Postvaccination Symptoms After a Third Dose of mRNA SARS-CoV-2 Vaccination in Patients With Inflammatory Bowel Disease: Results From CORALE-IBD.

BACKGROUND: The safety of a third dose of SARS-CoV-2 mRNA vaccination in patients with inflammatory bowel disease is unknown. METHODS: We compared symptoms following a third SARS-CoV-2 mRNA vaccine dose with symptoms after the second dose in IBD. RESULTS: The study group included 594 patients (70% female, 58% BNT162b2). Overall, 41% reported symptoms after a third dose. Symptom frequency and severity were lower after the third dose relative to the second dose for every organ system, except for gastrointestinal symptoms which were marginally worse. CONCLUSION: The frequency and severity of symptoms after a third mRNA vaccine dose are generally similar or milder than after a second dose for most organ systems.

The postvaccination symptom profile in patients with IBD is unknown after a third mRNA COVID vaccine dose. In a cohort of 594 subjects with IBD, we demonstrated that 41% experienced any symptoms after a third dose, the vast majority of which were mild and lasted less than 2 days. Symptoms after third dose were less frequently reported than after the second dose.

Evidence of premature lymphocyte aging in people with low anti-spike antibody levels after BNT162b2 vaccination.

SARS-CoV-2 vaccines have unquestionably blunted the overall impact of the COVID-19 pandemic, but host factors such as age, sex, obesity, and other co-morbidities can affect vaccine efficacy. We identified individuals in a relatively healthy population of healthcare workers (CORALE study cohort) who had unexpectedly low peak anti-spike receptor binding domain (S-RBD) antibody levels after receiving the BNT162b2 vaccine. Compared to matched controls, "low responders" had fewer spike-specific antibody-producing B cells after the second and third/booster doses. Moreover, their spike-specific T cell receptor (TCR) repertoire had less depth and their CD4+ and CD8+T cell responses to spike peptide stimulation were less robust. Single cell transcriptomic evaluation of peripheral blood mononuclear cells revealed activation of aging pathways in low responder B and CD4+T cells that could underlie their attenuated anti-S-RBD antibody production. Premature lymphocyte aging may therefore contribute to a less effective humoral response and could reduce vaccination efficacy.

Mission, Organization, and Future Direction of the Serological Sciences Network for COVID-19 (SeroNet) Epidemiologic Cohort Studies.

Background: Global efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies. Methods: In the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders). Results: Several studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes. Conclusions: In this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

Demographic and clinical characteristics associated with variations in antibody response to BNT162b2 COVID-19 vaccination among healthcare workers at an academic medical centre: a longitudinal cohort analysis.

OBJECTIVES: We sought to understand the demographic and clinical factors associated with variations in longitudinal antibody response following completion of two-dose regiment of BNT162b2 vaccination. DESIGN: This study is a 10-month longitudinal cohort study of healthcare workers and serially measured anti-spike protein IgG (IgG-S) antibody levels using mixed linear models to examine their associations with participant characteristics. SETTING: A large, multisite academic medical centre in Southern California, USA. PARTICIPANTS: A total of 843 healthcare workers met inclusion criteria including completion of an initial two-dose course of BNT162b2 vaccination, complete clinical history and at least two blood samples for analysis. Patients had an average age of 45±13 years, were 70% female and 7% with prior SARS-CoV-2 infection. RESULTS: Vaccine-induced IgG-S levels remained in the positive range for 99.6% of individuals up to 10 months after initial two-dose vaccination. Prior SARS-CoV-2 infection was the primary correlate of sustained higher postvaccination IgG-S levels (partial R2=0.133), with a 1.74±0.11 SD higher IgG-S response (p<0.001). Female sex (beta 0.27±0.06, p<0.001), younger age (0.01±0.00, p<0.001) and absence of hypertension (0.17±0.08, p=0.003) were also associated with persistently higher IgG-S responses. Notably, prior SARS-CoV-2 infection augmented the associations of sex (-0.42 for male sex, p=0.08) and modified the associations of hypertension (1.17, p=0.001), such that infection-naïve individuals with hypertension had persistently lower IgG-S levels whereas prior infected individuals with hypertension exhibited higher IgG-S levels that remained augmented over time. CONCLUSIONS: While the IgG-S antibody response remains in the positive range for up to 10 months following initial mRNA vaccination in most adults, determinants of sustained higher antibody levels include prior SARS-CoV-2 infection, female sex, younger age and absence of hypertension. Certain determinants of the longitudinal antibody response appear significantly modified by prior infection status. These findings offer insights regarding factors that may influence the 'hybrid' immunity conferred by natural infection combined with vaccination.

