BioNTech and Pfizer have announced initial data from their ongoing German Phase 1/2, open-label, non-randomised, non-placebo-controlled, dose-escalation trial, that is part of the global mRNA-based vaccine programme against SARS-CoV-2. The data are available on an online preprint server at medRxiv and are concurrently undergoing scientific peer-review for potential publication.
The preliminary clinical results are for the most advanced investigational vaccine candidate in Pfizer’s and BioNTech’s BNT162 mRNA-based vaccine programme against SARS-CoV-2, BNT162b1. This vaccine candidate is a lipid nanoparticle formulated, nucleoside-modified messenger RNA that encodes an optimised SARS-CoV-2 receptor-binding domain (RBD) antigen. Overall, the new preliminary data from this German study support and expand upon the recently disclosed early results from the corresponding US trial with BNT162b1.
Prelimanary findings
Preliminary data for BNT162b1 in the German Phase 1/2 trial were evaluated with a total of 60 healthy adults 18 to 55 years of age enrolled in the study. Of these 60 participants, 12 subjects per dose level (1 µg, 10 µg, 30 µg, and 50 µg; 48 participants in total) were vaccinated with BNT162b1 on day 1 and day 22 (n=12 per prime-boost cohort, except n=11 for the 10 µg and 50 µg cohorts from day 22 on). Furthermore, 12 participants received a single injection of 60 µg.
The vaccine elicited high, dose level-dependent SARS-CoV-2-neutralizing titers and RBD-binding IgG concentrations after the second dose. Day 43 SARS-CoV-2 neutralising geometric mean titers were in the range of 0.7-fold (1 µg) to 3.2-fold (50 µg) compared to that of a panel of SARS-CoV-2 infection convalescent human sera. Furthermore, sera of vaccinated subjects displayed broadly neutralising activity in pseudovirus neutralisation assays across a panel of sixteen SARS-CoV-2 RBD variants represented in publicly available SARS-CoV-2 sequences and against the newly dominant D614G strain.
In addition, the initial German trial results demonstrate, for the first time for the BNT62b1 candidate, a concurrent induction of high-level CD4+ and CD8+ T cell responses against the SARS-CoV-2 RBD.
The strength of T cell responses varied between subjects. There was no clear dose level dependency of the T cell response between 1 µg to 50 µg, indicating that stimulation and robust expansion of T cells might be accomplished at low mRNA dose levels.
All subjects in the prime-boost cohorts, except for two at the lowest dose level, had CD4+ T cell responses. Cytokine profiling of the RBD-specific CD4+ T cells demonstrated a TH1-dominant profile for these cells. 29 of the 36 tested subjects also mounted an RBD-specific functional, CD8+ T cell response that was comparable to memory responses observed against cytomegalovirus (CMV), Epstein Barr virus (EBV) and influenza virus.
Overall, the data suggested that BNT162b1 could potentially be administered safely, with a manageable tolerability profile. Local reactions and systemic events after injection with BNT162b1 at all dose levels were transient, generally mild to moderate, with occasional severe events (Grade 3) of flu-like symptoms and injection site reactions. All adverse events resolved spontaneously and were managed with simple measures. No serious adverse events (SAEs) were reported, and there were no withdrawals due to adverse events related to the vaccine.
Going forward
“It is encouraging that the data on BNT162b1 from the German study cohort are very much in line with what we have seen in the US study cohort. The preliminary data indicate that our mRNA-based vaccine was able to stimulate antibody as well as T-cell responses at remarkably low dose levels. We believe both may play an important role in achieving effective clearance of a pathogen such as SARS-CoV-2,” said Özlem Türeci, CMO and Co-founder of BioNTech.
“These interim results from the German study, combined with initial data from the U.S. study, highlight the potential of this mRNA-based vaccine approach and represent an important step forward in our development efforts for the BNT162 program,” said Kathrin Jansen, Senior VP and Head of Vaccine Research & Development at Pfizer. “We remain dedicated to developing an effective vaccine to fight the COVID-19 pandemic, with safety at the forefront and look forward to sharing additional data as the programme progresses.”
Preliminary data from both the German and US Phase 1/2 studies, together with additional preclinical and clinical data being generated, will be used by the two companies to determine a dose level and select among multiple vaccine candidates to seek to progress to an anticipated large, global Phase 2b/3 safety and efficacy trial. That trial may involve up to 30,000 healthy participants and is anticipated to begin in late July 2020, if regulatory approval is received.
The BNT162b1 candidate remains under clinical study and is not currently approved for distribution anywhere in the world. If the ongoing studies are successful and the vaccine candidate receives regulatory approval, the companies expect to manufacture up to 100 million doses by the end of 2020 and potentially more than 1.3 billion doses by the end of 2021. In that event, BioNTech and Pfizer would work jointly to distribute the potential COVID-19 vaccine worldwide (excluding China, where BioNTech has a collaboration with Fosun Pharma for BNT162 for both clinical development and commercialization).
