Association of systemic adverse reaction patterns with long-term dynamics of humoral and cellular immunity after coronavirus disease 2019 third vaccination.

The objective of this study was to clarify the impact of adverse reactions on immune dynamics. We investigated the pattern of systemic adverse reactions after the second and third coronavirus disease 2019 (COVID-19) vaccinations and their relationship with immunoglobulin G against severe acute respiratory syndrome coronavirus 2 spike 1 protein titers, neutralizing antibody levels, peak cellular responses, and the rate of decrease after the third vaccination in a large-scale community-based cohort in Japan. Participants who received a third vaccination with BNT162b2 (Pfizer/BioNTech) or mRNA-1273 (Moderna), had two blood samples, had not had COVID-19, and had information on adverse reactions after the second and third vaccinations (n = 2198) were enrolled. We collected data on sex, age, adverse reactions, comorbidities, and daily medicine using a questionnaire survey. Participants with many systemic adverse reactions after the second and third vaccinations had significantly higher humoral and cellular immunity in the peak phase. Participants with multiple systemic adverse reactions after the third vaccination had small changes in the geometric values of humoral immunity and had the largest geometric mean of cellar immunity in the decay phase. Systemic adverse reactions after the third vaccination helped achieve high peak values and maintain humoral and cellular immunity. This information may help promote uptake of a third vaccination, even among those who hesitate due to adverse reactions.

Varying Cellular Immune Response against SARS-CoV-2 after the Booster Vaccination: A Cohort Study from Fukushima Vaccination Community Survey, Japan.

Booster vaccination reduces the incidence of severe cases and mortality related to COVID-19, with cellular immunity playing an important role. However, little is known about the proportion of the population that has achieved cellular immunity after booster vaccination. Thus, we conducted a Fukushima cohort database and assessed humoral and cellular immunity in 2526 residents and healthcare workers in Fukushima Prefecture in Japan through continuous blood collection every 3 months from September 2021. We identified the proportion of people with induced cellular immunity after booster vaccination using the T-SPOT.COVID test, and analyzed their background characteristics. Among 1089 participants, 64.3% (700/1089) had reactive cellular immunity after booster vaccination. Multivariable analysis revealed the following independent predictors of reactive cellular immunity: age < 40 years (adjusted odds ratio: 1.81; 95% confidence interval: 1.19-2.75; p-value: 0.005) and adverse reactions after vaccination (1.92, 1.19-3.09, 0.007). Notably, despite IgG(S) and neutralizing antibody titers of ≥500 AU/mL, 33.9% (349/1031) and 33.5% (341/1017) of participants, respectively, did not have reactive cellular immunity. In summary, this is the first study to evaluate cellular immunity at the population level after booster vaccination using the T-SPOT.COVID test, albeit with several limitations. Future studies will need to evaluate previously infected subjects and their T-cell subsets.

Time course of adverse reactions following BNT162b2 vaccination in healthy and allergic disease individuals aged 5-11 years and comparison with individuals aged 12-15 years: an observational and historical cohort study.

We aimed to investigate the type and frequency of adverse events over 7 days following the first and second BNT162b2 vaccination. This observational and historical cohort study included patients aged 5-11 years who received two doses of BNT162b2 and provided consent along with their guardians. We collected data on sex, age, height, weight, blood type, history of Bacille Calmette-Guerin vaccination, allergic disease, medication, history of coronavirus disease 2019 (COVID-19), and adverse reactions 7 days following the first and second BNT162b2 vaccination using a questionnaire. Our results were compared with previously reported results for individuals aged 12-15 years. A total of 421 participants were eligible for this study. Among the 216 patients with allergic disease, 48 (22.2%) had experienced worsening of their chronic diseases, and the frequency of fatigue and dizziness after the second dose was higher than that of healthy individuals. The experience of systemic adverse reactions was associated with asthma. The frequency of headache, diarrhea, fatigue, muscle/joint pain, and fever after the second BNT162b2 vaccination was lower in individuals aged 5-11 years than in those aged 12-15 years. Fever was the only systemic adverse reaction that lasted longer than 5 days (1.0% of participants). CONCLUSIONS: Individuals with allergic diseases, who are potentially susceptible to COVID-19, may experience worsening of their chronic diseases and more frequent adverse reactions after BNT162b2 vaccination than healthy individuals. To ensure that children with allergic diseases receive the vaccine safely, further information needs to be collected. WHAT IS KNOWN: • Adverse reactions after BNT162b2 vaccination among individuals aged 5-11 years are generally nonserious, more common after second vaccination, and substantially less common compared to those observed among individuals aged 12-15 years. WHAT IS NEW: • Individuals with allergic diseases experienced worsening of their chronic diseases and more frequent adverse reactions after BNT162b2 vaccination than healthy individuals. • Systemic adverse reactions were associated with asthma. Fever was the only systemic adverse reaction that lasted longer than 5 days.

