-86.

doi: 10.1093/infdis/jiu579. Epub 2014 Oct 21.

Katie J Ewer 1, Carly M Bliss 1, Nick J Edwards 1, Thomas Rampling 1, Nicholas A Anagnostou 1, Eoghan de Barra 2, Tom Havelock 3, Georgina Bowyer 1, Ian D Poulton 1, Simone de Cassan 1, Rhea Longley 1, Joseph J Illingworth 1, Alexander D Douglas 1, Pooja B Mange 1, Katharine A Collins 1, Rachel Roberts 1, Stephen Gerry 4, Eleanor Berrie 5, Sarah Moyle 5, Stefano Colloca 6, Riccardo Cortese 7, Robert E Sinden 8, Sarah C Gilbert 1, Philip Bejon 9, Alison M Lawrie 1, Alfredo Nicosia 10, Saul N Faust 3, Adrian V S Hill 1

Affiliations

Clinical Trial

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 et al. J Infect Dis. 2015.

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.

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Figures

Figure 1.

Figure 1.

Flow of study design and volunteer recruitment. Twenty volunteers were excluded following screening for the following reasons: psychiatric history (n = 3), no medical screening letter returned (n = 3), multiple medical problems (n = 2), excessive alcohol use (n = 2), syncope (n = 1), connective tissue disease (n = 1), iron deficiency (n = 1), raised alanine aminotransferase level (n = 1), poor venous access (n = 1), gastrointestinal problems under investigation (n = 1), family history of heart disease (n = 1), lost to follow-up (n = 1), unavailable during challenge (n = 1), and history of recreational drug use (n = 1). Furthermore, 7 volunteers withdrew consent after screening but before enrollment. All immunizations were administered intramuscularly with sequential vaccines administered into the deltoid of alternating arms. No enrolled volunteers withdrew from the study and all volunteers completed study visits as scheduled. Abbreviations: ChAd63, simian adenovirus 63; CS, circumsporozoite protein; ME-TRAP, multiple epitope–thrombospondin-related adhesion protein; MVA, modified vaccinia virus Ankara; pfu, plaque-forming units; vp, viral particles.

Figure 2.

Figure 2.

Antigen-specific T-cell responses to vaccination measured by interferon γ enzyme-linked immunosorbent spot assay. Kinetics of T-cell responses after vaccination with ChAd63-MVA encoding either circumsporozoite protein (CS; group 1; A) or ME-TRAP (group 2; B). Each line represents an individual volunteer. **P < .01 and ***P < .001, by the Kruskal–Wallis test with the Dunn multiple comparison test. C, Median T-cell frequencies for both antigens by group. Mean T-cell frequencies at day 28 after vaccination were 304 and 673 spot-forming cells (SFCs) after ChAd63-MVA CS or ME-TRAP receipt, respectively, and at day 63 peaked at 1378 and 2068 SFCs after ChAd63-MVA CS or ME-TRAP receipt, respectively. Abbreviations: ChAd63, simian adenovirus 63; CHMI, controlled human malaria infection; controls, unvaccinated volunteers undergoing CHMI; ME-TRAP, multiple epitope–thrombospondin-related adhesion protein; MVA, modified vaccinia virus Ankara; PBMC, peripheral blood mononuclear cell.

Figure 3.

Figure 3.

Antibody responses to vaccination measured by enzyme-linked immunosorbent assay (ELISA). A, Anti- circumsporozoite protein (CS) immunoglobulin G (IgG) antibody responses after vaccination with ChAd63-MVA CS (group 1; red) or ME-TRAP (group 2; blue). Lines represent group medians. ***P = <.001 and *P = <.05, by the Friedman test comparing responses before and after vaccination with the Dunn post hoc test. B, Anti-TRAP IgG antibody responses after vaccination with ChAd63 ME-TRAP (group 2). ***P = .0002, by the 2-tailed Wilcoxon matched pairs test. C, Correlation between anti-CS IgG antibodies and CS-specific T-cell immunogenicity the day before challenge in group 1. Spearman r = 0.5; P = .08_._ Abbreviations: ChAd63, simian adenovirus 63; CHMI, controlled human malaria infection; controls, unvaccinated volunteers undergoing CHMI; ELISPOT, enzyme-linked immunosorbent spot assay; EU, ELISA units; ME-TRAP, multiple epitope–thrombospondin-related adhesion protein; MVA, modified vaccinia virus Ankara; PBMC, peripheral blood mononuclear cell; SFC, spot-forming cell.

Figure 4.

Figure 4.

