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.

We will determine the difference between the booster being administered as follows: Group
1: immediately prior to starting moderate-to-severe immunosuppression or at 6 months
after therapy start, by monitoring the relative sustained immunogenicity over 1 year.
Group 2: immediately at 6-months post-BMT or deferred until >12 months post-BMT.

Secondary Objectives:

1. To assess a range of secondary immunological endpoints including:

1. . To quantitate antibodies to tetanus toxoid integrated over the 12-month
period post-randomisation.

2. . To assess the safety and efficacy of the two approaches (immediate or
deferred vaccination) including any indication of vaccine-induced disease
flares and any breakthrough infections with SARS-CoV-2.

3. . To analyse the response to the SARS-CoV2 vaccine including: i. Breadth of NAb
against the SARS-CoV-2 variants of concern (VOC) ii. The kinetics of
neutralizing antibody over time including responses to VOC iii. Memory T cell,
B cell and natural killer (NK) cell responses to peptide sets representing
different domains of the SARS-CoV-2 spike protein

2. To assess these responses in populations stratified by broad disease type (i.e.
haematological malignancy (excluding bone marrow transplant recipients),
autoimmune/inflammatory disease or haematological malignancy post-BMT and different
modes of immunosuppression e.g. chemotherapy, bone-marrow transplant, B-cell
depleting therapies, cytokine inhibition.

3. To use a computational biology approach to a) model the level of protection over
time based on neutralizing antibody levels and b) model the boosting and decay of
anti-Spike IgG, specific memory B, T and NK cell response to provide information on
the impact of immunosuppression on vaccine protection over time.

4. To use this evidence-base to inform policies regarding timing of additional
SARS-CoV-2 boosters in vulnerable populations about to commence immunosuppression/or
following bone marrow transplant. These findings will identify those patient groups
most appropriate for synthetic COVID-19 monoclonal antibodies and will contribute to
our understanding of vaccinology in the setting of immunosuppression and BMT more
broadly, an area that remains poorly understood.

5. To compare the change in health-related quality of life over time between
"immediate" and "deferred" booster strategies.

Participant population

Participants will be recruited through a clinical network of specialist physicians at
Sydney hospitals who will be recruiting from their Departments of Haematology,
Immunology, Rheumatology, Gastroenterology and Neurology. A total of 320 participants
will be enrolled into one of two Groups will be enrolled as outlined below:

Group 1: will comprise 280 participants commencing immunosuppression for the management
of a pre-defined group of haematological malignancies (excluding bone marrow transplant
recipients) or autoimmune/inflammatory conditions as outlined below Group 2: will
comprise 40 participants who have undergone a bone marrow transplant for a haematological
malignancy as outlined below.

Group 1:

Haemato-Oncology: Haematological Malignancy (excluding bone marrow transplant recipients)
- B-CLL; Follicular or Marginal Zone Lymphoma; Multiple Myeloma; Diffuse large B-cell
lymphoma

Systematic Autoimmunity: to include: ANCA associated-vasculitis; polyarteritis nodosa;
Churg-Strauss syndrome; ankylosing spondylitis; autoimmune hepatitis; IgG4 disease;
inflammatory bowel disease; psoriatic arthritis; psoriasis; rheumatoid arthritis;
systemic lupus erythematosus; Sjogren's syndrome; myasthenia gravis; and multiple
sclerosis. Receiving the following agents:

B-Cell Depletion therapies e.g. rituximab, ocrelizumab, ofatumumab (N=40) Anti-metabolite
therapies: azathioprine, calcineurin inhibitors, mycophenolate or methotrexate (Moderate
Immunosuppression) (N=40) Tumour necrosis factor alpha inhibition (N=40) (with or without
azathioprine or methotrexate or leflunomide to prevent anti-drug antibodies)
Cyclophosphamide or alemtuzumab (severe immunosuppression) (N=40) Janus Kinase (JAK)
inhibitors +/- leflunomide (N=40) Anti-IL-17 and/or 23 monoclonal antibodies e.g.
sekukinumab (N=40).

Group 2:

Bone Marrow Transplant (N=40) Haematological malignancy - autologous or
allogenic-transplant (excluding for treatment of a primary Immunodeficiency).

Study Design

This is a randomised, open-label, multi-centre clinical trial to be conducted over 52
weeks.

Participants will be enrolled into one of two Groups as described above. Group 1
participants will be screened to confirm their diagnosis and that they are to commence
treatment that involves >1 year on moderate-to-severe immunosuppressive therapy.
Participants will be randomised in a 1:1 ratio to either Arm A; Immediate SARS-CoV-2
booster at week 0 and a booster of combined diphtheria toxoid/tetanus toxoid (dT vaccine)
at 24 weeks, or Arm B; dT vaccine at week 0 and a deferred SARS-CoV-2 booster at 24
weeks. Participants will be followed until week48 and attend study visits at screening,
randomisation, vaccination* and then at weeks 1, 4, 12, 24, 25, 28, 36 and 48.

Group 2 participants will be screened and randomised in a 1:1 ratio to either Arm C;
Immediate SARS-CoV-2 booster at week 0 or Arm D delayed SARS-CoV-2 booster at 24 weeks.