The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines were initially developed using the spike sequence of the ancestral strain, which is less effective against emerging variants of concern (VOCs). Therefore, updated vaccines have been developed to protect against emerging VOCs.
GlaxoSmithKline (GSK) and Sanofi developed a bivalent vaccine (CoV2 preS dTM-AS03 (D614+B.1.351)) containing stabilized prefusion spike proteins of the ancestral strain D614 and the Beta VOC (B.1.351) with the AS03 adjuvant system.
The vaccine is being evaluated as a two-dose primary series in unvaccinated people and as a booster in people with a previous infection. Results from the phase 2 study demonstrated robust immunogenicity and acceptable reactogenicity and safety in SARS-CoV-2 naïve and naïve individuals, supporting further evaluation.
Study: Efficacy of a Bivalent Recombinant Protein Vaccine (D614+B.1.351) Against SARS-CoV-2 with AS03 Adjuvant in Adults: A Phase 3, Parallel, Randomized, Modified Double-Blind, Placebo-Controlled Trial. Image Credit: Dmitry Kovalchuk/Shutterstock
About the study
In the present study, the investigators presented data on the clinical safety and efficacy of the bivalent CoV2 preS dTM-AS03 (D614 + B.1.351) vaccine as a primary series. This randomized, double-blind, phase 3, placebo-controlled trial had two stages. The first stage evaluated the efficacy of a monovalent vaccine prototype and the second stage explored the bivalent vaccine. Data from the second stage were reported in this study.
Participants were recruited in eight countries between October 19, 2021 and February 15, 2022. Eligible subjects were unvaccinated adults aged 18 years or older. Data on medical history and race/ethnicity were self-reported at enrollment. Participants were randomly assigned to receive the vaccine or placebo. The vaccine group received 0.5 ml injections containing 5 μg of D614 antigens and 5 μg of B.1.351 on days 1 and 22.
The placebo group received 0.9% normal saline. Nasopharyngeal swabs and blood samples were obtained before each vaccination. Participants were contacted weekly to determine whether they tested positive for COVID-19 or had symptoms of a COVID-19-like illness. Naïve and non-naïve status was determined by electrochemiluminescence immunoassays.
Nucleic acid amplification tests were performed to detect viral nucleic acids in nasopharyngeal swabs. The primary endpoint was vaccine effectiveness in preventing symptomatic COVID-19 ≥ 14 days after the second dose in all participants. Secondary endpoints were symptomatic disease in non-naïve and naïve subjects, disease severity, and hospitalization after the second dose.
The researchers enrolled and randomized 13,506 people and excluded 504 subjects from analyzes due to incomplete data from Ukrainian sites. The vaccine group had 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 average age of the participants was 36.1 years; 58.4% were men and 32.2% had high-risk medical conditions. About 75% of participants were naïve at the time of enrollment. Within the modified full analysis set, 121 cases of symptomatic COVID-19 were reported ≥14 days after the second dose, and overall vaccine efficacy was 64.7%. Placebo recipients showed a higher cumulative incidence of COVID-19 than vaccinated recipients.
Five cases developed severe disease, 12 had moderate or worse disease, and two subjects required hospitalization. There were no deaths due to COVID-19. The efficacy of the vaccine against symptomatic diseases in non-naïve subjects was greater than 75%, but 30.9% in naïve subjects. Overall, efficacy against symptomatic disease was 60.3% after the first dose. Efficacy against asymptomatic infection was 1.2%.
Vaccine effectiveness was generally higher in men. The causal variant was determined in 68 cases, and the Omicron subvariants (BA.1 and BA.2) caused 64 cases. The specific efficacy of Omicron was 72.5% in all subjects, 20.4% in treatment-naïve participants, and 93.9% in treatment-naïve individuals. There were five cases of the Delta variant, all in placebo recipients. Seven placebo recipients and four vaccine recipients had unsolicited immediate adverse events.
Solicited adverse reactions occurred in 1,398 vaccinees and 983 placebo subjects within seven days of any injection. Both groups had similar proportions of medically managed adverse events. Adverse events of particular interest, serious adverse events, and deaths occurred in less than 1% of participants and were not related to treatment. There were no reports of myocarditis, pericarditis, Guillain-Barré syndrome, Bell’s palsy, or thrombosis with thrombocytopenia.
Overall, the trial met the primary objective: to demonstrate efficacy against symptomatic COVID-19. The effectiveness of 75.9% against symptomatic diseases 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