#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

#MSCOVID19: ABN Guidance Update

Barts-MS rose-tinted-odometer: ★★★

The ABN have updated their COVID-19 guidelines, which are beginning to move towards the evidence. However, the guidance on cladribine is not supported by the evidence nor the science, i.e. how cladribine actually works and its impacts the immune system.

The latest guidance states “the risk of severe COVID-10 disease is increased for many months after ocrelizumab and cladribine”. I am not sure there is evidence to support the statement about cladribine. Ocrelizumab and other anti-CD20 therapies are given continuously and hence the risk does not go away. However, cladribine is an immune reconstitution therapy and is reversible. Even in the depletion phase of treatment, the level of immunodepletion is modest, particularly for CD8+ T cells (see slide show below) and innate immunity is left intact. In our opinion, this pattern of immunodepletion is not sufficient to pose a risk to people with MS treated with cladribine and is supported by the emerging pharmacovigilance data.

The good news is that the guidelines state that for both ocrelizumab and cladribine “self-isolation for all that time is not appropriate except for individuals with multiple other risk factors”, which is compatible with our practice.

I am also reassured that their guidance has also softened for alemtuzumab; i.e. “we would anticipate pwMS being advised to strictly self-isolate for at least four weeks after an alemtuzumab administration”. This has been our practice since we started dosing alemtuzumab again. The rationale for the 4 week time period I assume is based on the impact of alemtuzumab on innate immunity and is supported by trial data; i.e. the viral infection risk falls rapidly after four weeks, presumably because monocyte counts recover.

The ABN is also recommending two weeks of self-isolation after high-dose steroids, which is pragmatic advice based on the risk of severe COVID-19 identified in the Italian registry studies.

The new guidance has also made a comment about vaccine readiness; “patients contemplating ocrelizumab should be advised that they may not be able to receive a future SARS CoV2 vaccine if it is a live vaccine, and they may not respond immunologically to a dead or inactivated vaccine. Consideration should be given to delaying ocrelizumab re-treatment”. It is interesting that none of the other DMTs is specifically mentioned when it comes to vaccine readiness. I am sure live viral vaccines will also be contraindicated in patients on S1P modulators (fingolimod and siponimod) and on some of the other immunosuppressive DMTs such as natalizumab and possibly even teriflunomide based on their current SmPCs.

The interesting thing about vaccine readiness is we don’t know about how important T-cell responses are in relation to these emerging vaccines and whether or not people on anti-CD20 therapies will mount an adequate protective T-cell response to the SARS-CoV-2 spike protein and other antigens. Everyone focuses on antibody responses when they may not be that important in protective anti-SARS-CoV-2 immunity.

I am sure we haven’t heard the last on MS DMTs and vaccine readiness. This is why I would urge all the DMT manufacturers to do the necessary studies to provide us with the necessary evidence-base to make clinical decisions.

#MSCOVID19: round-2 a series of webinars

I would like to say thank you, thank you and thank you for your kind donations towards the Barts-MS coronavirus antibody study. With gift aid, we have now passed the £10,000 milestone and will be able to start the first phase of the study. This is great news.

To raise the additional money I won’t be running a double-marathon, but we have taken up your suggestion of hosting a series of webinars. We have not are not going to charge anyone as such for attending these webinars; instead, we will simply ask you to consider making a donation in kind towards our study.

“What is the real MS and why is it important to know the answer?” will be the first webinar, in a series of webinars, to raise funds for the Barts-MS Coronavirus Antibody Study.

This webinar will be delivered by Professor Gavin Giovannoni on Thursday 12th November 2020 from 17h30-18h30. The number of places is limited and will be allocated on a first-come basis. As a registrant, you are being asked to make a donation to support the Barts-MS COVID-19 Coronavirus MS Antibody study via our JustGiving page. The following is a short interview with main investigators explaining why this study is so important to people with MS.

