Safety and Immunogenicity Following the Second and Third Doses of the BNT162b2 mRNA COVID-19 Vaccine in Adolescents with Juvenile-Onset Autoimmune Inflammatory Rheumatic Diseases: A Prospective Multicentre Study.

BACKGROUND: To explore the long-term safety and dynamics of the immune response induced by the second and third doses of the BNT162b2 mRNA COVID-19 vaccine in adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRDs) compared with healthy controls. METHODS: This international prospective study included adolescents with AIIRDs and controls vaccinated with two (AIIRDs n = 124; controls n = 80) or three (AIIRDs n = 64; controls n = 30) doses of the BNT162b2 vaccine, evaluated for vaccine side-effects, disease activity, COVID-19 breakthrough infection rates and severity, and anti-spike S1/S2 IgG antibody titers in a sample from both groups. RESULTS: The vaccination safety profile was favorable, with most patients reporting mild or no side-effects. The rheumatic disease remained stable at 98% and 100% after the second and third doses, respectively. The two-dose vaccine induced comparable seropositivity rates among patients (91%) and controls (100%), (p = 0.55), which declined within 6 months to 87% and 100%, respectively (p = 0.3) and increased to 100% in both groups after the third vaccine dose. The overall post-vaccination COVID-19 infection rate was comparable between patients and controls, 47.6% (n = 59) and 35% (n = 28), respectively; p = 0.5278, with most infections occurring during the Omicron surge. In relation to the last vaccination, time-to-COVID-19 infection was similar between patients and controls, at a median of 5.5 vs. 5.2 months, respectively (log-rank p = 0.1555). CONCLUSION: The safety profile of three doses of the BNT162b2 mRNA vaccine was excellent, with adequate humoral response and similar efficacy among patients and controls. These results support the recommendation for vaccinating adolescents with juvenile-onset AIIRDs against COVID-19.

Cellular and humoral immune response to the fourth Pfizer-BioNTech COVID-19 vaccine dose in individuals aged 60 years and older.

With the emergence of the severe acute respiratory syndrome 2 (SARS-CoV-2) B.1.1.529/BA.1 (Omicron) variant in early 2022, Israel began vaccinating individuals 6o years of age or older with a fourth BNT162b2 vaccine. While the decision was based on little experimental data, longer follow-up showed clinical effectiveness of the fourth dose with reduction in the number of severely affected individuals. However, the immune response to fourth vaccine dose in this age group was not yet characterized, and little is known about the immunogenicity of repeated vaccine dosing in this age group. We therefore aimed to evaluate the humoral and cellular immune response pre- and 3-week post- the fourth vaccine dose in patients age 60 years or older. For this purpose, blood samples were collected from donors age 60 years or older, all received their 3rd vaccine dose 5 months prior. Serum samples were evaluated for the presence of anti-Spike protein (anti-S) antibodies (N = 133), and peripheral blood mononuclear cells (PBMCs) were evaluated by flow cytometry for their ability to respond to the SARS-CoV-2 wild type Spike-glycoprotein peptide mix, Membrane-glycoprotein (M) peptide mix and to the mutated Spike-regions of the Omicron variant (N = 34). Three weeks after the fourth vaccine dose, 24 out of 34 donors (70.5%) showed significant increase in the number of cells responding to the wild type S-peptide mix. Of note, out of 34 donors, 11 donors (32.3%) had pre-boost anti-M T-cell response, none of which had history of confirmed COVID-19, suggesting possible asymptomatic exposure. Interestingly, in M non-responding individuals, no statistically significant increase in the cellular response was observed following stimulation with omicron S-mutated regions. While there are limited data regarding the longevity of the observed response, our results are in accordance with the described clinical efficacy, provide mechanistic evidence to support it and argue against vaccine-induced or age-related immunosenescence.

Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

Importance: Administration of a BNT162b2 booster dose (Pfizer-BioNTech) to fully vaccinated individuals aged 60 years and older was significantly associated with lower risk of SARS-CoV-2 infection and severe illness. Data are lacking on the effectiveness of booster doses for younger individuals and health care workers. Objective: To estimate the association of a BNT162b2 booster dose with SARS-CoV-2 infections among health care workers who were previously vaccinated with a 2-dose series of BNT162b2. Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. The study cohort included 1928 immunocompetent health care workers who were previously vaccinated with a 2-dose series of BNT162b2, and had enrolled between August 8 and 19, 2021, with final follow-up reported through September 20, 2021. Screening for SARS-CoV-2 infection was performed every 14 days. Anti-spike protein receptor binding domain IgG titers were determined at baseline and 1 month after enrollment. Cox regression with time-dependent analysis was used to estimate hazard ratios of SARS-CoV-2 infection between booster-immunized status and 2-dose vaccinated (booster-nonimmunized) status. Exposures: Vaccination with a booster dose of BNT162b2 vaccine. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, as confirmed by reverse transcriptase-polymerase chain reaction. Results: Among 1928 participants, the median age was 44 years (IQR, 36-52 years) and 1381 were women (71.6%). Participants completed the 2-dose vaccination series a median of 210 days (IQR, 205-213 days) before study enrollment. A total of 1650 participants (85.6%) received the booster dose. During a median follow-up of 39 days (IQR, 35-41 days), SARS-CoV-2 infection occurred in 44 participants (incidence rate, 60.2 per 100 000 person-days); 31 (70.5%) were symptomatic. Five SARS-CoV-2 infections occurred in booster-immunized participants and 39 in booster-nonimmunized participants (incidence rate, 12.8 vs 116 per 100 000 person-days, respectively). In a time-dependent Cox regression analysis, the adjusted hazard ratio of SARS-CoV-2 infection for booster-immunized vs booster-nonimmunized participants was 0.07 (95% CI, 0.02-0.20). Conclusions and Relevance: Among health care workers at a single center in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was associated with a significantly lower rate of SARS-CoV-2 infection over a median of 39 days of follow-up. Ongoing surveillance is required to assess durability of the findings.

Humoral Response to the Third Dose of Sars-Cov-2 Vaccine in Kidney Transplant Recipients.

BACKGROUND: Most solid organ transplant recipients did not develop an appreciable serologic response after 2 doses of the mRNA SARS-CoV-2 vaccine. METHODS: We analyzed the humoral response after a third dose of the BNT162b2 vaccine in 130 kidney transplant recipients, compared to 48 health care workers, and associated factors, including prevaccine cellular immune response, by evaluating intracellular cytokine production after stimulation of donor's peripheral blood mononuclear cells. RESULTS: After 2 doses, most of the controls (47 out of 48, 98%) and only 40% of kidney recipients (52 of 130) kidney recipients were seropositive (P < .001). Most seronegative recipients developed a serologic response after the booster (47 out 78, 60%), thus bringing the total number of seropositive recipients to 99 out of 130 (76%). After the third dose, there was a significant increase in antibodies titers in both groups. Decreased humoral response was significantly associated with an older age, lower lymphocyte count, and a lower level of antibodies before booster administration. CD4+TNFα+ and CD4+INFγ+ were correlated with mean increase in antibody titers. CONCLUSIONS: A third dose of the BNT162b2 mRNA vaccine in kidney recipients is safe and effectively results in increased IgG anti-S levels, including in individuals who were seronegative after 2 doses. Long-term studies of the length of the immune response and protection are required.

Safety and immunogenicity of BNT162b2 mRNA COVID-19 vaccine in adolescents with rheumatic diseases treated with immunomodulatory medications.

