Tag: vaccines

#MSCOVID19 Endemic musings

Fudging the issues or bumbling along is how the public, opposition politicians and the journalists are interpreting the Government’s handling of the exit strategy for the COVID-19 epidemic in the UK. I don’t agree. I think the Government has a clear plan, which is being driven primarily by economic considerations. 

The primary objective of the lockdown was to protect the NHS and this has been successful. Well done! The primary objective of handling the epidemic’s tail is to get the country back to work and to try and turn COVID-19 into an endemic disease. 

For those of you who are not epidemiologists, an epidemic is the rapid spread of disease to a large number of people in a given population within a short period of time compared to endemic infection when that infection is maintained at a constant baseline level in the population.

Making COVID-19 endemic is like walking on a tightrope. By allowing very young children back to school first who are unable to self-isolate effectively is asking them to spread the infection amongst themselves, their siblings and their parents who will all be relatively young and at low risk of severe COVID-19. This will allow the gradual spread of infection to continue in the community and the gradual build-up of herd immunity. Most people I speak to don’t seem to understand this.

At the same time, the more vulnerable groups in the population have been asked to continue shielding and to be extra cautious about avoiding getting infected with SARS-CoV to reduce the risk of a second surge in the epidemic, protect the NHS and to keep the death rate relatively low. 

The Government is also putting in place the whack-a-mole strategy of active case finding and contact tracing to try and control local COVID flares. The whack-a-mole strategy is working well in China, South Korea and Singapore and it will almost certainly work well here if it is properly resourced.

The introduction of widespread antibody testing, with a reliable assay, to see who has been infected with SARS-CoV-2 will allow epidemiologists to track herd immunity and to finesse the Government’s strategy. The idea of getting a COVID-19 passport to show that you have been previously infected and are now immune to getting further infections, at least in the short-term, is unlikely to happen within the UK but may be required for safe international travel or to attend outpatient clinics or be admitted to cold (COVID-negative) hospitals for invasive procedures, etc. The latter is analogous to what happens with multi-drug resistant staphylococcus in clean surgical units in the NHS. Before you are allowed to be admitted for elective surgery you have a nasal swab taken to make sure you are not carrying the multi-drug resistant bacterium.

If the Government can allow herd immunity to gradually increase and to keep the R-value for the whole population at about 0.8 to 1.0 they will achieve their aims of making COVID-19 endemic, getting the economy going again and protecting the vulnerable. Clearly, this strategy will be a bit hit-and-miss and there will be collateral damage, i.e. people will continue to get severe COVID-19 and a proportion of them will die as a result. To expect anything else is unrealistic, which is why I find the posturing of the opposition politicians bewildering, to say the least. What is their solution; perpetual lockdown until we get a vaccine?

Most people think that a vaccine is the government’s end-game. I don’t want to disappoint you but there is no guarantee that a vaccine will work. I also worry that if the whole world exits lock-down with a trickle of cases we may not be able to test vaccines in an efficient manner. 

To develop and test an effective vaccine we really need the COVID-19 epidemic to be in full swing, i.e. on the upside of the curve and not on the tail. A vaccine trial is like a drug trial; subjects are randomised to an active or SARS-CoV-2 vaccine arm or a comparator arm (placebo or another vaccine) and then you see whether or not there are fewer cases of COVID-19 on the active arm compared to the comparator arm. However, if there are too few cases developing COVID-19 because of social distancing, using face masks, hygiene measures, etc. it will take too long to get enough events or trial subjects getting COVID-19, to show the vaccine is working. There is a way around this and that is to shift to an active-challenge vaccine paradigm, i.e. to get groups of young volunteers who are anti-SARS-CoV-2 antibody negative and to randomise them to receive the vaccine or placebo and to then challenge them with the live virus. This is how they test the effectiveness of the seasonal flu vaccine each year. You may ask why would anybody take the risk of getting COVID-19 and severe COVID-19 voluntarily? The answer is money. These volunteers tend to be paid very handsomely for their time. 

Another factor that may help the Government is that summer is on its way and as the temperature rises the less infectious coronaviruses become. SARS-CoV-2 viral particles are temperature sensitive and are viable for much shorter periods of time outside the body in hot climates. This may explain why we haven’t seen such rampant spread of the virus in warmer climates. 

I think Boris Johnson’s recent bumbling performances when questioned about the Government’s exit strategy is deliberate so as to avoid questions about herd immunity, whack-a-mole and collateral damage. The sad truth is that at some point we as a society are going to have to realise that quite a large number of people are still going to have to die from COVID-19 as part of the exit strategy to get us to a point when we can chop off the tail of the UK’s COVID-19 epidemic. The consequences of not doing this are potentially far worse for the UK in the longterm. For example, some epidemiologists predict that the increase in poverty and inequality that the COVID-19 epidemic has caused will result in more excess deaths than the number of people dying from severe COVID-19. This may be hard to comprehend, but the social determinants of health have a powerful effect on health, health outcomes and survival. The challenge for the government is getting the balance right, which is what they are trying to do.

I would be interested to know if any of you have any thoughts on these issues. 

CoI: none

#MSCOVID19: immunosuppression & vaccine-readiness

It is always a good idea to learn from others. We have stressed that the uneventful recovery from COVID-19 involves two processes. Firstly, an appropriate antiviral response, which is needed to clear the virus and secondly an anti-inflammatory response to prevent the delayed immunological damage to the lung that triggers ARDS (acute respiratory distress syndrome), which is the main cause of death with COVID-19. There clearly is a balancing act as if you suppress the delay immune response too much you may prevent clearing of the virus and ongoing damage from viral replication. 

It is very heartening to see that patients with other immune-mediated inflammatory disorders that are on immunosuppressive therapies, predominantly biological therapies, are not at increased risk of severe COVID-19 (see Haberman et al below). This experience is mirroring our experience in MS. 

However, in the transplant field where the levels of immunosuppression are an order of magnitude more intense, the message is mixed. Liver transplant recipients seem to do fine (see D’Antiga below) but in kidney transplant recipients those with the greatest T-cell depletion, particularly those who receive ATG (anti-thymocyte globulin), do the worst and have high mortality from COVID-19 (see Akalin below). The reason for the difference between liver transplant recipients and ATG-treated kidney transplant recipients are T-cells. ATG is one of the most potent T-cell depleting agents we have and rendering someone severely deficient in T-cells puts them at high risk of viral, in particular severe viral, infections. The latter does not only include exogenous (outside the body) viral infections such as SARS-CoV-2 but endogenous (inside the body) latent viruses such as CMV and EBV. The ATG treated transplant patients are likely to be succumbing to uncontrolled SARS-CoV-2 infection rather than the delayed immunological reactions or ARDS. 

What this is telling us is that moderate immunosuppression, with reasonable T-cell counts and T-cell function, does not increase your risk of getting COVID-19 or severe COVID-19 and may reduce your risks of the latter. However, as soon as you drop your T-cell counts and profoundly suppress T-cell function you are increased risk of severe COVID-19, probably from uncontrolled viral replication. 