CoI: multiple

#MSCOVID19: one microdonation at a time

Thank you for being such kind and generous supporters for our Barts-MS COVID-19 antibody study. It is clear that Prof G running the virtual NYC marathon this weekend, or next, depending on the weather, is not going to get us to the finish line. Therefore, we are going to take your advice and launch Barts-MS webinars. The webinar idea was suggested by one of you in the comments when we launched our fund-raising campaign.

There will be a limited number of places to watch these webinars, but to be allocated a ticket we are expecting viewer’s to make a microdonation towards our fundraising efforts so that Drs Ruth & Kang can start and complete our COVID-19 or coronavirus seroprevalence study.

At the end of the antibody study we should be able to answer some of the following questions:

  1. How many pwMS in the UK have antibodies to the SARS-CoV-2?
  2. What type of antibodies are they, i.e. IgM, IgG or IgA, what is the titre or level of these antibodies and are they neutralising? Neutralising means they inhibit coronavirus infection of cells in culture.
  3. How many pwMS seroconverted who had documented COVID-19, possible COVID-19 or no history of COVID-19?
  4. What is the seroconversion rate on different DMTs?
  5. We also hope to follow a group of pwMS longterm with repeat testing to see how long these antibodies last and to see how many seronegative pwMS convert to becoming seropositive with time.
  6. When a coronavirus vaccine or vaccines emerges we able to use the assay to see who makes an antibody response or not and hence we plan to compare different response rates on different DMTs.

The following are some suggestions for topics for the webinars:

  1. What are arguments for and against HSCT as a first-line treatment for MS?
  2. What is on the horizon for treatment of advanced MS?
  3. What will the management of MS look like in 2030?
  4. How can we make MS prevention a reality?
  5. What is smouldering MS and is it treatable?
  6. How are we managing MS during the COVID-19 pandemic?
  7. Will I be able to have a coronavirus vaccine when one arrives?
  8. Etc …..

These topics are not fixed in stone. If you have any suggestions let us know. Do you have any problems with us running these webinars? Would you be interested in attending? How do you feel about having to donate to attend the webinars?

For those of you interested the following is Prof G’s planned marathon route and if you want to make a micro-donation towards the study please click on the link below.

26.32 miles of bliss or hell

CoI: multiple

#MSCOVID19: Asymptomatic Shedders

Barts-MS rose-tinted-odometer: ★

The reason why so many people are coming down with COVID-19 and the second-surge is truly surging is the observation that three-quarters of people who are actively shedding SARS-CoV-2, i.e. have positive tests, are asymptomatic at the time of testing (see the latest study below).

In summary, having symptoms suggestive of COVID-19 is a very poor marker of whether or not you are infected with the virus and shedding. Therefore the only way to reduce the spread of the virus in the community is to assume that everyone who you come in contact with is infected and shedding. Therefore social distancing, masks, handwashing, avoiding high-risk environments, etc. becomes critical in slowing down the spread of the virus. 

Saying that there are many scientists and probably most politicians who are actively supporting the spread of the virus in low-risk communities, for example, University students, as an attempt to increase herd immunity. The danger of the latter is that it is very difficult to contain the virus in these low-risk communities and as a result, it is already spreading into high-risk groups which is why we are beginning to see an increase in hospital admissions and deaths from COVID-19. 

It is clear that we have many months still to run with this pandemic and sadly many more lives will be lost. On a positive note, the observation that many people in the general population and probably in the MS population as well, seem to have pre-existing cross-reactive immunity to the virus and hence seem to be resistant to infection. This means that we may get herd immunity at a population level much quicker than we expected. 

The latter may explain why the second-surge is not nearly as bad in London compared to some of our Northern cities, for example, Liverpool, Manchester and Newcastle. Many more people were infected in London in the first-wave, i.e. we have more herd immunity, which is acting as a firebreak and slowing down the spread in London. 

To paraphrase Robert Frost, we have many miles to go before we sleep. There is little doubt that 2020 is going to be a long hard year. We have just had to cancel our travel plans for Christmas; a small price to pay for being healthy and alive. Please try and stay positive things will get better; time is a great healer.

