BioNTech’s SARS-CoV-2 vaccine candidates and their characteristics
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For its mRNA vaccine platform, BioNTech has developed multiple formats and delivery formulations, some of which are being utilized in “Project Lightspeed.” mRNA vaccine platforms utilize lipid-complexed mRNA sequences encoding antigenic proteins.,
“Project Lightspeed” is an initiative to jointly develop and test multiple COVID-19 vaccine candidates as part of a global development program., BioNTech is collaborating with Pfizer Inc on the development and global clinical trials– – excluding China, where BioNTech has partnered with Fosun Pharma. Due to the accelerated vaccine development timeline (as discussed in the previous section), BioNTech was able to leverage its next-generation sequencing (NGS) capabilities (allowing for sequencing of an entire genome in a single day) in order to expedite development of its initial vaccine candidates from concept to clinical trials in less than 3 months.,
As part of the “Project Lightspeed” initiative, BioNTech has developed and tested a total of four SARS-CoV-2 mRNA vaccines utilizing the LNP delivery formulation and three of the mRNA formats (uRNA, modRNA, and saRNA).,
The nucleoside - modified mRNA (modRNA) format
The nucleoside (i.e., adenine, uracil, cytosine, or guanine—the four constituent bases of nucleic acids)-modified mRNA (modRNA) format was developed for use when an immunogenic reaction directly against the mRNA must be avoided for applications in which therapeutic proteins are produced.
BioNTech has demonstrated that the modification of select nucleosides in the manufactured mRNA suppresses its intrinsic immunogenic properties while resulting in superior protein production. These nucleoside modifications, coupled with structural engineering of the modRNA to have it resemble a stable, fully processed mature mRNA (i.e., 5’ cap, poly(A) tail, open reading frame (ORF) encoding the protein/antigen of interest, and 5’ and 3’ untranslated regions (UTRs)) results in a mRNA format that most closely resembles cellular mRNA.
An mRNA drug needs to be appropriately formulated to protect it from degradation by extracellular RNAases. The right formulation is critical to ensure appropriate delivery of the mRNA to the intended site of action. In addition to its multiple mRNA formats, BioNTech has developed three different lipid delivery formulations. The one used in BNT162b2 is a lipid nanoparticle (LNP).,
Because the spike glycoprotein of SARS-CoV-2 mediates entry into cells and is generally exposed while the virus travels in the extracellular spaces of the body, it represents an ideal antigenic target for vaccine development design strategies.
The RBD alone theoretically represents an attractive antigenic candidate, since it is indispensable in enabling the spike protein to bind to angiotensin-converting enzyme 2 (ACE2), which is the viral entry receptor for SARS-CoV-2.-
However, the full-length spike glycoprotein contains not only the RBD, but also other domains with potentially neutralizing epitopes – including multiple neutralizing antibodies and immunologically important T cell epitopes.,
Therefore, the full-length spike glycoprotein is an ideal antigenic target for vaccine development.
In pre-clinical development, BioNTech expedited its pre-clinical and clinical study programs to assess the safety and efficacy of four vaccine candidates. By July 2020 the most promising candidate was identified to go forward to a global Phase 2/3.-
After analyses of the data from their phase 1/2 trials in Germany and the U.S.,, BioNTech and its collaborators selected BNT162b2 for use in their phase 2/3 clinical trial, which is currently active. Additional reports detailing data analyses from the phase 2/3 clinical trial are pending, and updates will be posted when that information becomes available.
BNT162b2 is a LNP-formulated modRNA-format vaccine that encodes an optimized 2-proline (2P)-mutated SARS-CoV-2 full-length S glycoprotein. The structural components of the phase 3 BNT162b2 vaccine include:
- The D614G SARS-CoV-2 spike protein (S) variant is the most common viral variant observed in mutational analyses reported in the literature., Genome analyses of SARS-CoV-2 have identified thousands of viral variants, including those that have been associated with increased COVID-19-related mortality. However, the viral variant garnering the most attention from researchers is the D614G spike protein (S) variant.
- SARS-CoV-2 isolates encoding the D614G mutation have been demonstrated to predominate over time in multiple geographic locations, including across the European Union (including Germany), China, and the United States, implying that this change enhances viral transmission.,
- D614G has also been correlated with increased viral loads in COVID-19 patients.
- The D614G mutation was included in BioNTech’s phase 1/2 trials
- LNPs (lipid nanoparticles) are the lipid-based delivery system that functions to protect the mRNA from degradation, facilitate its entry into the cell, and promote endosomal escape of the mRNA into the cytoplasm (where it can be translated into protein/antigen).
- BNT162b2 vaccination elicited robust neutralizing antibody titers, as well as durable CD4 and CD8 T cell responses, and also protected against viral challenge with SARS-CoV-2 in pre-clinical models.
- Vaccination with BNT162b2 mounted robust targeted antigen-binding and neutralizing antibody responses across all ages and doses tested in phase 1/2 clinical trials.
- Many of the limitations of the phase 1/2 trials were addressed during phase 3. These included the relative importance of humoral and cellular immunity in protection from COVID-19, and the degree of protection against COVID-19 provided by serum neutralizing responses which were yet to be known during phase 1/2. In addition, participants in phase 1/2 were healthy and had limited racial and ethnic diversity as compared with the general population.
In addition, BNT162b2’s mild reactogenicity profile in phase 1/2 clinical trials demonstrated favorable tolerability across all ages and doses tested. Specifically, administration of the vaccine was generally well-tolerated, with mild to moderate transient pain at the injection site being the primary adverse event (AE) reported within 7 days of vaccination, and systemic AEs reported within 7 days of vaccination were primarily mild to moderate transient fever, fatigue, and chills.
The proposed mechanism of action of the BNT162b2 vaccine
mRNA is utilized as a vaccine to express the modified full-length SARS-CoV-2 S glycoprotein that is then processed into antigenic peptides, which are presented on major histocompatibility (MHC) class I and II molecules of antigen-presenting cells (APCs) to CD8 and CD4 T cells, respectively, stimulating expansion of a TH1-biased immune response, including generation of neutralizing antibodies and antigen-specific cytotoxic T-cell responses, as well as production of memory B cells and T cells.,
- mRNA occurs naturally in the body and is metabolized and eliminated by the body’s natural mechanisms; therefore, it is transiently expressed and considered a well-tolerated vaccine platform.
- mRNA is noninfectious and does not integrate into the human genome/DNA (stays in the cytoplasm, does not transport into the nucleus).
- mRNA vaccines do not utilize a vector thus avoiding issues with anti-vector immunity, making multiple vaccinations/boosts possible.
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