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Phase 1/2 Study: Safety and immunogenicity

In response to the global COVID-19 mRNA vaccine development effort, there are several ongoing pre-clinical and clinical studies dedicated to fulfilling the unmet clinical need for approved COVID-19 vaccines.[1] As part of this effort, BioNTech continues testing a total of five clinical candidates in ongoing Phase 1 / 2 studies conducted in multiple clinical testing sites in Germany (NCT04380701, EudraCT number 2020-001038-36, WHO UTN U1111-1249-4220; and NCT04537949, EudraCT number 2020-003267-26, WHO UTN U1111-1254-4840), and the U.S. (NCT04368728, EudraCT number 2020-002641-42, Pfizer clinical trial number C4591001).[2–4]

BioNTech’s Phase 1/2 clinical studies are ongoing at multiple sites in the U.S., Germany, China, and Japan[2–4]

The primary objectives of these studies are to assess the safety and immunogenicity of BioNTech's five vaccine candidates in order to identify the preferred candidate(s), as well as the effective dose(s), number of doses, and dosing schedule for administration.[2–4] The primary and secondary outcomes examined in these studies are safety and immunogenicity of the vaccines in healthy men and non-pregnant / non-breastfeeding women 18–85 years of age.[2–4]

Phase 1/2 interim data analyses were published online in the New England Journal of Medicine (U.S.-based studies) and in Nature (German-based studies) regarding the ongoing placebo-controlled, observer-blinded, dose-escalation study.[5],[6]

  • Healthy adults were randomized to receive either placebo or one of two lipid nanoparticle-formulated, nucleoside-modified mRNAs encoding the receptor-binding domain (RBD) of SARS-CoV-2 spike protein[5],[6]
  • Interim safety and tolerability data demonstrate that pain at the injection site was the most frequently reported local reaction within 7 days of vaccination, particularly after the second administration of vaccine.[5],[6] All reported events were mild or moderate in severity and no adult in the 65–85 years old age group who received BNT162b2 reported redness or swelling[5],[6]
  • The most common systemic events reported in the 7 days after each vaccination in the vaccine candidate and placebo recipients were mild-to-moderate fatigue and headache[5],[6]
  • Data from the U.S.-based study show that the vaccine antigen-binding IgG and SARS-CoV-2 neutralizing geometric mean titers elicited by vaccination with both vaccine candidates were similar; however, based on overall comparisons of the reactogenicity profiles of the two vaccines, BNT162b2 was selected for Phase 2/3 clinical testing[5]

Limitations to the Phase 1/2 clinical studies include:

  • Convalescent sera were used as a comparator; however, the kind of immunity (T cells versus B cells or both) and the extent of immunity needed to protect from COVID-19 are currently unknown[5],[6]
  • In addition, analysis of the available data did not assess immune responses or safety beyond 7 days after the second dose of vaccine[5],[6]
  • The participants in this early-stage clinical trial were all healthy and exhibited a limited racial and ethnic diversity profile compared with the general population[5],[6]
  • These studies assessed reactogenicity and immunogenicity but vaccine efficacy and safety remain to be assessed in Phase 2/3 clinical trials[5],[6]

Overall conclusions:

  • These studies demonstrate that vaccination stimulated robust targeted antigen-binding IgG and neutralizing antibody responses, as well as strong CD4+ and CD8+ T cell responses, across all ages and doses tested in Phase 1 / 2 clinical trials.[5],[6] In addition, there was a clear dose-dependent immune response observed after each administration of vaccine[5],[6]
  • Administration of both vaccines was generally well-tolerated, with mild-to-moderate transient local and systemic adverse events reported within 7 days of vaccination[5],[6]
  • Reactogenicity was generally higher after the second administration of vaccine; however, symptoms were generally transient and resolved within a few days[5],[6]
  • Based on these efficacy and safety data reported in these studies, and in comparison to reactogenicity data with other vaccine candidates, the BNT162b2 vaccine was selected for further clinical testing as a COVID-19 mRNA vaccine candidate in global Phase 2/3 clinical trials[5]

Ongoing research and future directions for these studies include:

  • Follow up on the durability of safety and immunogenicity beyond Day 28 (6-month follow up for all participants)
  • T-cell responses for BNT162b2 (CD4+ and CD8+) to be evaluated once further data are available
  • Level of immunity required for protection in humans to be assessed in Phase 2/3 trials

References

  1. World Health Organization. Draft landscape of COVID-19 candidate vaccines.
    https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines.
    Updated December 8, 2020. Accessed December 8, 2020.
  2. U.S. National Library of Medicine. A Multi-site, Phase 1/2, 2-Part, Dose-Escalation Trial Investigating the Safety and Immunogenicity of a Prophylactic SARS-CoV-2 RNA Vaccine (BNT162b3) Against COVID-19 Using Different Dosing Regimens in Healthy Adults. NCT04537949. ClinicalTrials.gov website.
    https://clinicaltrials.gov/ct2/show/record/NCT04537949?term=biontech&cond=Covid19&draw=2&rank=1
    Updated September 16, 2020. Accessed January 8, 2021.
  3. U.S. National Library of Medicine. A Trial Investigating the Safety and Effects of Four BNT162 Vaccines Against COVID-2019 in Healthy Adults. NCT04380701. ClinicalTrials.gov website.
    https://clinicaltrials.gov/ct2/show/record/NCT04380701?term=biontech&cond=Covid19&draw=2&rank=3
    Updated September 11, 2020. Accessed December 1, 2020.
  4. U.S. National Library of Medicine. Study to Describe the Safety, Tolerability, Immunogenicity, and Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Individuals. NCT04368728. ClinicalTrials.gov website.
    https://clinicaltrials.gov/ct2/show/NCT04368728?term=NCT04368728&draw=2&rank=1
    Updated November 23, 2020. Accessed December 1, 2020.
  5. Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates [published online ahead of print, 2020 Oct 14]. N Engl J Med. 2020;NEJMoa2027906. doi:10.1056/NEJMoa2027906
  6. Sahin U, et al. Nature. 2020;586(7830):594-599.

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