So how is this relevant to MS? As always it is a balancing act between being sufficiently immunosuppressed to prevent the immunological complications of SARS-CoV-2, but not too immunosuppressed that you can’t control the viral infection. In my opinion, in the MS space, the only treatments that we need to be concerned about are the acute effects of alemtuzumab and HSCT on the immune system in the depletion phase of treatment, i.e. the initial 3-6 months until total lymphocyte counts recover to a level that gives you adequate anti-viral responses. I have set the latter at above 500/mm3 in younger pwMS and above 800/mm3 on older people (older than 60 years of age). The reason for the latter is that as you get older and develop immunosenescence the proportion of your T-cells that are naive and able to respond to new viruses and antigens shrinks. This may explain why older people are at more risk of getting severe COVID-19, i.e. their immune systems are just not as good at responding to new viral infections. 

There is a third phase to SARS-CoV-2 and that is the delayed antibody response, which is B-cell dependent. The antibodies probably contribute to the tissue damage in the immune-mediated phase of COVID-19. However, you clearly don’t need B-cells and antibodies to recover from COVID-19. I base this on the case reports of two patients with agammaglobulinaemia from Italy who recovered from COVID-19. Please remember these patient don’t have B-cells. Another clue that B-cells are not needed is the fact that patients on anti-CD20 therapies tend to deal with viral infections, including novel or new viral infection, well and rarely get severe viral infections. The latter observation is borne out by how well anti-CD20 patients are weathering the COVID-19 storm. 

The one downside of anti-B-cell therapies, however, is that you may need anti-SARS-CoV-2 antibodies to prevent yourself from getting reinfected with the virus. The latter has major implications for when a SARS-CoV-2 vaccine arrives. Will pwMS on anti-CD20 therapies be able to respond to a vaccine? Based on the fact that the SARS-CoV-2 spike protein, the main immunogen in future vaccines, is heavily glycosylated and that anti-CD20 therapies block antibody responses to glycoproteins (proteins covered in sugar molecules) patients on anti-CD20 therapies are unlikely to be vaccine ready unless their dosing is interrupted to allow peripheral B-cell recovery. 

It is clear from social media activity and exchanges with my colleagues that many of us are now moving onto the next phase of preparedness for managing MS during COVID-19, i.e. how to ensure your patients are vaccine ready for a SARS-CoV-2  vaccine. The latter is something I have discussed before and is why I have added another column to my DMT table (version 4). 

Table is from www.ms-selfie.org

Haberman et al. Covid-19 in Immune-Mediated Inflammatory Diseases — Case Series from New York. N Engl J Med 2020 Apr 29. doi: 10.1056/NEJMc2009567.

A better understanding of the implications of Covid-19 in patients with immune-mediated inflammatory disease and the effects of anti-cytokine and other immunosuppressive therapies is urgently needed to guide clinicians in the care of patients with psoriasis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, and related conditions. Although our analysis was limited in sample size, our data reveal an incidence of hospitalization among patients with immune-mediated inflammatory disease that was consistent with that among patients with Covid-19 in the general population in New York City reported by the New York City Department of Health and Mental Hygiene (35,746 of 134,874 patients [26%]) (Table S5). These findings suggest that the baseline use of biologics is not associated with worse Covid-19 outcomes.

Lorenzo D’Antiga. Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic. Liver Transplantation 20 March 2020. 

… the available data on past and present coronavirus outbreaks suggest that immunosuppressed patients are not at increased risk of severe pulmonary disease compared with the general population. Children under the age of 12 years do not develop severe coronavirus pneumonia, regardless of their immune status, although they get infected and can, therefore, spread the infection. The risk factors for severe disease remain old age, obesity and its complications, other comorbidities, and male sex. Although the surveillance of this particular group of patients should continue, there are no reasons to postpone lifesaving treatments, such as transplantation or chemotherapy for cancer, during coronavirus outbreaks both in children and in adults.

Akalin et al. Covid-19 and Kidney Transplantation. N Engl J Med. 2020 Apr 24.

In conclusion, at our institution, kidney-transplant recipients with Covid-19 had less fever as an initial symptom,3 lower CD3, CD4, and CD8 cell counts,4 and more rapid clinical progression than persons with Covid-19 in the general population. The number of our patients with very low CD3, CD4, and CD8 cell counts indirectly supports the need to decrease doses of immunosuppressive agents in patients with Covid-19, especially in those who have recently received antithymocyte globulin, which decreases all T-cell subsets for many weeks. Our results show a very high early mortality among kidney-transplant recipients with Covid-19 — 28% at 3 weeks as compared with the reported 1% to 5% mortality among patients with Covid-19 in the general population who have undergone testing in the United States and the reported 8 to 15% mortality among patients with Covid-19 who are older than 70 years of age.

CoI: multiple

#MSCOVID19: wow!

I am on call at the Royal London Hospital and sitting in my office digesting some of my daily COVID-19 reading. However, something has just hit me between the eyes and I have to say wow aloud! 

WOW!!

The paper and editorial below show you just how infective SARS-CoV-2 really is and why we are not going to win this battle for our vulnerable people without an effective anti-viral and/or vaccine. It also tells me that if we don’t get a vaccine things will not normalise for a very long time. 

Who said the R0 (R-zero) for this virus was less than 3 and therefore we would get herd immunity at about a 60% seroprevalence rate? Not me! 

R-zero or the basic reproduction number for SARS-CoV-2 is the expected number of cases infected by one case in a population where all individuals are susceptible to infection. The original calculations were based on symptomatic index cases and symptomatic contacts with positive swabs. The fact that a large number of people (possibly up to 50%) have now been shown to get asymptomatic infections and that the test for the virus is not 100% specific. This means that approximately 25% of cases with COVID-19 defined by clinical definition have negative nasopharyngeal (nose & throat) swabs; i.e. 25% of infected people who may be shedding are not detected with the swab test. Based on these assumptions I have estimated that in normal life (no social distancing) that the R-zero is likely to be somewhere between 6 and 7. This means that to get herd immunity, a point when natural transmission in the population stops, you need somewhere between 80% and 86% of the population to have immunity. 

However, the study below just published in the New England Journal of Medicine makes me think this may even be an underestimate. In a well done ‘classic’ epidemiology study in a nursing home in Seatle, 23 days after the first positive test result in a resident, 64% tested positive for SARS-CoV-2; more than half (56%) of the residents were asymptomatic at the time of testing. Only half of these residents then went on to develop symptoms a few days later. A quarter of shedders never became symptomatic and most of these ‘asymptomatic shedders’ were shown to shedding viable virus. Tragically of the 57 residents who were shown to be infected with SARS-CoV-2 infection 15 died; a mortality rate of 26%. 

Why is this so important? In short, a high or very high R-zero means that the government policy of relying on herd immunity to protect the vulnerable is not going to work.

Let me explain. Whilst we are socially distancing we reduce the R-zero of SARS-CoV-2 to less than 1 and hence the number of new cases falls and we flatten the curve. This is what is happening in the UK and many other countries at present. However, as soon as we stop the lockdown and allow social interaction the R-zero will rise above one and we will get more cases. But because this virus is so infectious we may need herd immunity to be well above 80% (possibly 90%) for the epidemic to peter out. At which time point the government is hoping to let vulnerable people remerge from self-isolation and feel confident that they will not be susceptible to being infected and dying from severe COVID-19. 

