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[Preprint]. 2023 Jan 13:2022.12.05.22282933.
doi: 10.1101/2022.12.05.22282933.

Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 Protein Vaccine

Gustavo H Dayan  1 , Nadine Rouphael  2 , Stephen R Walsh  3 , Aiying Chen  1 , Nicole Grunenberg  4 , Mary Allen  5 , Johannes Antony  6 , Kwaku Poku Asante  7 , Amit Suresh Bhate  8 , Tatiana Beresnev  5 , Matthew I Bonaparte  1 , Maria Angeles Ceregido  9 , Dmytro Dobrianskyi  10 , Bo Fu  1 , Marie-Helene Grillet  11 , Maryam Keshtkar-Jahromi  12   13 , Michal Juraska  4 , Jia Jin Kee  4 , Hannah Kibuuka  14 , Marguerite Koutsoukos  9 , Roger Masotti  1 , Nelson L Michael  15 , Humberto Reynales  16 , Merlin L Robb  17 , Sandra M Villagómez Martínez  18 , Fredrick Sawe  19 , Lode Schuerman  9 , Tina Tong  5 , John Treanor  20 , T Anh Wartel  21 , Carlos A Diazgranados  1 , Roman M Chicz  22 , Sanjay Gurunathan  1 , Stephen Savarino  1 , Saranya Sridhar  23 ; VAT00008 study team
Affiliations

Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 Protein Vaccine

Gustavo H Dayan et al. medRxiv. .

Abstract

Background: COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern.

Methods: We conducted a global Phase 3, multi-stage efficacy study (NCT04904549) among adults aged ≥18 years. Participants were randomized 1:1 to receive two intramuscular injections 21 days apart of a bivalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (5 μg of ancestral (D614) and 5 μg of B.1.351 [beta] variant spike protein) or placebo. Symptomatic COVID-19 was defined as laboratory-confirmed COVID-19 with COVID-19-like illness (CLI) symptoms. The primary efficacy endpoint was the prevention of symptomatic COVID-19 ≥14 days after the second injection (post-dose 2 [PD2]).

Results: Between 19 Oct 2021 and 15 Feb 2022, 12,924 participants received ≥1 study injection. 75% of participants were SARS-CoV-2 non-naïve. 11,416 participants received both study injections (efficacy-evaluable population [vaccine, n=5,736; placebo, n=5,680]). Up to 15 March 2022, 121 symptomatic COVID-19 cases were reported (32 in the vaccine group and 89 in the placebo group) ≥14 days PD2 with a vaccine efficacy (VE) of 64.7% (95% confidence interval [CI] 46.6; 77.2%). VE was 75.1% (95% CI 56.3; 86.6%) in non-naïve and 30.9% (95% CI -39.3; 66.7%) in naïve participants. Viral genome sequencing identified the infecting strain in 68 cases (Omicron [BA.1 and BA.2 subvariants]: 63; Delta: 4; Omicron and Delta: 1). The vaccine was well-tolerated and had an acceptable safety profile.

Conclusions: A bivalent vaccine conferred heterologous protection against symptomatic infection with newly emergent Omicron (BA.1 and BA.2) in non-naïve adults 18-59 years of age.

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Conflict of interest statement

Declaration of interests GHD, MIB, BF, M-HG, CAG, RMC, SS are Sanofi employees. MIB, BF, M-HG, CAG, RMC, SS hold stock or stock options in Sanofi. SS hold patents pending on COVID-19 vaccine. 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. M-HG has received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events 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 Immunology/National Institutes of Health; and institutional grants or contracts from Janssen Vaccines/Johnson & Johnson, Moderna Tx, 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 funding from Sanofi, GSK and the National Institute of Allergy and Immunology/National Institutes of Health; and is in receipt of grants or contracts from the NIH/NIAID/DAIDS. MA is an employee of the NIAID, which funded aspects of the current study. MAC and MK are employees of GSK and owns shares in the GSK group of companies. LS is an employee of 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 is an employee 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). SSa was a Sanofi employee at the time of study conduct; and holds patents planned, issued of pending on COVID-19 vaccines. AC, JA KPA, ASB, TB, DD, MKJ, HK, RM, NM, HR, SMVM, FS, JT, TAW, SG have no interests to declare.

