Prof G's MS Blog Archive

Barts-MS rose-tinted-odometer: ★★

Guilty as accused!

I did a very one-sided post this weekend on the pros of oral cladribine as a treatment for MS during the COVID-19 pandemic. One commentator asked ‘what about the cons?’. As with all immunosuppressive therapies, there is a risk of secondary malignancies. In fact, both the EMA and FDA labels mention secondary malignancies as a complication of cladribine therapy. We think the short-term cancer risk, i.e. within the first 2 years, was driven by the very low numbers of cases in the placebo arms of phase 3 trials. The cancer rate in the cladribine-exposed subjects was in keeping with the expected background rates compared to subjects on other DMTs and people from the general population from data in an international population-based cancer registry (GLOBOCAN). So I am not convinced that cladribine is associated with a short term cancer risk. However, the jury is out in relation to the intermediate to longterm risk. However, the safety data from the extension and post-marketing surveillance studies look very promising and based on the biology and mode-of-action of cladribine I think this risk is likely to be low.

Although cladribine works via DNA mechanisms it is not a mutagen; i.e. it does not cause mutations in DNA. When cladribine is incorporated into DNA it inhibits DNA polymerases, the enzymes that extend the DNA chain. The cell then senses this as a problem and this triggers apoptosis the biological process that causes the cell to trigger a suicide programme called ‘programmed cell death’. The reason why cladribine is so selective for lymphocytes is that the enzyme that activates cladribine is only found in high concentrations in lymphocytes and the other cells that don’t express this enzyme are resistant to cladribine’s effects.

Saying this secondary malignancy is a complication with all immunosuppressive therapies regardless of their mode of action. The reason is that we rely on peripheral tumour immune surveillance, i.e. our immune system find early cancers and attacks and destroys them. Suppress the immune system intensely enough and for long enough and certain cancers will develop. For example, fingolimod, and I suspect the whole S1P modulator class, is associated with skin cancer (basal and squamous), lymphoma and potentially other cancers, e..g. Kaposi’s sarcoma. Anti-CD20 therapies may be linked to breast cancer. Natalizumab, CNS lymphoma. Alemtuzumab, cervical cancer and possibly thyroid cancer, although one could argue the thyroid cancer risks with alemtuzumab may be due to ascertain bias from the high rate of thyroid screening due to thyroid secondary autoimmunity. The only DMTs not associated with secondary malignancies are the immunomodulators, i.e. interferon-beta, glatiramer acetate and teriflunomide.

Is there anything you can do about the immunosuppressive cancer risk? Yes, there is. You need to enrol and stick to your country’s cancer screening programmes. In the UK there are three national programmes; cervical, breast and colon. Breast cancer screening starts at the age of 50 and stops at the age of 70. Colon cancer screening starts at the age of 50 or 60, which depends on where you live in the UK. Cervical cancer screening is for women between 25 and 64 years of age. However, there is a push to extend cervical cancer screening beyond 64 now that cervical smear screening is being replaced with vaginal swabs, which are self-administered, and use PCR testing to detect HPV, the virus that causes cervical cancer. HPV testing is so much more pleasant for women and more reliable and reproducible than looking for abnormal cells under a microscope.

In the UK the prostate cancer screening programme is available on request, i.e. you can request a PSA (prostate-specific antigen) test. National PSA prostate cancer screening was dropped as the PSA assay was too unreliable. It generated too many false positives or detected very small cancers that were unlikely to cause any problems. In comparison, some of the treatments for prostate cancer cause more harm. In fact, most men who die in old age have asymptomatic prostate cancer at post-mortem; if something else rather than the cancer was going to kill these men why bother about detecting cancer? Please note the dropping of the national prostate cancer screening programme has been controversial and some people think it was a mistake. In many countries, PSA screening is still being done at a national level.

In some parts of the UK, there are pilot lung cancer screening programmes with high-resolution spiral chest CT scans being offered. The early results are very impressive in targeted groups at high-risk of lung cancer such as heavy smokers or ex-smokers. I am convinced that lung cancer screening is likely to become routine in the UK in smokers in the not too distant future.

Other groups for cancer screening include high-risk subjects for example patients with dysplastic naevus syndrome of the skin, who are at risk of melanoma, those with well-defined genetic conditions associated with specific cancers, patients with a very strong family history of specific cancers, patients with inflammatory bowel disease, anal cancer screening in HPV and HIV postive men-who-have-sex-with-men, oesophageal cancer screening in patients with Barrett’s oesophagus, etc.

A few years ago I asked our renal transplant team for advice about their cancer screening programme for their transplant patients. In short, they don’t do anything that is outside of the national cancer screening programme. The reason they gave is that when you start screening a younger population than that defined by the national screening programmes you are likely to detect more false positives cancers, which leads to unnecessary intervention that cause more harm. You also create cancer anxiety syndrome; i.e. patients start to worry excessively about developing cancer. I have a few patients on DMTs who suffer from this condition; so it is real.

However, there are some self-screening programmes that you can engage in, for example, self-examination of your breasts and testes for woman and men, respectively, and the regular examination of worrisome skin lesions. The following are just three YouTube videos on how to do breast, testes and skin lesion self-examinations.

As MS HCPs we are meant to prompt you to make sure you are registered with your GP and are enrolled in the screening programmes. Outside of HPV screening in women about to start an immunosuppressive therapy, I tend to forget to do this. This is another example to have proformas of standardised checklists to make sure we don’t forget this important task.