Differences in SARS-CoV-2 Vaccine Response Dynamics Between Class-I- and Class-II-Specific T-Cell Receptors in Inflammatory Bowel Disease.

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vß gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.

The T-Cell Response to SARS-CoV-2 Vaccination in Inflammatory Bowel Disease is Augmented with Anti-TNF Therapy.

T-cell and antibody responses to severe acute respiratory syndrome coronavirus 2 vaccination in inflammatory bowel disease patients are poorly correlated. T-cell responses are preserved by most biologic therapies, but augmented by anti-tumor necrosis factor (anti-TNF) treatment. While anti-TNF therapy blunts the antibody response, cellular immunity after vaccination is robust.

Paradoxical sex-specific patterns of autoantibody response to SARS-CoV-2 infection.

BACKGROUND: Pronounced sex differences in the susceptibility and response to SARS-CoV-2 infection remain poorly understood. Emerging evidence has highlighted the potential importance of autoimmune activation in modulating the acute response and recovery trajectories following SARS-CoV-2 exposure. Given that immune-inflammatory activity can be sex-biased in the setting of severe COVID-19 illness, the aim of the study was to examine sex-specific autoimmune reactivity to SARS-CoV-2 in the absence of extreme clinical disease. METHODS: In this study, we assessed autoantibody (AAB) reactivity to 91 autoantigens previously linked to a range of classic autoimmune diseases in a cohort of 177 participants (65% women, 35% men, mean age of 35) with confirmed evidence of prior SARS-CoV-2 infection based on presence of antibody to the nucleocapsid protein of SARS-CoV-2. Data were compared to 53 pre-pandemic healthy controls (49% women, 51% men). For each participant, socio-demographic data, serological analyses, SARS-CoV-2 infection status and COVID-19 related symptoms were collected by  an electronic survey of questions. The symptoms burden score was constructed based on the total number of reported symptoms (N = 21) experienced within 6 months prior to the blood draw, wherein a greater number of symptoms corresponded to a higher score and assigned as more severe burden. RESULTS: In multivariable analyses, we observed sex-specific patterns of autoreactivity associated with the presence or absence (as well as timing and clustering of symptoms) associated with prior COVID-19 illness. Whereas the overall AAB response was more prominent in women following asymptomatic infection, the breadth and extent of AAB reactivity was more prominent in men following at least mildly symptomatic infection. Notably, the observed reactivity included distinct antigens with molecular homology with SARS-CoV-2. CONCLUSION: Our results reveal that prior SARS-CoV-2 infection, even in the absence of severe clinical disease, can lead to a broad AAB response that exhibits sex-specific patterns of prevalence and antigen selectivity. Further understanding of the nature of triggered AAB activation among men and women exposed to SARS-CoV-2 will be essential for developing effective interventions against immune-mediated sequelae of COVID-19.

Longitudinal SARS-CoV-2 mRNA Vaccine-Induced Humoral Immune Responses in Patients with Cancer.

Longitudinal studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced immune responses in patients with cancer are needed to optimize clinical care. In a prospective cohort study of 366 (291 vaccinated) patients, we measured antibody levels [anti-spike (IgG-(S-RBD) and anti-nucleocapsid immunoglobulin] at three time points. Antibody level trajectories and frequency of breakthrough infections were evaluated by tumor type and timing of treatment relative to vaccination. IgG-(S-RBD) at peak response (median = 42 days after dose 2) was higher (P = 0.002) and remained higher after 4 to 6 months (P = 0.003) in patients receiving mRNA-1273 compared with BNT162b2. Patients with solid tumors attained higher peak levels (P = 0.001) and sustained levels after 4 to 6 months (P < 0.001) compared with those with hematologic malignancies. B-cell targeted treatment reduced peak (P = 0.001) and sustained antibody responses (P = 0.003). Solid tumor patients receiving immune checkpoint inhibitors before vaccination had lower sustained antibody levels than those who received treatment after vaccination (P = 0.043). Two (0.69%) vaccinated and one (1.9%) unvaccinated patient had severe COVID-19 illness during follow-up. Our study shows variation in sustained antibody responses across cancer populations receiving various therapeutic modalities, with important implications for vaccine booster timing and patient selection. SIGNIFICANCE: Long-term studies of immunogenicity of SARS-CoV-2 vaccines in patients with cancer are needed to inform evidence-based guidelines for booster vaccinations and to tailor sequence and timing of vaccinations to elicit improved humoral responses.