Figures

Figure 1:
Figure 1:
CONSORT diagram for patient flow through the study Data are presented as number (%). *V1 for one participant did not appear in the database during the data extraction dated 09 June 2022 because the site was entering additional data for V01 at the time the data extraction was performed. However, this participant was included in mFAS-PD1, mFAS-PD2, mFAS-PD2 Non-naïve-D01/D22 analysis sets because both V01 and V02 were performed. Abbreviations: AE, adverse event. NP, nasopharyngeal. PD2, post dose 2. V, visit.
Figure 2:
Figure 2:
Variant distribution by country and calendar time in all participants, regardless of prior SARS-CoV-2 infections (mFAS-PD2)
Figure 3:
Figure 3:
Forest plots for efficacy outcomes against symptomatic disease in all participants and subgroups caused by (A) all variants and (B) for the Omicron variant A. Efficacy outcomes overall and by subgroups for the mFAS-PD2 analysis subset. The success criteria for demonstration of efficacy was defined as a point estimate >50% (black dotted line) and a lower bound confidence interval >30% (grey dotted line). Outcomes with too few cases to reliably calculate vaccine efficacy (severe COVID-19, moderate or worse COVID-19, hospitalization, and symptomatic COVID-19 in participants aged ≥60 years) are not shown. B. Vaccine efficacy is shown for all sequence-confirmed Omicron cases and for the sensitivity analysis, which included sequence confirmed cases and cases for which there were no sequencing results, assuming that the latter group were caused by the Omicron variant as this was the variant that was responsible for most of the symptomatic COVID-19 cases at the time of the study. The success criteria for demonstration of efficacy was defined as a point estimate >50% (black dotted line) and a lower bound confidence interval >30% (grey dotted line). Owing to the low number of cases due to the Delta variant, these are not shown in the Forest plot.
Figure 3:
Figure 3:
Forest plots for efficacy outcomes against symptomatic disease in all participants and subgroups caused by (A) all variants and (B) for the Omicron variant A. Efficacy outcomes overall and by subgroups for the mFAS-PD2 analysis subset. The success criteria for demonstration of efficacy was defined as a point estimate >50% (black dotted line) and a lower bound confidence interval >30% (grey dotted line). Outcomes with too few cases to reliably calculate vaccine efficacy (severe COVID-19, moderate or worse COVID-19, hospitalization, and symptomatic COVID-19 in participants aged ≥60 years) are not shown. B. Vaccine efficacy is shown for all sequence-confirmed Omicron cases and for the sensitivity analysis, which included sequence confirmed cases and cases for which there were no sequencing results, assuming that the latter group were caused by the Omicron variant as this was the variant that was responsible for most of the symptomatic COVID-19 cases at the time of the study. The success criteria for demonstration of efficacy was defined as a point estimate >50% (black dotted line) and a lower bound confidence interval >30% (grey dotted line). Owing to the low number of cases due to the Delta variant, these are not shown in the Forest plot.
Figure 4:
Figure 4:
Kaplan-Meier cumulative incidence of symptomatic COVID-19 in the mFAS-PD2 population (overall, naïve and non-naïve populations)
Figure 4:
Figure 4:
Kaplan-Meier cumulative incidence of symptomatic COVID-19 in the mFAS-PD2 population (overall, naïve and non-naïve populations)
Figure 4:
Figure 4:
Kaplan-Meier cumulative incidence of symptomatic COVID-19 in the mFAS-PD2 population (overall, naïve and non-naïve populations)
Figure 5:
Figure 5:
(A) Proportion of participants with solicited injection site reactions within 7 days of each study injection in participants aged 18–59 years and participants aged ≥60 years; (B) the proportion of participants with solicited systemic reactions within 7 days of each study injection in participants aged 18–59 years and participants aged ≥60 years
See this image and copyright information in PMC

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