HPV vaccination reduces cervical cancer by up to 90%

Barts-MS rose-tinted-odometer: ★★★★★
(Cancer Pink Thursday #ffbfc3)

News, news, news! 

In fact, great news (see Lancet paper below)! HPV vaccine cuts cervical cancer rates by close to 90%, using the new polyvalent HPV vaccine (Gardasil-9), which clovers 9 HPV strains. This stunning bit of innovation doesn’t address the other benefits of preventing HPV infection, which include preventing penile, anal, nasopharyngeal and oesophageal cancers not to mention the simple wart. 

So what to advise pwMS about the HPV vaccine?

The HPV vaccine prevents infection with the sexually transmitted human papillomavirus (HPV) which is known to cause cervical cancer and several other cancers.

Cervical cancer: image Medscape.

If you decide to go onto an immunosuppressive therapy, in particular, potent immunosuppressive therapies. The suppression of your immune system allows viruses to escape and to start replicating. This is a particular problem with alemtuzumab and potentially HSCT. So there is a strong augment to get yourself vaccinated, or to upgrade your immunity from the quadrivalent to the polyvalent vaccine, before starting a potent IRT and other immunosuppressive therapy.  

HPV is not only a problem for women. HPV is a well-established cause of penile and anal cancer and causes a small proportion of throat and oesophageal cancers. Therefore it makes sense for males to be vaccinated against HPV as well.

The epidemiology of HPV infection is also changing. People are becoming infected later in life and are spreading the virus. Social media and dating apps have revolutionised the dating world and many older people are becoming promiscuous and are having unsafe sex later in life. As a result of this, there has been a large increase in the incidence of sexually transmitted diseases in older people, including HPV infections. This has prompted some commentators to suggest that public health officials extend the HPV vaccine to all women and possibly all men. Why wouldn’t you want to reduce your risk of getting cervical cancer? Isn’t prevention better than having to treat HPV infection and its downstream effects, i.e. premalignant cervical lesions or cervical cancer?

Cutaneous warts

Question 1: If I have been vaccinated with the older quadrivalent vaccine could I receive the new vaccine to cover the other strains of the virus?

Yes, there is data that shows that the previous vaccination against HPV doesn’t stop your immune system from responding to the components that cover the new strains.

Question 2: As I am on a DMT can I have the HPV vaccine?

This all depends on the DMT you are on. For the non-immunosuppressive immunomodulators such as interferon-beta, glatiramer acetate and teriflunomide vaccination is unlikely to be a problem. Similarly for the fumarates, natalizumab, cladribine and alemtuzumab the level of immunosuppression and the window of vaccination are unlikely to affect vaccine responses. However, based on the COVID-19 vaccine studies if you are on an S1P modulator (fingolimod, siponimod, ozanimod or ponesimod) or an anti-CD20 (ocrelizumab, ofatumumab, rituximab) the response to the HPV vaccine is likely to be blunted. 

Question 3: I need to start a DMT, but I want to have the HPV vaccine or extend my cover with the new polyvalent vaccine, how long will I need to wait before I can start treatment?

The polyvalent vaccine at the moment requires 2 or 3 doses with the last dose given at 5 or 6 months. Ideally, to give your immune system a chance to respond to the vaccine you will need to wait until 4 weeks after the final booster, i.e. 6 or 7 months.

Question 4: Should I delay starting DMTs to have the vaccine?

There is no simple answer to this question. You have to balance the risks and benefits of having the vaccine against the risks of untreated MS. In relation to the IRTs, I would suggest going ahead and starting the IRT and delaying the vaccine until you have reconstituted your immune system. Delaying starting an IRT to have the vaccine does not make immunological sense in that the memory responses you have just made to the vaccine could potentially get depleted and depending on the intensity of the immunodepletion may not recover. For maintenance DMTs, in particular, the S1P modulators and anti-CD20 therapies you should probably delay starting treatment to have the vaccine.

Question 5: If I want the new polyvalent vaccine will the NHS cover it?

At present, the answer is no. The UK is in the process of switching from the quadrivalent (Gardasil-4) to the polyvalent vaccine (Gardasil-9) under the national vaccine programme. At present, if you want to be vaccinated against HPV you will have to cover the costs of the vaccine yourself. This is not too dissimilar to what happens with travel vaccines.

I predict that HPV vaccination is going to be one of those factors that have to be put in the mix when deciding which is the correct DMT for you. It is not a major factor but is an important factor nevertheless. I have only just started to routinely discuss this topic with my patients. It clearly has future health implications. 

What is your view on this? Do you think MS healthcare professionals should be obliged to discuss issues around HPV vaccination before pwMS start a DMT?

Falcaro et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. The Lancet 2021:November 03.