Antibody and T-Cell Responses against SARS-CoV-2 after Booster Vaccination in Patients on Dialysis: A Prospective Observational Study.

Intensive vaccination is recommended for populations more vulnerable to COVID-19 infection, although data regarding the built of immunity after vaccination for dialysis patients are lacking. This prospective, observational cohort study of maintenance hemodialysis patients examined IgG antibody levels against the SARS-CoV-2 spike (S1) protein, neutralizing activity, and interferon gamma levels after the third dose of the BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine. Humoral immunity was repeatedly measured for up to two months. The study includes 58 patients on hemodialysis. Median neutralizing antibodies reached a maximum at 56 and 9 days after booster vaccination with BNT162b2 and mRNA-1273, respectively. The median IgG antibody titer reached a maximum of 3104.38 and 7209.13 AU/mL after 16 days of booster dose, and cellular immunity was positive in 61.9% and 100% of patients with BNT162b2 and mRNA-1273 vaccination, respectively. By repeating the measurements over a period of two months, we clarified the chronological aspects of the acquisition of humoral immunity in dialysis patients after a booster COVID-19 vaccination; most dialysis patients acquired not only humoral immunity, but also cellular immunity against SARS-CoV-2. Future research should investigate the continued long-term dynamics of antibody titers and cellular immunity after the third or further vaccinations, evaluating the need for additional vaccinations for hemodialysis patients.

Waning of Humoral Immunity and the Influencing Factors after BNT162b2 Vaccination: A Cohort Study with a Latent Growth Curve Model in Fukushima.

Measuring long-term antibody titer kinetics and subsequent coronavirus disease 2019 (COVID-19) vaccinations are crucial for identifying vulnerable populations. Our aim was to determine the association between long-term antibody kinetics, including peak titers and factors, up to seven months post-second vaccination. A three-time antibody survey was conducted in 2021 among healthcare workers in Japan to investigate the changes in humoral immunity using chemiluminescence immunoassay. The study involved 205 participants who had received the second vaccine dose, completed the three-time survey, and were not infected with SARS-CoV-2. A latent growth curve model was used to identify factors affecting the peak titer and decreasing the antibody slope. Of the eligible participants, the mean titers of immunoglobulin G (IgG) against the spike (S) protein and the neutralizing activity 7 months after the second vaccination decreased to 154.3 (8.8% of the peak titer) and 62.1 AU/mL (9.5% of the peak titer), respectively. The IgG growth model showed that age significantly affected peak titers (p < 0.001); however, a significant difference was not found for the decreasing slope. Ultimately, aging adults had significantly low peak antibody titers; however, age was unrelated to the slope of log-transformed IgG against the S protein.

Humoral response to SARS-CoV-2 vaccination in haemodialysis patients and a matched cohort.

OBJECTIVES: SARS-CoV-2 vaccination is a crucial intervention for infection control; however, the immune response to vaccination in dialysis patients has been reported to be moderate compared with healthy adults. There are few studies available on humoral response in immunised dialysis patients compared with well-matched control group, we conducted a prospective cohort study measuring SARS-CoV-2 antibody titres in Fukushima Prefecture, Japan since September 2021. PARTICIPANTS: We compared the titres of both anti-SARS-CoV-2 S1 IgG and neutralising antibodies of 65 haemodialysis patients (dialysis group) with 500 residents in Soma, Fukushima (control group). METHODS: Coarsened exact matching was used to balance sex, age and days from the second dose between dialysis and control groups. RESULTS: Significant differences in the titres of anti-SARS-CoV-2 S1 IgG and neutralising antibodies were observed between the dialysis and control groups; anti-SARS-CoV-2 S1 IgG: 168.35 (4.48-1074.29) AU/mL and 269.81 (4.72-945.96) AU/mL in dialysis and control groups, p=0.02, neutralising antibodies: 35.77 (2.94-826.06) AU/mL and 62.22 (0.00-535.57) AU/mL, p=0.007, respectively). CONCLUSIONS: We observed significantly reduced anti-SARS-CoV-2 S1 antibody and neutralising antibodies in haemodialysis patients compared with cohorts matched for duration after vaccination. Patients receiving haemodialysis should be carefully monitored for immunological responses to the vaccination and COVID-19 infection.

