Safety and immunogenicity against ancestral, Delta and Omicron virus variants following a booster dose of an inactivated whole-virus COVID-19 vaccine (VLA2001): Interim analysis of an open-label extension of the randomized, controlled, phase 3 COV-COMPARE trial

Objectives: Booster doses for COVID-19 vaccinations have been shown to amplify the waning immune re-sponse after primary vaccination and to enhance protection against emerging variants of concern (VoCs). Here, we aimed to assess the immunogenicity and safety of a booster dose of an inactivated whole-virus COVID-19 vaccine (VLA2001) after primary vaccination with 2 doses of either VLA2001 or ChAdOx1-S (Oxford-Astra Zeneca), including the cross-neutralization capacity against the Delta and Omicron VoCs. Methods: This interim analysis of an open-label extension of a randomized, controlled phase 3 trial assessed a single booster dose of an inactivated whole-virus COVID-19 vaccine (VLA2001) in healthy or medically stable adults aged 18 years and above, recruited in 21 clinical sites in the UK, who had previously received two doses of either VLA2001 or ChAdOx1-S. Safety outcomes were frequency and severity of solicited in-jection site and systemic reactions within 7 days after booster vaccination as well as frequency and severity of any unsolicited adverse events (AE) after up to 6 months. Immunogenicity outcomes were the immune response to ancestral SARS-CoV-2 assessed 14 days post booster expressed as geometric mean titres (GMT), GMT fold ratios and seroconversion of specific neutralizing antibodies and S-protein binding IgG antibodies. Immunogenicity against the Delta and Omicron VoCs was assessed as a post-hoc outcome with a pseu-dovirus neutralization antibody assay. This study is registered with ClinicalTrials.gov, NCT04864561, and is ongoing.Results: A booster dose of VLA2001 was administered to 958 participants, of whom 712 had been primed with VLA2001, and 246 with ChAdOx1-S. Within 7 days following these booster doses, 607 (63.4%) parti-cipants reported solicited injection site reactions, and 487 (50.8%) reported solicited systemic reactions. Up to 14 days post booster, 751 (78.4%) participants reported at least one adverse event. The tolerability profile of a booster dose of VLA2001 was similar in VLA2001-primed and ChAdOx1-S-primed participants. In VLA2001-primed participants, the GMT (95% CI) of neutralizing antibodies increased from 32.5 (22.8, 46.3) immediately before to 521.5 (413.0, 658.6) 2 weeks after administration of the booster dose, this corresponds to a geometric mean fold rise (GMFR) of 27.7 (20.0, 38.5). Compared to 2 weeks after the second priming dose, the GMFR was 3.6 (2.8, 4.7). In the ChAdOx1-S primed group, the GMT (95% CI) of neutralizing antibodies increased from 65.8 (43.9, 98.4) immediately before to 188.3 (140.3, 252.8) 2 weeks after administration of the booster dose, a geometric mean fold rise (GMFR) of 3.0 (2.2, 4.0). Compared to 2 weeks after the second priming dose, the GMFR was 1.6 (1.1, 2.2). For S-protein binding IgG antibodies, the pre versus post-booster GMT fold ratio (95% CI) was 34.6 (25.0, 48.0) in the VLA2001-primed group and 4.0 (3.0, 5.2) in the ChAdOx1-S-primed group. Compared to 2 weeks after the second priming dose, the GMT fold rise of IgG antibodies was 3.8 (3.2, 4.6) in the VLA2001-primed group and 1.2 (0.9, 1.6) in the ChAdOx1-S-primed group. The GMT against Delta (B.1.617.2) and Omicron (BA.4/5) increased from 4.2 to 260, and from 2.7 to 56.7, respectively, when boosting subjects previously primed with VLA2001. Following the boost, 97% of subjects primed with VLA2001 had detectable Delta-and 94% Omicron-neutralizing antibodies. In subjects primed with ChAdOx1-S, the GMT against Delta and Omicron titres increased from 9.1 to 92.5, and from 3.6 to 12.3, respectively. After boosting, 99% of subjects primed with ChAdOx1-S had detectable Delta-and 70% Omicron-neutralizing antibodies. In both VLA2001 and ChAdOx1-S primed subjects, the additional VLA2001 dose boosted T cell responses against SARS-CoV-2 antigens to levels above those observed before the booster dose.Conclusion: A booster dose of VLA2001 was safe and well tolerated after primary immunization with VLA2001 and ChAdOx1-S. The tolerability of a booster dose of VLA2001 was similar to the favourable profile observed after the first and second priming doses. Both in a homologous and a heterologous setting, boosting resulted in higher neutralizing antibody titres than after primary immunization and significant increases in cross-neutralization titres against Delta and Omicron were observed after the booster dose. These data support the use of VLA2001 in booster programmes in ChadOx1-S primed groups.& COPY; 2023 Published by Elsevier Ltd on behalf of The British Infection Association.