2 research outputs found
Immunogenicity, safety, and preliminary efficacy evaluation of OVX836, a nucleoprotein-based universal influenza A vaccine candidate : a randomised, double-blind, placebo-controlled, phase 2a trial
Background: OVX836, a recombinant vaccine containing the nucleoprotein of the influenza A virus A/WSN/1933 (H1N1) and the oligomerisation domain OVX313, has displayed a good safety profile and elicited dose-dependent humoral and cellular immune responses at 90 μg or 180 μg (intramuscularly) in previous clinical trials. The aim of this study was to explore higher doses, since no maximum tolerated dose had been reached.
Methods: In this phase 2a, randomised, double-blind, placebo-controlled study, we recruited 137 healthy adults aged 18-55 years in a single centre in Belgium. Participants were randomly assigned (interactive web response system; block size=4) using SAS (version 9.4) to receive one single intramuscular administration of OVX836 influenza vaccine at three doses (180 μg [n=33], 300 μg [n=35], and 480 μg [n=36]) or placebo (n=33). The two primary endpoints were the safety and the cell-mediated immune response to OVX836 at the three doses in terms of change of nucleoprotein-specific IFNγ spot forming cell (SFC) frequencies in the peripheral blood mononuclear cell (PBMC) population, measured by IFNγ ELISpot, at day 8 versus pre-injection baseline (day 1). The population used for the safety analysis is the modified intention-to-treat cohort. The population used for the immunogenicity analysis is the per-protocol cohort. This trial is registered with ClinicalTrials.gov, NCT05060887, and EudraCT, 2021-002535-39.
Findings: Participants were recruited between Nov 15, 2021, and Feb 1, 2022. OVX836 had a favourable safety profile up to 480 μg without reaching the maximum tolerated dose, and showed a good safety profile at all doses with mild local and systemic reactogenicity. 7 days after vaccination, although no significant differences were observed between the doses, OVX836 increased the frequency of nucleoprotein-specific IFNγ SFCs per million PBMCs from days 1 to 8 (primary endpoint): by 124 SFCs per 106 PMBCs (95% CI 67 to 180; p=0·002) at 180 μg; by 202 SFCs per 106 PMBCs (95% CI 138 to 267; p<0·0001) at 300 μg; by 223 SFCs per 106 PMBCs (95% CI 147 to 299; p<0·0001) at 480 μg; and decreased by 1 SFCs per 106 PMBCs (95% CI -24 to 22] in the placebo group (Kruskal-Wallis test p<0·0001 followed by Mann-Whitney's tests; per-protocol cohort). Dose-dependent and polyfunctional nucleoprotein-specific CD4 T-cell responses were observed, and CD8 T-cell responses were elicited at 300 μg and 480 μg (secondary endpoints).
Interpretation: OVX836 appears to be a safe and well tolerated candidate vaccine that elicits humoral and cellular nucleoprotein-specific immune responses (including CD8 T cells at the highest dose levels) and showed a preliminary signal of protection against influenza. Therefore, OVX836 is a promising vaccine candidate for universal influenza A prevention, that warrants further trials.
Funding: OSIVAX, Bpifrance, Wallonia Region, and the EUs Horizon 2020 Research and Innovation Program
Efficacy, safety, and immunogenicity of a booster regimen of Ad26.COV2.S vaccine against COVID-19 (ENSEMBLE2) : results of a randomised, double-blind, placebo-controlled, phase 3 trial
Background Despite the availability of effective vaccines against COVID-19, booster vaccinations are needed to maintain vaccine-induced protection against variant strains and breakthrough infections. This study aimed to investigate the efficacy, safety, and immunogenicity of the Ad26.COV2.S vaccine (Janssen) as primary vaccination plus a booster dose.
Methods ENSEMBLE2 is a randomised, double-blind, placebo-controlled, phase 3 trial including crossover vaccination after emergency authorisation of COVID-19 vaccines. Adults aged at least 18 years without previous COVID-19 vaccination at public and private medical practices and hospitals in Belgium, Brazil, Colombia, France, Germany, the Philippines, South Africa, Spain, the UK, and the USA were randomly assigned 1:1 via a computer algorithm to receive intramuscularly administered Ad26.COV2.S as a primary dose plus a booster dose at 2 months or two placebo injections 2 months apart. The primary endpoint was vaccine efficacy against the first occurrence of molecularly confirmed moderate to severe-critical COVID-19 with onset at least 14 days after booster vaccination, which was assessed in participants who received two doses of vaccine or placebo, were negative for SARS-CoV-2 by PCR at baseline and on serology at baseline and day 71, had no major protocol deviations, and were at risk of COVID-19 (ie, had no PCR-positive result or discontinued the study before day 71). Safety was assessed in all participants; reactogenicity, in terms of solicited local and systemic adverse events, was assessed as a secondary endpoint in a safety subset (approximately 6000 randomly selected participants). The trial is registered with ClinicalTrials.gov, NCT04614948, and is ongoing.
Findings Enrolment began on Nov 16, 2020, and the primary analysis data cutoff was June 25, 2021. From 34 571 participants screened, the double-blind phase enrolled 31 300 participants, 14 492 of whom received two doses (7484 in the Ad26.COV2.S group and 7008 in the placebo group) and 11 639 of whom were eligible for inclusion in the assessment of the primary endpoint (6024 in the Ad26.COV2.S group and 5615 in the placebo group). The median (IQR) follow-up post-booster vaccination was 36 center dot 0 (15 center dot 0-62 center dot 0) days. Vaccine efficacy was 75 center dot 2% (adjusted 95% CI 54 center dot 6-87 center dot 3) against moderate to severe-critical COVID-19 (14 cases in the Ad26.COV2.S group and 52 cases in the placebo group). Most cases were due to the variants alpha (B.1.1.7) and mu (B.1.621); endpoints for the primary analysis accrued from Nov 16, 2020, to June 25, 2021, before the global dominance of delta (B.1.617.2) or omicron (B.1.1.529). The booster vaccine exhibited an acceptable safety profile. The overall frequencies of solicited local and systemic adverse events (evaluated in the safety subset, n=6067) were higher among vaccine recipients than placebo recipients after the primary and booster doses. The frequency of solicited adverse events in the Ad26.COV2.S group were similar following the primary and booster vaccinations (local adverse events, 1676 [55 center dot 6%] of 3015 vs 896 [57 center dot 5%] of 1559, respectively; systemic adverse events, 1764 [58 center dot 5%] of 3015 vs 821 [52 center dot 7%] of 1559, respectively). Solicited adverse events were transient and mostly grade 1-2 in severity.
Interpretation A homologous Ad26.COV2.S booster administered 2 months after primary single-dose vaccination in adults had an acceptable safety profile and was efficacious against moderate to severe-critical COVID-19. Studies assessing efficacy against newer variants and with longer follow-up are needed. Funding Janssen Research & Development.
Copyright (c) 2022 The Author(s). Published by Elsevier Ltd