I would be interested to know what your experience has been with regard to your awareness about cancer risk on immunosuppressive therapies, cancer screening and self-examination. In this study below despite the vast majority of the woman being aware of breast self-examination, a large minority didn’t examine their breasts every month. Does this apply to you?

Watanabe et al. Awareness of Self-Examination, Screening, and Risk Factors for Breast Cancer Among Women Awaiting Care at the Outpatient Clinic of a Mastology Unit. J Cancer Educ. 2020 Oct 9. doi: 10.1007/s13187-020-01892-1.

This study aimed to evaluate the awareness and practice of breast self-examination (BSE) and the awareness of screening and risk factors for breast cancer among patients from a mastology clinic and to associate such findings with sociodemographic factors of that population. A total of 202 randomly selected patients from the outpatient clinic of the Mastology Unit of São Paulo School of Medicine were interviewed. A structured questionnaire was used and included questions regarding sociodemographic variables, questions to assess the knowledge and practice of BSE, and knowledge of mammographic screening and risk factors for breast cancer. The vast majority of patients were aware of the existence of BSE (93.1%). BSE was performed by most patients (64.9%), although only 20.3% performed it adequately. Only 21.8% of respondents showed awareness of the best screening method for breast cancer. Furthermore, 17.3% of patients showed adequate awareness of risk factors for breast cancer. The analysis of sociodemographic variables showed that older, postmenopausal, and less-educated women showed better practice of BSE. Overall, the patients had no adequate awareness of BSE, mammographic screening, and risk factors for breast cancer, and the majority failed to practice BSE adequately, particularly the group of patients with the higher level of education. These data show that educational measures regarding the practice of BSE and, especially, mammograms should be emphasized, regardless of education level or family income of the patient.

PS (4-Mar-2021): In response to a request from one of the comments in the survey: “…you could you please comment on cancer risk for anti CD20+ treatments, as well as cancer-related topics for younger pwMS”. I have therefore added the presentation from Professor Hauser from the MSVirtual2020, the 8th Joint ACTRIMS-ECTRIMS Meeting, from September 2020. As you can see the rate of malignancies and female breast cancer in ocrelizumab-treated patients remained broadly within the range reported in the general population from epidemiological data. Please note these patients have been followed for over 7 years. I hope this helps.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

MS and the Inverse Care Law at 50

Barts-MS rose-tinted-odometer: ★

Variation in access to good medical care and better outcomes has never been higher in high-income countries such as the UK. Variation is simply a euphemism for inequality. The MS community in the UK realised this a few years ago, which prompted us to launch our ‘Raising the Bar’ initiative to address inequality in access to healthcare for people with MS living in the UK.

With this as a backdrop, it is worth reflecting on the 50th anniversary of the publication of Julian Tudor Hart’s paper “The Inverse Care Law”, which was published in The Lancet on the 27th Februrary 1971. The article opens with the following lines:

“The availability of good medical care tends to vary with the need for it in the population served. This inverse care law operates more completely where medical care is most exposed to market forces, and less so where such exposure is reduced.”

The Lancet is celebrating the 50th anniversary of the publication of Hart’s seminal paper with a hard-hitting editorial, which I would urge you to read.

Editorial. 50 years of the inverse care law. Lancet 27th Feb 2021.

Excerpts:

…. Globally, letting market forces dictate health care is still a major contributor to inequity—private health care can only be accessed by those who can afford to pay.

….. In many countries, social care and long-term care are managed by private providers too.

….. Although health care is widely endorsed as a basic human right, the systems that provide it inequitably embody capitalism at its worst, where the wealthy benefit, leaving behind those most in need.

What are we trying to do with our ‘Raising the Bar’ initiative? We simply want no patient with MS to left behind. Our programme of activities has coalesced around five main workstreams.

(1) The ‘Data & Audit’ workstream is focusing on measuring the wide variation in MS services in the UK. We hope the data will then be used as a catalyst for change, i.e. new business cases for service development.

(2) The ‘Patients as partners’ workstream is the improve health literacy amongst pwMS;p to help them navigate the NHS. There is compelling data showing that people with chronic disease who are engaged with their disease and its management do better, both in terms of health outcomes and improved quality of life. Similarly, when it comes to self-monitoring, self-management and behavioural interventions, which will be essential to transform MS outcomes we will need pwMS to become true partners in raising the bar.

(3) The ‘Wellness, lifestyle & social determinants of health’ workstream is promoting the holistic management of MS. This workstream focuses on wellness and lifestyle interventions to maximise brain and physical health. This workstream is also working on ways the MS community can address the social determinants that dominate health outcome in other disease areas; we are sure it is no different in MS.

(4) We acknowledge that if we want no patient to be left behind we are going to need a new generation of leaders; people with the vision, energy and drive to make the changes necessary to make our MS services equitable and valuable. This is why we have launched a ‘leadership programme’ to provide HCPs working in MS with the necessary leadership skills. Yes, not everybody is born a leader. Effective leadership skills need to be learnt.

(5) Finally, we have a workstream that addresses UK infrastructure such as ‘national registers and research’ studies that will provide the evidence base to change or implement new practices across the country.

