BNT162b2 Vaccine Induces Divergent B cell responses to SARS-CoV-2 S1 and S2

The first ever messenger RNA (mRNA) vaccines received emergency approvals in December 2020 and are highly protective against SARS-CoV-21-3. However, the contribution of each dose to the generation of antibodies against SARS-CoV-2 spike (S) protein and the degree of protection against novel variants, including delta, warrant further study. Here, we investigated the B cell response to the BNT162b2 vaccine by integrating repertoire analysis with single-cell transcriptomics of B cells from serial blood collections pre- and post-vaccination. The first vaccine dose elicits highly mutated IgA+ plasmablasts against the S protein subunit S2 at day 7, suggestive of recall of a memory B cell response generated by prior infections with heterologous coronaviruses. On day 21, we observed minimally-mutated IgG+ activated switched memory B cells targeting the receptor binding domain (RBD) of the S protein, likely representing a primary response derived from naive B cells. The B cell response against RBD is specifically boosted by the second vaccine dose, and encodes antibodies that potently neutralize SARS-CoV-2 pseudovirus and partially neutralize novel variants, including delta. These results demonstrate that the first vaccine dose activates a non-neutralizing recall response predominantly targeting S2, while the second vaccine dose is vital to boosting neutralizing anti-S1 RBD B cell responses.

New-Onset IgG Autoantibodies in Hospitalized Patients with COVID-19

Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), is associated with a wide range of clinical manifestations, including autoimmune features and autoantibody production. We developed three different protein arrays to measure hallmark IgG autoantibodies associated with Connective Tissue Diseases (CTDs), Anti-Cytokine Antibodies (ACA), and anti-viral antibody responses in 147 hospitalized COVID-19 patients in three different centers. Autoantibodies were identified in approximately 50% of patients, but in <15% of healthy controls. When present, autoantibodies largely targeted autoantigens associated with rare disorders such as myositis, systemic sclerosis and CTD overlap syndromes. Anti-nuclear antibodies (ANA) were observed in [~]25% of patients. Patients with autoantibodies tended to demonstrate one or a few specificities whereas ACA were even more prevalent, and patients often had antibodies to multiple cytokines. Rare patients were identified with IgG antibodies against angiotensin converting enzyme-2 (ACE-2). A subset of autoantibodies and ACA developed de novo following SARS-CoV-2 infection while others were transient. Autoantibodies tracked with longitudinal development of IgG antibodies that recognized SARS-CoV-2 structural proteins such as S1, S2, M, N and a subset of non-structural proteins, but not proteins from influenza, seasonal coronaviruses or other pathogenic viruses. COVID-19 patients with one or more autoantibodies tended to have higher levels of antibodies against SARS-CoV-2 Nonstructural Protein 1 (NSP1) and Methyltransferase (ME). We conclude that SARS-CoV-2 causes development of new-onset IgG autoantibodies in a significant proportion of hospitalized COVID-19 patients and are positively correlated with immune responses to SARS-CoV-2 proteins.