OBJECTIVES: Adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRDs) could be at risk for disease flare secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or to withholding anti-inflammatory therapy. While vaccination can protect against coronavirus disease 2019 (COVID-19), safety and immunogenicity data regarding anti-SARS-CoV-2 vaccines among adolescents with AIIRDs are limited. This international, prospective, multicentre study evaluated the safety and immunogenicity of the BNT162b2 anti-SARS-CoV-2 vaccine among adolescents and young adults with juvenile-onset AIIRDs, 80% of whom are on chronic immunomodulatory therapy. METHODS: Vaccine side effects, disease activity and short-term efficacy were evaluated after 3 months in 91 patients. Anti-spike S1/S2 IgG antibody levels were evaluated in 37 patients and 22 controls 2-9 weeks after the second dose. RESULTS: A total of 91 patients and 40 healthy controls were included. The safety profile was good, with 96.7% (n = 88) of patients reporting mild or no side effects and no change in disease activity. However, three patients had transient acute symptoms: two following the first vaccination (renal failure and pulmonary haemorrhage) and one following the second dose (mild lupus flare vs viral infection). The seropositivity rate was 97.3% in the AIIRD group compared with 100% among controls. However, anti-S1/S2 antibody titres were significantly lower in the AIIRD group compared with controls [242 (s.d. 136.4) vs 387.8 (57.3) BAU/ml, respectively; P < 0.0001]. No cases of COVID-19 were documented during the 3 month follow-up. CONCLUSION: Vaccination of juvenile-onset AIIRD patients demonstrated good short-term safety and efficacy and a high seropositivity rate but lower anti-S1/S2 antibody titres compared with healthy controls. These results should encourage vaccination of adolescents with juvenile-onset AIIRDs, even while on immunomodulation.

The effect of a third-dose BNT162b2 vaccine on anti-SARS-CoV-2 antibody levels in immunosuppressed patients.

OBJECTIVES: The recent surge in coronavirus disease 2019 cases led to the consideration of a booster vaccine in previously vaccinated immunosuppressed individuals. However, the immunogenic effect of a third-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine in immunosuppressed patients is still unknown. METHODS: This was an observational cohort study of 279 previously vaccinated immunosuppressed patients followed at a single tertiary hospital in Israel. Patients were administered a third dose of the Pfizer-BioNTech mRNA vaccine (BNT162b2) between July 14 and July 21, 2021. Levels of IgG antibodies against the spike receptor-binding domain of SARS-CoV-2 were measured 3 to 4 weeks after vaccination. RESULTS: Of the cohort of 279 patients, 124 (44.4%) had haematologic malignancies, 57 (20.4%) had rheumatologic diseases, and 98 (35.1%) were solid organ-transplant recipients. Anti-SARS-CoV-2 antibody levels increased in 74.9% of cases. Across the entire cohort, the median absolute antibody levels (expressed in AU/mL) increased from 7 (interquartile range (IQR), 0.1-69) to 243 (IQR, 2-4749) after the booster dose. The response significantly varied across subgroups: The transplant cohort showed the greatest increase in absolute antibody levels (from 52 (IQR, 7.25-184.5) to 1824 (IQR, 161-9686)), followed by the rheumatology (from 22 (IQR, 1-106) to 1291 (IQR, 6-6231)) and haemato-oncology (from 1 (IQR, 0.1-7) to 7.5 (IQR, 0.1-407.5)) cohorts. The χ2 test was 8.30 for difference in fold change (p = 0.016). Of the 193 patients who were seronegative at baseline, 76 became seropositive after vaccination, corresponding to a 39.4% (95% CI, 32.8%-46.4%) seroconversion rate. Transplant patients had the highest seroconversion rate (58.3% (95% CI, 44.3%-71.2%)), followed by rheumatology (44.1% (95% CI, 28.9%-60.5%)) and haemato-oncology (29.7% (95% CI, 22%-38.8%); χ2 = 11.87; p = 0.003) patients. DISCUSSION: A third dose of BNT162b2 is immunogenic in most immunosuppressed individuals, although antibody response may differ based on the type of disease and immunosuppression. The antibody level that correlates with protection is still unknown; thus, future studies are needed to evaluate clinical outcomes.

Short-Term Safety of Booster Immunization With BNT162b2 mRNA COVID-19 Vaccine in Healthcare Workers.

This study demonstrated a favorable short-term safety profile after a third dose of the BNT162b2 vaccine among healthcare workers (HCWs). There were more frequent local reactions and less systemic reactions compared to the second dose. The HCWs who reported reactions had higher prebooster titer of anti-S1 antibodies compared to those who reported no reactions.

