There is an urgent need to determine the immunogenicity and safety of COVID-19 vaccines in people living with rheumatic disease on immunomodulatory therapies. Given the experience with influenza, pneumococcal, shingles, and other vaccinations in rheumatic disease populations, it is clear that disease modifying therapies (DMARDs) and the immunomodulatory therapies used to treat immune-mediated inflammatory diseases have the capacity to blunt immune responses to vaccinations. A number of mostly small studies have examined the optimal management of DMARDs with regard to the timing of vaccination in order to maximize the immunogenicity of various vaccines, with immunogenicity serving as a lab-based proxy for clinical effectiveness. As various development programs near completion with regard to a vaccine for SARS-CoV-2 virus, it will be imperative to understand how best to vaccinate immunosuppressed patients, and in particular, to optimize vaccine response resulting from a supplemental (booster) dose in those patients using immunomodulatory biologic and targeted small molecule therapies. In concert with the American College of Rheumatology's (ACR) task force focused on developing COVID-19 vaccination guidance, the proposed real-world study will address major knowledge gaps that exist with the SARS-CoV-2 vaccination in rheumatic disease patients who have not been included in vaccine studies. Currently, the ACR task force for COVID-19 vaccination guidance recommends that patients temporarily (1-2 weeks) stop one of their medications for their autoimmune inflammatory disease. However, it is not known if stopping medications may increase risk of flares in their autoimmune condition. If these occur, they are expected to occur within 2-4 weeks of treatment interruption.
Approximately 1000 patients will be studied to address these questions about the vaccine response following supplemental (booster) dosing associated with the use of upadacitinib, baricitinib, abatacept, canakinumab, secukinumab, ixekizumab, tofacitinib, TNFi, guselkumab (conditional on resource availability), and ustekinumab (conditional on resource availability). Participants will be randomized to hold these treatments for two weeks, or to continue their medication without interruption.
Study Objectives and Hypotheses
To conduct a large, randomized controlled trial to evaluate SARS-CoV-2 vaccine supplemental dose response in a large population of patients with autoimmune conditions, designed to meet three specific objectives and aims:
1. Specific Aim 1: Evaluate the immunogenicity of SARS-CoV-2 vaccination in patients with autoimmune conditions, randomizing patients to briefly interrupt (i.e., hold for 2 weeks) versus continue various immunomodulatory therapies at the time that they receive a supplemental (i.e., booster) mRNA vaccine dose.
* Primary outcome: quantitative measurement of immunoglobulin G (IgG) against SARS-CoV-2 using electrochemiluminescent (ECL) technology against the receptor binding domain (RBD) of spike protein.
* Primary Hypothesis (H1a): The mean titer of anti-RBD IgG antibodies specific to SARS-CoV-2 measured post a third (booster) vaccine dose will be greater in patients randomized to temporarily hold (e.g., 2 weeks) versus those who continue immunomodulatory therapies.
* Exploratory outcomes (with the randomized patients as the primary analysis population, and all patients as an additional analysis population):
* Measures of cell-mediated immunity and neutralizing assay or other assays to be specified in the future (E1a).
* Live-viral neutralization capacity post-vaccination (E1b).
* Comparison of mean titer of anti-RBD IgG antibodies specific to SARS-CoV-2 measured post supplemental dose for each immunomodulatory therapy to be studied compared to tumor necrosis factor inhibitors.
* Comparison of mean titer of anti-RBD IgG antibodies specific to SARS-CoV-2 measured post supplemental dose compared to general population.
* Comparison of mean titer of anti-RBD IgG antibodies specific to SARS-CoV-2 measured post supplemental dose in patients receiving concomitant methotrexate (MTX) compared to patients not receiving concomitant MTX.
* Comparison of mean titer of anti-RBD IgG antibodies specific to SARS-CoV-2 spike protein measured at baseline, by immunomodulatory medication received at the time of the initial vaccine series, and according to whether the immunomodulatory medication was held or not.
2. Specific Aim 2: Evaluate the safety and tolerability of SARS-CoV-2 vaccination in patients with different autoimmune conditions.
* Secondary outcomes:
* Flare and disease worsening of underlying autoimmune/inflammatory disease within 4 weeks of the supplemental vaccine dose.
* Vaccine reactogenicity within 1 week of the supplemental vaccine dose.
* Other safety events (e.g., allergic reactions, anaphylaxis, potential immune mediated adverse events).
* Secondary Hypothesis #2 (H2b): the frequency of disease flare after the initial vaccine series and a supplemental vaccine dose will be higher in patients who hold immunomodulatory therapy compared to those who do not. Disease flare will be collected retrospectively through clinical measurements and patient reported outcomes for the initial vaccine series, and prospectively after receipt of the supplemental vaccine dose.
* Exploratory outcomes: Comparison of circulating measures of inflammation (e.g., autoantibodies, cytokines, chemokines) between those holding and those continuing immunomodulatory therapy at the time of receipt of a supplemental dose of vaccine \[conditional on funding availability\].
3. Specific Aim 3 : Determine the clinical effectiveness of SARS-CoV-2 vaccination in patients with different autoimmune conditions and the subgroups of patients receiving different immunomodulatory therapies.
* Exploratory outcome: clinical efficacy (i.e., clinically-recognized COVID infection events) as ascertained by active surveillance, as well as passive linkage to administrative health plan claims and electronic health record (EHR) data.
