Immunogenicity of the third and fourth BNT162b2 mRNA COVID-19 boosters and factors associated with immune response in systemic lupus erythematosus and rheumatoid arthritis patients
Authors: Assawasaksakul Theerada , Sathitratanacheewin Seelwan , Vichaiwattana Preeyaporn , Wanlapakorn Nasamon , Poovorawan Yong , Avihingsanon Yingyos , Assawasaksakul Nawaporn , Kittanamongkolchai Wonngarm 
Published: March 2022

AbstractObjectivesTo evaluate the safety and immunogenicity of third and fourth BNT162b2 boosters in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients.MethodsSLE and RA patients aged 18-65 years who completed a series of inactivated, adenoviral vector, or heterogenous adenoviral vector/mRNA vaccines for at least 28 days were enrolled. Immunogenicity assessment was done before and day 15 after each booster vaccination. The third BNT162b2 booster was administered on day 1. Patients with suboptimal humoral response to the third booster dose (anti-receptor binding domain (RBD) IgG on day 15 < 2,360 BAU/mL) were given a fourth BNT162b2 booster on day 22.ResultsSeventy one SLE and 29 RA patients were enrolled. The third booster raised anti-RBD IgG by 15 fold and patients with positive neutralizing activity against the Omicron variant increased from 0% to 42%. Patients with positive cellular immune response also increased from 55% to 94%. High immunosuppressive load and initial inactivated vaccine were associated with lower anti-RBD IgG titer.Fifty four patients had suboptimal humoral responses to the third booster and 28 received a fourth booster dose. Although anti-RBD IgG increased further by 7 fold, no significant change in neutralizing activity against the Omicron variant was observed. There were 2 severe SLE flares that occurred shortly after the fourth booster dose.ConclusionsThe third BNT162b2 booster significantly improved humoral and cellular immunogenicity in SLE and RA patients. The benefit of a short interval fourth booster in patients with suboptimal humoral response was unclear.Key messagesWhat is already known about this subject?- The SARS-CoV-2 omicron variant (B.1.1.159) has multiple mutations that have resulted in greater escape from immune protection elicited by COVID-19 vaccines.- More attenuated immune response to SARS-CoV-2 vaccination has been observed in patients with autoimmune rheumatic diseases. The additional third dose of SARS-CoV-2 vaccine has been recommended in immunocompromised populations.- Some immunocompromised patients have a suboptimal humoral response to a third booster dose. Factors associated with poor immune response have not been adequately studied.- Administration of more than 3 doses has been shown to enhance immune response in some severely immunocompromised patients.What does this study add?- The third BNT162b2 booster was well tolerated, and significantly improved both humoral and cellular immunogenicity in SLE and RA patients previously vaccinated with either inactivated, adenoviral vector, or heterogenous adenoviral vector/mRNA vaccines.- High intensity of immunosuppressive therapy and initial inactivated vaccine were associated with lower humoral immune response to the third BNT162b2 booster.- Administration of a fourth BNT162b2 booster in poor humoral immune responders may not offer additional protection against the omicron variant, and flares were observed in SLE patients.How might this impact on clinical practice or future developments?- This study supported a third BNT162b2 booster dose administration in SLE and RA patients to enhance immune protection against the Omicron variant.- Patients who receive a high dose of immunosuppressive therapy or initial inactivated vaccine could be unprotected from SARS-CoV-2 infection. Benefits and risks of additional boosters or second generation of SARS-CoV-2 vaccine should be further studied.