Background: Human papillomavirus (HPV) immunisation with a bivalent vaccine (Cervarix) was introduced in England, UK, in Sept 1, 2008: routine vaccination was offered to girls aged 12–13 years with a catch-up programme for females aged 14–18 years in 2008–10. We quantified the early effect of this immunisation programme on cervical cancer and cervical carcinoma in situ, namely grade 3 cervical intraepithelial neoplasia (CIN3), registrations.

Methods: In this observational study, we used an extension of the age-period-cohort Poisson model to estimate the relative risk of cervical cancer in three vaccinated cohorts compared with earlier cohorts that were not eligible for HPV vaccination. Data from a population-based cancer registry were extracted on Jan 26, 2021, and were assessed for diagnoses of cervical cancer and CIN3 from Jan 1, 2006 to June 30, 2019 in women aged 20–64 years and who were a resident in England. We used three vaccinated cohorts to account for differences in the school year in which the vaccine was offered and its national coverage. Adjustment for confounding was made using information on changes in cervical screening policy and historical events that affected cervical cancer incidence. Results were compared across models with different adjustments for confounders.

Findings: We used data from a total of 13·7 million-years of follow-up of women aged 20 years to younger than 30 years. The estimated relative reduction in cervical cancer rates by age at vaccine offer were 34% (95% CI 25–41) for age 16–18 years (school year 12–13), 62% (52–71) for age 14–16 years (school year 10–11), and 87% (72–94) for age 12–13 years (school year 8), compared with the reference unvaccinated cohort. The corresponding risk reductions for CIN3 were 39% (95% CI 36–41) for those offered at age 16–18 years, 75% (72–77) for age 14–16 years, and 97% (96–98) for age 12–13 years. These results remained similar across models. We estimated that by June 30, 2019 there had been 448 (339–556) fewer than expected cervical cancers and 17 235 (15 919–18 552) fewer than expected cases of CIN3 in vaccinated cohorts in England.

Interpretation: We observed a substantial reduction in cervical cancer and incidence of CIN3 in young women after the introduction of the HPV immunisation programme in England, especially in individuals who were offered the vaccine at age 12–13 years. The HPV immunisation programme has successfully almost eliminated cervical cancer in women born since Sept 1, 1995.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

#MSCOVID19: to delay anti-CD20 dosing or not

Barts-MS rose-tinted-odometer: ★ (It’s a Black-and-White Friday #000000 & #FFFFFF)

At the beginning of the COVID-19 pandemic, we made the case that B-cells and antibodies against SARS-CoV-2 were not necessary to clear the coronavirus and protecting you from severe disease. However, almost all emerging data challenges this position, therefore I have changed my position.  

It is now clear that cross-reactive immunity from common coronavirus infections provides some protection from COVID-19. IVIG (intravenous immunoglobulin) formulations collected prior to COVID-19 contain neutralizing anti-SARS-CoV-2 antibodies and may have contributed to the survival of agammaglobulinaemic patients who had COVID-19. 

Neutralizing monoclonal anti-SARS-CoV2 antibodies have been shown to be effective against COVID-19 and severe COVID-19 and are now part of our therapeutic armamentarium for treating COVID-19. 

People on anti-CD20 therapy are more likely to get COVID-19, severe COVID-19, are more likely to need ITU and hence more likely to die from COVID-19. 

The study below shows that antibody neutralization levels against SARS-CoV-2 and the observed protection from SARS-CoV-2 infection are clearly related. In other words, anti-SARS-CoV-2 antibodies are important.  

They estimate the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20% of the mean antibody level in convalescent serum from people who have recovered from COVID-19. The estimated neutralization level required for 50% protection from severe infection was significantly lower at 3% of the mean convalescent level. This means you need fewer antibodies to protect you against severe disease. Another interpretation, which I think is more likely,  is that antibodies are a marker of protective T-cell immunity. 

Worryingly the modelled decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained as you need less antibody. Again the latter may be due to T-cell immunity that must be present in the background. Despite this, it is quite clear that antibody neutralization level is highly predictive of immune protection be it via the antibodies themselves or the associated T-cell immunity. 

This study implies that if you don’t have antibodies you won’t be protected. The question that needs to be urgently answered is ‘ is T-cell immunity in the absence of antibody immunity sufficient to protect you against SARS-CoV-2 infection and severe disease?’. Unfortunately, we don’t have real-life data on this at the moment. 

My interpretation of this – based on the observation that people who are on anti-CD20 therapy have a higher risk of severe COVID-19 and hence have on average less cross-reactive anti-SARS-CoV-2 neutralizing antibodies – is that if possible it would be better to have anti-SARS-CoV-2 antibodies than not to have them. The is really important for pwMS on anti-CD20 therapies or S1P modulators who have blunted antibody responses to the COVID-19 vaccines. This is why I have moved my position from getting vaccinated ASAP to let’s time your vaccine to give you the best chance of seroconverting. This means waiting for B-cell reconstitution post-anti-CD20 before vaccinating

An adaptive vaccination/vaccine-booster strategy is logistically challenging for the simple reason that B-cell reconstitution post anti-CD20 therapy is quite variable. This means that after a certain period of time, say 9 months after your last dose of ocrelizumab, 6 months after your last dose of rituximab and 4 months after your last dose of ofatumumab you will have to have monthly B-cell counts to make sure your peripheral B-cell count is above 10 B-cells/mm3 before you can get vaccinated. I also suspect we will then have to check if you seroconvert and if not re-vaccinate you before redosing with the relevant anti-CD20. 

