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Comparing the protein sequence between the virus and vaccine, it looks like codons 986 and 987 code for different amino acids. I looked it up and it seems like
by subroutine 6y ago
Comparing the protein sequence between the virus and vaccine, it looks like codons 986 and 987 code for different amino acids. I looked it up and it seems like a very important bioengineered constraint. Membrane fusion can be blocked by mutating S residues 986 and 987 to prolines, producing an S antigen stabilised in the prefusion conformation. The introduction of this two-proline substitution yields soluble prefusion coronavirus S ectodomains (overcoming a major hurdle in subunit vaccine dev).
- flobosg 6y agoRelated paper: https://www.pnas.org/content/114/35/E7348 https://www.pnas.org/content/114/35/E7348
- subroutine 6y agoalso... This paper gives background on designing vaccines to maximize rapid antibody responses post-infection, ideally before the virus enters cells: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936610/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936610/ - This paper talks about how this is achieved specifically for SARS-CoV-2: https://www.biorxiv.org/content/10.1101/2020.06.15.152835v1.full.pdf https://www.biorxiv.org/content/10.1101/2020.06.15.152835v1....
- bitexploder 6y agoSimplified statement, please?
- flobosg 6y agoSpike proteins in coronaviruses are present in two structurally distinct conformations: pre- and postfusion. The conformational switch between them promotes the viral fusion to the host cell. To maximize the effectiveness of the vaccine, its spike protein should stay in the prefusion state no matter what. The two mutations in the engineered spike proteins allow exactly that.
- sunshinerag 6y agoNice explanation. Could you be able to tell how the vaccine effectiveness is affected by the new virus strains at that level?
- flobosg 6y agoMore or less so. Roughly speaking, the effectiveness of the vaccine should be the same as long as the shape of the spike protein doesn’t change. The most important mutation in the new VOC 202012/01 variant (N501T) translates to tighter binding to the ACE2 receptor, which should have no effect on its structure. However, that variant has also a double deletion (residues 69 and 70 are removed) that might induce slight conformational changes. Another thing to keep in mind is that vaccines are polyclonal: the antibodies produced by them target several different regions of the spike protein. This implies that the virus would need to mutate several times in separate parts to be able to evade immunity effectively.
- bitexploder 6y agoThanks for breaking that down.
- wrikl 6y agoThe author talked about this in part 1 (https://news.ycombinator.com/item?id=25538820 https://news.ycombinator.com/item?id=25538820).