The bad news is that 15.2% of the UK population is over 70 years of age (data from Age Concern) the government definition of the vulnerable population based on age. This is not taking into account all the other vulnerable groups who are less than 70 years of age, i.e. those who are obese and/or have diabetes, cardiovascular, respiratory diseases. This means that by the time we get herd immunity many more people will die from COVID-19. This is why the scientific community needs to push for anti-virals and an effective vaccine. But herein lies a problem. 

To develop and test an effective vaccine we really need an epidemic to be in full swing, i.e. on the upside of the curve and not on the tail. A vaccine trial is like a drug trial; subjects are randomised to an active or SARS-CoV-2 vaccine arm or a comparator arm (placebo or another vaccine) and then you see whether or not there are fewer cases of COVID-19 on the active arm compared to the comparator arm. However, if there are too few cases developing COVID-19 because of social distancing, using face masks, hygiene measures, etc. it will take too long to get enough events or trial subjects getting COVID-19, to show the vaccine is working. This is why we the rich-world may need to go to parts of the world where social distancing etc. is not feasible and the R-zero remains high, i.e. the squatter camps, shantytowns, favelas or slums of the low and middle-income countries of the world.

We, the rich world, may have no choice but to take this low/middle-income route for the sake of the world. But if ‘we’ do take this route to develop an effective vaccine we have to make it ethical. We will have to offer these countries priority access to the vaccine. If we don’t it will be a travesty. I can imagine the headlines in the press if we don’t. ‘Vaccine Imperialism: How the Rich World Exploited The Poor!’

What are the implications for you if you have multiple sclerosis. If you are vulnerable you need to be prepared to self-isolate/shield for a very long time. If you are not vulnerable then you really need to prepare yourself for becoming infected with SARS-CoV-2 and getting COVID-19. I have a section on MS-Selfie that addresses this issue. I will be updating this section over the weekend as there are additional things you can do as an individual and as a family to help derisk your chances further. 

I am sorry for bringing you bad news at the beginning of the weekend, but as always I feel it is important, to be honest, and frank.

The information in this post is quite complex so if you have any questions please feel free to ask. 

Gandhi et al. Asymptomatic Transmission, the Achilles’ Heel of Current Strategies to Control Covid-19. NEJM  April 24, 2020 DOI: 10.1056/NEJMe2009758

Arons et al. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. NEJM April 24, 2020 DOI: 10.1056/NEJMoa2008457

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can spread rapidly within skilled nursing facilities. After identification of a case of Covid-19 in a skilled nursing facility, we assessed transmission and evaluated the adequacy of symptom-based screening to identify infections in residents.

METHODS: We conducted two serial point-prevalence surveys, 1 week apart, in which assenting residents of the facility underwent nasopharyngeal and oropharyngeal testing for SARS-CoV-2, including real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), viral culture, and sequencing. Symptoms that had been present during the preceding 14 days were recorded. Asymptomatic residents who tested positive were reassessed 7 days later. Residents with SARS-CoV-2 infection were categorized as symptomatic with typical symptoms (fever, cough, or shortness of breath), symptomatic with only atypical symptoms, presymptomatic, or asymptomatic.

RESULTS: Twenty-three days after the first positive test result in a resident at this skilled nursing facility, 57 of 89 residents (64%) tested positive for SARS-CoV-2. Among 76 residents who participated in point-prevalence surveys, 48 (63%) tested positive. Of these 48 residents, 27 (56%) were asymptomatic at the time of testing; 24 subsequently developed symptoms (median time to onset, 4 days). Samples from these 24 presymptomatic residents had a median rRT-PCR cycle threshold value of 23.1, and viable virus was recovered from 17 residents. As of April 3, of the 57 residents with SARS-CoV-2 infection, 11 had been hospitalized (3 in the intensive care unit) and 15 had died (mortality, 26%). Of the 34 residents whose specimens were sequenced, 27 (79%) had sequences that fit into two clusters with a difference of one nucleotide.

CONCLUSIONS: Rapid and widespread transmission of SARS-CoV-2 was demonstrated in this skilled nursing facility. More than half of residents with positive test results were asymptomatic at the time of testing and most likely contributed to transmission. Infection-control strategies focused solely on symptomatic residents were not sufficient to prevent transmission after SARS-CoV-2 introduction into this facility.

CoI: none for this post

#MSCOVID19: good news for anti-CD20ers

I am being asked why I have moved ocrelizumab and other anti-CD20 therapies into the low-risk categories of DMTs in my latest version of my DMT table.

The reasons I use to justify the change are several-fold.

Anti-CD20 therapies deplete B-cells and only have a small impact on T-cell counts and innate immune cell function. This is important because anti-viral responses don’t seem to be affected to a great extent on ocrelizumab and other anti-CD20 therapies. In the phase three ocrelizumab trial programme apart from seeing a small herpes zoster signal there was no clear viral infection signal. When viral infections occurred they tended to be mild or moderate. The severe infections were bacterial (pneumonia, UTIs and cellulitis).

We are seeing an increasing number of patients who have been treated with anti-CD20 therapies who have had COVID-19 doing well. We have just published a case report in MSARDs of a man with PPMS treated with ocrelizumab who did well (see below). This has to be good news for patients on anti-CD20 therapies.

Ocrelizumab also blunts antibody responses, which may be important in severe COVID-19. This may delay or prevent damage to the COVID-19 lung as some of the damage seems to be mediated by complement activation and microthrombi. The latter is indicative of damage consistent with IgG3 anti-viral responses and IgG antibody-dependent cellular cytotoxicity by macrophages and in some instance neutrophils. Antibody production against the SARS-CoV-2 spike protein may promote cytokine production that activates macrophage to become more destructive. Blunting these antibody responses with an anti-CD20 therapy may actually be beneficial, which is why we are predicting that anti-CD20 treated patients will have a lower risk of getting severe COVID-19.

What about hypogammaglobulinaemia then?

Yes, this does occur with anti-CD20 therapies but occurs at a relatively low level. As SARS-CoV-2 is a new human pathogen and hence we don’t have immunological memory against the virus this makes little difference to the risk of becoming infected with SARS-CoV-2. Hypogammaglobulinaemia may, however, put you at risk of getting secondary bacterial infections. Fortunately, these can be treated with antibiotics. 

What about vaccine responses?

Yes, anti-CD20 and other immunosuppressive therapies can blunt antibody responses to some vaccines. And yes, contrary to the dogma patients on anti-CD20 therapies do make antibodies to viruses and vaccines. I assume this happens because we still have B-cells in secondary lymphoid organs and/or there may be CD20 negative B-cells that can takeover antibody production. Please note that the latter is a hypothesis.

Antibody responses to glycoproteins (sugar antigens) are particularly affected by anti-CD20 therapies and this may be important in the context of coronavirus immunity as the spike protein is heavily modified with sugar molecules. However, all these arguments are theoretical; until a vaccine emerges I would focus on getting MS treated. We can cross the vaccine bridge if and when it gets built. I am still of the opinion that the government’s strategy is herd immunity and hence the majority of us will at some point become infected with SARS-CoV-2. Waiting for a vaccine that never arises is going to be difficult for individuals; how long can you realistically self-isolate and/or shield? 