What this strategy won’t answer is even if these patients make an antibody response will the antibody and associated T-cell responses are good enough to protect you from infection or reinfection with the emerging variants? 

So until we have more evidence I am sitting on the fence. It is only fair to tell pwMS about the problem and the uncertainty around this issue and give them the choice to delay or miss their next dose of anti-CD20 therapy. So far some patients are delaying their next course of treatment and others are not on the grounds that they are not prepared to take a chance of undertreating their MS. A lot of the former group of patients are older with more comorbidities and hence are at higher risk of dying from COVID-19. In contrast, the latter group tend to be younger and hence are more willing to take their chances if they get COVID-19. As with all decisions around managing MS during the COVID-19 pandemic, there are no easy black-and-white answers. 

What is clear from this study below is that there is a clear hierarchy when it comes to vaccine potency with the mRNA vaccine, Moderna in particular, being superior to the other vaccines in inducing protective immunity. So if you have a choice I would go with one of the mRNA vaccines when it comes to maximising your antibody levels.

Image from Nature Medicine.

Khoury et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021 Jul;27(7):1205-1211. 

Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.

Conflicts of Interest

MS-Selfie Newsletter  /  MS-Selfie Microsite

Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

Laura’s story

Barts-MS rose-tinted-odometer: ★ (a very Black & Red Monday)

I received an email from Laura, a young woman with very active MS, who had been on natalizumab (Tysabri) for 7 years and had recently seroconverted to being high-index JCV seropositive. She was put onto natalizumab extended interval dosing (EID), i.e an infusion every 8 weeks, to derisk PML and to reduced the number of infusions she required during the COVID-19 pandemic. Before starting her switch therapy she was told she needed to be vaccinated with the COVID-19 vaccine. Her natalizumab was stopped and whilst she was waiting for vaccine immunity to develop she developed natalizumab-rebound. This is her story. 

“I’m Laura, a pwMS in the UK and I also work in the MS field. Currently, I’m not able to work due to recent rebound disease of MS, following discontinuation of Tysabri, to switch to another DMT. I believe the decision to delay the new treatment, to try to ensure I made antibodies to the second COVID-19 vaccination, was perhaps the wrong decision to be made on my behalf (I did not have any contribution to the decision, I was informed of the decision). 

To risk rebound disease is not a small matter and I would urge conversations around this prior to the switch from Natalizumab (Tysabri) or Fingolimod (Gilenya) and potentially other S1P modulators (siponimod, ozanimod and ponesimod). I was in hospital for several weeks and much more disabled than I usually am; even during a typical relapse.  It was a frightening and traumatic experience, and one I thought I would never endure. My mental health has also suffered as a direct result from the rebound relapse.  I’m now trying to recover at home, to increase my strength and stamina sufficiently to be able to go back to driving again, working and being a Mum to two autistic boys. Independence.

 I do not know of course if I will ever go back to my previous baseline. It saddens me that this was potentially avoidable; that we need to be mindful that rebound disease, by its very definition, is more severe than what has previously been experienced, and although COVID-19 vaccination is of course very important, I would have preferred to reduce my risk of rebound disease as the priority. It is my brain and spine after all. And as we know the more lesions we acquire the less reserve we have for the future. Perhaps rebound disease should be a never event, as when managed carefully it can be avoided.”

Laura’s story is tragic and should never have happened. We know enough about natalizumab rebound to prevent it from happening. It is more likely to occur in patients who have high disease activity and a high level of disability prior to starting natalizumab (see paper below). It also occurs around month 3-4 after the last infusion of natalizumab and probably slightly earlier in patients like Laura on 8-weekly EID when the steady-state levels of natalizumab are likely to lower. 

There is also no scientific evidence to suggest pwMS on natalizumab will make lower antibody responses to the COVID-19 vaccine whilst on natalizumab. In our centre, this patient will have been on 6-weekly and not 8-weekly EID. She would have had all her vaccine doses whilst on natalizumab. On the day of her last natalizumab infusion, she would have had an MRI and lumbar puncture to exclude subclinical or asymptomatic PML. Provided these were negative she would have been switched to her next DMT approximately 3-4 weeks later. If for some unforeseen reason a delay was going to occur we would have given her another infusion of natalizumab. In short, we have seen too many catastrophic rebound associated relapses and would want to prevent this from happening; we know how to prevent rebound relapses so why not? 