So if you are a healthcare professional working in MS you need to please join the MS Academy and become a part of our raising the bar initiative. With the waning of the COVID-19 pandemic the NHS promises to be more responsive to innovation, more inclusive and wants to address both inequality and it causes. I think there is no better time than now to make a difference.

If you want to hear more about what we are trying to do please log into the MS Trust’s virtual conference. In the Q&A session tomorrow afternoon we will be addressing many of these issues.

The following are my discussion points for my brief 10-minute introduction.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: specifically for NHS England

Barts-MS rose-tinted-odometer: ★★★★★

Early on in the pandemic, I did a blog post on why I thought oral cladribine was the ideal DMT for managing MS (26-April-2020) remotely. I summarised cladribine’s attributes in a simple 12-point list. This list can now be updated to include (1) data on good COVID-19 outcomes in pwMS who have been treated with cladribine, (2) about vaccine readiness, i.e. pwMS vaccinated with COVID-19 vaccine make a good antibody response and (3) on its cost-effectiveness and value.

The Mouse Doctor prodded me by email yesterday to ask NHS England to allow us to use cladribine more liberally because of the pandemic and the unique challenges it is placing on MS services. MD suggests using or at least offering it 1st-line to patients with just active MS and not only those with highly-active disease. I can’t really do what MD wants because NHS England has a process for changing its advice. I also need to remind MD that as the principal investigator on the phase 3 CLARITY study I am so conflicted that nobody would take anything I say seriously. Hence an updated blog post.

Cladribine’s pros:

Cladribine is a high-efficacy DMT therefore it potentially allows you to flip the pyramid and offer it first-line.

Cladribine is an oral therapy; hence no visits to COVID-19 hot hospitals or institutions.

Cladribine kills cells gradually by a process called apoptosis. Cells dying from apoptosis are phagocytosed or swallowed by macrophages and as a result, there is no cell lysis or bursting open of the cells and the release of their contents that causes a cytokine release syndrome. This means there is no need to pre-treat patients with steroids, which we try to avoid because they increase your chances of getting severe COVID-19.

Cladribine does not deplete monocytes and neutrophils and has a moderate impact on so-called NK cells. As the innate immune system is left intact there is a low risk of bacterial and other infections during the depletion phase and the innate cells can help fight viral infections, such as SARS-CoV-2.

T lymphocytes are in general depleted by about 40%-50% and most patients don’t drop their counts below 500/mm3. In the phase 3 programme about a quarter of patients had a grade 3 or 4 lymphopaenia, but this tended to occur after the second course in year 2 in subjects who were redosed when their lymphocyte counts had not recovered to above 800/mm3. We have used the trial data to model grade 3 and 4 lymphopaenia. I.e. less than 500/mm3, and estimate that less 5% of cladribine treated subjects will develop lymphocyte counts less than 500/mm3 if we stick to the redosing guidelines. This is very important as lymphopaenia is probably the most important risk factor for viral and severe viral infections.

In the T-cell compartment, the CD8+ T-cells were less effected than CD4+ T-cells. This is important because CD8+ T-cells are the cells responsible for fighting viral infections. This probably explains, apart from a small risk of herpes zoster reactivation, why we didn’t see an increase in viral infections compared to placebo in cladribine treated subjects in the phase 3 trial programme. The viral infections that did occur tended to be non-specific upper respiratory tract infections and were mild to moderate. In fact, the infection profile on cladribine, including the zoster signal, was much more similar to that which we see with ocrelizumab compared to alemtuzumab.

Cladribine-treated pwMS who get COVID-19 are not at increased risk of getting severe COVID-19.

Cladribine is a remarkably good depleter of B-cells. B-cells number drop quicker than T-cells numbers; i.e. within days to weeks. In addition, B-cells are depleted by about 85-90% and importantly memory B-cells are severely depleted and to a similar level that we see with alemtuzumab. Importantly, when the B-cell numbers return these are so-called naive B-cells, which come from the bone marrow and are not memory B-cells. These are the cells you need to make vaccine responses.

Please note that because ocrelizumab and rituximab are given as maintenance or continuous therapy there is a small increase in the incidence of serious infections over with time and the development of hypogammaglobulinaemia. This is not seen with cladribine. Once the immune system reconstitutes post-cladribine it can fight infections, immune survey the body for cancers and mount immune responses to new viral infections, such as SARS-CoV-2, and vaccines.

In relation to vaccines both live and inactivated component vaccines can be given after cladribine. New data indicates that cladribine-treated with MS make good antibody response to COVID-19 vaccines (see vaccine post from yesterday).

The other important thing about cladribine is the monitoring requirements are low. Once you have had a course you only need a full blood count to be done at month 4 and 7 in each treatment year. The rationale for this is that the 4-month time-point is where the nadir occurs and the 7-month time point is to check for recovery of lymphocyte counts.

When you look at how cladribine works, i.e. it needs to be activated by an enzyme call DCK (deoxycytidine kinase) and broken down by an enzyme called ADA (adenosine deaminase), the profile of cells expressing the correct ratio of these enzymes matches the B-cell population that expresses CD19 and CD20 and explains why B-cells are more susceptible to the effects of cladribine than T-cells.

Another advantage of cladribine is that as a small molecule it penetrates the CNS. Cerebrospinal fluid (CSF) levels are about 25% of what is found in the peripheral blood and at a level that would target B- and T-cells within the brain and spinal cord. I think this property of cladribine is very important and is one of the reasons why we are exploring cladribine as a treatment for progressive MS in the CHARIOT-MS trial.

