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 SARSCoV-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 mu g 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 naive 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 naive 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 naive and 7159 non naive participants. At the cut-off date (January 28, 2022), symptomatic COVID-19 was reported in 169 naive 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-naive 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 naive 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 naive 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.