Comparison of Immunity-boosting Regimens for COVID-19 Upon Initiation of Immunosuppressive Therapy

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 vaccines initiated 6 months post-BMT. In Group 2 "Immediate" is defined as 6 months post-BMT and "Deferred" as >12 months post-BMT.

The primary endpoint will be the integrated area under the curve (AUC) of anti-SARS-CoV-2 neutralizing antibody (NAb) activity over the first year of immunosuppression. At present the level of anti-SARS-CoV-2 is the most robust correlate of protection against COVID-19. In both study Groups the comparator of a delayed boost at 6 months is based on the premise of maximising peak NAb responses by administering the booster after induction therapy is completed. Such a delay must be weighed against the risk of reduced immunity and breakthrough COVID-19 infection during this period. Such a risk will be monitored closely during the study with scheduled interim safety analyses and reviews by an independent data safety monitoring board (DSMB).

Participants in Group 1 will also receive a single diphtheria/tetanus (dT) toxoid booster as a comparator vaccine with the aim of determining whether the results of the optimal timing of the COVID-19 booster also apply to more traditional protein vaccines. If this is found to be the case, the results of this study may have broader implications for the vaccinology field and optimal clinical guidelines.

Primary Objective: to determine the anti-SARS-CoV-2 NAb response over 12 months from a booster with a SARS-CoV2 vaccine over 12 months in a population who; Group 1: are commencing moderate-to-severe immunosuppression for treatment of either a haematological malignancy (excluding BMT patients) or an autoimmune/inflammatory condition and are previously fully-immunised (i.e. had received 3 or more doses of a SARS-CoV-2 vaccine including combinations) or, Group 2: have recently undergone a bone marrow transplant for a haematological malignancy and have previously received 3 post-BMT doses of a SARS-CoV-2 vaccine including combinations.