Safety and Immunogenicity of ChAd63/MVA Pfs25-IMX313 in a Phase I First-in-Human Trial

Abstract

Background: Transmission blocking vaccines targeting the sexual-stages of the malaria parasite could play a major role to achieve elimination and eradication of malaria. The Plasmodium falciparum Pfs25 protein (Pfs25) is the most clinically advanced candidate sexual-stage antigen. IMX313, a complement inhibitor C4b-binding protein that forms heptamers with the antigen fused to it, improve antibody responses. This is the first time that viral vectors have been used to induce antibodies in humans against an antigen that is expressed only in the mosquito vector.

Methods: Clinical trial looking at safety and immunogenicity of two recombinant viral vectored vaccines encoding Pfs25-IMX313 in healthy malaria-naive adults. Replication-deficient chimpanzee adenovirus serotype 63 (ChAd63) and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding Pfs25-IMX313, were delivered by the intramuscular route in a heterologous prime-boost regimen using an 8-week interval. Safety data and samples for immunogenicity assays were taken at various time-points.

Results: The reactogenicity of the vaccines was similar to that seen in previous trials using the same viral vectors encoding other antigens. The vaccines were immunogenic and induced both antibody and T cell responses against Pfs25, but significant transmission reducing activity (TRA) was not observed in most volunteers by standard membrane feeding assay.

Conclusion: Both vaccines were well tolerated and demonstrated a favorable safety profile in malaria-naive adults. However, the transmission reducing activity of the antibodies generated were weak, suggesting the need for an alternative vaccine formulation.

Trial registration: Clinicaltrials.gov NCT02532049.

Keywords: IMX313; Pfs25; malaria; transmission-blocking; vaccine.

Figure 1

VAC062 flow chart of study design and volunteer recruitment. The VAC062 study took place between October 2015 and May 2017. All immunizations were administered intramuscularly (IM) with sequential vaccines administered into the deltoid muscle of the non-dominant arm.

Figure 2

Solicited AEs following vaccination with ChAd63 and MVA Pfs25-IMX313. The solicited local and systemic adverse events (AEs) recorded for 7 days following ChAd63 Pfs25-IMX313 and MVA Pfs25-IMX313 are shown at the maximum severity reported by all volunteers. (A) Five volunteers received 5 × 10⁹ viral particles (vp) (Group 1), and (B) 21 received 5 × 10¹⁰ vp (Group 2) of ChAd63 Pfs25-IMX313. (C) Eight of the Group 2 volunteers went on to receive 1 × 10⁸ plaque-forming units (pfu) (Group 2B), or (D) Eight Group 2 volunteers received 2 × 10⁸ pfu (Group 2C) of MVA Pfs25-IMX313.

Figure 3

Ex-vivo IFN-γ T cell response against Pfs25 and IMX313. (A) Median ex vivo IFN-γ ELISPOT responses in PBMCs to the Pfs25 insert (summed response across all the individual peptide pools) are shown for all groups. Individual responses are shown in Supplementary Figure 1 . Median and individual responses are shown at (B) day 14, (C) day 63, and (D) day 140. Symbols are coded according to group. *P < 0.05. Responses between Groups 1 (n = 4) and 2 (n = 20) at day 14, and between Groups 2B (n = 7) and 2C (n = 8) at day 140 were assessed by Mann-Whitney test (B, D); responses between groups 2A (n = 4), 2B (n = 7), and 2C (n = 8) at day 63 were assessed by Kruskal-Wallis test with Dunn’s multiple comparison test (C). (E) Median ex vivo IFN-γELISPOT responses in PBMCs to the IMX313 insert (summed response across a single peptide pool) shown for all groups. SFU, spot-forming units.

Figure 4

Serum antibody response against Pfs25. (A) Median anti–Pfs25 serum total IgG responses shown for all groups over time. Median and individual responses are shown at (B, C) day 28, (D) day 74, and (E) day 140. The horizontal dotted line indicates the limit of detection of the assay. Symbols are coded according to group. *P < 0.05, **P < 0.01. Responses between Groups 1 and 2 were assessed by Mann-Whitney test (B). Responses in groups 2A (n = 4), 2B (n = 8), and 2C (n = 8) were assessed by Kruskal-Wallis test with Dunn’s multiple comparison test.

Figure 5

B cell response to vaccination. (A) Pfs25 and IMX313 –specific antibody-secreting cell (ASC) responses were assessed by ex-vivo ELISPOT using Pfs25 and IMX313 proteins and frozen PBMCs from the day 63 time point in Groups 2B and 2C. Individual and median responses are shown for each group and reported as Pfs25 and IMX313 –specific ASCs per million PBMCs used in the assay, or as (B) percentage of total number of IgG-secreting cells. (C) Pfs25 and IMX313 –specific memory B cell (mBC) responses were assessed by ELISPOT assay using Pfs25 and IMX313 proteins. Frozen PBMCs were thawed and underwent a 6-day polyclonal re-stimulation during which ASCs were derived from mBCs, before testing in the assay. Individual and median responses are shown from the day 74 and day 84 time point and are reported as mBC-derived Pfs25–specific ASCs per million cultured PBMCs or as (D) percentage of total number of IgG-secreting cells.

Figure 6

Transmission-reducing activity (TRA) in Groups 2B and 2C as measured by standardized membrane feeding assay. (A) Transmission-reducing activity of IgG from individuals of Group 2B. (B, C) Transmission-reducing activity of IgG from individuals of Group 2C. (D) Correlation between anti-Pfs25 specific IgG concentrations and TRA in individual of Groups 2B (in red) and 2C (in black); subject ID showing significant transmission-reducing activity is indicated. Total IgG was purified from D72 serum from volunteers vaccinated with ChAd63/MVA expressing Pfs25-IMX313. The purified IgG (15 mg/mL) was mixed with P. falciparum NF54 cultured gametocytes and fed to A. stephensi mosquitoes (n = 20 per test group) in SMFA. Midguts were dissected 7 days post-feeding. A pool of D0 vector immunized Group 2C volunteers was used as negative control.