In a recent medRxiv* paper, a research group from the U.S. and Germany showed a robust immunogenic response and a promising safety profile of the novel BNT162b1 RNA-based vaccine against coronavirus disease (COVID-19) – actively encouraging its accelerated clinical development and potential rapid production.
Since the COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still rampant in many parts of the world, a vast amount of research funds are directed towards finding an effective drug or vaccine. Many argue that the return to normality will not be possible without the latter.
The RNA vaccine platform has indeed opened the door for a rapid development approach in response to this pandemic, as RNA vaccines are known for their flexibility in the design and antigen structure representation/expression akin to the natural infection. In addition, there is a possibility for the rapid production of a large number of vaccine doses.
Why pick RNA vaccine against SARS-CoV-2?
In general, the vaccination with an RNA vaccine can elicit a robust innate immune response. It was already observed that RNA successfully directs the expression of the vaccine antigen in host cells, with intrinsic adjuvant effects.
Among several RNA-based SARS-CoV-2 vaccine candidates that are currently being studied and that are considered favorable to enter a safety and efficacy trial, BNT162b1 was quickly shown to be one of the most promising ones.
More specifically, the BNT162b1 vaccine candidate in current trials clinically incorporates nucleoside modified RNA and encodes the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein – a key target for virus-neutralizing antibodies.
Researchers from various notable institutions in the U.S. and Germany just reported available safety, tolerability, and immunogenicity data from the ongoing, placebo-controlled, and observer-blinded dose-escalation study of the aforementioned vaccine candidate.
Assessing the safety, tolerability and immunogenicity
This study was conducted in healthy men and non-pregnant women, aged between 18 to 55 years of age, to assess the 'vaccinologic trifecta' of safety, tolerability, and immunogenicity. Ascending dose levels of different BNT162 mRNA vaccine candidates have been used.
Study participants were randomized with the use of an interactive web-based response technology system, resulting in 15 participants in each group (12 vaccine recipients and 3 placebo recipients). Either BNT162b1 or placebo shots were administered intramuscularly into the shoulder muscle.
In short, a sentinel cohort design was utilized for this trial, with progression and dose escalation taking place after reviewing the data from the sentinel cohort at each dose level.
This interim report highlights the assessment of three dose levels (i.e., 10 μg, 30 μg, or 100 μg) of the BNT162b1 candidate at two sites in the United States. Most importantly, detailed immunogenicity and safety assessments were conducted.
Vigorous neutralization ability against SARS-CoV-2
"The RNA-based SARS-CoV-2 vaccine candidate BNT162b1 administered at 10 μg, 30 μg, or 100 μg to healthy adults 18-55 years of age exhibited a tolerability and safety profile consistent with those previously observed for mRNA-based vaccines", study authors explain their main findings.
Robust immunogenicity was evidenced in RBD-binding IgG concentrations that were detected at 21 days after the first dose, and then significantly increased 7 days after the second dose (which was administered on day 21).
Moreover, neutralization titers were detectable after a single vaccination dose at day 21 for all dose levels. At day 28 (or seven days after the second dose), substantial SARS-CoV-2 neutralization titers were observed.
In a nutshell, all local reactions and systemic events were dose-dependent and generally mild-to-moderate and transient. Transient decreases in lymphocytes were seen within a few days after vaccination but without any clinical significance.
Limitations and further steps
"These clinical findings for the BNT162b1 RNA-based vaccine candidate are encouraging and strongly support accelerated clinical development and at-risk manufacturing to maximize the opportunity for the rapid production of a SARS-CoV-2 vaccine to prevent COVID-19 disease", say study authors.
Naturally, there are certain limitations to this study approach. Although the researchers utilized convalescent sera as a comparator, the type of immunity (T cells versus B cells) and the level required for protection against COVID-19 are unknown.
Additionally, the analysis of available data did not appraise immune responses or safety profiles beyond the two weeks following the second vaccine dose of vaccine. Both of these facets are indispensable to inform the pervasive public health use of this vaccine.
Of course, this is only an interim study; therefore, the follow-up process needs to continue for all study participants, which includes the collection of serious adverse events for six months, as well as COVID-19 infection rates and multiple ancillary immunogenicity measurements for up to two years.
“We are encouraged by the clinical data of BNT162b1, one of four mRNA constructs we are evaluating clinically, and for which we have positive, preliminary, topline findings,” said Kathrin U. Jansen, Ph.D., Senior Vice President and Head of Vaccine Research & Development, Pfizer. “We are dedicated to develop potentially groundbreaking vaccines and medicines, and in the face of this global health crisis, we approach this goal with the utmost urgency. We look forward to publishing our clinical data in a peer-reviewed journal as quickly as possible.”
“These preliminary data are encouraging, showing that BNT162b1 which exploits RBD SARS-CoV-2 as a target antigen is able to produce neutralizing antibody responses in humans at or above the levels observed in convalescent sera – and that it does so at relatively low dose levels. We look forward to providing further data updates on BNT162b1,” said Ugur Sahin, M.D., CEO and Co-founder of BioNTech.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
- U.S. National Library of Medicine - ClinicalTrials.gov. Study to Describe the Safety, Tolerability, Immunogenicity, and Potential Efficacy of RNA Vaccine Candidates Against COVID-19 in Healthy Adults. Available at: https://clinicaltrials.gov/ct2/show/NCT04368728.
- Mulligan, M.J. et al. (2020). Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report. medRxiv. https://doi.org/10.1101/2020.06.30.20142570.