Efficacy of a monovalent (D614) SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3, multi-country study.

Background: The literature on first generation COVID-19 vaccines show they were less effective against new SARS-CoV-2 variants of concern including Omicron (BA.1, BA.2, BA.4 and BA.5 subvariants). New vaccines developed against variant strains may provide cross-protection against emerging variants when used as boosters and facilitate vaccination across a range of countries, healthcare settings and populations. However, there are no data on such vaccines when used as a primary series.
Methods: A global Phase 3, multi-stage efficacy study (NCT04904549) among adults (≥18 years) was conducted in 53 research centres in eight countries (United States, Honduras, Japan, Colombia, Kenya, India, Ghana, Nepal). Participants were randomized 1:1 to receive two intramuscular injections of a monovalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (10 μg of the spike (S) protein from the ancestral D614 strain) or placebo on Day 1 (D01) and Day 22 (D22). The primary efficacy endpoint was prevention of virologically confirmed SARS-CoV-2 infection with symptoms of COVID-19-like illness (CLI) ≥14 days after the second injection (post-dose 2 [PD2]) in participants who were SARS-CoV-2 naïve on D01 + D22. Safety and reactogenicity were also evaluated.
Findings: Between May 26 and November 7, 2021, 10,114 participants received ≥1 study injection, and 9441 participants received both injections. 2108 (20.8%) participants were SARS-CoV-2 naïve at D01 and D22. The primary endpoint was analysed in a subset of the full analysis set (the modified full analysis set PD2 [mFAS-PD2], excluding participants who did not complete the vaccination schedule or received vaccination despite meeting one of the contraindication criteria, had onset of symptomatic COVID-19 between the first injection and before 14 days after the second injection, or participants who discontinued before 14 days after the second injection [n = 9377; vaccine, n = 4702; placebo, n = 4675]). Data were available for 2051 SARS-CoV-2 naïve and 7159 non-naïve participants. At the cut-off date (January 28, 2022), symptomatic COVID-19 was reported in 169 naïve participants (vaccine, n = 81; placebo, n = 88) ≥14 days PD2, with a vaccine efficacy (VE) of 15.3% (95% CI, -15.8; 38.2). VE regardless of D01/D22 serostatus was 32.9% (95% CI, 15.3; 47.0) and VE in non-naïve participants was 52.7% (95% CI, 31.2; 67.9). Viral genome sequencing was performed up to the data cut-off point and identified the infecting strain in 99/169 adjudicated cases in the PD2 naïve population (Delta [25], Omicron [72], other variants [3], one participant had infection with both Delta and Omicron variants and has been included in the totals for both Delta and Omicron). The vaccine was well-tolerated with an acceptable safety profile.
Interpretation: In the context of changing circulating viral variants, it is challenging to induce protection in naïve individuals with a two-dose priming schedule based on the parental D614 strain. However, while the primary endpoint of this trial was not met, the results show that a monovalent D614 vaccine can still be of value in individuals previously exposed to SARS-CoV-2.
Funding: This study was funded in whole or in part by Sanofi and by federal funds from the Biomedical Advanced Research and Development Authority, part of the office of the Administration for Strategic Preparedness and Response at the U.S. Department of Health and Human Services under contract number HHSO100201600005I, and in collaboration with the U.S. Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense under contract number W15QKN-16-9-1002. The views presented here are those of the authors and do not purport to represent those of the Department of the Army, the Department of Health and Human Services, or the U.S. government.
Competing Interests: GHD, JA, MIB, MC, M-HG, JA, CAD, RMC, MC and SSa are Sanofi employees. JA, MIB, M-HG, JA, CAD, RMC, MC, CAD, SSr and SSa hold stock or stock options in Sanofi. SSr and SSa are the named inventors on a patent associated with the vaccine reported in this manuscript. RMC has received institutional funding from BARDA for the present study; has received support for attending meetings and/or travel from Sanofi; and holds patents planned, issued or pending from Sanofi. NR has received institutional funding from the National Institutes of Health; and institutional grants or contracts from Merck, Sanofi, Quidel, Pfizer and Lilly. SRW has received institutional funding from Sanofi and the National Institute of Allergy and Infectious Diseases/National Institutes of Health; and institutional grants or contracts from Janssen Vaccines/Johnson & Johnson, Moderna Tx, Pfizer, Vir Biotechnology and Worcester HIV Vaccine; has participated on data safety monitoring or advisory boards for Janssen Vaccines/Johnson & Johnson; and his spouse holds stock/stock options in Regeneron Pharmaceuticals. NG has received institutional grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID). LS, MAC and MK are employees of the GSK group of companies and own shares in the GSK group of companies. MJ and JJK have received institutional support from Sanofi and the NIAID/NIH with respect to this study. MLR has received institutional support/contracts for the present manuscript from WRAIR IPA and the US Medical Research and Development Command. MA, and MKJ are employees of the NIAID, which funded aspects of the current study; The NIAID provides grant funding to the HIV Vaccine Trials Network (HVTN) Leadership and Operations Center (UM1 AI 68614HVTN), the Statistics and Data Management Center (UM1 AI 68635), the HVTN Laboratory Center (UM1 AI 68618), the HIV Prevention Trials Network Leadership and Operations Center (UM1 AI 68619), the AIDS Clinical Trials Group Leadership and Operations Center (UM1 AI 68636), and the Infectious Diseases Clinical Research Consortium leadership group 5 (UM1 AI 148684-03). One of the sites in Kenya in this study received funding from NIAID. LC has received grant funding from the NIAD/NIH. The Center for Vaccine Development and Global Health (CVD) receives grants from Pfizer to conduct clinical trials of COVID-19 vaccines: KMN receives no salary support for this grant. KMN receives grants from NIH to participate in overall organization of COVID vaccine trials and for participation in vaccine trials. ASB has received honorarium for the conduct of this trial as Principal Investigator from Sanofi Healthcare India Private Limited. TT, SK, BF, AC, KPA, TB, RM, NLM, HR, FS, JT, SG, KS, AU and RS have no interests to declare.
(© 2023 The Author(s).)