Humoral immunity after second dose of BNT162b2 vaccine in Japanese communities: an observational cross-sectional study, Fukushima Vaccination Community Survey.

To reveal waning humoral immunity after second dose BNT162b2 vaccinations in a rural Japanese community and determine factors affecting antibody titers. We aimed to report Immunoglobulin G (IgG) antibody against the SARS-CoV-2 spike (S1) protein levels and neutralizing activity in a large scale community based cohort. METHODS: Participants in the observational cross-sectional study received a second dose of vaccination with BNT162b2 (Pfizer/BioNTech) and were not previously infected with COVID-19. Questionnaire-collected data on sex, age, adverse vaccine reactions, and medical history was obtained. RESULTS: Data from 2496 participants revealed that older age groups reached a low antibody titer 90-120 days after the second vaccination. Neutralizing activity decreased with age; 35 (13.3%) of those aged ≥ 80 years had neutralizing activity under the cut-off value. Neutralizing activity > 179 days from the second vaccination was 11.6% compared to that at < 60 days from the second vaccination. Significantly lower IgG antibody titers and neutralizing activity were associated with age, male sex, increased time from second vaccination, smoking, steroids, immunosuppression, and comorbidities. CONCLUSIONS: Antibody titer decreased substantially over time. Susceptible populations, older people, men, smokers, steroid users, immunosuppression users, and people with three or more comorbidities may require a special protection strategy.

Factors associated with anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein antibody titer and neutralizing activity among healthcare workers following vaccination with the BNT162b2 vaccine.

The purpose of this study was to identify factors associated with the increase in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S1) protein and neutralizing antibody titer following SARS-CoV-2 vaccination. This observational study was conducted among healthcare workers working for a private hospital group in Fukushima Prefecture, Japan. Two blood samples were obtained from each participant. The first sample was obtained before the first dose of BNT162b2 (Pfizer-BioNTech) vaccine, and a second sample was obtained approximately 6 weeks later. Immunoglobulin G (IgG) antibody against the SARS-CoV-2 spike (S1) protein, immunoglobulin M (IgM) antibody against SARS-CoV-2 N-protein, and neutralizing activity were measured using the chemiluminescent immunoassay with iFlash 3000. A total of 231 healthcare workers who agreed to participate, and were negative for anti-SARS-CoV-2 IgM antibodies at enrollment, were included in the analysis. All participants had elevated IgG antibodies and neutralizing activity above the cutoff values. A total of 174 (75.3%) and 208 (90.0%) participants experienced adverse reactions after the first and second vaccine doses, respectively. Younger age, female sex, not taking immunosuppressive or antipyretic analgesic medication regularly, a lack of local adverse reactions after the first dose, and the presence of adverse reactions (fever, muscle, and joint pain) after the second dose were associated with higher IgG antibody titers and neutralizing activity. Intake of analgesic antipyretic for adverse reactions to vaccines was not significantly associated with antibody and neutralizing activity titer production. Immune responses after vaccination may differ among individuals, and continued countermeasures to prevent SARS-CoV-2 infection are vital.

Peak IgG antibody titers against SARS-CoV-2 spike protein following immunization with the Pfizer/BioNTech BNT162b2 vaccine.

This study investigated the immune response and outcome of BNT162b2 vaccination among 12 staff at a hospital in Fukushima, Japan. Blood samples were collected from participants before their first vaccination, with subsequent sampling performed during the participants' work days for six weeks thereafter. Antibody titers peaked 6-13 days after the second vaccination (days 27-34 after the first), followed by a steady decrease. Six males had significantly lower peak antibody titers than six females (p = 0.016 with t-test); the older six (median age 53 years) had lower antibody titers than the younger six (median age 35 years) but without statistical significance (p value=0.24 with t-test).

Factors Associated with COVID-19 Vaccine Booster Hesitancy: A Retrospective Cohort Study, Fukushima Vaccination Community Survey.

