#MSCOVID19: antigenic sin

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.

Figure 1. SARS-CoV-2 Whole-Genome Viral Sequencing from Longitudinally Collected Nasopharyngeal Swabs. Shown is a maximum-likelihood phylogenetic tree with patient sequences (red arrow) at four-time points with high levels of SARS-CoV-2 viral loads.

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.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

24 thoughts on “#MSCOVID19: antigenic sin”

  1. Cheery story as usual from Prof G. So the vaccines won’t work against a mutating virus and we’re all doomed! Never mind, the snowdrops have come out in my garden which puts a smile on my face.

    I thought Team G’s New Year’s resolution was to focus on MS research (purpose of this blog) and not Covid 19. Leave the latter to the experts – virologists and immunologists, and the good guys such as Prof Whitty and JVT.

    1. I haven’t made any New Year’s resolution except to point out unjustified dogma when I see it. Whitty is clearly more worried than he lets on; everyone wants to blame the 2nd/3rd surge on the new variant using epidemiological data. What we need are the virologists’ to show us the lab data to support the current claims.

  2. Prof G don’t listen to your comrads. Please continue to provide these updates concerning the virus. This virus and its new strains affect those of us with MS & other immune issues as well as those of us who may have compromised immune systems via medications we take for MS. Thank you for providing your knowledge.

  3. Happily there were fewer than 3 cases in my local area as of yesterday, hows that for positive?

  4. So what on earth do we do now then?

    Supposedly the vaccine was what we wait for. So now that isn’t going to work. So we just lock up immunocompromised people forever?

    Why can’t we ever have a ray of hope without someone telling us a catastrophic scenario like this. You say the likelihood is low, but you say Whitty is clearly concerned. Now you have planted the seed it will cause a lot of us an awful lot of worry!

    1. Calm down, this is speculation at this point. Whitty is more concerned about the NHS being overwhelmed, due to our serially incompetent government, which it is on the brink of being in several areas of the country.

    2. Stop reading the technical medical information if you can’t cope!

      I appreciate the honesty and the education provided.
      Thank you, Prof G

  5. I did wonder how close we might be to herd immunity in London. 2% of people in my local area currently have the virus, I have no idea how many have already had it but it must be a large number. Anecdotally, many people I know have had it but no one particularly close. The closest was a man I sat near to in a meeting in March who ended up in hospital shortly after, and then my boiler engineer, who I didn’t see personally but my other engineer picked up some screws from him before coming to mine. Neither of us fell ill so I’m assuming she took adequate precautions! She had a sore throat at the time but I was desperate for a working boiler and we both wore masks and distanced too. And I opened the kitchen window next to where she was huffing and grunting! (

    The most alarming report comes from a colleague of mine whose daughter is in hospital for a second time with the virus, having had it early in the first wave.

    How is this affecting your team this time around? Both in terms of staff absence and redeployments? I have been told my nurse appointment with Queen Square may not go ahead at the allotted time next week.

    1. Interesting point! I know of multiple colleagues, most of the staff at my children’s’ school, plus friends and most notably my husband (!) who have had covid. We live in the North East. I would also love to know how close we are to herd immunity as I feel like most people I know have been touched by it now.
      Glad you remained well!

  6. Without an adequate track and trace system the UK will be unable to avoid overloading the NHS without a lockdown. The government have had 9 months to get this thing together – they can look at what countries such as South Korea have done to successfully avoid lockdown by control the spread of the disease.

    Whatever is going on in the UK isn’t working – compliance with basic measures like masks is very poor – messaging from the government is very poor. The whole thing is a mess.

    In terms of loss of vaccine efficacy against the mutated virus protein spike – this could be the case. However the vaccines currently in use are reasonably easy to modify so they can add an mRNA message to produce the newer “spike” as well within 4 – 6 weeks. It’s certainly not a deal breaker for the current vaccines in place.

    In terms of reinfection – don’t discount the idea that antibodies DO work but the seroconversion for coronavirus is poor so the immunity wears off very quickly. Vaccines are the game changer here – vaccine response antibodies are way more targeted than the scattergun approach of the human immune system. Thus vaccine immunity to the same strain of the virus is likely to last rather longer than natural immunity – vital for herd immunity to be a reality rather than a bunch of libertarians spouting wooly nonsense about “protecting the vulnerable” without having realised what such a thing costs (because when they realise the cost of protecting the vulnerable it will be all about NOT spending that kind of money…)

    Fact is, vaccines are our only hope against a pandemic. But that’s always been the case.