Please note that I am not saying cladribine is entirely safe. It has a well-defined risk-benefit profile that is less risky than what has been suggested by many people. These risk-benefit profiles simply allow you to counsel patients with active MS about their treatment options during the COVID-19 pandemic.

Oral cladribine is cost-effective. NHS England has negotiated a value-based pricing deal with the manufacturer for a rebate if anyone treated with cladribine switches to another agent within 4-years of starting treatment. This makes cladribine a very good option; you are only paying for the drug if it is effective. Isn’t this the future of pharmaceutical drug pricing?

We think cladribine is a highly effective therapy that has many positive attributes for managing MS during the COVID-19 pandemic.

P.S. MD adds Point 17. Risk of PML in JC+ individuals is low (Thanks Jason)

Do you agree?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: cladribine is being unfairly tarnished with alemtuzumab’s brush

Barts-MS rose-tinted-odometer: ★★★★★

I think the North American MS community have made some mistakes with their COVID-19 vaccine recommendations, in particular, the NMSS COVID-19 vaccine guidelines for cladribine. In view of the immunology of cladribine’s mode of action and new data that is emerging, I would suggest the NMSS considers updating its guidelines.

Lemtrada and Mavenclad

If you are about to start Lemtrada or Mavenclad, consider getting the Pfizer BioNTech or Moderna COVID-19 vaccine so that the second vaccine injection is done 4 weeks or more prior to starting Lemtrada or Mavenclad. If you are already taking Lemtrada or Mavenclad, consider administering the vaccine injections starting 12 weeks or more after the last Lemtrada or Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose². When possible, resume Lemtrada or Mavenclad 4 weeks or more following the second vaccine injection. This suggested scheduling is not always possible and getting the vaccine when it becomes available to you may be more important than timing the vaccine with your DMT. Work with your MS healthcare provider to determine the best schedule for you.

Lumping cladribine and alemtuzumab together as being immune-depleters of the same ilk is simply wrong. Alemtuzumab is more of a sledgehammer and is relatively non-selective in depleting both T-cells and B-cells and it also hits innate immunity, in particular monocytes. This is why there is a major infection signal (e.g. listeriosis) with alemtuzumab in the 4-6 weeks after each course of treatment. The latter does not occur with the doses of cladribine we use to treat people with MS.

In comparison, the mode of action of cladribine is very subtle and more in keeping with a selective B-cell depleting agent. Cladribine depletes B-cells by about 85-90% and hits mainly memory B-cells, in other words, large numbers of naive B-cell persist in the peripheral blood. We think as memory B-cells are being killed fresh naive B-cells are being released from the bone marrow. This is important because it is the naive B-cell population that is required to make new antibody responses to vaccines.

Cladribine only depletes T-cells by about 50% a level that in general is not sufficient to put patients at risk of opportunistic infections or even viral infections. When we recently reanalysed all of the cladribine safety data there was no novel or new exogenous (from outside the body) viral infection signal. The only viral infection signal we saw was zoster or shingles, i.e. a reactivation of a latent virus, which is common and occurs with all immunosuppressive therapies.

Another very big difference between cladribine and alemtuzumab is the fact that cladribine leaves the innate immune system intact, which is important for fighting infections and for processing vaccine antigens and presenting them to the immune system.

Another factor that is different is the temporal profile of immunodepletion that occurs with alemtuzumab and cladribine. Alemtuzumab causes rapid cell lysis with its effect noticeable in hours to days; in other words, peripheral blood lymphocyte and monocyte counts are depleted to very low levels (nadir) very quickly. In comparison, cladribine works by triggering apoptosis of cells and lymphocytes die slowly over weeks to months reaching a nadir at about 3 to 4 months after each course. Therefore for the NMSS guidance to say “consider administering the vaccine injections starting 12 weeks or more after the last Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose” is actually recommending giving the vaccine from the start of the nadir.

Unlike alemtuzumab, I think the timing of vaccination in patients treated with cladribine is unlikely to make much of a difference because both the afferent (antigen processing and presentation) and efferent (B-cells/antibodies and T-cells) limbs of the immune system is intact, i.e. there is enough hardware or cells at all times post cladribine to make an immune response. Saying this the summary of product characteristics of cladribine clearly states that live vaccines should be avoided until the immune system has reconstituted and the cells counts have returned to normal. Please note this refers to live vaccines and doesn’t apply to the currently licensed COVID-19 vaccines, which are not live attenuated vaccines or LAVs.

The good news is that the above predictions are being borne out by some real-life flu and VZV vaccine data in cladribine-treated patients that have been presented at ACTRIMS this week. My interpretation of this data is that regardless of when a vaccine is administered in patients on cladribine the appear to mount a good antibody response. I agree the number of subjects studied is small and no subject has had grade 4 lymphopaenia (<200/mm3), but these data at least confirm what you would expect to happen based on immunological principles.

My advice, therefore, remains the same for pwMS on DMTs; during the height of the pandemic having some immunity to SARS-CoV-2 is better than having no immunity. This is why you should get vaccinated ASAP. If you live in an environment where the background risk of COVID-19 is low then you may want to optimise the timing of your vaccine, when you are next dosed with an immunodepleting therapy or when you start or switch therapies.