Laura, if you are reading this blog post, thank you for agreeing to allow us to publish your story and I sincerely hope you make a good recovery from your relapse. If anything can be learnt from Laura is that please don’t let vaccine-readiness delay starting a natalizumab-switch therapy. 

Laura’s case illustrates my biggest fear during COVID-19 that untreated or undertreated MS is more of a concern than COVID-19. The good news is that we should be getting a definitive answer on whether or not EID is as effective as standard interval dosing (SID) in the near future from the NOVA study (ClinicalTrials.gov Identifier: NCT03689972)

Mustonen et al. Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation. Mult Scler Relat Disord. 2020 Feb;38:101498. 

Background: Natalizumab (NTZ) is widely used for highly active relapsing-remitting multiple sclerosis (MS). Inflammatory disease activity often returns after NTZ treatment discontinuation. We aimed to identify predictive factors for such reactivation in a real-life setting.

Methods: We conducted a retrospective survey in four Finnish hospitals. A computer-based search was used to identify all patients who had received NTZ for multiple sclerosis. Patients were included if they had received at least six NTZ infusions, had discontinued treatment for at least three months, and follow-up data was available for at least 12 months after discontinuation. Altogether 89 patients were analyzed with Cox regression model to identify risk factors for reactivation, defined as having a corticosteroid-treated relapse.

Results: At 6 and 12 months after discontinuation of NTZ, a relapse was documented in 27.0% and 35.6% of patients, whereas corticosteroid-treated relapses were documented in 20.2% and 30.3% of patients, respectively. A higher number of relapses during the year prior to the introduction of NTZ was associated with a significantly higher risk for reactivation at 6 months (Hazard Ratio [HR] 1.65, p < 0.001) and at 12 months (HR 1.53, p < 0.001). Expanded Disability Status Scale (EDSS) of 5.5 or higher before NTZ initiation was associated with a higher reactivation risk at 6 months (HR 3.70, p = 0.020). Subsequent disease-modifying drugs (DMDs) failed to prevent reactivation of MS in this cohort. However, when subsequent DMDs were used, a washout time longer than 3 months was associated with a higher reactivation risk at 6 months regardless of whether patients were switched to first-line (HR 7.69, p = 0.019) or second-line therapies (HR 3.94, p = 0.035). Gender, age, time since diagnosis, and the number of NTZ infusions were not associated with an increased risk for reactivation.

Conclusion: High disease activity and a high level of disability prior to NTZ treatment seem to predict disease reactivation after treatment cessation. When switching to subsequent DMDs, the washout time should not exceed 3 months. However, subsequent DMDs failed to prevent the reactivation of MS in this cohort.

Figure from Front. Immunol.

Riancho et al. Does Extended Interval Dosing Natalizumab Preserve Effectiveness in Multiple Sclerosis? A 7 Year-Retrospective Observational Study. Front Immunol. 2021 Mar 25;12:614715. 

The extended interval dosing (EID) of natalizumab has been suggested to be associated with a reduced risk of progressive multifocal leukoencephalopathy (PML) and short-term preservation of efficacy but its long-term effectiveness remain unknown. We aimed to determine the long-term effectiveness and safety of natalizumab in an EID setting in a cohort of patients with multiple sclerosis (MS) treated for more than 7 years. We conducted an observational retrospective cohort study, including 39 (34 female, 5 male) patients with clinically definite relapsing-MS, initially treated with standard interval dosing (SID) of natalizumab (mean time 54 months [SD29]) who were then switched to EID, every 8 weeks (mean time 76 months [SD13]). The main outcome measures included the following: i) annualized relapse rate (ARR), ii) radiological activity, iii) disability progression, and iv) NEDA-3 no evidence of disease activity index. EID preserved ARR, radiological activity, and prevented disability worsening during follow-up. The proportion of patients maintaining their NEDA-3 status after 24, 48, and 72 months of natalizumab administration in EID was 94%, 73%, and 70%, respectively. Stratified analysis according to history of drug therapy showed that the EID of natalizumab was slightly more effective in naïve patients than in those previously treated with other immunosuppressive drugs. No cases of PML or other severe adverse reactions were reported. In conclusion, long-term therapy with natalizumab in an EID setting following an SID regimen maintained its disease-modifying activity, and was safe and well tolerated for over 7 years. These encouraging observational results need to be confirmed in controlled clinical trials.

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Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

#MSCOVID19 – the fourth wave

Barts-MS rose-tinted-odometer: ★★★ (a blueish-green Thursday; looking forward to being a weekend warrior  #0d98ba )

My heart sank when I saw the latest COVID-19 UK case numbers. Here we go again? I don’t think so simply because the vaccines are working as well as the protective immunity induced by wild-type SARS-CoV-2 infection. I just wish the Government would take a pragmatic approach to the science and allow people who have been vaccinated (double-dose) and with confirmed previous SARS-CoV-2 infection to get back to normal. 

