Barts-MS rose-tinted-odometer: zero-★s
The scale and intensity of the 2nd or 3rd wave of COVID-19 in London, the SouthEast of England and now in the remainder of the UK is worrying. It is being blamed on a new more infectious ‘British’ variant of SARS-CoV-2. This variant has many more mutations in its RNA genome and resulting changes in its protein structure. Most pundits are confident that this variant is not an immune-escape variant, i.e. that anti-viral immunity to the original SARS-CoV-2 via wild-type natural infection or a vaccine will work against the new variant. Their position is based on the observation that only one epitope (area of the spike protein) has been altered and that immunity to the remainder of the spike protein will be sufficient to provide immunity.
Until basic lab work is done using animal and cell culture models we can’t assume the above as fact. Therefore, I am going to propose a contrary position that until proven otherwise we need to entertain the possibility that this new variant of SARS-CoV2 is an immune-escape variant. What I mean is that pre-existing immunity, and by implication vaccine immunity, to the original SARS-CoV-2 spike protein may not be sufficient to stop its spread or being reinfected with the new variant.
The immune system is a remarkable thing. It has mainly evolved to protect us from infections and has multiple intricate systems to detect and respond to novel infections. However, coronaviruses are low fidelity viruses and don’t have mechanisms for checking how accurately their genomes are copied. As a result, they are highly mutagenic. Within the body, there is this evolutionary race between the virus and the immune system. As the body neutralises a specific variant of the virus, new variants or mutants that are able to avoid being neutralised escape and multiply and are selected to dominate. This is almost certainly how the new more infectious British and South African variants emerged. The latter process is much more likely to happen in people who are immunocompromised and have defects in innate or adaptive immunity that allow the virus to persist. We know this happens with SARS-CoV-2 it has recently been written up as a case report in the New England Journal of Medicine (see below). Please note how rapidly the virus mutated in this individual.
The reason why I am proposing a contrary view is the fact that we were supposed to be getting towards some kind of herd immunity in London and this 2nd/3rd wave of COVID-19 seems oblivious to herd immunity and there are increasing anecdotal reports, which I am hearing via the grapevine, of people being infected twice.
Another factor that needs more air time is the immunological phenomenon called antigenic sin. This is when the immune response to one variant or strain of a virus increases your chance of symptomatic infection and/or severe infection with a second variant or strain. The best example of this is Dengue fever, which is caused by an arbovirus (transmitted by mosquito bite). There are different subtypes of dengue virus. If you are infected with one subtype and develop antibodies to first subtype these antibodies (original antigenic sin) prevent an adequate immune response to subsequent infection with a different subtype of the virus. This results in subsequent dengue virus infections being more likely to be symptomatic and severe.
Is it possible that immunity to the original SARS-CoV-2 wildtype virus is selecting for infection with (preexisting antibodies may actually enhance infection) and shedding of the new strain and driving the 2nd/3rd wave of COVID-19? This infection and shedding do not necessarily have to be occurring in people with symptomatic COVID-19; this could be asymptomatic shedding. I am aware that public health officials are simply saying the new strain has a higher R-number and hence is more infectious, which is their explanation for the new rise in COVID-19 cases numbers. However, until we have lab-based hardcore virology data we need to entertain the possibility that the new variants may be immune-escape variants and/or original antigenic sin is neutralising or cancelling-out pre-existing herd immunity. In the latter context, herd-immunity may actually be acting as a catalyst for the new wave of infections.
This is why we need to take this third lock-down seriously and wait for the data to emerge to refute these hypotheses or to confirm them. This clearly has major implications for how we manage the pandemic going forward. In hindsight, we should have been much more vigilant about the management of immunocompromised patients with COVID-19 as they are likely to be the source of these new variants.
P.S. I estimate that likelihood of the above hypotheses being correct is low (<10%) and hence this post is a low-likelihood scenario and is simply a counterbalance to the current public health dogma.
Choi et al. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N Engl J Med. 2020 Dec 3;383(23):2291-2293. doi: 10.1056/NEJMc2031364. Epub 2020 Nov 11.
Weisblum et al. Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants. Elife. 2020 Oct 28;9:e61312. doi: 10.7554/eLife.61312.
Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor-binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.
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