Efficacy of ChAd63-MVA circumsporozoite protein (CS) and ME-TRAP immunization following Plasmodium falciparum 3D7 sporozoite challenge. Kaplan–Meier survival analyses. Log-rank test for significance. A, Kaplan–Meier survival analysis of time to treatment. Median time, 12.0 days for group 1 (CS), 12.5 days for group 2 (ME-TRAP), and 10.3 days for unvaccinated controls. B, Kaplan–Meier survival analysis of time to first sample with >500 parasites/mL detected by quantitative polymerase chain reaction (qPCR). Median time, 10.5 days for group 1 (CS), 12.0 days for group 2 (ME-TRAP), and 7.5 days for unvaccinated controls. C, Kaplan–Meier survival analysis of time to first sample with >20 parasites/mL detected by qPCR. Median time, 7.5 days for group 1 (CS), 9.0 days for group 2 (ME-TRAP), and 7.0 days for unvaccinated controls. Abbreviations: CHMI, controlled human malaria infection; controls, unvaccinated volunteers undergoing CHMI; ME-TRAP, multiple epitope–thrombospondin related adhesion protein.

Figure 5.

Figure 5.

Comparison of mean parasite density, measured by quantitative polymerase chain reaction, 7.5 days after controlled human malaria infection (CHMI) between vaccinees and control volunteers. P values were determined by the Mann–Whitney U test_._ Abbreviations: ChAd63, simian adenovirus 63; Control, unvaccinated volunteers undergoing CHMI; CS, circumsporozoite protein; group 1, ChAd63-MVA CS recipients; group 2, ChAd63 ME-TRAP recipients; ME-TRAP, multiple epitope–thrombospondin-related adhesion protein; MVA, modified vaccinia virus Ankara.

Figure 6.

Figure 6.

Comparison of areas under the curve (AUCs) of parasite densities, measured by quantitative polymerase chain reaction (PCR), between vaccinees and control volunteers. A, Group mean log-transformed PCR data. The AUC of parasite density over the first 3 replication cycles in infected volunteers was a significant predictor of the time to diagnosis (hazard ratio, 1.000015 [95% confidence interval, 1.000008–1.000022], by Cox proportional hazards regression analysis; P < .000). B, AUC analysis of parasite densities, comparing controls to vaccinees at days 6.5–8 (the first cycle after hepatocyte release), days 8.5–10 (the second cycle), and days 10.5–12 (the third cycle) after controlled human malaria infection (CHMI). Means of log [parasite density + 1] were compared for each vaccine group to those of controls, using a 2-tailed t test. Abbreviations: ChAd63, simian adenovirus 63; controls, unvaccinated volunteers undergoing CHMI; CS, circumsporozoite protein; ME-TRAP, multiple epitope–thrombospondin-related adhesion protein; MVA, modified vaccinia virus Ankara; SP, sterile protection.

Figure 7.

Figure 7.

Associations between immunological outcomes and vaccine efficacy. Correlation between parasite density at day 7.5, measured by quantitative polymerase chain reaction (qPCR), and levels of anti–circumsporozoite protein (CS) immunoglobulin G (IgG) antibody in group 1 (CS; Spearman r = −0.6; P = .03; A) and group 2 (ME-TRAP; Spearman r = −.3_; P_ = .34; B). C, Correlation between parasite density at day 7.5, measured by qPCR, and anti-TRAP IgG antibody responses in group 2 (ME-TRAP; Spearman r = −0.5; P = .05). D, Correlation between interferon γ (IFN-γ)–secreting T-cell frequency to CS measured by enzyme-linked immunosorbent spot (ELISPOT) parasite density at day 7.5 (parasite/mL measured by qPCR) in group 1 (CS; Spearman r = −0.2; P = .50. E, Correlation between IFN-γ–secreting T-cell frequency to ME-TRAP measured by ELISPOT and parasite density at day 7.5 (parasite/mL measured by qPCR) in group 2 (ME-TRAP; Spearman r = 0.1; P = .6). Abbreviations: Black filled points, sterilely protected vaccinees; EU, enzyme-linked immunosorbent assay units; group 1, ChAd63-MVA CS; group 2, ChAd63-MVA ME-TRAP; ME-TRAP, multiple epitope–thrombospondin-related adhesion protein; PBMC, peripheral blood mononuclear cell; SFC, spot-forming cell; unfilled points, vaccinees demonstrating delay to start of antimalarial therapy in comparison to unvaccinated control volunteers.

References

    1. White NJ, Pukrittayakamee S, Hien TT, et al. Malaria. Lancet. 2014;383:723–35. - PubMed
    1. WHO World Malaria Report. 2013.
    1. 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. - PMC - PubMed
    1. 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. - PMC - PubMed
    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. - PMC - PubMed

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