Immunogenicity and safety of inactivated whole virion Coronavirus vaccine with CpG (VLA2001) in healthy adults aged 18 to 55: a randomised phase 1 /2 clinical trial
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Abstract
Background
We assessed the safety, tolerability and immunogenicity of VLA2001 is a whole-virion inactivated SARS-CoV-2 vaccine adsorbed to alum with a toll-like receptor 9 agonist adjuvant in healthy volunteers aged 18-55.
Methods
The first 15 participants were enrolled, in groups of 5, to receive two doses, separated by 21 days, of one of three dose concentrations, administered intramuscularly. 138 further participants were randomised 1:1:1 to receive the same 3 dose concentrations, in a double blinded manner. Primary outcomes were solicited adverse reactions 7 days after each vaccination and neutralising antibody geometric mean titres (GMT) against SARS-CoV-2, 2 weeks after the second vaccination (day 36), measured by live microneutralisation assay against wild-type virus (MNA50). Secondary outcomes included unsolicited adverse events, and humoral and cellular responses at day 36, measured by IgG ELISA against Spike protein and interferon-γ secreting T-cells by ELISpot stimulated with multiple SARS-CoV-2 antigens. ( ClinicalTrials.gov NCT04671017 , ISRCTN 82411169 )
Findings
Between December 16, 2020 and January 21, 2021, 153 participants were enrolled and randomised evenly between the dose groups. The rates of solicited reactions were similar after the first and second doses and between the three dose groups. The most frequent local reactions were tenderness (58·2%) and pain (41·8%) and systemic reactions were headache (46%) and fatigue (39·2%).
In the high dose group, two weeks following the second dose, the geometric mean titres were 530.4 (95% CI: 421·49, 667·52) for neutralizing antibodies and 2147·9 (95% CI: 1705·98, 2704·22) for S-binding antibodies. There was a dose dependent response with 90·0% (95% CI:78·0%.,97·0%) seroconversion (4-fold rise) at day 36 in the high dose group, which was significantly higher than rates in both the medium (73.5%; 95% CI: 59%,85%), CIs) and low dose (51%; 95%CI: 37%,65%) rate, CIs) groups (both p < 0.001). Antigen-specific interferon-γ T-cells reactive against the S, M and N proteins were observed in 76, 36 and 49% of high dose recipients, respectively.
Interpretation
VLA2001-201 was well tolerated and produced both humoral and cellular immune responses, with a clear dose-response effect.
Funding
This study was funded by the Department of Health and Social Care, UK
The funder had no role in the study design, implementation or analysis.
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SciScore for 10.1101/2021.08.13.21262021: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Written informed consent was obtained from all participants, and the trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.
IRB: The study was approved in the UK by the Medicines and Healthcare products Regulatory Agency (43185/0002/001-0001) and the London, Brent ethics committee ref 20/HRA/5205Sex as a biological variable All women of childbearing potential had a serum HCG test performed at screening and urine pregnancy tests at all subsequent visits. Randomization Following an initial open-label dose escalation phase, the second phase of the study had a randomised, double-blind parallel group design with a 1:1:1 allocation … SciScore for 10.1101/2021.08.13.21262021: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics Consent: Written informed consent was obtained from all participants, and the trial was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice.
IRB: The study was approved in the UK by the Medicines and Healthcare products Regulatory Agency (43185/0002/001-0001) and the London, Brent ethics committee ref 20/HRA/5205Sex as a biological variable All women of childbearing potential had a serum HCG test performed at screening and urine pregnancy tests at all subsequent visits. Randomization Following an initial open-label dose escalation phase, the second phase of the study had a randomised, double-blind parallel group design with a 1:1:1 allocation to three dose levels. Blinding IMP allocation was based on an identifier linked to the randomisation, therefore as there was no visual difference between the doses, study staff and participants remained blinded to dose allocation. Power Analysis Statistical analysis: This is a descriptive study and formal power calculations were not performed. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources All participants were screened with full medical history and physical examination and blood and urine samples were sent to assess HIV, hepatitis B and C, SARS-CoV2 antibodies, full blood count, clotting function, inflammatory markers, liver and renal function and urinary abnormalities (including blood, protein and glucose). SARS-CoV2suggested: NoneExperimental Models: Cell Lines Sentences Resources The virus was cultured in Vero cells and inactivated with β-propiolactone. Verosuggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)Software and Algorithms Sentences Resources Statistical analysis using SAS® version 9.4 was performed by Valneva and were independently verified by LD using R version 4.0.2. SAS®suggested: (SASqPCR, RRID:SCR_003056)Results 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:Our study has several limitations. Firstly, the population studied was young, healthy adults, who typically have higher immune responses post vaccination than older adults. While this is a classical approach in Phase 1/2, it will be necessary and important to include an older population in future trials. Secondly, we did not study the response to immunization in subjects seropositive for SARS-CoV-2, so we cannot yet quantify any safety issues or a potential booster effect of the first dose that might be present in such individuals, as has been seen for other vaccines Thirdly, we have only assessed antibody titres at 2 weeks after the second dose at the moment. Further follow-up of participants is ongoing to provide immunogenicity data from time points later after the primary series. The highest dose group has been selected for further clinical development based on comparable safety and superior immunogenicity results. At the time of this publication, the sponsor has initiated a comparative, immunogenicity Phase 3 trial that will aim to predict vaccine efficacy by employing a primary endpoint of superiority of the GMT ratio of neutralizing antibody titres following 2 doses of VLA2001 compared to 2 doses of AZD1222.17
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04671017 Active, not recruiting Dose Finding Study to Evaluate Safety, Tolerability and Immu… ISRCTN82411169 NA NA 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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