Stopping by Woods on a Snowy Evening

Whose woods these are I think I know.
His house is in the village though;
He will not see me stopping here
To watch his woods fill up with snow. 

My little horse must think it queer
To stop without a farmhouse near
Between the woods and frozen lake
The darkest evening of the year.

He gives his harness bells a shake
To ask if there is some mistake.
The only other sound’s the sweep
Of easy wind and downy flake.

The woods are lovely, dark and deep,
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.

Petersen & Phillips. Three-Quarters of People with SARS-CoV-2 Infection are Asymptomatic: Analysis of English Household Survey Data. Clinical Epidemiology. 8 October 2020 Volume 2020:12 Pages 1039—1043.

Background: To reduce transmission of SARS-CoV-2, it is important to identify those who are infectious. However, little is known about what proportion of infectious people are asymptomatic and potential “silent” transmitters. We evaluated the value of COVID-19 symptoms as a marker for SARS-CoV-2 infection from a representative English survey.

Methods: We used data from the Office for National Statistics Coronavirus (COVID-19) Infection Survey pilot study. We estimated sensitivity, specificity, the proportion of asymptomatic cases (1 – sensitivity), positive predictive value (PPV) and negative predictive value (NPV) of COVID-19 symptoms as a marker of infection using results of the SARS-CoV-2 test as the “gold standard”.

Results: In total, there were 36,061 individuals with a SARS-CoV-2 test between 26 April and 27 June 2020. Of these, 625 (1.7%) reported symptoms on the day of the test. There were 115 (0.32%) with a positive SARS-CoV-2 test result. Of the 115, there were 27 (23.5%) who were symptomatic and 88 (76.5%) who were asymptomatic on the day of the test. Focusing on those with specific symptoms (cough, and/or fever, and/or loss of taste/smell), there were 158 (0.43%) with such symptoms on the day of the test. Of the 115 with a positive SARS-CoV-2, there were 16 (13.9%) reporting symptoms. In contrast, 99 (86.1%) did not report specific symptoms on the day of the test. The PPV for all symptoms was 4.3% and for the specific symptoms 10.1%. The specificity and NPV of symptoms were above 98%.

Conclusion: COVID-19 symptoms are poor markers of SARS-CoV-2. Thus, 76.5% of this random sample who tested positive reported no symptoms, and 86.1% reported none of those specific to COVID-19. A more widespread testing programme is necessary to capture “silent” transmission and potentially prevent and reduce future outbreaks.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

#MSCOVID19: anti-CD20 nuances

Barts-MS rose-tinted-odometer: ★★★

I had to have a detailed discussion with a patient this week about starting ocrelizumab during the COVID-19 pandemic. This patient was concerned about (1) the data showing an increased risk of COVID-19 in anti-CD20 treated patients, (2) an increasing number of cases not seroconverting when being infected with the coronavirus and (3) she will not be able to have a coronavirus vaccine when one emerges. 

All of these three concerns are not black-and-white, but very grey, and need explaining. 

1. The increased risk of COVID-19 and severe COVID-19 on anti-CD20 therapy

This finding has been reported by the Italian register, the Iranians, the Swedes and the MSIF’s Data Alliance initiative. There is also a similar signal in the US data and French data. However, despite the increased risk of COVID-19 it is not associated with increased mortality. In the Italian data there is a weak signal that the longer you have been on an anti-CD20 therapy, particularly more than 3 years, the greater the risk of COVID-19. 

One issue that is not adequately addressed is reporting bias, i.e. more severe COVID-19 cases get reported and the less severe ones don’t because they are not registered as having COVID-19. Reporting bias is likely to affect DMTs that require patients to attend hospitals, i.e. treatments that bring them into contact with HCPs and hence they have a chance to report symptoms, and those DMTs that are the most widely prescribed. It is clear that both of these factors play a role in anti-CD20 therapies. One clue in support of this is the fact that there is a similar signal of a greater COVID-19 and severe COVID-19 signal emerging with natalizumab, i.e. another DMT that requires frequent hospital visits (reporting bias) but is less prescribed than anti-CD20 so the signal is not quite significant yet. 