We are very keen to do an anti-SARS-CoV-2 seroprevalence study in pwMS to see how many have been exposed to the virus and have not developed COVID-19 and to also look at antibody responses to SARS-CoV-2 in patients on different DMTs. We hypothesise that patients on anti-CD20 therapies will have as good an antibody response to  SARS-CoV-2 as patients not on anti-CD20 therapies. This hypothesis refers to qualitative antibody responses, i.e. neutralising or protective antibody responses.  

For the reasons above I have not stopped offering patients with active MS anti-CD20 therapies during the pandemic. This refers to both starting and retreatment. Some patients have chosen to delay their treatments until the pandemic is over and others have taken my advice and gone ahead with their treatments; this is their choice. But as I have said before the pandemic won’t be over anytime soon; the tail is likely to extend for 18-24 months and possibly longer. Therefore all the guidelines that have recommended delaying or postponing treatment with depletion therapies, i.e. the anti-CD20s, cladribine, alemtuzumab, mitoxantrone, cyclophosphamide and HSCT will have to be reviewed. We can’t stop treating MS or offering patients less effective options for the next 18-24 months. If we do what will be the consequences?

How many swallows does it take to make a summer? I am aware that one case report is not much, but there are an increasing number of patients being reported on social media who have been treated with an anti-CD20 and have had gotten through COVID-19 without a problem. 

I would urge all the national register studies to be please report your data on COVID-19 outcomes in pwMS as soon as possible. We need the data to formalise our treatment guidelines and to help allay the fears of our patients. Please use one of the archive repositories to get your data out to the MS community as soon as possible. Thank you.

Giovanni Novi et al. COVID-19 in a MS Patient Treated With Ocrelizumab: Does Immunosuppression Have a Protective Role? Mult Scler Relat Disord 2020 Apr 15;42:102120.

Background: Coronavirus disease 19 (COVID-19) is a novel disease entity that is spreading throughout the world. It has been speculated that patients with comorbidities and elderly patients could be at high risk for respiratory insufficiency and death. Immunosuppression could expose infected patients to even higher risks of disease complications due to dampened immune response. However, it has been speculated that overactive immune response could drive clinical deterioration and, based on this hypothesis, several immunosuppressants are currently being tested as potential treatment for COVID-19.

Methods: In this paper we report on a patient that has been treated with ocrelizumab (a B-cell depleting monoclonal antibody) for primary progressive multiple sclerosis who developed COVID-19.

Results: Despite complete B cell depletion, patient symptoms abated few days after hospitalization, and he was discharged to home-quarantine. Phone interview follow-up confirmed that, after 14 days, no new symptoms occurred.

Discussion: This report supports the putative role of immunosuppressive therapy in COVID-19 affected patients.

CoI: multiple

#MSCOVID19: vaccines and DMTs

So if you are someone with MS who is shielding or being very careful about social distancing and want to avoid getting COVID-19 you may be considering what your own exit strategy is. How do you de-risk yourself and prevent yourself from becoming infected with SARS-CoV-2? 

At present, it looks as if the UK government’s strategy is to ring-fence you with people who are immune to SARS-CoV-2, the so-called herd immunity paradigm, and hope an effective vaccine emerges in the next 12-18 months to secure the safety of the high-risk or vulnerable population. This strategy is high-risk because there is no guarantee that sufficient numbers of healthy people in the general population will get COVID-19 to ring-fence the vulnerable. To be honest there are too many vulnerable people. In addition, there will always be holes in the science behind the herd-immunity paradigm; who says immunity to SARS-CoV-2 will be long-term and why wouldn’t new strains of virus emerge to fool the immune system. This means that vulnerable people will have to live in fear that they may acquire COVID-19 unless they get an asymptomatic/mild infection and/or vaccinated and have proof they have neutralising anti-viral protective immunity against SARS-CoV-2. 

So the next questions are if and when an effective SARS-CoV-2 vaccine emerges (1) how good will the vaccine be and (2) if I am on a disease-modifying therapy will I respond to the vaccine? 

In general, vaccines can be hit and miss. Politicians, particularly Donald Trump, and the general public seem to think that an effective vaccine is imminent. Yes, it may be but it is more likely, based on industry timelines, that an effective vaccine for SARS-CoV-2 is years away. Developing a vaccine for respiratory viruses is not easy, particularly for viruses that mutate rapidly and have mechanisms built into their nucleic acid which results in antigenic drift, i.e. the proteins they express on their surface rapidly mutate to escape immune detection. The latter is a particular problem with for example the influenza virus; antigenic drift happens annually. We also know this is a problem with coronaviruses because immunity is not life long and wanes within years. This is why we get recurrent common colds.  

The other problem with viruses and vaccines is the so-called original antigenic sin. This is when you make an immune response to a virus or vaccine antigen. The virus then mutates and when you get infected with the new strain the antibodies you make to the original strain or vaccine don’t neutralise the new strain and may even enhance infection with the new strain. In addition, your immune system doesn’t treat the new strain as a new infection and thinks it is the original strain and hence doesn’t make new antibodies against the new strain. This why it is referred to as antigenic sin. Vaccine development has a long history of failing because of these sorts of issues and is why we haven’t got highly effective vaccines against major viruses such as dengue fever. 

Another issue with SARS-CoV-2 is that it looks like some of the important binding sites on the spike protein of the virus are heavily modified with sugar molecules. This means that neutralizing antibodies against SARS-CoV-2 may need to be against so-called glycoprotein segments of the spike protein. Glycoprotein vaccines are much more difficult to make and in themselves are less effective in inducing antibodies than pure protein vaccines. The reason for this is that the immune system processes sugar (glyco) antigens differently to protein antigens. 

I am telling you all this to make you aware that vaccine development is difficult, very difficult, and there are a lot of issues that will need to be considered to make sure a vaccine against SARS-CoV-2 is effective and safe. 

The other issue is having an immune system that is capable of mounting an immune response to a vaccine. I  think in general a live-attenuated SARS-CoV-2 vaccine is unlikely to be developed. Live vaccines tend to be legacy vaccines from an era before we had the tools to make recombinant proteins. Therefore it is highly likely that all the vaccines that will be developed will either be nucleic acid, protein or glycoprotein component vaccines. In general immune responses to vaccines are blunted by immunosuppressive therapies. This has relevance to pwMS because the DMT you are on may block the required immune response to the vaccine. So your careful and patient waiting for an effective vaccine may be futile.  

In general, interferon-beta, glatiramer acetate, teriflunomide, dimethyl fumarate and natalizumab are unlikely to block or attenuate immune responses to a component SARS-CoV-2 vaccine. Similarly, once immune system reconstitution has occurred post alemtuzumab, cladribine, mitoxantrone or HSCT vaccine responses should be restored to normal or near normal. In the depletion phase of IRTs (immune reconstitution therapies) it is likely that vaccine responses will be blunted. In the case of S1P modulators, such as fingolimod and siponimod, and the anti-CD20 therapies (ocrelizumab and rituximab), which are continuous immunosuppressive therapies, vaccine responses are likely to be blunted. I use the term blunted rather than inhibited responses because pwMS on these therapies may still make antibodies to the vaccine components but not to the required level to create protective immunity. 