It is clear from Israel that people who have had COVID-19 are as immune as vaccinated people to (re)infection with the virus. This will almost certainly apply to the circulating variants that as yet are not immune escape variants, i.e. capable of reinfecting large numbers of people who are meant to be immune to SARS-CoV-2. 

The biggest concern with the current Indian or Delta SARS-CoV-2 variant is that it is more transmissible and more virulent, which means people who are not vaccinated are taking a big risk. This is very relevant to the East end of London where the vaccination rates in adults are below 50% because of significant vaccine hesitancy in the local population. We are therefore at high risk of a significant fourth wave of infections, which will have implications for our hospital and other services, including the MS service. We really need some respite from fighting and dealing with COVID-19 so that we can get back to normal or at least near normal. So please think carefully about resisting vaccination; you are not only putting yourself at risk but are impacting the health of others.

Please remember that COVID-19 and SARS-CoV-2 are going nowhere soon and will almost certainly become endemic, i.e. the virus and its variants will remain with us forever. So if you have not been vaccinated you will at some point in time get exposed to SARS-CoV-2 and get COVID-19. The risks of COVID-19 and its consequences, including long-COVID, are orders of magnitude worse than the risks of the vaccine. Therefore please #GetVaccinatedASAP. In my opinion there really are very few reasons to say no! Do you agree?

Goldberg et al. Protection of previous SARS-CoV-2 infection is similar to that of BNT162b2 vaccine protection: A three-month nationwide experience from Israel.  medRxiv preprint doi: https://doi.org/10.1101/2021.04.20.21255670.

Worldwide shortage of vaccination against SARS-CoV-2 infection while the pandemic is still uncontrolled leads many states to the dilemma whether or not to vaccinate previously infected persons. Understanding the level of protection of previous infection compared to that of vaccination is critical for policy making. We analyze an updated individual-level database of the entire population of Israel to assess the protection efficacy of both prior infection and vaccination in preventing subsequent SARS-CoV-2 infection, hospitalization with COVID-19, severe disease, and death due to COVID-19. Vaccination was highly effective with overall estimated efficacy for documented infection of 92·8% (CI:[92·6, 93·0]); hospitalization 94·2% (CI:[93·6, 94·7]); severe illness 94·4% (CI:[93·6, 95·0]); and death 93·7% (CI:[92·5, 94·7]). Similarly, the overall estimated level of protection from prior SARS-CoV-2 infection for documented infection is 94·8% (CI:[94·4, 95·1]); hospitalization 94·1% (CI:[91·9, 95·7]); and severe illness 96·4% (CI:[92·5, 98·3]). Our results question the need to vaccinate previously-infected individuals.

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Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 

How many ofatumumab doses should I miss?

Barts-MS rose-tinted-odometer: ★★★ (It feels like a sky blue rainy Friday =  #87ceeb)

“Prof G how many of my monthly ofatumumab injections should I miss to guarantee that I will have an adequate antibody response to the COVID-19 vaccine?”

This was the gist of one of the direct messages I received on Twitter from a person with MS living in the US. 

I really don’t know. However, I have tried extrapolating data from the repopulation kinetics of ofatumumab given 3-monthly and the modelling data below on ocrelizumab and rituximab. For ocrelizumab and rituximab to have 80% confidence it requires at least 9 months from the last infusion to the first vaccination to have a >50% chance of seroconversion in response to an RNA-based COVID-19 vaccine. This equates to missing close to one dose of ocrelizumab or rituximab as you have to wait 9 months then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommencing your 6-monthly infusions. i.e. ~11 months after your last infusion. Although Mike Famulare has treated rituximab and ocrelizumab as being equipotent in his modelling I suspect he is wrong and the gap for ocrelizumab may in fact have to be substantially longer. I predict that the average person will need to wait about 11-12 months post their last infusion of ocrelizumab to be confident of an antibody response.

As ofatumumab, is a lower dose anti-CD20, with more rapid B-cell repopulation kinetics than ocrelizumab or rituximab (see figure below). I estimate that you will need to wait about 6 months from your last injection before being vaccinated and you would then have two vaccine doses and wait 3-4 weeks after your second or booster dose of vaccine before recommending your monthly injections. i.e. ~8 months later. As this is all based on modelling I suspect in real life you will simply need to wait for peripheral blood B-cell reconstitution to occur before being vaccinated. The problem with the latter is how high do your peripheral B-cells have to be before being vaccinated; more than 3, 5, 10, 20, 50 or 80 CD19+ B-cells per mm3? Clearly, this is something that needs further study and I would urge Pharma or one of the MS groups interested in answering this question to do the study.  Let’s call it the ‘Peripheral B-cell Threshold Vaccine Study‘ or the ‘PerBeC Vax Study‘.

I want to reiterate that vaccine immunity is not only about B-cell and antibody immunity, T-cells also have an important role to play. Granted that if you don’t make antibodies it indicates that your follicular T-helper cells memory may not be that great, but this does not tell you about other CD4+ and CD8+ T-cell memory responses. Therefore, please be patient until these data emerge. 

