SARS CoV2 is continuously mutating. However, at least three mutations are known to have an impact on various aspects of the pandemic. N501V1.0, B.1.1.7, and D614G each have an impact on the pandemic. These mutations mat impact the diagnostic testing, severity, infectivity, efficacy of the vaccine, modulating the effect of medicines (such as Remdesivir) and finally, recalibrating the policies. Thus, the most appropriate action immediately after understanding the new variant is to evaluate the potential impact on public health.
Recently, at least two aggressive variants have been identified, one in the UK N501V1.0 and the other, B1.1.7 in South Africa. Multiple spike protein mutations define these variants. Apart from the nine mutations or 20 mutations on either of the variants. deletion 69-70, deletion 144, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H. It has multiple spike protein mutations (deletion 144, A570D, deletion 69-70, N501Y, D614G, D1118H, P681H, T716I, and S982A).
D614G is increasing in frequency at an alarming rate”. It had rapidly become the dominant SARS-CoV-2 lineage in Europe. It had then taken hold in the United States, Canada, and Australia. D614G represented a “more transmissible form of SARS-CoV-2 (https://www.nature.com/articles/d41586-020-02544-6).
What are the implications for diagnosis, the severity of the disease, policies, infectivity, and efficacy of the vaccine?
- Diagnosis: Ideally, at least two epitopes are considered while designing an RT PCR test for SARS CoV2. One of the proteins is on Spike protein. If the mutation affects the exact domain as the epitope, there is a strong possibility of redesigning the primers for RT PCR. Labs should revisit their primer design if those are based on the S-gene.
Does that invalidate the Antigen based or Antibody-based test? Possibly the first one may need to be revisited closely. However, the antibody test may still be valid and relevant.
- Severity: Severity of the disease is depends upon intrinsic factors, whereas infectivity is based upon extrinsic factors, predominant amongst those are the avidity and affinity of the virus for the receptor ACE2, and priming of these receptors via TMPRSS also plays a significant role.
However, noteworthy amongst the intrinsic factors are the IFN genes. A down-regulation, Loss of heterozygosity, methylation, or other factors that reduce the expression is one of the major putative factors in the progression of severity.
- Policies and Complacency: Just today, I read the news that there are no new cases in Mumbai. Absolutely, hats off. Great achievement, but let’s not forget the empire strikes back. Right now, Mumbai and places like Mumbai have dismantled their Covid hospitals. We need to be prepared earlier or possibly better if the virus strikes back. These mutations come at a (mis) opportune time of vacations, Christmas and New year when the society wants to revile and enjoy with their near and dear ones.
Some communities are basking that Covid has disappeared from their communities. Often, mutations within the virus are likely to be highly deleterious, preventing the invasion of the virus into the host resulting in the purging of the population. Policymakers need to understand that selective mutation in the virus might have conferred a disadvantage to the virus, rendering the virus into oblivion. However, aggressive variants like the one from the Uk or South Africa, may rekindle the reinfection within the community. I will caution; kindly watch out; it’s not over. The enemy strikes best when we let our guards down, a perfect situation for a storm.
- Infectivity: R-actor will be affected since the new variant is more infective if not aggressive in severity. The new variant is estimated to increase the reproductive number (R) by 0.4 or greater, along with an estimated increase in the transmissibility by 70%. Those R factor reporters will be back into play. However, remember, the R-factor has less reliability. It’s not a game of statistics. The complexity is compounded by several factors. R factor experts should reinvent themselves.
- Effect on the Vaccines: it is too early to say if these variants are likely to affect the efficacy of the vaccine. If the mRNA vaccines are designed on the epitopes with putative mutants, it is likely to affect the vaccine’s efficacy. However, it is too early to say that.
- Effect on Medications: The D614G variant has a mutation that affects the action of the drug Remdesivir. The new mutants from the UK or South Africa may or may not have any impact on the known mechanism of the existing drugs.
In a nutshell:
SARS CoV2 is known to mutate at least once in two weeks, primarily because of three distinct mechanisms – a. the RDRP enzyme’s intrinsic vulnerability during replication resulting in proof-reading errors, b. host RNA-editing systems, which is considered as a defense mechanism, and c. existence of multiple lineages simultaneously in the same patient (https://www.nature.com/articles/s41467-020-19818-2).
Another possible mechanism for the emergence of a variant is the persistent and prolonged infection, thus offering the virus an opportunity to evade the immune mechanism, called an immune escape. (https://www.ecdc.europa.eu/sites/default/files/documents/SARS-CoV-2-variant-multiple-spike-protein-mutations-United-Kingdom.pdf).
We have to revisit our primer design, severity, policies, and operational procedures, while the studies will unravel the impact on vaccine efficacy. R factor experts should consider renegade, relent, and renovate their R factor formulae and models to guide the policymakers and community.
Shashank Heda, MD