The story with anti-CD20 therapies is potentially more complex. Surprisingly, antibody response to common vaccines occur on anti-CD20 therapies, but antibody response to glycoprotein vaccines, for example, the pneumococcal vaccine are blunted or inhibited the most. This may be particularly relevant to a SARS-CoV-2 vaccine that is likely to require antibodies to glycoprotein antigens to generate neutralizing antibodies, i.e. antibodies that neutralise the virus and prevent infection. 

Is this information important for pwMS? Yes, I think it is and may affect whether or not pwMS start or continue treatment with S1P modulators or anti-CD20 therapies.  In other words, if you want to make yourself ‘vaccine ready’ you need to consider your DMT choice.

As a research group, we are very interested in the antibody responses to SARS-CoV-2 in pwMS who have had COVID-19. We are in the process of trying to rapidly develop an antibody assay for IgG and IgM antibodies that can differentiate between binding and neutralizing anti-SARS-CoV-2 antibodies. This will allow us to study whether or not the immune response to SARS-CoV-2 is different in patients on S1P-modulators and anti-CD20 therapies and to compare these responses to patients on other DMTs and to patients who are not on DMTs. This will potentially allow us to give patients detailed information in the future about their risk of getting delayed COVID-19 and whether or not they respond to emerging vaccines once they arrive.

In conclusion, as we start to think about exit strategies for pwMS post-COVID-19 being able to respond to a future SARS-CoV-2 vaccine is a major factor HCPs and pwMS need to consider when deciding on what DMT to start or continue with for the long-term. 

Now some questions for you. For those of you who consider yourself, ‘COVID-19 vulnerable’ is being able to respond to a future SARS-CoV-2 vaccine relevant to you? Does it affect your thinking about which DMT you want to be treated with? Please let’s start a discussion on this important topic. 

I think the vaccine issues is important enough for me to have added a new column to my DMT COVID-19 table (version 4.0) and to change the colouring scheme to a patchwork. 

CoI: multiple

Pandemic

Yesterday I had the experience of a patient with highly active MS pull out of being treated with ocrelizumab (Ocrevus) because of concerns around being infected with the coronavirus COVID19. I suspect this will be the first of many patients with multiple sclerosis to do so. 

It is clear that COVID19 epidemic is now a pandemic, i.e. it has involved enough continents and countries to be considered a major and very serious global health emergency. This was predicted to happen many weeks ago. Several basic epidemiological factors indicated that this would occur: 

  1. A long asymptomatic period during which infected people shed the virus and are infectious
  2. Asymptomatic shedders who don’t get ill
  3. An estimated R0 (r-zero) of 3-5, which is an estimate of how many people or contacts that an infected person infects 
  4. The identification of superspreaders; individuals who seem to be able to infect a large number of people
  5. Excessive national and international travel; the initial epidemic in Wuhan happened to coincide with the largest annual human migration of people (see graph below). Approximately 400 million people migrate in relation to the Chinese New Year and a lot of that migration was international, which explains why the virus has spread so rapidly to other countries
  6. Ubiquitous air travel, involving large airports and hubs, which has the ability to spread viruses very rapidly to people on the same aircraft and then to disperse them to all corners of the world before they get symptomatic disease
  7. COVID19 is also a new human pathogen having jumped to humans from animals and as a result of this, we have no pre-existing herd immunity that could buffer or reduce its rate of spread.

Infographic: The Biggest Human Migrations in the World | Statista You will find more infographics at Statista

At the moment the mortality or death rate form the virus is approximately 2%, or 1 in 50, with the majority of deaths affecting the elderly or infirm. The mortality is likely to fall as case ascertainment and reporting gets better. This occurs because the less ill get counted into the so-called denominator. At a population level, this death rate has major implications for healthcare systems. The majority of the deaths are due to pneumonia and these sicker patients require intensive care support. All countries simply don’t have enough ITU beds to support large numbers of ventilated patients. In fact, Britain has too few ITU beds already, without having to deal with the coronavirus pandemic. 

What to look out for?

Coronavirus infection presents very non-specifically with flu-like symptoms, i.e. fever, a cough, or difficulty breathing. Most cases are mild. Those who have died in often have pre-existing health conditions and this is where the problem lies for pwMS. If you have advanced MS, a history of recurrent chest infections and/or you are on immunosuppressive therapies you are considered at high risk of complications from coronavirus infection. The latter risk extends to other infections as well, which is why, for example, it is our policy to recommend the annual flu vaccine to all of our patients with MS. 

What to do?

If you have symptoms following travel to a high-risk area or after coming into contact with someone who has had coronavirus infection you should contact the NHS hotline so that appropriate samples can be submitted to Public Health England for testing. In addition, you will need to self-isolate or be treated in isolation. 

I would not recommend stopping your disease-modifying therapy. The immunosuppression associated with MS DMTs is relatively mild-moderate and hence most pwMS can handle infections relatively well. The exception being alemtuzumab (Lemtrada), and possibly cladribine (Mavenclad), during the lymphocyte depletion phase. Cladribine is less of a problem as T-cells are on average depleted by ~50%, whereas with alemtuzumab the T- and B-cell depletion is typically greater than 90%. The good thing about IRTs (immune reconstitution therapies) is that once your immune systems have reconstituted they are competent to deal with infections.

Although fingolimod (Gilenya) causes lymphopaenia it is not an absolute lymphopaenia as lymphocytes are sequestered or trapped in lymph nodes. Therefore, pwMS on fingolimod can in general deal with viral infections, although they have more frequent and possibly more severe infections. This also applies to other S1P modulators (siponimod, ponesimod, ozanimod, etc.), in other words it is a class effect.

Viral response on anti-CD20 therapies (rituximab, ocrelizumab and ofatumumab) should also be maintained, but maybe blunted as B-cell and antibody responses may be necessary to help clear the virus. The infections that people on anti-CD20 therapies have a problem with are encapsulated bacteria (pneumococcus, meningococcus, Haemophilus, etc.).

Coronaviruses can rarely cause and encephalitis, typically in severely immunocompromised patients. This would indicate that as a class coronaviruses are neurotropic. I am not aware of any data on whether or not COVID19 causes encephalitis. If COVID19 is neurotropic encephalitis would be a risk for people on natalizumab (Tysabri). As natalizumab blocks immune surveillance of the CNS, a person on natalizumab who develops a COVID19 encephalitis would be in danger of succumbing to the infection. The latter is analogous to PML, which is also viral encephalitis. 

DMF (Tecfidera) is only mildly immunosuppressive and in my opinion, is unlikely to be a major worry in the event of you acquiring a COVID19 infection. The one caveat being patients on DMF with a significant lymphopaenia, i.e. with a total lymphocyte count of less than 0.8 x 109/L or 800/mm3.

