SARS coronavirus (SARS-CoV2) or the causative agent of COVID19 pandemic is a lethal pathogen that has killed millions of people worldwide. The development of a vaccine is a critical component in the mitigation of this pandemic. Endocytosis of SARS-CoV2 is facilitated by the host ACE2 receptor which is bound by the viral spike protein or S-protein. The spike protein has a domain that is directly involved in binding to ACE2 receptor and this is called ‘receptor binding domain’ or RBD. During the natural course of infection by SARS- CoV2, neutralising antibodies are produced by immune system against receptor binding domain or RBD of S-protein. Convalescent sera, ie. the sera obtained from recovered individuals have high concentration of antibodies against RBD of viral S-protein . Therefore, rationale of majority of COVID19 vaccines is to use RBD as an immunogen to generate effective immune response against SARS-CoV2 in human. Neutralising antibodies will block interactions between the viral ligand and ACE-2 receptor preventing invasion of healthy cells by the virus.
Many vaccines are subunit based vaccines using a recombinant RBD with an appropriate adjuvant but there are certain mRNA vaccines also in the race, and amongst them the leading ones are BNT162b1, BNT162b2 (Pfizer and BioNTech), both are nucleoside-modified RNAs, formulated in lipid nanoparticles. BNT162b1 encodes an optimized receptor-binding domain (RBD) of spike protein whereas BNT162b2 encodes an optimized full-length spike protein antigen. Another leading candidate mRNA vaccine is Moderna’s mRNA1273 which encodes for a prefusion stabilised full length spike protein. Similar to BNT162b1 and BNT162b2, the mRNA1273 is also a codon optimised mRNA vaccine where uridine has been replaced by 1-methyl- pseudouridine, which dampens innate immune sensing and increases the expression of encoded protein.
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In a previous protein man's blog article, we have already discussed about the mRNA vaccines in general, including details such as how they are made, what is their mode of action and why they are considered superior to conventional subunit or recombinant protein based vaccines. Here, we are going to talk about the science and technology behind one of the most promising and the only vaccine for which the interim phase 3 trial results are available. This is BNT162b1 co-developed by Pfizer and BioNTech and approved by FDA for a fast track development. So what is inside this vaccine ?
BNT162b1 mRNA encodes the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein The RBD antigen expressed by BNT162b1 is modified by the addition of a T4 fibritin-derived foldon trimerization domain to increase its immunogenicity. The mRNA is formulated in lipid nanoparticles for efficient delivery into cells after intramuscular injection. It has been found that even a dose of 1 microgram produce sufficient quantities of virus neutralising antibodies. This is because mRNA vaccines are delivered into the cells where they continue to produce the encoded protein for some time unlike subunit vaccine formulations where a defined quantity of protein antigen is delivered in different doses.
It was found that immunisation with BNT162b1 elicits robust antibody response and the mean neutralizing titres of anti-RBD antibodies reached 2–4.6 fold that of a panel of COVID-19 convalescent human sera from individuals recovered from natural SARS-CoV-2 infection. A comparison with titres of convalescent serum is done to evaluate the efficacy of immune response generated. So far the results from interim Phase 3 trial of BNT162b1 have been very promising and shows more than 90% efficacy which is a very good number. The availability of an effective vaccine is going to be major victory in ongoing war of mankind with SARS- CoV2 and the global pandemic. The choice of mRNA platform for a SARS-CoV2 vaccine is also apt because unlike protein subunit vaccines, the large scale production of mRNA vaccines is much cheaper and faster.
Suggested Readings:
- Mulligan MJ, Lyke KE, Kitchin N, Absalon J, Gurtman A, Lockhart S, Neuzil K, Raabe V, Bailey R, Swanson KA, Li P, Koury K, Kalina W, Cooper D, Fontes-Garfias C, Shi PY, Türeci Ö, Tompkins KR, Walsh EE, Frenck R, Falsey AR, Dormitzer PR, Gruber WC, Şahin U, Jansen KU. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature. 2020 Oct;586(7830):589-593. doi: 10.1038/s41586-020-2639-4. Epub 2020 Aug 12. PMID: 32785213.
- Sahin U, Muik A, Derhovanessian E, Vogler I, Kranz LM, Vormehr M, Baum A, Pascal K, Quandt J, Maurus D, Brachtendorf S, Lörks V, Sikorski J, Hilker R, Becker D, Eller AK, Grützner J, Boesler C, Rosenbaum C, Kühnle MC, Luxemburger U, Kemmer-Brück A, Langer D, Bexon M, Bolte S, Karikó K, Palanche T, Fischer B, Schultz A, Shi PY, Fontes-Garfias C, Perez JL, Swanson KA, Loschko J, Scully IL, Cutler M, Kalina W, Kyratsous CA, Cooper D, Dormitzer PR, Jansen KU, Türeci Ö. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature. 2020 Oct;586(7830):594-599. doi: 10.1038/s41586-020-2814-7. Epub 2020 Sep 30. PMID: 32998157.
- https://www.sciencemag.org/news/2017/02/mysterious-2-billion-biotech-revealing-secrets-behind-its-new-drugs-and-vaccines
