Background/Purpose: Patients with rheumatic diseases (RD) on rituximab (RTX) have increased mortality following COVID-19 and reduced antibody response post-vaccine. We tested whether a mix-and-match strategy using a novel protein subunit vaccine (PSV) is safe and enhances vaccine-specific responses in those who have received >3 messenger RNA (mRNA) vaccine doses.

Methods: We recruited adults with RDs on RTX post-3^rd/4^th dose of a mRNA COVID-19 vaccine in an open label, non-randomized, comparative trial. Post-3^rd dose participants chose to receive either a 4th dose of mRNA Spikevax® (Moderna mRNA-1273) or PSV Nuvaxovid® (Novavax NVX-CoV2373) vaccines. Patients enrolled post-4^th mRNA dose were offered Nuvaxovid®as their 5th. Self-reported reactogenicity at 7 days and adverse events at 28 days were noted. Humoral and cellular vaccine-responses were determined pre and 28 days post-vaccine. We tested for anti-spike (anti-S) by plasma binding on D614G Spike transfected HEK293T cells and measured by flow cytometry, anti-receptor binding domain (anti-RBD) and anti-nucleocapsid (anti-N) by in-house ELISA, and serum neutralizing antibodies (NAbs) using Wuhan and BA.5 pseudotyped lentiviruses. In 19 participants receiving a 4^th dose, we tested for spike-specific B, CD4 and CD8 T cell responses by flow cytometry using RBD-B and activation-induced marker (AIM) assays. We used descriptive statistics for demographics, reactogenicity and immunogenicity and ANOVA tests to assess the impact of a booster dose on vaccine-induced immune responses.

Results: Table 1 summarizes data on the first 71 participants (4^th dose Spikevax® = 30, 4^th dose Nuvaxovid® = 13 and 5^th dose Nuvaxovid® = 28). Reactions to the vaccine at 7 days were frequent but not severe. Most common was fatigue, headache, injection site pain and arthralgias. At day 28, five new COVID-19 infections (one requiring hospitalization) and seven disease flares were reported. Table 2 reports anti-S, anti-RBD, anti-N, and NAbs to Wuhan and BA.5. Anti-S levels (Figure 1) were higher in those receiving 5^th versus 4^th dose. In those to whom we gave a 4^th vaccine, we observed higher anti-S levels post mRNA (p < 0.001) but this was not clearly seen when the 4^th dose was PSV. Most (16/19) of those tested post 4^th dose had no detectable RBD B cell responses while three patients had higher B cells numbers and measurable RBD B cell responses. In contrast, the cohort demonstrated good Spike-specific intact and measurable AIM+ CD4 and CD8 T cell responses that did not increase post 4^th dose.

Conclusion: Mix-and-match booster dosing was not clearly associated with unusual vaccine reactions, adverse events or disease flares in RTX-treated RD patients. In those who had already received 3 mRNA doses, there was a significant increase in anti-S levels after receiving a 4^th mRNA vaccine but not when the 4^th vaccine was PSV. Humoral and RBD-B-cell responses increased with a fourth dose. AIM+ CD4 and CD8 T cell responses were intact, showing a disconnect with weak B cell frequencies. We did not see a clear benefit for PSV compared to mRNA booster (after primary mRNA vaccine series) in RTX-treated RD patients. This may have important implications for COVID vaccine strategies in 2023-2024.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-mix-and-match-covid-19-vaccination-strategy-in-patients-with-rheumatic-diseases-on-rituximab/