Karen Joyce Hager, Gonzalo Pérez Marc, Philipe Gobeil, Ricardo Sobhie Diaz, Gretchen Heizer, Conrado Llapur, Alexander I. Makarkov, Eduardo Vasconcellos, Stephane Pillet, Fernando Riera, Kapil Bhutada, Priscila Geller Wolff, Garry Wallace, Hessam Aazami, Christine E Jones, Fernando P. Polack, Judith Atkins, Iohann Boulay, Jiwanjeet Dhaliwall, Nathalie Charland, Manon Couture, Julia Jiang-Wright, Nathalie Landry, Sophie Lapointe, Aurélien Lorin, Asif Mahmood, Lawrence H Moulton, Emmy Pahmer, Julie Parent, Pooja Saxena, Annie Seguin, Luan Tran, Thomas Breuer, Maria Angeles Ceregido, Marguerite Koutsoukos, Francois Roman, Junya Namba, Marc-André D'Aoust, Sonia Trepanier, Yosuke Kimura, The CoVLP Study Team, Brian J Ward
Abstract
Background: Several COVID-19 vaccines are currently being deployed but supply constraints, concerns over durability of immune responses, solidifying vaccine hesitancy/resistance and vaccine efficacy in the face of emerging variants mean that new vaccines continue to be needed to fight the ongoing pandemic. The vaccine described here is an enveloped, coronavirus-like particle produced in plants (CoVLP) that displays the prefusion-stabilized spike (S) glycoprotein of SARS-CoV-2 (ancestral Wuhan strain) and is adjuvanted with AS03 (CoVLP+AS03). Methods: This Phase 3 randomized, observer-blind, placebo-controlled trial was conducted at 85 centers in Argentina, Brazil, Canada, Mexico, the UK, and the USA. Adults ≥18 years of age including those at high risk for COVID-19 complications were randomly assigned 1:1 to receive two intramuscular injections of CoVLP (3.75 μg) adjuvanted with AS03 or placebo, 21 days apart. The primary efficacy endpoint was prevention of symptomatic (≥ 1 symptom), PCR-confirmed SARS-CoV-2 infection with onset at least 7 days after the second injection and was triggered by the identification of ≥160 virologically-confirmed cases. Tolerability and safety of CoVLP+AS03 were also determined. Results: A total of 24,141 volunteers were randomly assigned 1:1 to receive vaccine or placebo (N= 12,074 and 12,067, respectively: median age 29, range 18 to 86 years). Overall, 83% received both doses. 14.8% were SARS-CoV-2 seropositive at baseline. Symptomatic SARS-CoV-2 infection was confirmed in 165 study participants in the intention to treat (ITT) set and 157 in the per-protocol population (PP) set. Of the 157 in the PP set, 118 COVID-19 cases were in the placebo group and 39 COVID-19 cases were in the CoVLP+AS03 group for an overall vaccine efficacy (VE) of 71.0% (95% confidence interval (CI) 58.6, 80.0). Moderate-to-severe COVID-19 occurred in 8 and 32 participants in the CoVLP+AS03 and placebo groups, respectively: VE 78.1% (95% CI: 53.9, 90.5) in the PP set overall and 84.5% (95% CI: 62.0, 94.7) in those seronegative at recruitment. To date, 100% of the sequenced strains (122/165 cases: 73.39%) were variants, dominated by Delta (45.9%) and Gamma (43.4%) strains. Vaccine efficacy by variant was 75.3% (95% CI 52.8, 87.9) against Delta and 88.6% (95% CI 74.6, 95.6) against Gamma. Cross-protection was also observed against Alpha, Lambda and Mu variants; although fewer cases were identified, all were in the placebo group. At diagnosis, viral loads in the CoVLP+AS03 breakthrough cases were >100-fold lower than in the placebo cases. Reactogenicity data for solicited adverse events (AEs) was analysed for a subset (N=4,136 in vaccine arm and N=3,683 for placebo) of participants. Reactogenicity was mostly mild to moderate, and transient, and occurred more frequently in the CoVLP+AS03 group. The safety analysis set used for unsolicited AE assessment comprised 24,076 participants who received at least one study injection: 12,036 received CoVLP+AS03 and 12,040 received placebo. All serious adverse events were assessed as unrelated, except two events reported in the same subject in the placebo group. No significant imbalance or safety concern was noted in medically attended AEs (MAAEs), adverse event of special interest (AESIs), AEs leading to withdrawal, deaths, or adverse events potentially associated with currently authorized vaccines. Conclusions: The CoVLP+AS03 vaccine candidate conferred an efficacy of 71.0% in preventing symptomatic SARS-CoV-2 infection caused by a spectrum of variants. Vaccine efficacy of 78.1% was observed against moderate and severe disease, while variant-specific efficacy ranged from 75.3% to 100%. Markedly lower viral loads in the CoVLP+AS03 group at the time of diagnosis suggests a significant virologic impact of vaccination even in the breakthrough cases. CoVLP+AS03 vaccine candidate was well tolerated, and no safety concerns were identified during the study. If approved by regulators, this more traditional protein+adjuvant vaccine produced using the novel plant-based platform may be able to make an important contribution to the global struggle against the increasingly complex family of SARS-CoV-2 viruses (Funded by Medicago with grants from the governments of Quebec and Canada; NCT04636697).
Competing Interest Statement
During the period of the study KJH, PG, GH, AIM, SP, KB, JA, IB, JD, NC, MC, JJW, NL, SL, AL, AM, EP, JP, PS, AS, LT, JN, MAD, ST, YK, BJW were either employees of Medicago Inc. or received salary support from Medicago Inc. TB, MAC, MK, FR are employed by the GlaxoSmithKline (GSK) group of companies and hold restricted shares in the group of companies. LHM received compensation from Medicago as a consultant.
Clinical Trial
NCT04636697
Clinical Protocols
https://clinicaltrials.gov/ct2/show/NCT04636697
Funding Statement
The study was sponsored by Medicago Inc.
https://www.medrxiv.org/content/10.1101/2022.01.17.22269242v1
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