Roy & Boschert. Analysis of Influenza and Varicella-Zoster Virus Vaccine Antibody Titers in Patients with Relapsing Multiple Sclerosis Treated with Cladribine Tablets. P059 – ACTRIMS 2021

Background: There is a lack of data available to determine the effect of cladribine tablets (CladT) on the antibody response to vaccination in patients with relapsing multiple sclerosis (MS).

Objectives: To investigate the immunoprotective response to seasonal influenza and varicella-zoster virus (VZV) vaccination in patients treated with CladT (3.5mg/kg over 2 years) for relapsing MS.

Methods: Blood samples collected during the MAGNIFY-MS study (NCT03364036) from 9 patients with relapsing MS treated with CladT who received seasonal influenza (n=8) or VZV vaccinations (n=1; Shingrix) as a standard of care were retrospectively analyzed. Two control blood samples (baseline sample before starting CladT and closest sample available just before vaccination) and two post-vaccination blood samples (closest sample available after vaccination) were examined. Quantitative antibody titers in response to the seasonal influenza and VZV vaccine were measured by hemagglutination inhibition (HAI) assay and Enzyme-Linked Immunosorbent Assay (ELISA), respectively. The seroprotection titer level for the seasonal influenza vaccine is considered ≥40, and was ≥100 IU/L for the VZV vaccine.

Results: Influenza: All patients vaccinated against influenza A and B during year 1 or 2 of CladT treatment retained seroprotection titers of ≥40 in post-vaccination samples across all strains present in the vaccine administered. The number of seropositive patients (HAI ≥40) with a ≥4-fold and ≥2-fold increase against at least 1 strain in post-vaccination titers were 3/8 and 7/8, respectively. VZV: Post-vaccination antibody titers were 40-fold increased over the protective titer at all time points (titers >4748 IU/L).

Conclusions: In this small retrospective investigation, post-vaccination antibody titers in patients treated with CladT for relapsing MS remained at levels that offer protective immunity against seasonal influenza and VZV.

Wu et al. Evaluating the Impact of Cladribine Tablets on the Development of Antibody Titers: Interim Results from The CLOCK-MS Influenza Vaccine Substudy. P071 ACTRIMS 2021

Background: Cladribine tablets have been approved in more than 80 countries for the treatment of relapsing forms of multiple sclerosis (RMS), and are hypothesized to function as an immune reconstitution therapy with potential to cross the blood-brain barrier. The CLOCK-MS study (cladribine tablets: collaborative study to evaluate impact on central nervous system biomarkers in multiple sclerosis), is a 24-month, open-label, randomized, multicenter, collaborative Phase IV biomarker research study. The COVID-19 pandemic, and pending vaccine availability, have raised important questions around the impact of MS disease modifying therapies on vaccine efficacy.

Objectives: To evaluate the potential impact of prior treatment with cladribine tablets on the development of antibody titres post-influenza vaccination via a sub-study of CLOCK-MS.

Methods: The CLOCK-MS main study will enroll approximately 50 subjects age 18-65, diagnosed with relapsing-remitting MS or active secondary progressive MS, who had inadequate response to, or were unable to tolerate, an alternate drug indicated for the treatment of RMS. Study participants who have taken at least one dose of cladribine tablets and are planning to obtain one standard-of-care influenza vaccine are eligible to take part in the sub-study if they consent to blood draws. Blood sampling will occur 1) 3 Weeks Pre-Vaccine (within 21 days prior to obtaining a standard of care vaccine), 2) 4 Weeks Post-Vaccine (+/- 7 days), and 3) 6 Months Post-Vaccine (+/- 7 days). Measurements of antibody responses will be performed.

Results: So far 5 patients have been enrolled in this sub-study and had initial titers drawn. All patients fulfilled the per-label requirements for vaccination after cladribine tablets treatment. Initial results at Week 4 post-vaccination will be presented.

Conclusions: The impact of cladribine tablets, a lymphocyte-lowering agent, on the immune system’s ability to develop antibodies in response to a vaccine has not yet been studied. These results are expected to provide preliminary observations around the impact of cladribine tablets on influenza vaccine efficacy in patients with RMS.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Barts-MS Livestream

A reminder that we are hosting the Barts-MS Question & Answer session on COVID-19 vaccines and our vaccination policy from 16h30-17h30 this afternoon. We will be live-streaming the event via YouTube. If you can’t watch the event live it will be recorded and remain available for asynchronous viewing at your leisure.

As of yesterday we had received 111 questions; too many to get through in an hour. However, there were many repeats. I will be joined by Prof K (Professor of Neurology), MD1 (mouse doctor and immunologist), Dr Saul Reyes (neurologist and MS vaccine expert), Joela Mathews (neuroscience pharmacist) and Andrea Stennett (neuro-physiotherapist).

CoI: multiple

Remyelination: why have we failed?

Barts-MS rose-tinted-odometer: ★

I sit on several steering committees and advisory boards for projects that are exploring remyelination or recovery of function as a treatment strategy in MS. Doing this allows you to think or groupthink, which has prompted me to consider whether remyelination in MS is necessary or not. I have been scratching my head about why in 2020 three remyelination strategies failed.

High-dose biotin (MedDay) – Effect of MD1003 in Progressive Multiple Sclerosis (SPI2) (ClinicalTrials.gov Identifier: NCT02936037)

Primary outcome: Proportion of patients Improved on either the EDSS or 25TW
Bexarotene (Cambridge University) – A trial to determine bexarotene’s safety and tolerability and its ability to promote brain repair in patients with multiple sclerosis (EudraCT number 2014-003145-99)

Secondary or remyelination outcome: Change in mean lesional MTR between month 0 and month 6 for lesions selected for each patient.
Opincinumab (Biogen) – Efficacy and Safety of BIIB033 (Opicinumab) as an Add-on Therapy to Disease-Modifying Therapies (DMTs) in Relapsing Multiple Sclerosis (MS) (AFFINITY) (ClinicalTrials.gov Identifier: NCT03222973)

Primary outcome: Overall Response Score, a multicomponent score based on 4 components: EDSS, T25FW, 9HPT in the dominant hand and non-dominant hand.

Have we the MS community made a fundamental mistake in assuming that remyelination is an ongoing persistent problem that needs fixing in MS? Have we got the biology wrong? Is biotin-dependent mitochondrial dysfunction and biotin-dependent remyelination pathways a problem in MS? Is the activation of retinoid X receptors (RXRs) to promote remyelination the correct target in MS? Is the inhibition of an inhibitor of remyelination with opicinumab (anti-LINGO-1) sufficient to promote remyelination across the central nervous system? At least with anti-LINGO-1 or opicinumab, there was proof of biology, i.e. the drug did improve conduction speed in demyelinated optic nerves.

Were the trial designs correct? For high-dose biotin, the population of pwMS was quite old with a lot of disability. Maybe the population was too old and hence ageing mechanism prevented any recovery of function from being detected. Maybe there was too much axonal or nerve loss and hence remyelination was doomed to fail.

Maybe focusing on the individual MS lesion with bexarotene using MRI techniques is too fickle? It is clear that in the bexarotene study there were too few new, presumably actively demyelinating, lesions to generate a signal.

The overall response score in the opicinumab trial may not be good enough to capture the recovery of function due to remyelination. The idea of using a composite score to detect recovery of function makes clinical and biological sense. However, using the limbs as the main read-out may not be sensitive enough. What about vision, cognition, balance, bowels, bladder, fatigue, etc. Do we need a better outcome measure? Do we have to go back to the drawing board with our clinical outcome measures?

Or is the answer staring us in the face? When you treat MS early with the big guns, i.e. alemtuzumab or HSCT, it is quite remarkable how many pwMS have spontaneous recovery of function. Are alemtuzumab and HSCT doing something fundamental to the pathogenesis of MS that then allows for spontaneous recovery of function? Are we curing a proportion of people with MS with these treatments?

One of the latest theories that is being tested in MS is that because of premature ageing and senescence the oligodendrocyte precursors and oligodendrocytes (myelin-producing cells) can’t function properly. The solution is to reprogramme them, i.e. dial back the ageing clock by using diet (caloric restriction, intermittent fasting or ketosis) and/or medication (e.g. metformin or fumarates) before hitting them with drugs to stimulate myelin formation. The latter is backed by animal data, but will it work in MS? Possibly; however, this is based on the assumption that the tools we have for measuring remyelination in pwMS actually work.

The danger with all these strategies is tossing the baby out with the bathwater, i.e. once a trial is negative with a compound it is very rare that the community goes back to the compound or biology. So we need to be confident that our methods are sound and reliable. I am not sure we can be that confident after the three failures above.

Another aspect that is lacking in all our trials is neurorehabilitation, i.e creating the biological stimulus to promote recovery of function. Nobody would perform a spinal cord injury recovery of function trial without active rehabilitation on top of the treatment being tested. The latter is backed up by sound science and compelling animal studies. Why do we in the MS community expect spontaneous recovery of function without rehab? If you don’t use it you lose it! To encourage the recovery of function you need to stress the pathway. I thought this concept would be a no-brainer, but I have yet to convince one Pharma company to add-on a rehab programme to their recovery of function trials.

Maybe instead of trying to promote remyelination and recovery of function in pwMS, our aim should be to treat MS effectively early on, i.e. to prevent the need for remyelination therapies in the first place? The question is how do we get the wider MS community to promote the use of alemtuzumab and HSCT, or similar agents, as the default first-line therapy for MS? Some of us have tried, including me, but have failed miserably with this seemingly easy task. By the time most pwMS get to alemtuzumab or HSCT, they have so much damage that they need restoration therapies.

As we think we now know the potential cause of MS trying to put out a fire without correcting the upstream pathology is folly. Therefore maybe we should only be trying remyelination and neurorestorative therapies in people who have stable fixed deficits, with no ongoing evidence of any inflammatory disease activity, post alemtuzumab or HSCT? The irony of letting pwMS become disabled before being treated with alemtuzumab or HSCT is inadvertently creating a trial-ready population of subjects for remyelination therapy trials.

I encourage thoughts or counter arguments on the above. Let’s have an open discussion and debate on the points I have raised in this post. I think we need to answer some fundamental questions about remyelination and neurorestorative therapies before we spend more money on futile trials and throw the baby out with the bathwater.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: Vaccine Q&A page is now live

Barts-MS rose-tinted-odometer: ★★★★★

Just to let you know that the I have answered all the reasonable questions that have come in via the COVID-19 decision aid. To keep it simple and to allow me to be more responsive I will simply update the online document every day or so. This is similar to what I did with the MS-Selfie Microsite I ran for at the beginning of the pandemic.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: Vaccine Decision Aid ver. 2.0

Barts-MS rose-tinted-odometer: ★★★★★

Thank you for the feedback on my rough-and-ready decision aid. It is clear there is a need for it. I have spent a bit of time adding DMT-specific pages to the aid and added sections on ‘Which vaccine?’ and ‘Pregnancy’. I have also added a page with useful links. I have also set the sound to be on-demand rather than being automatic; so you need to click on the icon if you want to hear me talk to the question or topic on a specific slide.

Please note this is still a beta version, albeit version 2.0, using the Google Slide’s technology as an easy-to-use platform for prototyping. I will continue to update the decision aid as questions come in. The survey results are quite telling in that you prefer a text document in a downloadable format and a web application. Now I need a grant to be able to pay our ClinicSpeak design team to make this beautiful and more user-friendly.

Your feedback is very much appreciated so keep the comments coming in. Thanks.

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

#MSCOVID19: What is vaccination?

Barts-MS rose-tinted-odometer: ★★★★★

What is vaccination? A not so simple medical procedure.

Vaccination is probably one of, if not, the most important scientific/medical inventions in modern history. We need to celebrate it for just that and appreciate the number of saved lives and improved quality of life it has brought to us as a species.

Now that we broadly know how the immune system functions there is nothing magic, dark or sinister about vaccines and vaccinations work.

Vaccines simply hijack components of the immune system and fool it into thinking you are being invaded by something foreign and dangerous, e.g viruses, bacteria, parasites, toxins, cancers or foreign bodies. The immune system reacts to the vaccine and rejects the foreign component in the vaccine, but in doing so the immune system remembers the foreign component so in the event of being exposed to it again in the future it can respond to it quickly and prevent it causing too much damage, i.e. disease or some cases death.

The immune system is primarily responsible for keeping us safe from infectious agents, i.e. parasites (e.g. malaria), bacteria (e.g. pneumococcus) and viruses (e.g. coronaviruses), toxins and cancer. Immune systems are endowed with the ability to remember a previous exposure to an infectious agent.

Immunological memory is hardwired into our DNA, which includes so-called pathogen-associated or damage-associated recognition receptors (PAMPs or DAMPs). PAMPs and DAMPs are part of our innate immunity and provide a very rapid response to infections. However, as there is an arms race between our immune system and the pathogens, which can mutate and evolve very quickly (e.g. the UK/Kent, South African and Brazilian variants of SARS-CoV-2), we have had to evolve a second or an acquired memory system called adaptive immunity. The latter involves both B-cells or antibodies and T-cells or killer cells that are able to destroy the pathogen using highly targeted mechanisms that in most people don’t cause collateral damage to the body.

All that a vaccine does is expose the immune system to a part of the whole of the pathogen in the correct context so the immune system remembers the pathogen so that when it is exposed to the pathogen in real-life it can mount a rapid immune response, which prevents you becoming infected and spreading the organism, or prevents you from getting a severe disease or dying from the infection.

Now there are many different ways of fooling the immune system into remembering the organism. In the past, we used to use related, but benign, viruses. For example, immunity to cowpox, a live virus from cows, cross-reacted with the more dangerous and severe smallpox virus to protect milkmaidens from getting smallpox. This is how Jenner identified and created the original smallpox vaccine. Following Jenner’s smallpox vaccine, the scientific community developed the ability to attenuate viral and bacterial strains in the laboratory, i.e. to create mutant strains that didn’t cause disease, but were similar enough to the original organism to generate a protective immune response. This is how the medical community tackled polio, measles, mumps, rubella, TB, yellow fever and influenzae. This group of vaccines are referred to as LAVs or live-attenuated vaccine strains.

The problem with LAVs is that the organisms have the ability to mutate back to being dangerous and can cause vaccine strain outbreaks, which has happened many times with the oral polio vaccine. This is why LAVs have in general fallen out of favour. I am not aware of any LAVs being developed for coronavirus; mainly because it is an outdated technology.

Another way of developing vaccines is to grow the organism in the laboratory and then inactivate or kill them and then to administer either the whole killed organism or a part of it as a vaccine. This is how the seasonal flu virus is currently made. The current circulating strains are cultured in chicken eggs and then the eggs are broken and processed to extract the important surface proteins to go into the vaccine. One of the Chinese vaccines that is currently been tested in COVID-19 uses the whole SARS-CoV-2 virus as an immunogen.

The term immunogen simply refers to the component of the vaccine you want the immune system to respond to, for example, the spike or surface protein on the coronavirus. When we make vaccines that only have one or a limited number of immunogens we call this a component vaccine.

Now that we have developed so recombinant protein technology we don’t have to culture live and often very dangerous organisms, but instead engineer other organisms to make the immunogen in large quantities. To do this we alter the genomes of bacteria, mammalian cells, whole animals or even plants to make the protein we want. For example, we can use E. coli bacteria, Chinese hamster ovarian cells, monkey cells or even insect cells to make proteins. The choice of the type of cell is important as many immunogens have sugar molecules on them and cells from different species add sugar molecules in different configurations and combinations. E. coli, for example, does not have the necessary molecular pathways to add sugar molecules to proteins.