One way to address this issue is to study non-biased trial populations, which has to be the data gold-standard. Roche presented 51 COVID-19 cases in over 4,000 ocrelizumab exposed trial patients (1.3%) (see presentation below). There was clearly no link between COVID-19 and treatment duration (slide 6). Three patients out of 51 patients died (5.9%). The numbers are too small to make a call on whether this represents a higher mortality than the background rate. Another important factor is that COVID-19 was not linked to hypogammaglobulinaemia. This ‘gold-standard’ data challenges some of the dogma that has emerged around CD20 therapies and COVID-19 and alters my interpretation of the Italian data.   

(2) An increasing number of ocrelizumab-treated cases not seroconverting when being infected with the coronavirus

Although there are several cases of SARS-CoV-2 positive COVID-19 cases on ocrelizumab who have been reported that have not seroconverted (detectable antibodies) there are many more normal people who have have COVID-19 who haven’t seroconverted as well. Whether this observation is assay dependent, i.e. insensitive assays that don’t detect low level antibody, or true biology needs further investigation. The fact that these people, ocrelizumab-treated or normal people, recover from COVID-19 is telling us that an antibody response is not necessary to clear the virus and for recovery from COVID-19. It is likely these patients have very good cellular immune responses that will protect them from reinfection in the future.

These observations have implications for vaccine responses and hence we may have had the wool pulled over our eyes focusing on the easier to measure antibody responses. I suspect, as do many others, that it is not humoral, but cellular, immunity that will be important for  protective immunity against SARS-CoV-2. I am not saying antibody responses won’t be important, but it is likely the dominant protection will come from cellular immunity. 

(3) Not being able to have a coronavirus vaccine when one emerges

This is clearly not correct. Patients on ocrelizumab will be able to have DNA, RNA and component coronavirus vaccines. The only vaccines they may not be able to have are live attenuated vaccines and potentially vaccines using a live viral vector to deliver the immunogen. The question is whether or not ocrelizumab-treated patients will be able to mount an adequate protective immune response to these vaccines is a moot point, which is why I have been urging Roche to plan and set-up registry studies to see if ocrelizumab-treated patients develop adequate immune responses to these vaccines. It is important that these studies are well designed and include both antibody or humoral and cellular components. 

Another thing to remember is that no vaccine is likely to be 100% effective. Even if the vaccine is only 60% to 70% effective it will be sufficient to create herd immunity and stop the spread of coronavirus. Vaccines are about population health and not necessarily about individual health, which is why regulators are fixated on safety.

I also told this patient that there are many other factors at play. For one the death rate or mortality from COVID-19 is falling. This is happening for several reasons. Firstly, we now have approved treatments for COVID-19 and the circulating strains are likely less virulent than the initial strains. Based on simple evolutionary principles the more benign strains are out competing the virulent strains. Another factor that I have commented on before is that we may be nearing herd immunity in some areas of the country, for example in London. This is based on the observation that many people have cross-reactive cellular and humoral immunity, presumably from other coronaviruses, that are protecting them from getting COVID-19. Therefore the risks of getting COVID-19 are falling. Add to this sensible personal hygiene and social distancing and the risks remain low. The second surge is really happening in areas of the country with low herd immunity and amongst care-free populations who are not being adherent to the government’s guidelines; for example, University students. 

