Extended SARS-CoV-2 RBD booster vaccination induces humoral and cellular immune tolerance in mice

“Summary: The repetitive applications of vaccine boosters have been brought up in face of continuous emergence of SARS-CoV-2 variants with neutralization escape mutations, but their protective efficacy and potential adverse effects remain largely unknown. Here, we compared the humoral and cellular immune responses of an extended course of recombinant receptor binding domain (RBD) vaccine boosters with those from conventional immunization strategy in a Balb/c mice model. Multiple vaccine boosters after the conventional vaccination course significantly decreased RBD-specific antibody titers and serum neutralizing efficacy against the Delta and Omicron variants, and profoundly impaired CD4+ and CD8+T cell activation and increased PD-1 and LAG-3 expressions in these T cells. Mechanistically, we confirmed that extended vaccination with RBD boosters overturned the protective immune memories by promoting adaptive immune tolerance. Our findings demonstrate potential risks with the continuous use of SARS-CoV-2 vaccine boosters, providing immediate implications for the global COVID-19 vaccination enhancement strategies…

Discussion: Currently, vaccination against COVID-19 has been promoted worldwide, although sustained protection against the newly emerged SARS-CoV-2 variant strains has been continuously challenged. Clinical evidence has proven that the inclusion of an additional booster vaccine can re-stimulate the protective immune response (Cheng et al., 2022; Gruell et al., 2022). Whether such re-establishment of vaccine-induced immune response could be repeated by continued application of boosters is being questioned, yet largely unknown at present. Here, we compared the effects of repeated RBD vaccine boosters with a conventional immunization course to those with an extended vaccination strategy, in a Balb/c mice model. We found that the protective effects from the humoral immunity and cellular immunity established by the conventional immunization were both profoundly impaired during the extended vaccination course. Specifically, extended vaccination not only fully impaired the amount and the neutralizing efficacy of serum RBD-specific antibodies, but also shortened the long-term humoral memory. This is associated with immune tolerance in germinal center response, along with decreased numbers of spleen germinal center B and Tfh cells. Moreover, we demonstrated that extended immunization reduced the functional responses of CD4+ and CD8+T cells, restrained the population of memory T cells, and up-regulated the expression of PD-1 and LAG-3 in Te sub-type cells. An increased percentile of Treg cells was also observed, accompanied by significant elevation of IL-10 production. Together, we provided crucial evidence that repetitive administration of RBD booster vaccines may negatively impact the immune response established by a conventional vaccination course and promote adaptive immune tolerance.”