My message remains the same; #GetVaccinatedASAP. During this phase of the pandemic, some immunity is better than no immunity. The risk associated with getting COVID-19, particularly if you are on a B-cell depleting agent, far outweighs the risks associated with vaccination. 

Seroconversion rate following complete COVID-19 vaccination vs. time since most recent b-cell depleting therapy (BCDT). Best fit, 80%, and 95% confidence interval shows logistic regresssion model of seroconversion probability over time.

Mike Famulare. Seroconversion after COVID-19 vaccination in patients using B-cell depleting therapies to manage multiple sclerosis increases with time between treatment and vaccination. Github v0.2 03 June 2021.

B-cell depleting therapies (BCDT) such as ocrelizumab and rituximab used for the management of multiple sclerosis are associated with reduced seroconversion rates following COVID-19 vaccination. In this note, I reanalyze data from the literature to examine how the probability of seroconversion depends on the time interval between the last BCDT dose and the first vaccine dose. While uncertainty is high due to limited data, the results show that the seroconversion probability increases with time. Under a Bayesian interpretation of logistic regression, I estimate with 80% confidence that it requires at least 9 months from last BCDT to first vaccination to have a >50% chance of seroconversion following complete mRNA vaccination, with large uncertainty on when higher confidence of seroconversion can be expected. Among subjects who do seroconvert following vaccination, anti-Spike IgG levels correlate with time since last BCDT. Limited data indicate that levels comparable with immunocompetent response can be achieved with intervals of 12 or more months between BCDT and vaccination. With combined data from multiple sources, I argue that time development of the seroconversion probability and antibody response parallels that of CD19+ and naive B-cell repopulation following BCDT, suggesting that monitoring B-cell repopulation will be useful at the individual level for optimizing vaccine response while maintaining adequate MS control.

Pharmacodynamic response showing dose-response depletion of CD19 B cells and repletion kinetics (safety population). The median time to repletion based on Kaplan-Meier estimates was ≈11 months for the ofatumumab 3 and 30 mg every 12 weeks groups and ≈14 months for the ofatumumab 60 mg every 12 and 4 weeks groups.

Bar-Or et al.Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology. 2018 Sep 11;91(11):538. 

Objective: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).

Methods: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.

Results: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.

Conclusion: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.

Classification of evidence: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.

Trial registration: ClinicalTrials.gov NCT01457924.

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Stay calm and get vaccinated

Barts-MS rose-tinted-odometer: ★★★

We can speculate until the cows come home, but speculation remains guesswork. Until a similar study to the one below on T-cell responses to the COVID-19 vaccine is done in people with MS on different DMTs we can’t be confident that people who don’t seroconvert after the vaccine have adequate or protective anti-SARS-CoV2 spike protein T-cell responses.

However, my message remains the same around vaccinations. The COVID-19 vaccines are safe and we don’t have any reason to suspect the vaccines have any effect on your MS in the long term. Apart from transient worsening of symptoms, which are reversible, in response to the flu-like symptoms from the vaccine pwMS seem to be tolerating the vaccine without any problems. The latter is more common in patients with advanced disability and can be managed with prophylactic paracetamol and/or ibuprofen. 

Good things come to communities who are patient. My advice would be to stay calm and #GetVaccinatedASAP

Image from bioRxiv

Painter et al. Rapid induction of antigen-specific CD4+ T cells guides coordinated humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination. bioRxiv 2021 doi: https://doi.org/10.1101/2021.04.21.440862

The SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses in healthy individuals following mRNA vaccination. Vaccination induced rapid near-maximal antigen-specific CD4+ T cell responses in all subjects after the first vaccine dose. CD8+ T cell responses developed gradually after the first and second dose and were variable. Vaccine-induced T cells had central memory characteristics and included both Tfh and Th1 subsets, similar to natural infection. Th1 and Tfh responses following the first dose predicted post-boost CD8+ T cell and neutralizing antibody levels, respectively. Integrated analysis of 26 antigen-specific T cell and humoral responses revealed coordinated features of the immune response to vaccination. Lastly, whereas booster vaccination improved CD4+ and CD8+ T cell responses in SARS-CoV-2 naive subjects, the second vaccine dose had little effect on T cell responses in SARS-CoV-2 recovered individuals. Thus, longitudinal analysis revealed robust T cell responses to mRNA vaccination and highlighted early induction of antigen-specific CD4+ T cells.

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#MSCOVID19: Cladribine 3 vs. Ocrelizumab 1 vs. Fingolimod 0

Barts-MS rose-tinted-odometer: ★★★★★

Finally, the early Israeli COVID-19 vaccine seroconversion rates are out as a peer-reviewed publication. This data is not new but comes with being vetted by the scientific community and hence can be quoted and discussed at scientific meetings.

