1303: Minutes of Virtual Meeting of CMAAO NMAs on ‘Will the new mutations affect the vaccine or molecular diagnostics?’

9^th January, Saturday, 9.30am-10.30am

Participants, Member NMAs: Dr KK Aggarwal, President CMAAO; Dr Yeh Woei Chong, Singapore Chair CMAAO; Dr Alvin Yee-Shing Chan, Hong Kong, Treasurer, CMAAO; Dr Md Jamaluddin Chowdhury, Bangladesh Medical Association; Dr Marie Uzawa Urabe, Japan Medical Association; Dr Ravi Naidu, Malaysia; Dr Prakash Budhathoky, Treasurer, Nepal Medical Association

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

Key points from the discussion

• A mutation can be suspected when molecular diagnostic tests are not as effective, S gene negative, ORF 1ab/N positive, plasma and monoclonal antibodies do not work, vaccine failure, high viral load leading to a second peak/wave.
• Every time a virus mutates, the number of deletions will increase. When deletions occur, the virus changes its structure and diagnostic tests may not be as effective as they were.
• The function of coronavirus non-structural protein (NSP) 14 is proof reading. If this is lost, proof reading will become defective and mutations will occur. Therefore any drug which inhibits activity of NSP 14 will increase chances of mutations.
• Overuse/misuse of remdesivir, favipiravir, plasma therapy may lead to mutations.
• Any mutation in the RBD is significant; any mutation in RBM is even more significant.
• The current viral strain is D614G. This mutation has increased the replication and infectivity of the coronavirus, but has also made it more vulnerable to neutralization antibodies.
• The Nigeria mutation P681H (proline to histidine) is a single mutation occurring at 681 (near the S1/S2 furin cleavage site). 681 is a virus favorable mutation.
• A mutation named N440K (asparagine to lysine) has been detected in India. This mutation is in the RBM. It is found in Andhra Pradesh (34% of genomes analyzed) and also in Karnataka, Maharashtra and Telangana. One case of reinfection with this mutant strain has been reported in Noida.
• In India, two more mutations - C1240Y and P84T - have been seen in the state of Kerala. These are not in the RBD or RBM and hence this mutation will die out.
• Another mutation is in Australia S477N (serine to asparagine); this is in the RBM.
• Cluster 5 mutation from Denmark, with 69/70 deletion. Since it was an isolated strain, it died out. But, this was adopted by the UK strain.
• The UK variant VOC 2020-12/01 adopted 681 from Nigeria and 69/70 deletion from Denmark strain. There are 23 gene mutations. The major substitution is N501Y (asparagine (N) has been replaced with tyrosine (Y)). It has deletions (Hi 69 histidine, 70 Vi Valine), Y145 deletion, and 144. Other substitutions are A570 D, D614G, P681H (near the S1/S2 furin cleavage site), T716I, S982A and D1118H.
• Of the 23 mutations, the UK strain has 4 deletions and 13 non-synonymous mutations (which mean variant of concern – may affect how antibodies work, how molecular diagnostics work and may affect how vaccines work). The Y145 deletion is in a region known to bind to neutralizing antibodies.
• The UK strain is causing more cases in the age group 7-11 years.
• To diagnose UK strain by the existing RT PCR tests, look for labs doing three-target assay and look for S gene target failure (negative S gene, positive N and ORF). Therefore, S gene target failure is a sign that this is a UK strain.
• A recent case report of an immunocompromised individual persistently infected with SARS-CoV-2 acquired around 10 mutations in the spike protein over 154 days, notably including N501Y. This mutation was due to killing of NSP 14; this mutation was also adopted by the UK strain.
• The South Africa variant 501.V2; there are three mutations (two are in RBD and one in RBM). 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). The new variant has become the predominant strain in South Africa.
• This is an opportune time to take the vaccine. We do not know yet if these new strains will adopt mutations of other strains and make the vaccine less effective. Early vaccination is the answer before the virus mutates further.
• Singapore is soon rolling out the Pfizer-BioNTech vaccine. After thawing, this vaccine can be kept in the fridge for 5 days. The vaccine will be administered in a resuscitation available setting. Everybody will be monitored for 30 minutes. The vaccine is not mandatory.
• Logistics will be a challenge in vaccine delivery.
• The COVID virus may become chronic like hepatitis B and C virus.
• Vitamin D has been shown to improve mortality and reduced ICU use in COVID patients; vitamin D upregulates ACE2 receptors.
• Ivermectin is used for prevention and treatment in the state of Uttar Pradesh in India. It reduces viral load if started early, by reducing virus replication. Its anti-inflammatory role is doubtful.
• In a pandemic-like situation, any drug which may work, and will not harm, may be given.

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA