Report 81: Summary of 2.4 Nonclinical Overview – Pfizer mRNA COVID-19 Vaccine, BNT162b2

Nonclinical Testing Strategy:

Investigational vaccine contents: Nonclinical studies tested two variants, BNT162b2 V.8 and BNT162b2 V.9, that differ in codon optimization designed to “improve antigen expression.” P6¶2 V9 was the candidate submitted for EUA and was the only version used in clinical trials. S proteins produced by V8 and V9 were reported to be identical. mRNA is formulated in lipid nanoparticles for preservation of mRNA and to facilitate delivery to ACEII cells.

Reference document Pfizer confidential document “2.4 NONCLINICAL OVERVIEW,” Version 3 (36 pages) while reading this summary. [ https://phmpt.org/wp-content/uploads/2022/03/125742_S1_M2_24_nonclinical-overview.pdf]Table of Contents pps. 4-5Nonclinical Testing Strategy Overview pps 6-9Pharmacology pps. 21-29Genotoxicity, Carcinogenicity, Reproductive and Developmental Toxicity pps. S proteins produced by V8 and V9 were reported to be identical.

Th1/Th2

Challenge study in NHP to assess protection against infection and “…to demonstrate lack of disease enhancement.” P.7 ¶1. Analysis of LNPNon-SARS-CoV-2 platform supporting BNT162b2 was demonstrated in LNP-formulated modRNA encoding luciferase testing and the pharmokinetics (PK) of ALC-0315 and ALC-0159 using BALB/c mice and Wistar Han rats. A Developmental and Reproductive Toxicology (DART) study was performed on V9 in rats. The location of records for inspection is included in each final study report.  Pharmacology:Mechanism of action: the nucleoside-modified mRNA encodes SARS-CoV-2 full length spike glycoprotein (S). The functional and structural lipids encapsulate the mRNA for preservation and to facilitate entry into the host ACEII cells. Human neutralizing antibodies demonstrate BNT162b2 authentically “…presents the ACE2 binding site and other epitopes targeted by many SARS-CoV-2 neutralizing antibodies.” P 10 ¶1.Most antibodies with SARS-CoV-2 neutralizing activity are directed against the RBD. &#

Th1-dominant INFg+ T-Cell responses were detected in all immunized rhesus macaques. RNA is degraded by cellular RNases and subjected to nucleic acid metabolism. Nucleotide metabolism occurs continuously within the cell, with the nucleoside being degraded to waste products and excreted or recycled for nucleotide synthesis. Hepatocyte vacuolation in the liver.“All changes in clinical pathology parameters and acute phase proteins were reversed at the end of the recovery phase with the exception of higher RDW, higher globulins and lower A:G ratios in animals administered BNT162b2 (V9).”Single dose toxicity study was not done. 8220;Additionally, higher GGT was not observed in the second repeat-dose toxicity study, conducted with the clinical candidate submitted for licensure.” P26 P23¶5.1.Albumin was down 0.87 x controls on day 4 and 0.76 x controls on day 17.Alpha-1-acid glycoprotein 21 x controls on day 17 and alpha-2-macroglobulin 217x controls on day 17 in both males and females. Nonadverse macroscopic changes at injection sites, spleen, lymph nodes, increased hematopoiesis in marrow and spleen, liver vacuolation with ongoing recovery at end of study period.

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