Protective humoral immunity was 97.9% in healthy subjects, 100% untreated pwMS, 100% in cladribine-treated pwMS, 22.7% in ocrelizumab-treated pwMS and 3.8% in fingolimod-treated pwMS. As I have said before this is only half the story and we need to know what happens on the T-cell side. 

IgG antibodies to the virus implies a good T-cell response as well; this is because to class switching to IgG happens in the germinal centres with T-cell help. The corollary does not necessarily hold, i.e. if you don’t make IgG antibodies you can’t assume that vaccine-induced T-cell responses are absent. This is why I predict, based on the fact that both ocrelizumab and fingolimod treated pwMS recover from COVID-19 implying their T-cells are working and helping to clear the virus, that both ocrelizumab- and fingolimod-treated patients are likely to have some T-cell immunity to SARS-CoV-2 spike protein post-vaccination. 

Please note this is a prediction and we will need to wait for more detailed immunological studies. Even if patients on these agents have some T-cell responses the question will remain whether this blunted vaccine-induced immunity against SARS-CoV-2 will be sufficient to protect these patients against getting COVID-19 or repeated episodes of COVID-19? This question will take much longer to answer, but I suspect this limited immunity won’t be sufficient because vaccine immunity is likely to wane with time and new immune escape variants of SARS-CoV2 will emerge. Already public health officials are planning for rounds of booster vaccines to cover new variants. What this means is that vaccine-readiness will become uppermost in the minds of pwMS and HCPs when deciding on which DMTs to choose for particular patients.

The good news is that if you have MS and have been treated with cladribine there is no blunting of vaccine-induced responses. This is not surprising and was predicted based on the immunology of cladribine and justifies my previous blog post taking the NMSS to task on their ill thought out initial COVID-19 vaccine guidelines. Fortunately, these have been updated and pwMS on cladribine can be confident to go ahead with getting vaccinated ASAP. 

Figures from Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

I would extrapolate the ocrelizumab vaccine data to the other anti-CD20 therapies, i.e. rituximab, ofatumumab and ublituximab, but not necessarily the fingolimod data to the other S1P modulators. There is evidence that fingolimod not only traps lymphocytes in lymph nodes but also depletes lymphocytes. In comparison to fingolimod, ozanimod and ponesimod deplete lymphocytes less intensely and at least for ponesimod, the recovery of lymphocytes is very rapid implying lymphocytes are not depleted on this drug.  So I would not be surprised if ponesimod, and possibly ozanimod, have less of an effect on vaccine responses than fingolimod. As for siponimod, I predict it will be closer to fingolimod in terms of its effect on neoantigen (new antigen) vaccine responses such as the COVID-19 vaccines. 

Does this data change anything about my current practice? No, not really, it is entirely in keeping with what I predicted. My advice is still #GetVaccinatedASAP. This data however may impact what treatment patients with MS decide to start off on; if vaccine responses are important to you, say for travel and/or work reasons, you may want to avoid S1P modulators and anti-CD20 therapies.

Please note I have put on my rose-tinted glasses; the sun is shining outside and spring is wonderful 😉

Achiron et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Ther Adv Neurol Disord 2021, Vol. 14: 1–8.

Background and Aims: The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs.

Methods: We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated.

Results: Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects (N = 47), untreated MS patients (N = 32), and MS patients treated with cladribine (N = 23), ocrelizumab (N = 44), and fingolimod (N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5–55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination.

Conclusions: Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.

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#MSCOVID19: adenoviral vector vaccines

Barts-MS rose-tinted-odometer: ★

You may have heard that the FDA has suspended dosing of the J&J COVID-19 vaccine as they have identified 6 cases of thrombosis in young woman similar to that described below with the Oxford-AstraZeneca vaccine (see articles below).  It looks like the complication may therefore be due to the vectors, i.e. adenoviruses, rather than the SARS-CoV-2 spike protein. If this is the case there is likely to be similar cases identified with the Russian Sputnik V vaccine, which uses two different adenoviral vectors. 

Please remember that this thrombotic complication is still very rare, i.e. likely to be less than 1 person affected in over 100,000 vaccinated people, which is why the EMA, MHRA and WHO have made it clear that the potential benefit of the Ox-AX vaccine outweighs the risk of thrombosis. In other words, the risk of getting COVID-19 is far worse than the risks associated with the vaccine. So our message remains the same; #GetVaccinatedASAP.

Thrombotic (blood clots) thrombocytopaenia (low platelets) is an immune-mediated condition, in which your own immune system makes antibodies against a protein called platelet factor 4 expressed on platelets. In other words, it is an antibody-mediated autoimmune disease. This will allow haematologists and vaccinologists to study the condition and work out why it is happening and then manage the risk or hopefully prevent it from happening in the future. For example, it could simply be due to molecular mimicry to a protein or stretch of protein in one of the adenoviral proteins that could be engineered out of the next generation of vaccines. 

