Efficacy and Safety of a Recombinant Plant-Based Adjuvanted Covid-19 Vaccine

Abstract

Background: Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine.

Methods: In this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases.

Results: A total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%).

Conclusions: The CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697.).

Figure 1. Enrollment, Randomization, and Analysis Populations.

The data-cutoff date for the primary vaccine efficacy analysis was August 20, 2021. Of the 25,170 participants who were recruited, 24,141 underwent randomization in the intention-to-treat population. These participants had no virologic evidence of Covid-19 before receiving the trial injection. The safety population included 24,076 participants who had received one or more trial injections. The per-protocol population included 20,090 participants who had received two trial injections as scheduled and had no major protocol deviations. Participants may have discontinued their involvement in the trial after qualification as part of the per-protocol population (shown in the bottom set of boxes). An additional 10 participants withdrew from the study (4 in the vaccine group and 6 in the placebo group), and the timing of their discontinuation (by day 21, by day 42, or after day 42) could not be ascertained with confidence.

Figure 2. Vaccine Efficacy, According to Subgroup and Variant.

Shown are the results of the efficacy analysis of the CoVLP+AS03 vaccine in preventing Covid-19 according to subgroup of participants (Panel A) and according to variant (Panel B) in the intention-to-treat population; 22 samples had not yet been sequenced. In both panels, the incidence rate was calculated as the number of cases per person-year. Variant-specific values probably overestimate the true vaccine efficacy, since cases that were positive on polymerase-chain-reaction (PCR) assay but had no available sequencing data were asymmetrically distributed (14 in the vaccine group and 7 in the placebo group). The implications of these missing data for the variant-specific efficacy estimates are discussed in the Supplementary Appendix. Race or ethnic group was reported by the participants. NA denotes not applicable.

Figure 3. Cumulative Incidence of Covid-19, According to Population and Presence of Variants.

Shown is the cumulative incidence of adjudicated Covid-19 in the intention-to-treat population (Panel A), in the per-protocol population (Panel B), and according to the presence of the delta or gamma variant in the intention-to-treat population (Panel C), starting 7 days after the second vaccination. Covid-19 cases were confirmed on the basis of PCR-positive nasopharyngeal swabs and were independently adjudicated by a subcommittee of the data and safety monitoring committee.

Figure 4. Viral Load at the Time of Covid-19 Diagnosis.

Panel A shows viral loads for patients for whom data were available in the two groups, arranged in violin plots. Within each plot, the red dashed line indicates the median, and the black dashed line indicates the lower limit of detection (LLOD). Panel B shows mean viral loads, presented as log₁₀ virus copies per milliliter, according to subgroup. All analyses were performed in the intention-to-treat population. NE denotes not estimable.

Figure 5. Solicited Local and Systemic Adverse Events during 7 Days after the First or Second Dose.

Participants were monitored for local and systemic solicited adverse events through 7 days after administration of the trial injection. Participants who reported having no adverse events or who had missing data make up the remainder of the 100% calculation (not shown). For each category, adverse events are classified as follows: grade 1, mild; grade 2, moderate; and grade 3, severe. In addition, six grade 4 events (potentially life-threatening) were reported in 3 participants after the second injection: in 2 participants in the vaccine group (1 participant with chills, general discomfort, headache, and muscles aches and 1 participant with fever) and in 1 participant in the placebo group (headache) (proportional representation not visible in the graph). If a participant had different grades of the same adverse event, the highest grade was reported. If any of the solicited adverse events persisted beyond day 7 after administration of the trial injection, it was recorded as an unsolicited adverse event. Fever was defined as an oral temperature of at least 38.0°C.