This was a retrospective cohort study, which aimed to investigate the factors associated with hesitancy to receive a third dose of a coronavirus disease 2019 (COVID-19) vaccine. A paper-based questionnaire survey was administered to all participants. This study included participants who provided answers in the questionnaire about whether they had an intent to receive a third dose of a vaccine. Data on sex, age, area of residence, adverse reactions after the second vaccination, whether the third vaccination was desired, and reasons to accept or hesitate over the booster vaccination were retrieved. Among the 2439 participants, with a mean (±SD) age of 52.6 ± 18.9 years, and a median IgG-S antibody titer of 324.9 (AU/mL), 97.9% of participants indicated their intent to accept a third vaccination dose. The logistic regression revealed that participants of a younger age (OR = 0.98; 95% CI: 0.96-1.00) and with a higher antibody level (OR = 2.52; 95% CI: 1.27-4.99) were positively associated with hesitancy over the third vaccine. The efficacy of the COVID-19 vaccine and concerns about adverse reactions had a significant impact on behavior regarding the third vaccination. A rapid increase in the booster dose rate is needed to control the pandemic, and specific approaches should be taken with these groups that are likely to hesitate over the third vaccine, subsequently increasing booster contact rate.

The serological diversity of serum IgG/IgA/IgM against SARS-CoV-2 nucleoprotein, spike, and receptor-binding domain and neutralizing antibodies in patients with COVID-19 in Japan.

Background: We compared the temporal changes of immunoglobulin M (IgM), IgG, and IgA antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleoprotein (N), spike 1 subunit (S1), and receptor-binding domain (RBD), and neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with coronavirus disease 2019 (COVID-19) to understand the humoral immunity in COVID-19 patients for developing drugs and vaccines for COVID-19. Methods: A total of five confirmed COVID-19 cases in Nissan Tamagawa Hospital in early August 2020 were recruited in this study. Using a fully automated chemiluminescence immunoassay analyzer, we measured the levels of IgG, IgA, and IgM against SARS-CoV-2 N, S1, and RBD and NAbs against SARS-CoV-2 in COVID-19 patients' sera acquired multiple times in individuals from 0 to 76 days after symptom onset. Results: IgG levels against SARS-CoV-2 structural proteins increased over time in all cases but IgM and IgA levels against SARS-CoV-2 showed different increasing trends among individuals in the early stage. In particular, we observed IgA increasing before IgG and IgM in some cases. The NAb levels were more than cut-off value in 4/5 COVID-19 patients some of whose antibodies against RBD did not exceed the cut-off value in the early stage. Furthermore, NAb levels against SARS-CoV-2 increased and kept above cut-off value more than around 70 days after symptom onset in all cases. Conclusion: Our findings indicate COVID-19 patients should be examined for IgG, IgA, and IgM against SARS-CoV-2 structural proteins and NAbs against SARS-CoV-2 to analyze the diversity of patients' immune mechanisms.

Serologic Survey of IgG Against SARS-CoV-2 Among Hospital Visitors Without a History of SARS-CoV-2 Infection in Tokyo, 2020-2021.

BACKGROUND: Tokyo, the capital of Japan, is a densely populated city of >13 million people, so the population is at high risk of epidemic severe acute respiratory coronavirus 2 (SARS-CoV-2) infection. A serologic survey of anti-SARS-CoV-2 IgG would provide valuable data for assessing the city's SARS-CoV-2 infection status. Therefore, this cross-sectional study estimated the anti-SARS-CoV-2 IgG seroprevalence in Tokyo. METHODS: Leftover serum of 23,234 hospital visitors was tested for antibodies against SARS-CoV-2 using an iFlash 3000 chemiluminescence immunoassay analyzer (Shenzhen YHLO Biotech, Shenzhen, China) with an iFlash-SARS-CoV-2 IgG kit (YHLO) and iFlash-SARS-CoV-2 IgG-S1 kit (YHLO). Serum samples with a positive result (≥10 AU/mL) in either of these assays were considered seropositive for anti-SARS-CoV-2 IgG. Participants were randomly selected from patients visiting 14 Tokyo hospitals between September 1, 2020 and March 31, 2021. No participants were diagnosed with coronavirus disease 2019 (COVID-19), and none exhibited COVID-19-related symptoms at the time of blood collection. RESULTS: The overall anti-SARS-CoV-2 IgG seroprevalence among all participants was 1.83% (95% confidence interval [CI], 1.66-2.01%). The seroprevalence in March 2021, the most recent month of this study, was 2.70% (95% CI, 2.16-3.34%). After adjusting for population age, sex, and region, the estimated seroprevalence in Tokyo was 3.40%, indicating that 470,778 individuals had a history of SARS-CoV-2 infection. CONCLUSIONS: The estimated number of individuals in Tokyo with a history of SARS-CoV-2 infection was 3.9-fold higher than the number of confirmed cases. Our study enhances understanding of the SARS-CoV-2 epidemic in Tokyo.