Teriflunomide (Aubagio), glatiramer acetate (Copaxone) and interferon beta (Betaferon, Avonex, Rebif, Plegridy) are not immunosuppressive agents and hence should not increase your chances of having a severe COVID19 infection. 

Whilst the risk of COVID19 infection to the general public, and hence pwMS, is very low I would not recommend changing your DMT or avoiding starting any planned infusions. I would, however, recommend that if you are immunosuppressive to be extra-vigilant about hygiene (handwashing, etc.) and to avoid travelling to high-risk areas. If you are travelling through high-risk areas, for example, China, Hong Kong or Singapore you need to be more vigilant.

I am also getting asked for advice about face masks. The evidence that cheap surgical masks work for coronaviruses is limited. Coronaviruses are spread in a different way to the flu virus. Coronaviruses are not aerosolized in the same way as the flu virus and hence are not breathed in, but are rather spread by droplets. These stick to surfaces and hence the need to wash your hands. So masks are likely to work both ways for coronavirus, where they are not very effective for flu. One thing masks do is they make you wearer change your behaviour in other ways.

If you are travelling to a high-risk area and are going to use a face mask can I suggest using a good quality one, i.e. an FFP3 mask that filters out small particulate matter? These work for larger organisms such as TB and may help reduce transmission of COVID19. It is important that you have the masks fitted and you know how to use them properly. Within the NHS the latter is typically done by a healthcare professional with the necessary training on how to assess adequate mask fitting and usage.

As we are not infectious disease experts or virologists I would recommend following the NHS’ and Public Health England’s website for up to date advice. 

What did I recommend for my patient above?

As there was no way he was going to be treated with ocrelizumab I ended-up recommending teriflunomide. The advantage of teriflunomide is that it is not immunosuppressive and has pan anti-viral activity against many viruses.

Clearly the advice given above applies to pwMS living in the UK. In COVID19 hotspots, e.g. China, it may be safer to delay treatment with immunosuppressive therapies until the epidemic has passed and there is herd immunity to protect you. In addition, a COVID19 vaccine may become available within the next 6-12 months. Therefore, it may be worthwhile initially choosing an immunomodulatory DMT that won’t interfere with future vaccine responses. 

P.S. (27-Feb-2020): Please be aware that the advice above may be time-limited. Once the coronavirus becomes established in the community and person-to-person spread becomes more common and the source of infection can’t be traced, which is happening in China and Italy at the moment, then the public health advice may change. In this situation reverse quarantine may be necessary, i.e. to ask high-risk individuals to self-isolate themselves so as not expose themselves to the virus. At the moment this is not necessary in the UK as all the cases have been linked to a clearly identifiable source.

CoI: multiple

Measles encephalitis the unknown known

Barts-MS rose-tinted-odometer – zero stars

We ran our third triMS-online this week and apart from a technical problem in the satellite symposium it went reasonably smoothly. The participants were very engaged and asked lots of questions. The topic of vaccination was particularly well received. Which vaccine? Component or live vaccines? When to give the vaccines and whether or not to delay starring a DMT to complete the schedule.? Interestingly and importantly MMR, or mumps, measles and rubella, was not on the radar.

It is my impression that the MS community assume these childhood infections and vaccinations are done and dusted. However, with the rise of the anti-vaccine movement, there is an increasing number of people not being vaccinated in childhood with the MMR. This means that an undefined number of pwMS will be MMR seronegative. Is this a problem? You bet it is! 

To explain the consequences of getting measles infection as an adult on immunosuppression I penned this fictional case scenario. According to the “Donald Rumsfeldometer”, this is an unknown known.

 Rumsfeldometer

  1. Known-knowns – there are things we know that we know
  2. Unknown-knowns – these are the things we know will occur
  3. Known-unknowns – there are things that we now know we don’t know
  4. Unknown-unknowns – there are things we do not know we don’t know

“There are known knowns; there are things we know that we know. There are known unknowns; that is to say, there are things that we now know we don’t know. But there are also unknown unknowns – there are things we do not know we don’t know.” 

Donald Rumsfeld, former United States Secretary of Defense.

Fictional Case

When she finally arrived on the ward she was unable to speak and was clearly confused and disorientated. All four of her limbs were twitching and would jerk when touched; i.e. she had generalised myoclonus. She was drooling from the mouth. Her latest MRI showed hyperintense signal change in the cortical ribbon or the grey matter on the surface of her brain.

Since her last MRI 8 days ago, the involvement of cortex had spread from the left parietal lobe to involve the entire left frontal lobe, the medial surface of the right frontal lobe, the left occipital lobe and the left temporal lobe. There was new signal change in the left thalamus and pulvinar and the white matter of the left hemisphere was diffusely involved. Interestingly, the post-contrast scans showed no obvious gadolinium-enhancement. Her EEG showed diffuse slowing over the left hemisphere with occasional sharp waves. The neurophysiologist did not think the pattern was a burst suppression pattern. 

She was only 24 years of age and had been on natalizumab for 37 months. She was JC virus seronegative and her most recent CSF examination was negative on PCR for JC virus DNA. Apart from a mildly raised protein, the CSF was acellular. Her referring neurologist thought the most likely diagnosis was a secondary CNS lymphoma and had referred to our centre for a brain biopsy. 

What the neurologist had missed was that this patient had recently come into contact with her friend’s 4-year old daughter who had been diagnosed with measles. In fact, there had been a cluster of eight cases of measles in the nursery school her friend’s daughter had attended. The tragedy is that this patient had not received her MMR vaccine as a child because her mother had been concerned about the safety of the MMR vaccine after the now retracted and fraudulent Andrew Wakefield study linking MMR vaccine to autism. 

Once we had this history our working diagnosis was that of a measles inclusion body panencephalitis and our diagnosis was confirmed once we got back the CSF measles PCR result from her repeat lumbar puncture. Sadly the patient passed away 5 days after admission. A post-mortem examination confirmed the diagnosis of measles inclusion-body panencephalitis.

Interestingly, despite being on natalizumab there were was quite a heavy CD8+ T-cell infiltrate, which would indicate that natalizumab does not necessarily block all trafficking of lymphocytes into the brain of someone with viral encephalitis. 

So if you have MS and are about to start an immunosuppressive DMT please review your vaccine history. If you discover you have not had the MMR vaccine or other vaccines you may need, please discuss this with your neurologist or MS nurse. Once you are on specific DMTs live vaccines such as the MMR are contraindicated.

I am sure some of you will be saying that I am scaremongering, but I know that it is only a matter of time before we see MMR-naive patients with MS succumb to wild-type or community-acquired infection with one or more of these viruses (see case study below).

Please note measles and mumps are circulating at present in the community and because of lower rates of MMR vaccine uptake you can’t necessarily rely on herd immunity to shield you from infection. 

Isn’t prevention better than managing the consequences of these infections?

Freeman et al. A new complication of stem cell transplantation: measles inclusion body encephalitis. Pediatrics. 2004 Nov;114(5):e657-60.