The bottom line is that if you are low risk of getting COVID-19 and you double that risk the risk remains low. I would also only cross the vaccination bridge when it arises. Trying to preempt when and what vaccine will emerge first is really a guessing game. What is not a guess is that this patient has active MS, with a relatively poor prognostic profile (spinal cord disease) and needs treatment. She does not have highly-active MS therefore the only high-efficacy DMT available to her first-line on the NHS is ocrelizumab. She could select a platform therapy, which has also been offered to her, and to then see how she does, but as she is very well informed and understands the concept of ‘flipping the pyramid’ and that ‘time is brain’ doesn’t want to take a chance on a lower efficacy DMT. The outcome from our discussion is that she has decided to go ahead with ocrelizumab after she has had her pneumococcal and seasonal influenza vaccines. 

As you can see the COVID-19 anti-CD20 data is quite complex with a lot of nuances, which makes it difficult to communicate to patients. But if you take time to explain it to patients, not only do you allay their fears, but you end-up with a well informed patient who knows what they are signing up for. 

CoI: multiple

Twitter: @gavinGiovannoni             Medium: @gavin_24211

#MSCOVID19: dropping dead

Barts-MS rose-tinted-odometer: ★★★★★

“Did you hear that Professor Giovannoni dropped dead after attempting to complete the virtual New York Marathon trying to raise money for a multiple sclerosis research project?” 

“Prog G finally throws in the towel and arranges to see an orthopaedic surgeon about his failing right hip. His attempt to complete a marathon to raise money for MS research was one run too many.”

“Prof G’s kidneys finally pack-in after excessive use of non-steroidal anti-inflammatories in his futile attempt to complete a marathon and raise money for MS research.”

These are some of the comments I am getting back from my colleagues, who are concerned about my potentially foolish attempt to run a marathon. Please don’t be concerned about me I wouldn’t be taking on this challenge if I didn’t think I could complete it. As proof that I am getting close, I managed to complete a 20-mile run on Sunday; all I need to do is extend that by 6.2 miles in a few weeks time. 

The reason for taking on this challenge is to raise money to complete a very time-sensitive research project that is very relevant for people with MS. We have developed an ultrasensitive GloBody assay to detect antibodies against coronavirus that can be run on blood spots that are collected at home and posted to our laboratory. 

Our preliminary data indicates that our assay is more sensitive than the two commercial assays (Roche Diagnostics and Abbott laboratories) that are currently available via the NHS. The GloBody assay is detecting antibodies in people who are ‘antibody-negative’ on the commercial assays. This finding may be very important going forward and to help pwMS come to terms with their risk of getting COVID-19 and potentially help to detect antibody responses to any future coronavirus vaccine. 

To borrow a metaphor we have an oven-ready study that needs to be done in the next month or two. We lost our funding when the charity that was funding this project realised they had a funding shortfall due to COVID-19. Prior to hearing this bad news, we had already been given the green-light by our research office and ethics committee to proceed with the study; this is why the study is oven-ready.

As our assay is now running and is closed to being validated would you be interested in getting yourself tested for a small amount? The result will then be sent to you and we would use the money collected from providing a service to pay for the service and to support the costs of the laboratory component of the MS seroprevalence study. Your thoughts, please?

If you haven’t done so already we would appreciate any microdonations so that we can start the study as soon as possible. 

Thank you. 

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

#MSCOVID19: digital health – what will survive?

Barts-MS rose-tinted-odometer: ★★★

I am doing a webinar with Professor Tjalf Ziemssen, a good friend and colleague from Dresden, Germany, this afternoon on the digital management of MS. Interestingly, many of the changes and innovations we have put in place to manage MS during the COVID-19 pandemic will survive and actually thrive in the new NHS, simply because we are a socialist healthcare system at the point of delivery. In comparison, in Germany, the reimbursement for digital consultations are an order of magnitude lower than old-fashioned face-2-face synchronous consultations. Therefore the adoption of digital tools to manage MS will be much slower due to the lack of financial incentives.

If you are interested in hearing about the differences between the UK and Germany please register and log-in today’s webinar.  