A, relatively, new technology is to create genetically modified whole complex organisms that produce your protein of choice. One vaccine company has created a tobacco plant that produced the protein for the hepatitis B vaccine. You then grow the tobacco plant and extract the hepatitis B surface antigen from tobacco leaves. Another company has created a breed of goat that expresses and produces the vaccine immunogen in breast milk. All you have to do is milk these goats and extract the immunogen from their milk.

Many of the SARS-CoV-2 component vaccines are using standard cell-based methods to produce vast quantities of the immunogen, which at present are mainly targeting the SARS-CoV-2 spike protein. The recent positive Novavax coronavirus vaccine is using spike protein manufactured using insect cells.

Component vaccines are not that immunogenic unless they are combined with an adjuvant. Adjuvants are substances that enhance the immune system’s response to the vaccine. Adjuvants are often referred to as the immunologist’s dirty little secret. The reason for this is we simply didn’t know how many of the early adjuvants worked. This is not the case anymore and the newer generation of adjuvants that are being used in component vaccines are well defined in terms of their mode of action and are safe.

Some scientists have used molecular biology to engineer other relatively benign viruses so that they make immunogens of other viruses. Instead of making the protein in the laboratory, you produce infectious viruses, that then make the protein in your body. You infect people with these engineered viruses, which are also called vectors, as part of the benign infection your own cells make the protein or immunogen that your immune system then responds to.

Vaccinia virus used to be the most commonly used virus, but vaccinologists have moved onto adenovirus one of the viruses that cause the common cold. The Russian sputnik COVID-19 vaccine uses a human adenovirus as the vector. The Oxford-AstraZeneca vaccine uses a chimpanzee adenovirus vector. The problem with using these types of vaccines is that if your immune system has seen the virus in the past, i.e. from natural wild-type viral infection, your immune system reacts to and rejects the vaccine virus before it can infect enough cells to make the necessary quantity of immunogen to be effective. This is why the Oxford-AstraZeneca vaccine uses a chimpanzee adenovirus, which humans are unlikely to have been exposed to in the past. The immune response to the vector itself has implications for booster and additional vaccine using the same technology; i.e. it is likely that boosters and new vaccines using the same vector will be less effective in the future, because of immunity against the vector itself.

Please note these viral vector vaccines are relying on the virus to infect cells and then use the cells own machinery to manufacture the immunogen. Because these vaccines are an actual infection these vaccines don’t need adjuvants. The final trick with these viral vector vaccines is to create disabled viruses, i.e. viruses that lack the ability to replicate and cause ongoing infection. This is important to prevent the viral vector itself causing an infection in the host or recipient of the vaccine. This is also the reason why the Oxford-AstraZeneca vaccine is not referred to as a live viral vaccine.

Finally, why waste time with viruses and simply give the viral message without the virus. This is how DNA and RNA vaccines work. You package the necessary code for the immunogen in a DNA plasmid or piece of RNA that is then transcribed into the necessary proteins to induce an immune response.

Do RNA and DNA vaccines need adjuvant? The cell sees foreign RNA itself as being foreign as being potentially from a virus, which acts via internal danger signalling pathways to alert the immune system to the possibility of an infection. The DNA vaccines incorporate segments of DNA that fool the cell into thinking this DNA is from a bacterium, which also stimulates specific danger signalling pathways telling the immune system there is an infection. This is why RNA and DNA vaccines don’t require additional adjuvants.

Please be aware that adenoviral vaccines, such as the Russian Sputnik and the Oxford-AstraZeneca vaccines, the DNA vaccine and the RNA vaccines don’t contain the code for manufacturing the necessary enzymes that insert DNA into the genome. The latter is unique to so-called retroviruses such as HIV. Therefore, these coronavirus vaccines don’t affect the human genome and won’t affect the germline, i.e. DNA transmitted via the eggs in the ovary of the sperm in the testes. All that these vaccines do is highjack the cells protein synthesis machinery to make SARS-CoV-2 spike protein and to tell the immune system that there is an infection. This then allows the immune system to make both B-cell or antibody and T-cell responses to coronavirus and protect that individual from being infected or becoming ill from wild-type infection.

I want to stress that the short summary above represents centuries of research and discovery and that vaccinology is now using cutting edge molecular biology. The rapid development of the DNA, RNA and adenoviral vector vaccines have changed vaccine development for good and I anticipate these becoming the norm for future vaccines.

I hope the above summary explains how vaccines have developed and debunks the myths about what they are and how they work. Instead of us accepting off-the-wall conspiracy theories about vaccines and what they do please join me in celebrating their success and what they offer mankind.

One of my driving ambitions is to see an EBV vaccine licensed to prevent MS. If you and the general population are not prepared to trust vaccines and the science behind their development, who is going to want their child to have an EBV vaccine to prevent MS, infectious mononucleosis and many different types of EBV-associated cancers?

CoI: multiple

Twitter: @gavinGiovannoni Medium: @gavin_24211

Prof G's MS Blog Archive

#MSCOVID19: transverse myelitis is not a reason to avoid being vaccinated

Prof G guilty as accused!

#MSCOVID19: specifically for NHS England

#MSCOVID19: cladribine is being unfairly tarnished with alemtuzumab’s brush

Barts-MS Livestream

Remyelination: why have we failed?

#MSCOVID19: Vaccine Q&A page is now live

#MSCOVID19: Vaccine Decision Aid ver. 2.0

#MSCOVID19: What is vaccination?