Phase 2 Randomized Trial of an AS03 Adjuvanted Plant-Based Virus-Like Particle Vaccine for Covid-19 in Healthy Adults, Older Adults and Adults with Comorbidities
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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 the needs of specific populations. We report herein a pre-specified interim analysis of the phase 2 portion of an ongoing 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 subjects were recruited between 25 November 2020 and 24 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 CoVLP (3.75 μg/dose + AS03) or placebo 21 days apart. This report presents safety, tolerability and immunogenicity data collected up to 21 days after the second dose. The immune outcomes presented include neutralizing antibody (NAb) titres and cellular (IFN-γ and IL-4 ELISpot) responses. 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. CoVLP+AS03 induced seroconversion in >35% of subjects in each group after the first dose and in ∼98% of subjects 21 days after the second dose. In all treatment groups, NAb levels were ∼10-fold higher than those in a panel of convalescent sera. A significant minority (∼20%) of subjects had evidence of a pre-existing IFN-γ response to the S protein and almost all subjects 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 dose two. These data demonstrated that CoVLP+AS03 will likely be well-tolerated and highly immunogenic in adults ≥18 years of age with and without comorbidities.
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SciScore for 10.1101/2021.05.14.21257248: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by a central Research Ethics Review Board (Advarra 372 Hollandview Trail, Suite 300
Consent: Written informed consent was obtained from all study participants prior to any study procedure.Sex as a biological variable Study Design: The phase 2 portion of the study is a randomized, observer-blinded, placebo-controlled study with male and female subjects. Randomization Study Design: The phase 2 portion of the study is a randomized, observer-blinded, placebo-controlled study with male and female subjects. Blinding The participants and the personnel collecting the safety information and working in testing laboratories remained blinded to treatment allocation. Power Analysis T… SciScore for 10.1101/2021.05.14.21257248: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: The study was approved by a central Research Ethics Review Board (Advarra 372 Hollandview Trail, Suite 300
Consent: Written informed consent was obtained from all study participants prior to any study procedure.Sex as a biological variable Study Design: The phase 2 portion of the study is a randomized, observer-blinded, placebo-controlled study with male and female subjects. Randomization Study Design: The phase 2 portion of the study is a randomized, observer-blinded, placebo-controlled study with male and female subjects. Blinding The participants and the personnel collecting the safety information and working in testing laboratories remained blinded to treatment allocation. Power Analysis The sample size was not large enough to detect all types of, including less frequent or rare, AEs. Table 2: Resources
Antibodies Sentences Resources Although a test for SARS-CoV-2 antibodies was performed at screening using a commercial ELISA that targets the nucleocapsid (N) protein (ElecSys: Roche Diagnostics), both seronegative and seropositive subjects were enrolled. SARS-CoV-2suggested: NonePrimary immunogenicity outcomes were i) neutralizing antibody (NAb) titers measured using a pseudovirion neutralization assays and ii) interferon (IFN)-γ and IL-4 ELISpot responses at 21 days after each dose of vaccine. IL-4suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Consistent with the observations that adjuvants can enhance vaccine-induced responses in older individuals 46, these results suggest that two-doses of CoVLP+AS03 can overcome these age-associated limitations for NAb production at least. The number of Adult or Older Adult subjects in the current study with pre-existing NAb titers to SARS-CoV-2 was very low (n=9, 1.5%) but vaccination with CoVLP+AS03 nonetheless appeared to induce a substantial increase in NAb titers, suggesting that this vaccine candidate can significantly boost a pre-existing memory response 47,48. This is consistent with observations made by Goel et al.49 following mRNA vaccination. The increase in NAb titers was greater after the first dose of CoVLP+AS03 (GMT 58.7 → 5458) than the second dose (GMT of 5458 → 7035) suggesting there may be limited additional benefit in providing a second dose to such individuals. These observations provide strong support for vaccinating both infection naïve and previously infected individuals with CoVLP+AS03. Overall, the NAb titers induced by CoVLP+AS03 in both the Adult and Older Adult populations compared well to a panel of convalescent serum/plasma. While this method can be used to draw broad comparisons between studies 8,16, there is a growing consensus that this approach has serious limitations for comparing responses between groups and between trials with different vaccines. For this reason, we included the WHO reference standard 20/136, pooled antibodies from recovered...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04636697 Recruiting Study of a Recombinant Coronavirus-Like Particle COVID-19 Va… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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