Please note this webinar will not be a didactic lectures, but more of a casual chat; banter between colleagues. I hope to see you later.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

#MSCOVID19: good news

Barts-MS rose-tinted-odometer: ★★★★★

The late late-breaking session at the MSVirtual2020 meeting, which covered COVID-19 has already received a lot of air-time on social media. The big-data alliance confirmed the Italian data, i.e. that people with MS (pwMS) on anti-CD20 are at higher risk of getting COVID-19 and severe COVID-19 (hospitalisation, intensive care admission and/or ventilation) compared to pwMS on dimethyl fumarate. Importantly there was no mortality signal, i.e. pwMS on anti-CD20 don’t appear to be at higher risk of dying from COVID-19 and its complications. This is very good news! 


However, the Big-Data alliance couldn’t confirm what the Italians have shown that treatment duration on an anti-CD20 is a risk factor. A clue to the latter is the observation that the COVID-19 risk was higher with rituximab compared to ocrelizumab in the Big-Data alliances graphs. As it is likely that rituximab-treated pwMS have been on treatment longer than ocrelizumab-treated patients would support this. Ocrelizumab has only recently been licensed and hence most people on ocrelizumab are likely to have been on it for a shorter period of time compared to rituximab-treated patients. 

Is all this good news? Yes, very good news. 

It clearly shows that people on anti-CD20 therapy have the ability to mount a robust immune response and recover from coronavirus infections, despite having a reduced B-cell and antibody response. This means that innate immunity and adaptive cellular immune responses are all that is required to recover from coronavirus and other viral infections. It will be important to study how robust the T-cell memory responses are post-COVID-19 in these patients as this will have implications for studying vaccine response when vaccines arise. What this means is that even if pwMS on an anti-CD20 don’t make an antibody response to a SARS-CoV-2 vaccine they may still have protective cellular immunity. This will also be good news. I sincerely hope Roche-Genentech and Novartis are planning to study vaccine responses in ocrelizumab- and ofatumumab-treated patients when the vaccines arrive. 

The observation that the longer you have been on an anti-CD20 the greater your chances of getting COVID-19 and severe COVID-19 implies the risk may be related to hypogammaglobulinaemia and blunting of past cross-reactive immunity from being exposed to other circulating community-acquired coronaviruses. I illustrate this in the following slide. In short pwMS on anti-CD20 therapy are shifted to the right and are less likely to have asymptomatic infections and more likely to have severe infections. 

This cross-reactive immunity to other coronaviruses may be the silver lining to the ominous grey clouds that have been hanging over us for months. It seems that between 40-60% of people in the general population have T-cell responses to SARS-CoV-2 without a history of having had COVID-19 and without an anti-SARS-CoV-2 antibody response. It now seems that these cellular memory responses protect these individuals from getting COVID-19. If this proves to be the case then herd immunity might be much higher than we realise and this could explain why the second surge in places like London and New York are much lower than other places that had smaller peaks during the initial wave of COVID0-19. 

If this background cross-reactive coronavirus immunity hypothesis, backed by the observations we see in pwMS on anti-CD20 therapy, turns out to be true we may have already reached herd immunity in London and are not far off it in other areas of the country. New models by Gomes and colleagues, at the University of Strathclyde, and Lourenco and colleagues, at the University of Oxford, suggest herd immunity may occur at levels of exposure of 20% or lower. If this is the case then we will see it first in London. So please watch the London COVID-19 numbers if they stay low this will be very good news. 

Gomes et al. Individual variation in susceptibility or exposure to SARS-CoV-2 lowers the herd immunity threshold. MedRxIV doi: https://doi.org/10.1101/2020.04.27.20081893

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads, the susceptible subpopulation is depleted causing the incidence of new cases to decline. Variation in individual susceptibility or exposure to infection exacerbates this effect. Individuals that are more susceptible or more exposed tend to be infected earlier, depleting the susceptible subpopulation of those who are at higher risk of infection. This selective depletion of susceptibles intensifies the deceleration in incidence. Eventually, susceptible numbers become low enough to prevent epidemic growth or, in other words, the herd immunity threshold (HIT) is reached. Although estimates vary, simple calculations suggest that herd immunity to SARS-CoV-2 requires 60-70% of the population to be immune. By fitting epidemiological models that allow for heterogeneity to SARS-CoV-2 outbreaks across the globe, we show that variation in susceptibility or exposure to infection reduces these estimates. Accurate measurements of heterogeneity are therefore of paramount importance in controlling the COVID-19 pandemic.

