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,
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.