Pfizer and BioNTech Announce Preclinical Results for BNT162b2 mRNA-Based COVID-19 Vaccine Candidate

Today, Pfizer and BioNTech announced preliminary results from their jointly developed candidate COVID-19 vaccine, BNT162b2, in mouse and non-human primate models. BNT162b2 is a nucleoside-modified mRNA vaccine. Preclinical study results demonstrated that BNT162b2 successfully protected against SARS-CoV-2 lung infection in rhesus macaques during challenge experiments conducted 55 days post-vaccination. This candidate vaccine is currently undergoing evaluation in Phase 2/3 clinical trials. The preclinical data have been posted on the preprint server bioRxiv and are under peer review.

Design of the BNT162b2 Vaccine

BNT162b2 is an mRNA vaccine featuring nucleoside modification and codon optimization. Nucleoside modification reduces the intrinsic immunogenicity of mRNA, while codon optimization enhances protein expression levels. BNT162b2 encodes the SARS-CoV-2 spike protein in its prefusion conformation. Structural analysis of the spike protein expressed by BNT162b2 reveals that in some spike trimers, one of the three receptor-binding domains (RBDs) adopts an "up" conformation. This RBD conformation exposes more epitopes involved in binding to the ACE2 receptor, thereby facilitating the generation of neutralizing antibodies. Spike proteins exhibiting this conformation account for 20% of those expressed by BNT162b2.

▲Design of BNT162b2 (a) and the 3D structure of the expressed spike protein (c, d, e) (Image source: Reference [1])

Vaccine-Induced Neutralizing Antibody Response

Researchers evaluated the antibody and T-cell immune responses elicited by this vaccine in mouse and rhesus macaque models. In the rhesus macaque model, two intramuscular doses of BNT162b2 administered 21 days apart resulted in significantly elevated levels of spike protein-specific IgG antibodies and SARS-CoV-2 neutralizing antibody titers. Using a SARS-CoV-2 strain expressing fluorescent protein (USA_WA1/2020) for assessment, the peak geometric mean titers (GMTs) of neutralizing antibodies in rhesus macaques vaccinated with 30 µg and 100 µg doses of BNT162b2 reached 962 and 1689, respectively. On day 56 after the first vaccination, the neutralizing antibody GMTs remained at 285 (30 µg dose) and 310 (100 µg dose). In comparison, the neutralizing antibody GMT in human convalescent serum was 94.

▲Spike protein-specific IgG levels (a) and neutralizing antibody titers (b) induced by BNT162b2 (Image source: Reference [1])

Vaccine-Induced T Cell Immune Response

Researchers also found that the BNT162b2 vaccine elicited a robust IFN-γ response while hardly inducing any IL-4 response. Intracellular cytokine staining (ICS) assays showed that BNT162b2 significantly increased the number of CD4+ T cells producing IFN-γ, IL-2, and TNF, whereas the number of CD4+ T cells producing IL-4 remained virtually unchanged. These results indicate that BNT162b2 can induce a Th1 response conducive to maintaining long-lasting immunity. Furthermore, BNT162b2 also increased the number of spike protein-specific CD8+ T cells producing IFN-γ.

▲BNT162b2 increases the number of IFNγ-producing CD4+ (a) and CD8+ T cells (b) (Image source: Reference [1])

Results of Challenge Studies in Rhesus Macaque Models

To evaluate the efficacy of BNT162b2 in protecting against SARS-CoV-2 infection, researchers conducted a challenge study in rhesus macaques 55 days after the administration of the second vaccine dose. The results showed that among the three rhesus macaques inoculated with saline, two had SARS-CoV-2 RNA detected in their bronchoalveolar lavage (BAL) fluid three days post-challenge, and one had viral RNA detected in BAL fluid six days post-challenge. In contrast, none of the six rhesus macaques vaccinated with BNT162b2 showed detectable SARS-CoV-2 RNA in their BAL fluid.

In nasal and pharyngeal swab samples, rhesus macaques vaccinated with BNT162b2 tested positive for viral RNA only on day 1 after virus challenge, and viral RNA levels were undetectable by day 3.

▲ SARS-CoV-2 RNA levels in bronchoalveolar lavage fluid (a) and nasal swab samples (b) from the challenge study (Image source: Reference [1])

“These preclinical study data, combined with the clinical data we are currently collecting, continue to support the prospects and rationale of the mRNA-based COVID-19 vaccine development program. We believe it has the potential to prevent millions of COVID-19 cases,” said Dr. Kathrin U. Jansen, Senior Vice President and Head of Vaccine Research and Development at Pfizer.

References:

[1] Pfizer and BioNTech Announce Data from Preclinical Studies of mRNA-based Vaccine Candidate Against COVID-19. Retrieved September 9, 2020, from https://www.businesswire.com/news/home/20200909005570/en

[2] Vogel et al., (2020). A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates. bioRxiv, doi: https://doi.org/10.1101/2020.09.08.280818

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