Lourenco et al. The impact of host resistance on cumulative mortality and the threshold of herd immunity for SARS-CoV-2. MedRxIV doi: https://doi.org/10.1101/2020.07.15.20154294

It is widely believed that the herd immunity threshold (HIT) required to prevent a resurgence of SARS-CoV-2 is in excess of 50% for any epidemiological setting. Here, we demonstrate that HIT may be greatly reduced if a fraction of the population is unable to transmit the virus due to innate resistance or cross-protection from exposure to seasonal coronaviruses. The drop in HIT is proportional to the fraction of the population resistant only when that fraction is effectively segregated from the general population; however, when mixing is random, the drop in HIT is more precipitous. Significant reductions in expected mortality can also be observed in settings where a fraction of the population is resistant to infection. These results help to explain the large degree of regional variation observed in seroprevalence and cumulative deaths and suggest that sufficient herd-immunity may already be in place to substantially mitigate a potential second wave.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

#MSCOVID19 running the talk

Barts-MS rose-tinted-odometer: ★★★★★

In anticipation of a second-lockdown at a meeting with colleagues last night I was asked the question about what positive experiences I could reflect on from the first lockdown. Firstly, no international travel and a focus on family, home life and the realisation that we can live more sustainably. Secondly, walking or running the talk. I decided to take my own prehabilitation advice seriously and I have managed to rehabilitate my physical and mental self and get my right hip working again. This is quite remarkable. Three years ago I had written off any future prospect of running long distance never mind a marathon. Six months into the pandemic and I am getting ready to try and complete a marathon in a months time.  Why? Funding and important time-sensitive research for people with multiple sclerosis. 

We have a problem with the current antibody tests for detecting past infection with coronavirus. The current assays are not sensitive enough and are not detecting antibodies in a large number of people with asymptomatic or mild infection and possibly in pwMS who are on certain immunosuppressive disease-modifying therapies, in particular the anti-CD20 treatments rituximab, ocrelizumab and ofatumumab. Detecting antibodies in these people is really important in that it would indicate that they have been exposed to the virus and therefore likely to have cellular immunity. 

In response to this challenge and  thanks to a grant from the Barts Charity, our group (Dr Kang and his team) have developed an ultrasensitive assay (GloBody) that will work on blood spots. Preliminary results show  that the assay is detecting antibodies in samples that have been called negative with commercial antibody assays. This is not unexpected because the assay was designed to have amplification steps to detect very low levels of antibodies. We did this because we want to study low-level antibody responses in pwMS on and off different DMTs.

This assay will now allow us to test a large number of pwMS using self-collected blood spots to see if they have been infected with coronavirus and are now immune. The tragedy is we have been promised a grant to do the initial part of this study by a charity. However, as donations have dried up this charity can’t afford to give us the money to cover the initial costs of the study. This is when I took up your suggestion to crowdfund. To show how serious I am about the crowdfunding I have decided to run the virtual New York City Marathon. All I have to do is record a single 42.2km run using the GPS-tracking application STRAVA sometime between the 18th October and 1st November. 

one run at a time.

In reality, I started my training very late and don’t really have the time to get truly marathon ready. However, as it is so important for us to raise the money so we can get this critical time-sensitive research done I am going to give it a go anyway. 

I would like to thank those of you who have already sponsored me. I would also like to urge you to donate to our cause. Even a small donation or £2-£5 would help. Microdonations all add-up. 

Thank you. 

CoI: multiple

Twitter: @gavinGiovannoni 

Medium: @gavin_24211