Safety and immunogenicity of an AS03-adjuvanted plant-based SARS-CoV-2 vaccine in Adults with and without Comorbidities

Abstract

The rapid spread of SARS-CoV-2 continues to impact humanity on a global scale with rising total morbidity and mortality. Despite the development of several effective vaccines, new products are needed to supply ongoing demand and to fight variants. We report herein a pre-specified interim analysis of the phase 2 portion of a Phase 2/3, randomized, placebo-controlled trial of a coronavirus virus-like particle (CoVLP) vaccine candidate, produced in plants that displays the SARS-CoV-2 spike glycoprotein, adjuvanted with AS03 (NCT04636697). A total of 753 participants were recruited between 25th November 2020 and 24th March 2021 into three groups: Healthy Adults (18–64 years: N = 306), Older Adults (≥65 years: N = 282) and Adults with Comorbidities (≥18 years: N = 165) and randomized 5:1 to receive two intramuscular doses of either vaccine (3.75 µg CoVLP/dose+AS03) or placebo, 21 days apart. This report presents safety, tolerability and immunogenicity data up to 6 months post-vaccination. The immune outcomes presented include neutralizing antibody (NAb) titres as measured by pseudovirion assay at days 21 and 42 as well as neutralizing antibody cross-reactivity to several variants of concern (VOCs): Alpha, Beta, Gamma, Delta, and Omicron (BA.1), up to 201 days post-immunization. Cellular (IFN-γ and IL-4 ELISpot) response data in day 21 and 42 peripheral blood are also presented. In this study, CoVLP+AS03 was well-tolerated and adverse events (AE) after each dose were generally mild to moderate and transient. Solicited AEs in Older Adults and Adults with Comorbidities were generally less frequent than in Healthy Adults and the reactogenicity was higher after the second dose. CoVLP+AS03 induced seroconversion in >35% of participants in each group after the first dose and in ~98% of participants, 21 days after the second dose. In all cohorts, 21-days after the second dose, NAb levels in sera against the vaccine strain were ~10-times those in a panel of convalescent sera. Cross-reactivity to Alpha, Beta and Delta variants was generally retained to day 201 (>80%) while cross-reactivity to the Gamma variant was reduced but still substantial at day 201 (73%). Cross-reactivity to the Omicron variant fell from 72% at day 42 to 20% at day 201. Almost all participants in all groups (>88%) had detectable cellular responses (IFN-γ, IL-4 or both) at 21 days after the second dose. A Th1-biased response was most evident after the first dose and was still present after the second dose. These data demonstrated that CoVLP+AS03 is well-tolerated and highly immunogenic, generating a durable (at least 6 months) immune response against different VOCs, in adults ≥18 years of age, with and without comorbidities.

Durability and cross-reactivity of immune responses induced by a plant-based virus-like particle vaccine for COVID-19

“…Although Th2 skewing was initially considered a potential risk for SARS-CoV-2 vaccines and assessment of Th1/Th2 polarization was considered essential during early COVID-19 vaccine development 62,63 , to our knowledge no suggestion of VAED with or without a link to inappropriate Th2 responses has been observed with any SARS-CoV-2 vaccine 64 . In the case of CoVLP +AS03 specifically, there has been no suggestion of VAED in either a macaque challenge study 15 or in the clinical trials conducted to date despite the strong induction of both Th1-and Th2-type cytokine responses 33,40,65 . In fact, the IL-4 response elicited by the combination of CoVLP and AS03 may play an important role in the strength of the antibody responses observed, possibly by supporting follicular T-cell involvement and germinal center development [66][67][68][69] .…”

“…As previously described 65 , WHO International Standard anti-SARS-CoV-2 immunoglobulin (human; NIBSC code: 20/136) was included in antibody binding and neutralization assays for the purpose of facilitating comparison of results with other studies. This standard material is pooled plasma from eleven individuals who recovered from SARS-CoV-2 infection with very high NAb responses 35 .…”

Current Advances of Plant-Based Vaccines for Neurodegenerative Diseases

“…For example, once the SARS-CoV-2 spike protein sequence became available, Medicago Inc. generated the VLP vaccine candidates in just 20 days [ 47 ]. Moreover, phase 1 randomized trials; the phase 2 portion of a phase 2/3 randomized, placebo-controlled studies; and phase 3, multinational, randomized, placebo-controlled trials have indicated that the SARS-CoV-2 spike glycoprotein VLP (CoVLP) expressed in Nicotiana benthamiana L. is highly immunogenic, well tolerated, and can effectively prevent COVID-19 [ 64 , 65 , 66 ].…”

Chemical and biological conjugation strategies for the development of multivalent protein vaccine nanoparticles

“…[ 111–113 ] Plant‐derived VLPs were also developed against Covid‐19 by transfecting N. benthamiana with full‐length S glycoprotein of SARS‐CoV‐2 and the vaccine nanoparticles were evaluated through different phases of clinical trials. [ 114–116 ] During phase 3, a total of 24,141 participants were intramuscularly vaccinated with a combination of the plant‐derived coronavirus‐like particles (CoVLP) and Adjuvant System 03 (AS03) or placebo, resulting in vaccine efficacy ranging from 69.5% in preventing any symptomatic Covid‐19 infection to 78.8% in preventing moderate‐to‐severe disease. In general, these studies suggest plant‐derived VLPs with anchored antigens on the surface are a promising vaccine candidate against various pathogens.…”