Response kinetics of different classes of antibodies to SARS-CoV2 infection in the Japanese population: The IgA and IgG titers increased earlier than the IgM titers.

To better understand the immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with COVID-19, it is important to investigate the kinetics of the antibody responses and their associations with the clinical course in different populations, since there seem to be considerable differences between Western and Asian populations in the clinical features and spread of COVID-19. In this study, we serially measured the serum titers of IgM, IgG and IgA antibodies generated against the nucleocapsid protein (NCP), S1 subunit of the spike protein (S1), and receptor-binding domain in the S1 subunit (RBD) of SARS-CoV-2 in Japanese individuals with COVID-19. Among the IgM, IgG, and IgA antibodies, IgA antibodies against all of the aforementioned viral proteins were the first to appear after the infection, and IgG and/or IgA seroconversion often preceded IgM seroconversion. In regard to the timeline of the antibody responses to the different viral proteins (NCP, S1 and RBD), IgA against NCP appeared than IgA against S1 or RBD, while IgM and IgG against S1 appeared earlier than IgM/IgG against NCP or RBD. The IgG responses to all three viral proteins and responses of all three antibody classes to S1 and RBD were sustained for longer durations than the IgA/IgM responses to all three viral proteins and responses of all three antibody classes to NCP, respectively. The seroconversion of IgA against NCP occurred later and less frequently in patients with mild COVID-19. These results suggest possible differences in the antibody responses to SARS-CoV-2 antigens between the Japanese and Western populations.

Seroprevalence of SARS-CoV-2 antibodies among hospital staff in rural Central Fukushima, Japan: A historical cohort study.

Performing a cohort-based SARS-CoV-2 antibody assay is crucial for understanding infection status and future decision-making. The objective of this study was to examine consecutive antibody seroprevalence changes among hospital staff, a high-risk population. A two-time survey was performed in May and October 2020 for 545 hospital staff to investigate the changes in the results of the rapid kit test and chemiluminescence immunoassay (CLIA). The seroprevalence of each assay was summarized at both the survey periods. The proportion of seropositive individuals in the CLIA for each survey period and the number of confirmed COVID-19 cases in Central Fukushima were then compared. We chose 515 participants for the analysis. The proportion of IgM seroprevalence in CLIA increased from 0.19% in May to 0.39% in October, and IgG seroprevalence decreased from 0.97% in May to 0.39% in October. The proportion of IgM seroprevalence in the rapid kit test decreased from 7.96% in May to 3.50% in October, and IgG seroprevalence decreased from 7.77% in May to 2.14% in October. The IgG and IgM antibody seroprevalence among hospital staff in rural Central Fukushima decreased; the seroprevalence among hospital staff was consistent with the number of confirmed COVID-19 cases in the Central Fukushima area. Although it is difficult to interpret the results of the antibody assay in a population with a low prior probability, constant follow-up surveys of antibody titers among hospital staff had several merits in obtaining a set of criteria regarding the accuracy of measures against COVID-19 and estimating the COVID-19 infection status among hospital staff.

The difference between IgM and IgG antibody prevalence in different serological assays for COVID-19; lessons from the examination of healthcare workers.

OBJECTIVES: The objective of this study was to investigate the differences between the results of two serology assays for detection of COVID-19 among medical staff, who are at higher risks of infection. METHODS: The immunochromatography (ICG) rapid test kit and the chemiluminescence immunoassay (CLIA) quantitative antibody test were performed. The differences in IgM and IgG antibody prevalence in different serological assays were descriptively analyzed. RESULTS: A total of 637 participants were included in this research. Two staff were IgM positive in the CLIA quantitative antibody test (cutoff value: 10 AU/ml) of 51 staff who were IgM positive in the rapid test kit. Six staff were IgG positive in the CLIA quantitative antibody test of 56 staff who were IgG positive in the rapid test kit. The proportion of antibody positive staff differed greatly between the rapid test kit and the CLIA quantitative antibody test. CONCLUSIONS: There was a vast difference in the proportions of IgG and IgM antibody positive staff in the rapid test kit and the CLIA quantitative antibody test results. The results from the only rapid test kit might have to be interpreted with caution. Further studies to evaluate antibody testing accuracy are required to promote the understanding of each assay's characteristics and determine their purposes in each community.