BNT162b2 mRNA COVID-19 vaccine booster induces seroconversion in patients with B-cell non-Hodgkin lymphoma who failed to respond to two prior vaccine doses.

This prospective study evaluated seroconversion rates in response to BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine booster in 44 B-cell non-Hodgkin lymphoma (B-NHL) patients who failed to respond to two prior doses [42 previously exposed to anti-CD20 monoclonal antibodies (moAbs) including 13 under maintenance treatment]. Seroconversion was obtained in 29.5% of the patients. Longer time from last anti-CD20 moAb (>6 months) and diagnosis of aggressive lymphoma compared to other, incurable B-NHLs were associated with increased seroconversion rates (47.8% vs.10.5%, p = 0.019 and 50% vs. 17.9%, p = 0.025 respectively). Thus, seronegative patients with B-NHL that completed anti-CD20 therapy more than 6 months prior to the booster have greater chances to achieve seroconversion.

Association Between Vaccination With BNT162b2 and Incidence of Symptomatic and Asymptomatic SARS-CoV-2 Infections Among Health Care Workers.

IMPORTANCE: Randomized clinical trials have provided estimates of the effectiveness of the BNT162b2 vaccine against symptomatic SARS-CoV-2 infection, but its effect on asymptomatic infections remains unclear. OBJECTIVE: To estimate the association of vaccination with the Pfizer-BioNTech BNT162b2 vaccine with symptomatic and asymptomatic SARS-CoV-2 infections among health care workers. DESIGN, SETTING, AND PARTICIPANTS: This was a single-center, retrospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. Data were collected on symptomatic and asymptomatic SARS-CoV-2 infections confirmed via polymerase chain reaction (PCR) tests in health care workers undergoing regular screening with nasopharyngeal swabs between December 20, 2020, and February 25, 2021. Logistic regression was used to calculate incidence rate ratios (IRRs) comparing the incidence of infection between fully vaccinated and unvaccinated participants, controlling for demographics and the number of PCR tests performed. EXPOSURES: Vaccination with the BNT162b2 vaccine vs unvaccinated status was ascertained from the employee health database. Full vaccination was defined as more than 7 days after receipt of the second vaccine dose. MAIN OUTCOMES AND MEASURES: The primary outcome was the regression-adjusted IRR for symptomatic and asymptomatic SARS-CoV-2 infection of fully vaccinated vs unvaccinated health care workers. The secondary outcomes included IRRs for partially vaccinated health care workers (days 7-28 after first dose) and for those considered as late fully vaccinated (>21 days after second dose). RESULTS: A total of 6710 health care workers (mean [SD] age, 44.3 [12.5] years; 4465 [66.5%] women) were followed up for a median period of 63 days; 5953 health care workers (88.7%) received at least 1 dose of the BNT162b2 vaccine, 5517 (82.2%) received 2 doses, and 757 (11.3%) were not vaccinated. Vaccination was associated with older age compared with those who were not vaccinated (mean age, 44.8 vs 40.7 years, respectively) and male sex (31.4% vs 17.7%). Symptomatic SARS-CoV-2 infection occurred in 8 fully vaccinated health care workers and 38 unvaccinated health care workers (incidence rate, 4.7 vs 149.8 per 100 000 person-days, respectively, adjusted IRR, 0.03 [95% CI, 0.01-0.06]). Asymptomatic SARS-CoV-2 infection occurred in 19 fully vaccinated health care workers and 17 unvaccinated health care workers (incidence rate, 11.3 vs 67.0 per 100 000 person-days, respectively, adjusted IRR, 0.14 [95% CI, 0.07-0.31]). The results were qualitatively unchanged by the propensity score sensitivity analysis. CONCLUSIONS AND RELEVANCE: Among health care workers at a single center in Tel Aviv, Israel, receipt of the BNT162b2 vaccine compared with no vaccine was associated with a significantly lower incidence of symptomatic and asymptomatic SARS-CoV-2 infection more than 7 days after the second dose. Findings are limited by the observational design.