[Geneco]

We next tested total IgG4 levels given emerging evidence that this isotype may have a role in the development of immunotolerance, and the association between COVID-19 mRNA vaccines and plasma IgG4 increases (7). Indeed, there was a trend for higher concentrations of total IgG4 Abs in the Vax vs NVax COVID-19 patients in week 3 (Supplementary Figure 4).

Comorbidities and age are the known contributors to increased mortality among COVID-19 patients (5). Nonetheless, in our study, mortality remained significantly higher in the Vax patients even after adjustment for CCI, suggesting there are other risk factors in vaccinated patients.

This led us to investigate the immunological basis for our clinical observations. We observed reduced SARS-CoV-2-reactive Ab levels in Vax non-survivors. As a possible explanation for this observation, recent studies have shown that mRNA (but not vector-based) vaccine-associated increases in SARS-CoV-2 S-specific IgG4 levels vaccines did not contribute to increased protection (7, 8, 15). In contrast, they were thought to suppress antiviral immune responses, promoting immune tolerance and, possibly, unrestricted SARS-CoV-2 replication (7, 8, 16). In our study, the observed trend for increased total IgG4 concentration in week 3 for Vax patients may explain the reduced protective Ab responses. Of significance, clinical onset of IgG4-related non-infectious diseases is most often recorded in patients older than 50 years, which further corroborates our findings of increased mortality in this age group (16, 17).