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Although a third dose of mRNA vaccine significantly increased antireceptor-binding domain (RBD) titer in a previous study, clinical factors associated with the immunogenicity in immunosuppressed populations have not been adequately studied.
A third booster dose of the BNT152b2 COVID-19 vaccine was shown to significantly improve both humoral and cellular immunogenicity in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, benefits regarding a fourth booster shot in patients exhibiting suboptimal humoral response was unclear, according to a study published in Lupus Science and Medicine.1
“According to a recent study, a third dose of mRNA 1273 vaccine significantly increased antireceptor-binding domain (RBD) titer in transplant recipients compared with placebo,” investigators noted. “However, in approximately half of the patients who received a booster, the anti-RBD titer remained low (<100 U/mL). Clinical factors associated with the immunogenicity in immunosuppressed populations have not been adequately studied…The safety and risk of disease flare associated with repetitive vaccination in patients with autoimmune rheumatic diseases remain unknown.”
Patients with a clinical diagnosis of either SLE or RA, aged 18-65 years, who had completed a series of inactivated, adenoviral vector, or heterogenous adenoviral vector/mRNA vaccines for 28 days or more were enrolled in the prospective, single arm, open-labelled study. Information, including demographics, disease activity, and current medications was collected at baseline. The third dose was administered on day 1. Immunogenicity assessment was performed before and at day 15 after each booster dose, when immune responses were at their peak. Those who experienced suboptimal humoral response to the third booster (anti-RBD IgG less than 2350 BAU/mL [16503 AU/mL]) were given a fourth dose on day 22. Blood samples were then collected again on day 36.
Investigators enrolled 71 patients with SLE and 29 patients with RA, all of which were in a stable disease state. The third booster raised anti-RBD IgG by 15-fold (from 69 [95% CI 42 to 112] BAU/mL to 1034 BAU/mL [95% CI 677 to 1577], p<0.0001). Those with positive neutralizing activity against the Omicron variant increased from 0% to 42%. Patients with a positive cellular immune response increased from 55% to 94%.
Of the 54 patients (39 with SLE, 15 with RA) with suboptimal humoral responses to the third dose, 28 (23 with SLE, 5 with RA) were given a fourth dose. No significant changes in neutralizing activity against the Omicron variant was observed; however, anti-RBD IgG increased by 7-fold (88 BAU/mL [range 49–155] to 644 BAU/mL [range 398–1041], p<0.0001). Two patients with SLE (8.7%) experienced a severe flare after the fourth dose. No breakthrough COVID-19 infections were observed in the 90-day period after the third booster dose.
The study was limited by its small sample size and observational nature. Further, the results may not be generalizable to other autoimmune rheumatic diseases and those receiving B-cell depletion therapy or initial mRNA vaccine. Lastly, the immunosuppressive load calculation was subjectively determined based on a prior study.
“The third BNT162b2 booster was well tolerated and significantly improved humoral and cellular immunogenicity in patients with SLE and RA,” investigators concluded. “The intensity of immunosuppressive therapy and the type of initial vaccine appear to affect the humoral immune response to the third booster. In poor humoral responders, a fourth BNT162b2 booster administered at a short interval may not provide additional protection against the omicron variant. Our finding that severe flares were observed in patients with SLE after the fourth booster is also cause for caution and additional research on the appropriateness of a fourth booster and the timing of such booster in our population.”
Assawasaksakul T, Sathitratanacheewin S, Vichaiwattana P, et al. Immunogenicity of the third and fourth BNT162b2 mRNA COVID-19 boosters and factors associated with immune response in patients with SLE and rheumatoid arthritis. Lupus Sci Med. 2022;9(1):e000726. doi:10.1136/lupus-2022-000726