1259:   Minutes of Virtual Meeting of CMAAO NMAs on “New Strains of the COVID-19 Virus”

26^th December, 2020, Saturday, 9.30am-10.30am

Participants: Member NMAs: Dr KK Aggarwal, President CMAAO, Dr SM Qaisar Sajjad, Secretary General, Pakistan Medical Association, Dr Md Jamaluddin Chowdhury, Bangladesh Medical Association, Dr Marie Uzawa Urabe, Japan Medical Association, Dr Prakash Budhathoky, Treasurer, Nepal Medical Association

Invitees: Dr Russell D’Souza, Australia UNESCO Chair in Bioethics, Dr Ajay Kumar, Dr S Sharma, Editor IJCP Group

Key points from the discussion

• The UK, as are many countries in Europe, is showing a second peak. Whenever there is a second peak, this may be due to either relaxation in the behavior of the public with naïve population or mutation of the virus.
• If the second wave is larger and is of greater duration than the first peak, look for viral mutation. This is what we are seeing in England and South Africa.
• The terms variant, strain and lineage are synonymous in scientific language; for the public, the term used is mutant.
• VUI is “variant under investigation”; once the investigation is over, it becomes VOC (variant of concern). The UK mutation has changed from VUI to VOC.
• RNA viruses are likely to replicate as they are unstable. Coronavirus is less likely to replicate than HIV because of the size.
• Mutations allow for evolution.
• Selective pressure: Multiple mutations keep on occurring. Only those mutations which will help the virus in any of its functions will survive “Survival of the fittest”.
• The study of genomics has helped to discover the virus which caused COVID-19; it has helped to develop diagnostics, vaccines; to track transmission; to identify re-infection and also to understand host-virus interaction.
• The implications of emergence of the new variants are their ability to spread more quickly in humans, ability to cause either milder or more severe disease in humans, ability to evade detection by specific diagnostic tests, ability to evade vaccine-induced immunity and decreased susceptibility to therapeutic agents such as monoclonal antibodies.
• The non structural proteins are ORF1a/1b, ORF3a/b, 7a/b, 8a/b and 9b. The structural proteins are spike (S), nucleocapsid (N), membrane (M), and envelope (E) proteins.
• S protein is made up of 1255 genes; it is divided into S1 and S2. S1 has the RBD (receptor binding domain), which enters the ACE2 receptor. Under the RBD is RBM (receptor binding motif), the actual part which locks with the ACE2 receptor.
• Whenever there is mutation, find the location of the mutation. Out of 23 mutations in the UK strain, 8 are in S protein. The South Africa mutation has 3 mutations in the RBD.
• The non-structural protein (NSP) 14 is most important and is responsible for proofreading.
• There are currently 7 clades/strains of SARS-CoV-2 as per GISAID classification. It started with the L strain (the original Wuhan strain) followed by S, V, G, GH, GR and GV. O is unclassified. India has all the six clades circulating similar to the global picture.
• D614G (aspartic acid to glycemic acid) is the strain that is prevalent throughout the world. It is in the non-RBD part of the virus. This mutation increases the coronavirus replication and infectivity and the virus is more vulnerable to neutralization by antibodies.
• The influenza virus lacks proof reading activity, whereas proof reading activity (NSL-14) is present in the COVID-19 virus. No proof reading means more mutations.
• Another mutation in Nigeria is P681H (proline replaced by histidine); this is a localized mutation.
• UK strain: VUI (VOC) 2020-12/01 (the first variant under investigation in December 2020); there are 23 gene mutations. The main substitution is N501Y, N asparagine is replaced by Y tyrosine; it has three deletions - Hi 69 histidine, 70 Vi Valine and 144. Other substitutions are A570 D, D614G, P681H, T716I, S982A and D1118H.
• Spike protein mutation: Deletion of 69/70 is changing the shape of the spike protein. This deletion may make the S gene RT PCR test unreliable. N501Y may make the receptor binding more strong. Y145 deletion occurs in a region known to bind to neutralizing antibody. So we don’t know how it will affect the neutralizing antibodies.
• The South Africa variant is 501.V2; there are three mutations and all are in RBD. N501Y is the main substitution (enhances binding affinity to ACE2); other substitutions are K417N lysine with asparagine (would abolish key interactions with Class 1 Nabs and likely contributes towards immune evasion at this site) and E484K glutamic acid with lysine (enhances binding affinity to ACE2 and confers resistance to class 2 Nabs). These mutations are in the RBD. In the first wave, there were multiple lineages circulating; since early November, the new variant has become the dominant strain in South Africa. It has replaced all other strains to all practical purposes.
• Cluster 5 is a mutated strain of coronavirus detected in Northern Jutland, Denmark. It is believed to spread from minks to humans via mink farms - “mink-associated SARS-CoV-2 variant”.
• A theory has come up that if convalescent plasma is given to immunocompromised persons and the virus remains alive, then multiple mutations may occur. One of the mutations in the South African variant “N439K” in a 65-year-old cancer patient due to multiple plasma therapy, may allow the virus to bypass monoclonal antibodies.

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA