Immunosuppression and COVID-19 Boosters

It is important people receiving immunosuppressive therapy are provided with the best protection against COVID-19 because they are at greater risk of severe illness should they become infected. As severe immunosuppression can reduce the efficacy of COVID-19 vaccination, doctors agree that COVID-19 boosters is are important to maximise the vaccine response in these people. However, we don't currently know the best time to give booster vaccines to people about to start immunosuppressive therapy. This research aims to address this knowledge gap by examining whether the greatest protection is provided by giving the COVID-19 booster just before the immunosuppressive therapy starts or by waiting and giving the booster 6 months after treatment start. At the 6-month timepoint, in many cases the more intensive immunosuppression is often weaning and the immune system is starting to rebuild.

Current guidelines for SARS-CoV2 vaccination in immunosuppressed populations are based on limited evidence. Additionally, guidelines for the use of SARS-CoV2 vaccines in autoimmune populations are somewhat contradictory, with the 2019 European League Against Rheumatism (EULAR) recommendations including advice to where possible administer booster vaccinations prior to commencing immunosuppression but to preferably vaccinate while the autoimmune disease is not active. In haematological conditions it is suggested that vaccination occur prior to B cell depletion therapies e.g. rituximab, or \>6 months after its use. While these guidelines were developed for non-live vaccines in general, the evidence for COVID-19 vaccines is almost entirely based on expert opinion. Clearly, with these gaps and inconsistencies in the clinical guidelines there is equipoise for the optimal timing of a booster vaccination. One of the difficulties in this field is the wide diversity of patients receiving a variety of immunosuppressive therapies. We have therefore taken a pragmatic 'real-world' approach in our design by focusing on two broad patient groups that are more specifically stratify based on pre-define disease conditions and specific treatments. Recent data studying COVID-19 vaccine responses in patients on immunosuppressive therapies for autoimmune/inflammatory conditions demonstrate the greatest compromise in anti-Spike IgG occurs in those receiving combination immunosuppression particularly regimens that include methotrexate and other antimetabolites, and B cell depleting therapies. In patients with haematological malignancies the lowest vaccine responses were seen in chronic lymphocytic leukaemia, lymphoma and multiple myeloma. In patients with a haematological malignancy who have undergone a bone marrow transplant, immunisation to COVID-19 \<6 months following transplantation resulted in poor IgG response to vaccine, while those immunised \>6 months post-transplant had superior responses. In contrast, other targeted therapies including the integrin inhibitor vedoluzimab or anti IL-17/23 therapy (in the absence of concurrent methotrexate) have relatively preserved response to the initial vaccine regimen. Given the available data, we propose to study defined populations of two major immunosuppressed patient groups: Group 1): Haematological Malignancy (excluding bone marrow transplant recipients) and Autoimmune/Inflammatory Disease, and Group 2: Autologous and Allogeneic Bone marrow transplant (BMT) recipients. We will compare the difference between an immediate COVID-19 "booster" dose and a deferred COVID-19 "booster". In Group 1 "Immediate" is defined as prior to the commencement of moderate-to-severe immunosuppression and "Deferred" is defined as 6 months post commencement of moderate-to-severe immunosuppression. For Group 2 BMT patients, current national guidelines recommend 3 doses of pre-BMT COVID-19 vaccines followed by 3 doses of post-BMT COVID-19 vaccin trial.show_full_description

Inclusion Criteria: * Adult aged at least 18 years * Previously vaccinated with 2 (or more) doses of any licensed COVID-19 vaccine who requires initiation of moderate-to-severe immunosuppression; most recent COVID-19 vaccine dose must have been given \&gt; 3 months prior * Planned significant immunosuppressive therapy for at least 1 year * No cyclophosphamide, alemtuzumab or rituximab treatment in the past 5 years. Note: patient may have concurrent steroids with any treatments listed in protocol * Voluntarily given written informed consent Exclusion Criteria: * Pregnant or breastfeeding * Has underlying primary immunodeficiency * Has received or likely to receive intravenous/subcutaneous immunoglobulin (IVIg/ScIg). * Projected treatment is likely to involve plasma exchange * Contraindication to receipt of SARS-CoV-2 vaccine * Intolerance of or previous allergic reaction to tetanus vaccination * Patients switching immunosuppressive therapies following enrolment with an absolute lymphocyte count \&lt;0.5 x 109/L immediately prior to screening