Lumping the immunosuppressed together gives a good result, drill down and there are too few of the problematic groups to raise alarm bells for the bean counters. More data reporting seroconversion problems with anti-CD20 but again a T cell response.

L

The government has done some mega studies on immunosuppressed people but their focus is on cancer and solid cancers and the message comes back that most people seroconvert. This allows the bean counters to be happy, but it tells me that as we move forward, we should focus attention on anti-CD20 treated individuals for MS. Whether the scientists can do this I wonder as they focus on their area of interest. In this paper they call for further vaccination strategies. I agree they need to sort out the anti-CD20 conundrum and do this quickly before every one starts their booster jab. This is important because we know that protective vaccination responses wane with time.

Indeed yesterday (1:9:2021) the JCVI said that immunosuppressed people will be offered a third dose. They said “Preliminary results from UK studies of real-world vaccine effectiveness (VE) in persons who are immunosuppressed suggest only a modest reduction in VE against symptomatic COVID-19, but confidence intervals are wide and overlap with VE estimates for persons who are not immunosuppressed”…..However there is a potential issue and that issue was that in their studies there were not enough people with MS and importantly they good news does not extend to anti-CD20 depletion,

They say

Individuals on immunosuppressive or immunomodulating therapy at the time of vaccination including:

  • those who were receiving or had received immunosuppressive therapy for a solid organ transplant in the previous 6 months
  • those who were receiving or had received in the previous 3 months targeted therapy for autoimmune disease, such as JAK inhibitors or biologic immune modulators including B-cell targeted therapies (including rituximab but in this case the recipient would be considered immunosuppressed for a 6-month period), T-cell co-stimulation modulators, monoclonal tumour necrosis factor inhibitors (TNFi), soluble TNF receptors, interleukin (IL)-6 receptor inhibitors, IL-17 inhibitors, IL 12/23 inhibitors, IL 23 inhibitors (note: this list is not exhaustive)
  • those who were receiving or had received in the previous 6 months immunosuppressive chemotherapy or radiotherapy for any indication

For those aged 18 years and over, JCVI advises a preference for mRNA vaccines for the third primary dose, with the option of the AstraZeneca Vaxzevria vaccine for individuals who have received this vaccine previously where this would facilitate delivery.

In general, vaccines administered during periods of minimum immunosuppression (where possible) are more likely to generate better immune responses. The third primary dose should ideally be given at least 8 weeks after the second dose, with special attention paid to current or planned immunosuppressive therapies guided by the following principles.

Where possible, the third primary dose should be delayed until 2 weeks after the period of immunosuppression, in addition to the time period for clearance of the therapeutic agent

Re-vaccination with a 2-dose schedule should be considered 3 to 6 months post autologous and allogeneic human stem cell transplant or CAR-T therapy. A third primary dose of vaccine should be administered at least 8 weeks after the second dose (in line with the advice above).

Now the one that I do not understand

Most individuals whose immunosuppression commenced at least 2 weeks after the second dose of vaccination do not require a third primary dose at this stage. Alongside those with lower levels of immunosuppression, they are likely to become eligible for a booster dose as part of a routine booster programme from around 6 months after the second dose, pending further advice.

So the UK is not following the dosing schedule in the USA

Finally they say “To optimise vaccine use, specialists should take responsibility for providing clear advice to the patient’s general practitioner about the need for a third primary dose of vaccine and the optimal timing“.

What is the advice?

Kearns, Pamela and Siebert, Stefan and willicombe, michelle and Gaskell, Charlotte and Kirkham, Amanda and Pirrie, Sarah and Bowden, Sarah and Magwaro, Sophia and Hughes, Ana and Lim, Zixiang and Dimitriadis, Stavros and Murray, Sam M. and Marjot, Thomas and Win, Zay and Irwin, Sophie L. and Meacham, Georgina and Richter, Alex G. and Kelleher, Peter and Satsangi, Jack and Miller, Paul and Rea, Daniel and Cook, Gordon and Turtle, Lance and Klenerman, Paul and Dunachie, Susanna and Basu, Neil and de Silva, Thushan I. and Thomas, David and Barnes, Eleanor and Goodyear, Carl S. and McInnes, Iain, Examining the Immunological Effects of COVID-19 Vaccination in Patients with Conditions Potentially Leading to Diminished Immune Response Capacity – The OCTAVE Trial. Available at SSRN:  http://dx.doi.org/10.2139/ssrn.3910058

SARS-COV-2 vaccines have been shown to be efficacious primarily in healthy volunteer populations and population level studies. Immune responses following SARS-CoV-2 vaccination are less well characterised in potentially immune vulnerable patient groups, including those with immune-mediated inflammatory and chronic diseases (inflammatory arthritis [IA] incorporating rheumatoid arthritis [RA] and psoriatic arthritis [PsA]; ANCA-Associated Vasculitis [AAV]; inflammatory bowel disease [IBD]); hepatic disease (HepD), end stage kidney disease requiring haemodialysis (HD) without or with immunosuppression (HDIS); solid cancers (SC) and haematological malignancies (HM), and those that have undergone haemopoietic stem cell transplant (HSCT).

The OCTAVE trial is a multi-centre, multi-disease, prospective cohort that will comprehensively assess SARS-CoV-2 vaccine responses within and between the abovementioned disease cohorts using common analytical platforms in patients recruited across the United Kingdom (UK). The majority of subjects received either COVID-19 mRNA Vaccine BNT162b2 (Pfizer/BioNTech) or ChAdOx1 Vaccine (AstraZeneca formerly AZD1222) as part of the UK National COVID19 vaccination programme. As of 13 th August 2021; 2,583 patients have been recruited.

We report herein the humoral and T cell immune response results from the first 600 participants recruited where serology data are available at baseline, pre-second vaccine dose (boost) and/or 4 weeks post second dose. We also include in the analysis, data obtained from 231 healthy individuals from the PITCH (Protective Immunity from T cells in Healthcare workers) study. Overall, in comparison to PITCH where 100% of tested individuals (n=93) generated anti-Spike antibodies after vaccine doses, 89% of patients within OCTAVE seroconverted 4 weeks after second vaccine dose. (Here is the problem by lumping everyone together there maybe to few problem child diseases) By corollary, approximately 11% of patients across all disease cohorts fail to generate antibodies that react to SARS-CoV-2 spike 4 weeks after two vaccines. Failure to generate spike reactive antibodies was found at a higher proportion in some specific patient subgroups, particularly AAV (72.4%), HD-IS (16.7%) and HepD (16.7%). Importantly, all recruited AAV patients had received Rituximab; a targeted B cell depletion therapy. Furthermore, even in those who seroconverted, 40% of patients across disease cohorts generate lower levels of SARS-CoV-2 antibody reactivity compared to healthy subjects after two SARS-CoV-2 vaccines; the functional significance of these findings in providing protection from subsequent SARS-CoV-2 exposure is not currently known. In contrast to the observed serological response, evaluation of the Spike-specific T cell response revealed that across all patient sub-groups (including AAV) a response similar to healthy individuals was generated. Our data argue strongly for further vaccination strategies to optimise humoral immune responses against SARS-CoV-2 in patients with chronic diseases and/or patients on immune suppressive therapies.

However fear not………the Americans are coming to the rescue because they have seen the same light as me

NIH launches study of extra COVID-19 vaccine dose in people with autoimmune disease

The US National Institutes of Health (NIH) has begun a clinical trial to assess the antibody response to an extra dose of an authorised or approved coronavirus disease 2019 (COVID-19) vaccine in people with autoimmune disease who did not respond to an original COVID-19 vaccine regimen. The trial will also investigate whether pausing immunosuppressive therapy for autoimmune disease improves the antibody response to an extra dose of a COVID-19 vaccine in this population.

The NIH noted that “researchers have reported higher rates of severe COVID-19 and death in people with autoimmune disease than in the general population,” and that “it is unclear whether this is attributable to the autoimmune disease, the immunosuppressive medications taken to treat it, or both.” 

“The recent findings in solid organ transplant recipients also suggest that an extra dose of a COVID-19 vaccine may help some people with autoimmune disease who take certain immunosuppressive medications.”

The trial, called COVID‐19 Booster Vaccine in Autoimmune Disease Non‐Responders, initially will include people with one of five autoimmune diseases: multiple sclerosis, pemphigus, rheumatoid arthritis, systemic lupus erythematosus or systemic sclerosis. The immunosuppressive therapies commonly taken by people with these diseases have been associated with poor immune responses to vaccines.

The study team will enroll approximately 600 participants ages 18 years and older at 15 to 20 sites nationwide. Participants must have had a negative or suboptimal antibody response to two doses of the Moderna COVID-19 vaccine, two doses of the Pfizer-BioNTech COVID-19 vaccine, or one dose of the Johnson & Johnson COVID-19 vaccine, all received prior to enrollment. Participants also must be taking one of three immunosuppressive therapies: mycophenolate mofetil (MMF)/mycophenolic acid (MPA), methotrexate (MTX), or B cell- depleting drugs.

According to the NIH, all participants will receive an extra dose of the same COVID-19 vaccine as they received originally. Further, those participants who are taking MMF/MPA or MTX will be assigned at random either to continue taking their immunosuppressive medication without alteration or to pause taking their medication for a short period before and after receiving the extra vaccine dose

“The main goal of the study is to determine the proportion of participants who have a significantly better antibody response four weeks after receiving the extra vaccine dose than they did after their original vaccinations,” the NIH noted, adding that “study participants will be followed for a total of 13 months” and “preliminary results are expected in November 2021.”Reference: https://www.nih.gov/news-events/news-releases/nih-launches-study-extra-covid-19-vaccine-dose-people-autoimmune-diseaseSOURCE: National Institutes of Health

This is good news but they have missed an opportunity not to test delaying the dosing of anti-CD20, because the data in cancer says that the non-responsive CD-20 depleters remain non-responsive

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.

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MouseDoctor

19 comments

  • What do think of approach taken by Texas: a statewide seroprevalance study on the human antibody response to the coronavirus to determine # affected in population, how long antibodies last in body, and type of people who don’t develop antibodies.? It think it is funded by the state’s department of health and federal Covid relief funds. The public is given incentive to participate with offer of free semi-quantitative Covid spike test and Covid natural induced antibody test. This is an effective carrot here because spike vaccine antibody tests are not easy to access. The survey includes questions about immune disorders and immune suppressants but doesn’t parse out types of immune suppressants. (Missed opportunity???) A possible unexpected surprise is the participant is not only getting antibody results but also a compilation of all their personal health laboratory tests from prior 7 years. It’s presented in a user friendly detailed dashboard but it’s a large privacy waiver to get antibody results. I hope organizers of this study maximize the windfall of health data it gets out of study. Link to Texas CaREs study info https://sph.uth.edu/projects/texascares/

    • The UK government can answer ths as quick as you like they have been testing 250,000 people once a month…the carrot I get is £25 a pop to spend. It is a pain doing 500mL bleeds witha finger prick…

      • I’m presuming you meant microlitres not millilitres? Getting 500 mls from a finger prick doesn’t bear thinking about! 😉

  • I see Javid has announced (at 9 pm over twitter) that SEVERLEY immunocompromised will be offered a third covid jab. Is being on Ocrevus considered as being severley immunocompromised or not do you know?

    • Yes, anti-CD20 therapies are considered in this class. The problem is when to have the jab? I am now beginning to recommend delaying anti-CD20 treatment to allow some B-cell reconstitution for booster vaccine responses.

      • That’s good news. Would it be possible to know how long a delay are you recommending and/or will it be based on B cell monitoring? I’m due ocrelizumab at the end of September and so timings will already be tight unless I move it back. All thoughts would be very welcome. Thank you

        • There’s really no way to know without b cell testing to confirm that some have come back.

          The question I have is how frequent we should test for them?

        • Same dire question here – 1 month overdue for Ocrevus and I’ve delayed until end of September in hopes high level of community spread will flatten some. (Note High spread in my area is due to low vaccination rate and non masking population that strongly believe individuals have civil liberty right to choose what to do to their own body regardless of potential harm to others….) As a pwms immune compromised person at risk for serious Covid infection or death at least I can take comfort in knowing how strongly my fellow Texans feel about personal choice and liberties.

        • the problem with B cell monitoring is that there seems to be a severe shortage of blood vacutainer tubes in the UK, so could they even give us tests to monitor?

      • My last dose of ocrevus was May, when would you advice getting the 3rd booster. I had 2x AZ 7 months post ocrevus infusion but still tested negative for vaccine antibodies. When would you think it would be best to take the booster vaccine?

        • Good question and it is clear that there is no magic answer, there are people years from infusion that have no response. It seems to depend when your B cells come back for some that doesnt happen after twelve months but 7 months late is unlucky. AZ vaccine is also part of the problem it doesnt give a big response compared to others

      • I got the letter today of the write-up on phone convo with the MS nurse re being in no more danger that anyone else (on Ocrevus) from about a month ago. I joked to hubby that nurse has been very kind in sending me written proof she’s told me to get out and about in a pandemic, on Ocrevus. I almost copied the letter + put it on line to show how flipping dangerous her advice is. My next Ocrevus is next week. No word from consultant tells me they obviously think it’s ok to go ahead. If I don’t turn up, would they give me OCr in a few months, or will I have blown my chances of more treatment. What a blimming quandry to be in

        • I’ve been advised to start fingolimod following relapse. I was advised by neurologist that it was perfectly safe to work with public whilst on it. He also informed me that all dmts have rebound, that was his complete answer when I asked him about fingolimod rebound.
          Am baffled!! Upset!! Head in a whirl!!
          What to believe & what to do?

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