With my preventive medicine hat on I am concerned that this rare complication of the adenoviral vaccines will feed the anti-VAXX lobby and turn people off having the COVID-19 vaccine. This would be a great tragedy as it is the adenoviral vaccines that are going to save the world from this pandemic; they are relatively cheap and easy to manufacture and don’t have to be stored at -20 or -80. All these attributes make them the vaccines of choice for low and middle-income countries. 

Please note I would not have a problem being vaccinated with a COVID-19 adenoviral vaccine nor would I have a problem recommending these vaccines to my family members. 

Greinacher et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104840. Online ahead of print.

Background: Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.

Methods: We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay.

Results: Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity-purified antibodies in 2 patients confirmed PF4-dependent platelet activation.

Conclusions: Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).

Schultz et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021 Apr 9. doi: 10.1056/NEJMoa2104882. Online ahead of print.

We report findings in five patients who presented with venous thrombosis and thrombocytopenia 7 to 10 days after receiving the first dose of the ChAdOx1 nCoV-19 adenoviral vector vaccine against coronavirus disease 2019 (Covid-19). The patients were health care workers who were 32 to 54 years of age. All the patients had high levels of antibodies to platelet factor 4-polyanion complexes; however, they had had no previous exposure to heparin. Because the five cases occurred in a population of more than 130,000 vaccinated persons, we propose that they represent a rare vaccine-related variant of spontaneous heparin-induced thrombocytopenia that we refer to as vaccine-induced immune thrombotic thrombocytopenia.

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Should we abandon the ADIOS study?

Barts-MS rose-tinted-odometer: ★★★

If you have been on ocrelizumab for two years would you be prepared to participate in the ADIOS (adaptive dosing ocrelizumab study)? One of the study arms would mean that you would not receive any ocrelizumab until you had a relapse or new MRI activity. In other words, we would be using ocrelizumab like we use alemtuzumab or cladribine, i.e. as an immune reconstitution therapy (IRT). 

Some of our colleagues doubt whether people with MS would volunteer for such a study. I personally think they being affected by their own preconceived biases. We don’t know if we can use ocrelizumab or other anti-CD20 therapies as an IRT, which means we have equipoise. It is clear that using anti-CD20 therapy in this way will be safer, i.e. you would be less likely to develop hypogammaglobulinaemia and infections as a complication of continuous therapy. Similarly, the risk of secondary malignancies should be lower and you will be vaccine ready. The latest paper below shows that the time from the last dose of an anti-CD20 therapy predicts seroconversion after a COVID-19 vaccination; i.e. the longer you wait after a dose of rituximab, and probably ocrelizumab, the more likely you are to seroconvert after having the COVID-19 vaccine. I suspect going forward people on anti-CDC20 therapy may have to take drug holidays anyway to make sure they respond to vaccines. In fact, I was on a Medscape recording yesterday with a colleague from UCSF and a vaccinologist and they both said that most MSologists and rheumatologists in North America are already doing this. At the moment I have been saying get #GetVaccinatedASAP and cross the vaccine-readiness bridge when the boosters arrive. We will also have evidence, such as below, to guide us in the future.

Deepak P et al. Glucocorticoids and B Cell Depleting Agents Substantially Impair Immunogenicity of mRNA Vaccines to SARS-CoV-2. MedRxiv https://doi.org/10.1101/2021.04.05.21254656.

The following data from Anat Achiron will hopefully be out as a pre-publication this week.

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Disclaimer: Please note that the opinions expressed in this blog post are those of Professor Giovannoni and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

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#MSCOVID19: triMSx-online

You may remember that about 6 years ago the idea was germinated on this blog to launch an online version of ECTRIMS to reach people in low- and middle-income countries and to allow more women with family commitments to attend meetings. The other aim was to usher in the next generation of young MSologists; more women, younger people, more ethnic diversity and from all regions of over the world, i.e. not stale, pale and male 😉 Unfortunately, ECTRIMS didn’t want us to use the name OCTRIMS so we launched with the name triMS-online.

The concepts behind triMS-online have now been adopted, in part, because of COVID-19 by many other conference organisers. However, we think we have something special and we are not just trying to duplicate the face-2-face 3-5 day conferences the other platforms are doing. Since launching triMS-online we have extended the concept into standalone themed meetings with single sponsors. These meetings are to address specific unmet needs and hot topics.

The next triMSx-online meeting, which is being held this evening and tomorrow evening, is covering COVID-19 vaccines and their relevance to MS. If you have not registered please do so now. Don’t worry if you can’t watch it live the talks will be recorded and available via the triMSx-online portal for asynchronous viewing. In addition, we will be also doing a podcast on the meeting for you to listen to in your own time.

COVID-19 and MS: where are we now and where next?

8 and 9 April 2021
19:00–19:45 BST I 14:00–14:45 EDT I 20:00–20:45 CEST

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