RESUMEN
BACKGROUND: We report data from Stage 1 of an ongoing two-staged, phase I/II randomized clinical trial (NCT05073003) with a 4-component Generalized Modules for Membrane Antigens-based vaccine against Shigella sonnei and S. flexneri 1b, 2a and 3a (altSonflex1-2-3, GSK). METHODS: 18-50-year-old Europeans (N=102) were randomized (2:1) to receive two injections of altSonflex1-2-3 or placebo at 3- or 6-month interval. Safety and immunogenicity were assessed at pre-specified timepoints. RESULTS: The most common solicited administration-site event (until 7 days post-each injection) and unsolicited adverse event (until 28 days post-each injection) were pain (altSonflex1-2-3: 97.1%; Placebo: 58.8%) and headache (32.4%; 23.5%), respectively. All serotype-specific functional IgG antibodies peaked 14-28 days post-injection 1 and remained substantially higher than pre-vaccination at 3 or 6 months post-vaccination; the second injection did not boost but restored the initial immune response. The highest seroresponse rates (≥4-fold increase in titers over baseline) were obtained against S. flexneri 2a (ELISA: post-injection 1: 91.0%; post-injection 2 [Day {D}113; D197]: 100%; 97.0%; serum bactericidal activity (SBA): post-injection 1: 94.4%; post-injection 2: 85.7%; 88.9%) followed by S. sonnei (ELISA: post-injection 1: 77.6%; post-injection 2: 84.6%; 78.8%; SBA: post-injection 1: 83.3%; post-injection 2: 71.4%; 88.9%). Immune responses against S. flexneri 1b and S. flexneri 3a, as measured by both ELISA and SBA, were numerically lower compared to those against S. sonnei and S. flexneri 2a. CONCLUSIONS: No safety signals or concerns were identified. altSonflex1-2-3 induced functional serotype-specific immune responses, allowing further clinical development in the target population.
What is the context? Shigella bacteria cause severe and often bloody diarrhea, called shigellosis, that affects mostly young children and can be life-threatening. Shigellosis is particularly common in low- and middle-income countries due to inadequate sanitation and limited access to healthcare. Since the immune response to Shigella is serotype-specific, an ideal vaccine should include multiple Shigella serotypes to ensure broad protection. What is new? We developed a novel vaccine against Shigella that includes Shigella sonnei and three prevalent Shigella flexneri serotypes. In Stage 1 (phase I) of the study, healthy European adults received two vaccine injections given 3 or 6 months apart. We found that: The vaccine was well tolerated, and no safety signals or concerns were identified.Regardless of the interval between injections, specific antibodies were elicited against all four Shigella serotypes, with highest levels against Shigella flexneri 2a and Shigella sonnei.Functional antibody levels peaked after the first injection, remaining higher than the baseline up to 6 months. A second injection did not boost responses but restored functional antibody levels to those after the first injection. What is the impact? The vaccine can now be tested in Stage 2 (phase II) of the study in Africa, a region highly affected by shigellosis.
RESUMEN
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.