    Meanwhile is anyone holding the government to account about the horrendous sick rates amongst medics treating Covid-19? Or about the fact that hospital staff NOT treating Covid-19 are twice as likely to catch it (at work) than those who ARE treating it – mostly down to the quality of the PPE being provided? Or the aforementioned lack of effective track and trace? Those are scandals. Viruses mutating as they always do is annoying but expected. So are criminal levels of governmental incompetence but they shouldn’t be. We deserve better.

    1. we have a track and trace system it is called andriod it knows where we are ever second of the day, who we are talking to and who we are near, South Korea tracked thousands of people by their phones

      Scandal they have moved NHS treatment into the private sector but not giving frontline secondline or anyone vaccines

      1. I know people will find this hard to believe, but, not everyone has a mobile phone and not all phones use mainstream programming like Apple. But, I guess a large percentage of the population do. Which is why when I read that some people won’t have the vaccine because they think that Bill Gates is putting chips in it to track us I nearly spat my coffee out and nearly wet myself from laughing so much.

    2. I agree, but the point I am making is that increasing background immunity (herd immunity) should bring the R-number down and slow the trajectory of the 2nd/3rd wave. As this has not happened we simply need to ask the question about immunological escape.

      I am not sure the regulators will simply allow you to retool the vaccine backbone without doing another clinical trial. Changing the construct is like changing the structure of a molecule; if this was a small molecule it would require a new development programme. This will be an interesting test for vaccine development and the future of vaccine design.

  7. We’ve had continuous disfunction here in the U.S.A. regarding the governments and public’s response to Covid, and now to the roll out of the vaccine. That coupled with the sheer ignorance of people with regards to mask wearing, and social distancing. God help us if you’re right Dr. G!!

    1. The sheer ignorance is definitely the biggest part of problem here in the Northeast USA! My city alone yesterday 9100 total cases. Current Active approx 2150+ with a few dying each day. My kid & I currently at end of 14day quarantine due to daughter exposed at work by a co-worker who tested positive after ignoring everything & the co-worker seeing people at holiday who became positive. Then co-worker brings it to work. Day 10… My daughter just tested negative! Whew. I am still awaiting my results. Both symptomless but still scary! And they are starting to roll out vaccine but now this new strain…

  8. As an American, I do not want to imagine what would happen if we had to deal with antigenic sin and a more rapidly spreading variant of the Covid virus.
    We are vaccinating the most vulnerable people and our most essential workers and then to find out that the vaccine not only won’t protect you against this new strain, but will make your illness significantly worse….
    I am not sure the U.S. political, medical, and economic institutions could bare the strain. Good luck administering another vaccine or even the flu vaccine. Childhood immunizations go down.
    Long Covid would almost certainly increase.
    And the civic life of the U.S. isn’t exactly the most robust at the moment.

  9. Some good news coming in the media is that lab testing of the Pfizer/BioNtech vaccine indicates that neutralising antibodies to the vaccine are protective against both the UK and South African Covid variants.
    So, as you were guys and gals!!

    1. Great news to hear. How many people don’t understand the big picture, how many people blew off the Flu Vaccine this year, Thus 40 percent in the USA may not get jabbed. These types and anti-vaccine people are gonna propagate the problem. I finally found the Magic website accepting my criteria, allowing me to receive the Vaccine in TEXAS. Now the waiting starts. Thank you UK for Vaccinating last year, I feel more at ease. Millions of doses have been given, the Safety Odds have improved regarding the Vaccine.

      1. also the UK variant mutation is inhibited by vaccine so we are led to believe

    2. Lukewarm news; the data is from cell culture experiments. We also need to see what happens to vaccinated people and whether or not the immunity stops them from becoming infected and more importantly becoming active viral shedders at a mucosal level. The good news is the circulating antibodies are likely to protect against systemic infection.

      It is hard to reconcile the current data with what we expect to be happening as significant background herd immunity builds up; the R-value should be going down not up.

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