Measles inclusion body encephalitis (MIBE) is a disease of the immunocompromised host and typically occurs within 1 year of acute measles infection or vaccination. We report a 13-year-old boy who had chronic granulomatous disease and presented 38 days after stem cell transplantation with afebrile focal seizures that progressed despite multiple anticonvulsants. After an extensive diagnostic evaluation, brain biopsy was performed, revealing numerous intranuclear inclusion bodies consistent with paramyxovirus nucleocapsids. Measles studies including reverse transcriptase-polymerase chain reaction and viral growth confirmed measles virus, genotype D3. Immunohistochemistry was positive for measles nucleoprotein. Despite intravenous ribavirin therapy, the patient died. MIBE has not been described in stem cell recipients but is a disease of immunocompromised hosts and typically occurs within 1 year of measles infection, exposure, or vaccination. Our case is unusual as neither the patient nor the stem cell donor had apparent recent measles exposure or vaccination, and neither had recent travel to measles-endemic regions. The patient had an erythematous rash several weeks before the neurologic symptoms; however, skin biopsy was consistent with graft-versus-host disease, and immunohistochemistry studies for measles nucleoprotein were negative. As measles genotype D3 has not been seen in areas where the child lived since his early childhood, the possibility of an unusually long latency period between initial measles infection and MIBE is raised. In addition, this case demonstrates the utility of brain biopsy in the diagnosis of encephalitis of unknown cause in the immunocompromised host.

CoI: multiple

The cause of MS

When I posted the link to our EBV and MS meta-analysis on social media yesterday I was taken to task because of the slow progress we have made in MS prevention. 

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Can I remind you that science moves steadily and slowly and the biggest problem we have is the slow adoption, or rejection, of innovations or new ideas. 

“The human mind treats a new idea the same way the body treats a strange protein; it rejects it.”
Peter Medawar, Nobel prize laureate, in Physiology or Medicine, 1960.

I was convinced by the evidence already back in 1999 that EBV was the likely cause of MS. I have been working on EBV ever since and the progress has been very slow. The main reason I left the Institute of Neurology (Queen Square) was to move to a multi-disciplinary institute, that would allow me space and time to work on EBV. However, it takes more than just moving to a new research environment to build momentum around a new research hypothesis. 

I have had more grant applications rejected around the viral hypothesis of MS than I care to count. It is very depressing. Despite this, we are pushing on slowly with our plans to create a trial-ready cohort of people at high risk of MS for exploratory MS prevention studies. Dr Ruth Dobson is doing quite an amazing job at getting this off the ground. We are also pushing forward with our ideas around treating MS with antivirals that target EBV. To say that the funding for doing these trials has been difficult is an understatement, but I am hoping if we can get pilot data we can convince the sceptics to fund definitive trials. 

We are also not the only team working on the EBV hypothesis of MS. Michael Pender in Brisbane, Australia, is doing great things and Atara Bio has taken up the baton in industry. I have recently posted on their preliminary results that were presented at ECTRIMS.

I spend most of my waking day doing MS and a large part of that is thinking about EBV and MS prevention. The main strand of MS prevention is an EBV vaccination study. The vaccine is not in our hands, but the capable hands of Jeff Cohen at the NIH, and hopefully a deep-pocketed Pharma company to commercialise it. Even if we get an effective EBV vaccine developed and launched we will still have to overcome the public resistance to vaccination and to convince public health officials that this is a worthy idea. 

The battles ahead are numerous, but we will get there in the end. We have to. We don’t want the next generation of MSers asking us why we haven’t done anything to prevent MS given the current state of knowledge.

EBV is almost certainly the cause of MS. What are we doing about it?  

Jacobs et al. Systematic review and meta-analysis of the association between Epstein-Barr virus, Multiple Sclerosis, and other risk factors. https://doi.org/10.1101/19007450

Background: EBV infection is thought to play a central role in the development of Multiple Sclerosis (MS). If causal, it represents a target for interventions to reduce MS risk. 

Objective: To examine the evidence for interaction between EBV and other risk factors, and explore mechanisms via which EBV infection may influence MS risk. 

Methods: Pubmed was searched using the terms multiple sclerosis AND Epstein Barr virus, multiple sclerosis AND EBV, clinically isolated syndrome AND Epstein Barr virus and clinically isolated syndrome AND EBV. All abstracts were reviewed for possible inclusion. 

Results: 262 full-text papers were reviewed. There was evidence of interaction on the additive scale between anti-EBV antibody titre and HLA genotype (AP 0.48, p<1×10-4; RERI 3.84, p<5×10-3; S 1.68, p=0.06). Previous IM was associated with increased OR of MS in HLA-DRB1*1501 positive but not HLA-DRB1*1501 negative persons. Smoking was associated with a greater risk of MS in those with high anti-EBV antibodies (OR 2.76) but not low anti-EBV antibodies (OR 1.16). No interaction between EBV and risk factors was found on a multiplicative scale. 

Conclusions: EBV appears to interact with at least some established MS risk factors. The mechanism via which EBV influences MS risk remains unknown.

CoI: multiple

Measles a known unknown

I was called to casualty to assess one of my patients with MS who was on natalizumab. She had been admitted with a temperature, confusion, seizures and a generalised skin rash. Within thirty minutes of seeing her, she went into status epilepticus and had to be sedated, intubated and admitted to ITU. Within 72 hours she was dead. At post-mortem, she had a measles pan-encephalitis. Four days before presentation she had unknowingly come into contact with a friend’s child who had measles. The friend was a staunch anti-vaxxer who believed that the measles vaccine caused autism and would corrupt her child’s immune system. 

The above scenario is fictitious, but could happen, or more likely will happen sometime in the near future. This is a ‘known unknown’.

Things have a tendency to happen in threes; I experienced two today let’s hope the third remains science fiction. 

(1) As I left home this morning on my daily commute to Whitechapel I finished listening to an Audm podcast “FEAR, MISINFORMATION, AND MEASLES SPREAD IN BROOKLYN” by Amanda Schaffer (Wired,  24-06-2019); scary stuff about the real impact of the anti-VAXX campaign on residents in Brooklyn, New York.

(2) I followed this by reading a review about measles in the latest NEJM (Strebel & Orenstein. Measles. N Engl J Med. 2019 Jul 25;381(4):349-357), which reminded me of medical school and my time on the medical wards in South Africa. 

I then had flashbacks to my days as a neurology registrar in South Africa seeing and managing many patients with SSPE (subacute sclerosing panencephalitis) a relatively rare, but fatal, complication of measles infection.

More recently there was a fatal case of measles inclusion body encephalitis presented at our Association of British Neurologists meeting; tragically this young woman had not been vaccinated against measles. 

Why is this important? We are living through a measles epidemic. The anti-VAXX campaigners have convinced enough parents over the last two decades to not vaccinate their children against measles, mumps and rubella (MMR). Once a certain proportion of the population is not immune to measles, so-called herd immunity becomes ineffective; i.e. the shield offered by a population of people immune to measles is too porous to isolate susceptible people from wild-type infection in the community. In fact, vaccination works because of herd immunity. 

Image from BioNinja

Another factor to consider is that unvaccinated people also get MS. If you are unvaccinated and have not been exposed to the wild virus you are now at relatively high-risk of acquiring measles as an adult. If you then decide to go onto longterm immunosuppression to treat your MS you are putting yourself at risk of serious complications from these infections, in particular measles. In addition, once you are on a longterm immunosuppressive therapy you can’t be vaccinated with the MMR vaccine as it is a live attenuated vaccine. 

