Rheumatoid arthritis and older age are associated with lower humoral and cellular immune response to primary series COVID-19 mRNA vaccine

Abstract

Objective: People with autoimmune disease have worse COVID-19 infection-related outcomes, lower antibody responses to COVID-19 vaccine, and higher rates of breakthrough infection. Immunosuppressive medications used to treat rheumatoid arthritis (RA) are associated with lower COVID-19 vaccine responses, though independent contributions of comorbidities, T-cell immunity, and age are less clear. We sought to test the hypothesis that RA, immunosuppressive medications used to treat RA, and older age, contribute to reduced B and T cell response to COVID-19 vaccine.

Methods: We evaluated serum samples, taken the day of 1st vaccine dose, the day of 2nd dose, 2-6 weeks after 2nd dose, 7-12 weeks after 2nd dose, 13-24 weeks after 2nd dose, and 2-6 weeks after the 3rd dose, for anti-spike IgG and neutralizing antibody levels to Wuhan and Omicron BA.1 and peripheral blood mononuclear cells (PBMC) for spike-specific IFN-γ and IL-2 production by ELISPOT assay in 46 RA and 101 non-autoimmune control participants before and after the primary series COVID-19 mRNA vaccination.

Results: RA participants had lower spike-specific IgG and Wuhan-strain neutralizing antibody levels 2-6 weeks compared to controls after the second dose of primary vaccine series. Neutralizing antibody levels against Omicron BA.1 were low in both groups. IFN-γ production correlated with Wuhan neutralizing antibody levels, while older age negatively correlated with spike-specific IL-2, IFN-γ and IgG. Lower antibody levels were associated with older age, RA status, and medication usage, while lower T cell responses were associated primarily with older age.

Conclusions: These data indicate lower COVID-19 mRNA vaccine-induced antibody levels in persons with RA compared to individuals without RA, likely partially attributable to immune suppressive medications. At the same time, older age is associated with lower antibody and cellular immune response to COVID-19 vaccines.

Fig. 1.. Participants with RA as well as those with older age have lower SARS-CoV-2 spike specific IgG levels following COVID-19 vaccination.

Panel A: SARS CoV-2 Wuhan Spike specific IgG levels over course of primary vaccine series in RA participants. Panel B: Comparison of RA and non-RA control spike specific IgG levels over the course of vaccine. Panel C: Correlation between spike IgG level and age for all participants. Trend line shown for both RA and control groups. Dotted lines on Panels A and B indicate pre-determined spike specific IgG positive response cutoff.

Fig. 2.. Wuhan neutralizing ab is lower in RA as well as with older age and correlates with total IgG while Omicron is lower in all groups at all timepoints.

SARS Cov2 Neutralizing capacity. Panel A: Comparison of RA and non-RA control neutralizing titers. Panel B: Control group comparison of Wuhan vs. Omicron BA.1 neutralizing titers. Panel C: RA group comparison of Wuhan vs. Omicron BA.1 neutralizing titers. Panel D: Correlation between Spike specific IgG level and neutralizing antibody level for all participants combined.

Fig. 3.. Older age correlates with lower levels of spike-specific IFN-γ, and spike specific IFN-γ correlates with neutralizing antibody levels.

Panel A: Spike specific IFN-γ sfu over the course of COVID-19 vaccine. Panel B: Spike specific IL-2 sfu over the course of COVID-19 vaccine. Panel C: Correlation between age and spike specific IFN-γ sfu. Panel D: Correlation between age and spike specific IL-2 sfu. Panel E: higher IFN-γ sfu correlates with higher neutralizing titers in the control population. Dotted line in Panels A-B indicate pre-determined spike specific positive response.