Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were initially developed using the spike sequence from the ancestral strain, which is less effective against emerging variants of concern (VOCs). Therefore, updated vaccines have been developed to protect against the emergent VOCs.
GlaxoSmithKline (GSK) and Sanofi developed a bivalent vaccine (CoV2 preS dTM-AS03 [D614 + B.1.351]) containing stabilized pre-fusion spike proteins from the ancestral D614 strain and the Beta VOC (B.1.351) with the AS03 adjuvant system.
The vaccine is being assessed as a two-dose primary series in non-vaccinated individuals and as a booster in people with a prior infection. Results from the phase 2 study demonstrated robust immunogenicity and acceptable reactogenicity and safety in people naïve and non-naïve for SARS-CoV-2, supporting further evaluation.
Study: Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial. Image Credit: Dmitry Kovalchuk / Shutterstock
About the study
In the present study, researchers presented data on the clinical safety and efficacy of the bivalent CoV2 preS dTM-AS03 (D614 + B.1.351) vaccine as the primary series. This randomized, double-blind, phase 3, placebo-controlled trial had two stages. The first stage evaluated the efficacy of a prototype monovalent vaccine, and the second stage explored the bivalent vaccine. Data from the second stage were reported in this study.
Participants were recruited from eight countries between October 19, 2021, and February 15, 2022. Eligible subjects were non-vaccinated adults aged 18 or older. Data on medical history and race/ethnicity were self-reported at enrolment. Participants were randomized to receive the vaccine or placebo. The vaccine group received 0.5 ml injections containing 5 μg D614 and 5 μg B.1.351 antigens at days 1 and 22.
The placebo group received 0.9% normal saline. Nasopharyngeal swabs and blood specimens were obtained before each vaccination. Participants were contacted weekly to determine if they tested COVID-19-positive or had symptoms of a COVID-19-like illness. Naïve and non-naïve status was ascertained by electrochemiluminescence immunoassays.
Nucleic-acid amplification tests were performed to detect the viral nucleic acids in nasopharyngeal swabs. The primary endpoint was vaccine efficacy in preventing symptomatic COVID-19 ≥ 14 days after the second dose in all participants. Secondary endpoints were symptomatic illness in non-naïve and naïve subjects, disease severity, and hospitalization after the second dose.
The researchers enrolled and randomized 13,506 individuals and excluded 504 subjects from analyses due to incomplete data from Ukrainian sites. The vaccine group comprised 6,515 participants, and the placebo group had 6,490 subjects. The modified full analysis set included 11,416 participants who received two injections. In total, 12,924 subjects received at least one injection.
The mean age of participants was 36.1; 58.4% were males, and 32.2% had high-risk medical conditions. About 75% of participants were non-naïve at enrolment. Within the modified full analysis set, 121 cases of symptomatic COVID-19 were reported ≥ 14 days after the second dose, and the overall vaccine effectiveness was 64.7%. Placebo recipients showed a higher cumulative incidence of COVID-19 than vaccinees.
Five cases developed severe illness, 12 had moderate or worse illness, and two subjects required hospitalization. No deaths occurred due to COVID-19. Vaccine efficacy against symptomatic disease in non-naïve subjects was over 75%, but 30.9% in naïve subjects. Overall, the efficacy against symptomatic illness was 60.3% after the first dose. Efficacy against asymptomatic infection was 1.2%.
Vaccine efficacy was generally higher in males. The causal variant was determined in 68 cases, with the Omicron sub-variants (BA.1 and BA.2) causing 64 cases. The Omicron-specific efficacy was 72.5% in all subjects, 20.4% in naïve participants, and 93.9% in non-naïve individuals. There were five cases of the Delta variant, all in placebo recipients. Seven placebo recipients and four vaccinees had immediate unsolicited adverse events.
Solicited adverse reactions occurred in 1,398 vaccinees and 983 placebo subjects within seven days after any injection. Both groups had similar proportions of medically-attended adverse events. Adverse events of special interest, serious adverse events, and deaths occurred in less than 1% of participants and were unrelated to treatment. There were no reports of myocarditis, pericarditis, Guillain-Barré syndrome, Bell’s Palsy, or thrombosis with thrombocytopenia.
Taken together, the trial met the primary objective, demonstrating efficacy against symptomatic COVID-19. The effectiveness of 75.9% against symptomatic disease in non-naïve subjects is particularly relevant. The findings suggest the vaccine could be a potential booster at a time when most of the population is already exposed to the virus or vaccinated.
- Dayan GH, Rouphael N, Walsh SR, et al. Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3, parallel, randomized, modified double-blind, placebo-controlled trial. The Lancet Respiratory Medicine, 2023, DOI: 10.1016/S2213-2600(23)00263-1, https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00263-1/fulltext