Measles is also a neurotropic virus and hence seeds to the brain. If you are on natalizumab and contract measles you will be in serious trouble. Natalizumab works by blocking trafficking of lymphocytes to the CNS and hence will stop your lymphocytes detecting, attacking and clearing the virus from the brain. The consequences of an unimpeded measles virus infection of the brain will be in all likelihood be lethal. This is a similar scenario to what happens with PML. Although natalizumab is being fingered here there is a risk will all of our immunosuppressive DMTs.

Because of this known unknown, I am proposing that all MSers are screened at baseline, i.e. before initiating a maintenance immunosuppressive therapy, to make sure they have immunity to MMR. If they are antibody negative they should be offered the option of receiving the MMR vaccine, or at least the individual components of the vaccine if they are still available in your country, to make sure they are immune to these viruses before they start treatment with the DMT concerned. 

I sincerely hope my case scenario remains fiction and things don’t have to happen in threes. 

To vaccinate or not?

Should your vaccine status be checked and updated before you start treatment?

As part of our programme to derisk disease-modifying therapies (DMTs) for pwMS in our service, we are reviewing our vaccination policy. One issue that has emerged is the possible need to boost immunity to certain types of bacteria that are known to pose a risk in patients on long-term immunosuppression, in particular B cell depleters, such as rituximab, ocrelizumab and ofatumumab. Why?

Chronic B-cell depletion essentially prevents B-cells mounting an adequate antibody response to new antigens. It does this by preventing the formation of so-called germinal centres in the spleen and/or lymph nodes. In other words patients on longterm anti-CD20 therapy behave, from an immunological perspective, if they have had a functional splenectomy. This put patients with longterm B cell depletion at risk of hypogammaglobulinaemia (low immunoglobulin levels) in the future and predisposes them to infections caused by so-called encapsulated bacteria; these include pneumococcus, meningococcus and Haemophilus Influenzae.

When you review the rheumatoid arthritis literature in relation to longterm rituximab (anti-CD20) therapy both these problems have been documented. How do the rheumatologists deal with these problems? They appear to routinely monitor immunoglobulin levels and they proactively vaccinate their patients prior to starting long-term anti-CD20 therapy.

It seems pretty obvious to me, reading the rheumatology literature, that before you start long-term anti-CD20 therapy you should have your vaccination status checked and we should start vaccinating patients against pneumococcus, meningococcus and Haemophilus Influenzae B. In fact, pneumococcal vaccine is already recommended, if possible, for all patients before starting immunosuppressive treatments. It is clear for anti-CD20 therapies that the vaccines will need to be given prior to starting treatment (see Nguyen paper below).

We also recommend doing baseline immunoglobulin levels on all patients before starting treatment as a reference and then to start checking levels from year 3 onwards. I say year 3 because in the ocrelizumab trials we only saw a  significant drop in IgM and IgA levels over 2 years and IgG levels were stable. Based on the rituximab data a drop in IgG levels is, therefore, only likely to emerge after 2 years of treatment.

I would be interested to know if any of you had your vaccine status discussed before you started maintenance immunosuppression?

Makatsori et al. Hypogammaglobulinaemia after rituximab treatment-incidence and outcomes. QJM. 2014 Oct;107(10):821-8.

BACKGROUND: Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions. Transient peripheral B-cell depletion is expected following rituximab therapy. Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature.

METHODS: We performed a retrospective review of patients previously treated with rituximab that were referred to Clinical Immunology with symptomatic or severe hypogammaglobulinaemia. Patient clinical histories, immunological markers, length of rituximab treatment and need for intravenous immunoglobulin replacement therapy (IVIG) were evaluated. An audit of patients receiving rituximab for any condition in a 12-month period and frequency of hypogammaglobulinaemia was also carried out.

RESULTS: We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8-16.3 g/l). All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination. Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months-7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia.

CONCLUSION: With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.

Nguyen et al. Initial Serological Response after Prime-boost Pneumococcal Vaccination in Rheumatoid Arthritis Patients: Results of a Randomized Controlled Trial. J Rheumatol. 2017 Dec;44(12):1794-1803.

OBJECTIVE: To evaluate the initial serological responses to pneumococcal vaccination with the 13-valent protein-conjugated pneumococcal vaccine (PCV13) followed by the 23-valent polysaccharide pneumococcal vaccine (PPV23) among patients with rheumatoid arthritis (RA) treated with biological disease-modifying antirheumatic drugs (bDMARD) according to dosing and intervals between immunizations.

METHODS: Investigator-initiated clinical trial. Patients with RA receiving bDMARD were randomized (1:1:1) to immunization with single dose PCV13 followed by PPV23 after 16 or 24 weeks, or double dose PCV13 followed by PPV23 after 16 weeks. A comparison group of patients with RA treated with conventional synthetic (cs)DMARD received single dose PCV13 followed by PPV23 16 weeks later. Pneumococcal antibodies were collected before and 4 weeks after each vaccination. The primary endpoint was the proportion of participants responding to ≥ 6/12 pneumococcal serotypes 4 weeks after both vaccinations.

RESULTS: Sixty-five participants receiving bDMARD and 35 participants receiving csDMARD were included. After PPV23 vaccination, 87% (95% CI 0.76-0.94) and 94% (95% CI 0.77-0.99), respectively, of participants treated with bDMARD and csDMARD had reached the primary endpoint. There was no significant difference in primary endpoint between the 3 randomization arms. The response for rituximab-treated participants was 25% compared to ≥ 89% in participants treated with bDMARD with other mode of action.

CONCLUSION: The early serological response to prime-boost vaccination with PCV13 followed by PPV23 was very similar among participants receiving bDMARD and csDMARD. However, notable differences in response were observed according to individual bDMARD. It is important to consider the RA treatment when planning pneumococcal vaccination in patients with RA.

Friedman & Winthrop. Vaccinations for rheumatoid arthritis. Curr Opin Rheumatol. 2016 May;28(3):330-6.

PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients experience increased infectious disease-related morbidity and mortality, and vaccinations represent an important element in their care. However, vaccine immunogenicity can be affected by disease-modifying antirheumatic drug (DMARD) therapy, such that vaccine choice and timing can be clinically challenging. We review the indications, safety, and immunogenicity of vaccines in the setting of RA.

RECENT FINDINGS: Recent recommendations highlight the use of influenza, pneumococcal, and shingles vaccines in RA patients. Studies suggest influenza and pneumococcal vaccines are underutilized, but well tolerated in RA patients and generally immunogenic during DMARD use with the exception of rituximab. Though data for other nonlive vaccines are more limited, hepatitis B virus and human papilloma virus vaccines also appear well tolerated and immunogenic in this population. Live vaccines for shingles and yellow fever remain contraindicated in some RA patients; however, limited data suggest they might be well tolerated in certain individuals.

SUMMARY: The review updates rheumatologists on the optimal use and timing of routine vaccinations in the care of RA.

CoI: multiple