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Poor post-vaccination production of antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a concern among solid organ transplant (SOT) recipients. Furthermore, the timing and kinetics of antibody titers after the second vaccine dose are unknown. We conducted a multicenter prospective observational study that included 614 SOT recipients: 460 kidney, 53 heart, 50 liver, 20 lung, and 31 simultaneous pancreas-kidney (SPK). The participants received two doses of the mRNA vaccine (Pfizer BNT162b2 or Moderna mRNA-1273), as indicated. Serum samples were collected before the first and second vaccinations and at 1, 3, and 6 months after the second vaccine dose, which were then assessed for SARS-CoV-2 antibodies. The overall seropositivity rate was 43% at 1 month after administration of the second vaccine dose; it gradually increased to 68% at 3 months after second dose administration and to 70% at 6 months. In addition, recipient of kidney, lung or SPK transplants had lower antibody titers at the 3- and 6-month time points than did the other recipients. SOT recipients acquired SARS-CoV-2 S-IgG antibodies slowly, and the peak titer differed significantly from that of the general population., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yoshio Hirota reports financial support was provided by Health Labor Administration. Yoshio Hirota reports a relationship with Japan Health Labor Administration that includes: funding grants. The authors of this manuscript have no conflicts of interest to disclose as described by the Vaccine. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In Japan, the Ministry of Health, Labour and Welfare (MHLW) designates one specific virus strain for each component of the quadrivalent seasonal influenza vaccine, and four domestic manufacturers produce egg-based influenza vaccines with the same formulation (inactivated, split-virus) using uniform vaccine strains. Thus, discussions of the development of effective seasonal influenza vaccines so far has focused solely on the antigenic match between the vaccine strains and epidemic viruses. However, in 2017, the Japanese selection system of vaccine viruses demonstrated that even a candidate vaccine virus that is antigenically similar to the predicted circulating viruses is not necessarily suitable for vaccine production, given lower productivity of the vaccine. Taking this experience into account, the MHLW reformed the scheme of vaccine strain selection in 2018, and instructed the Vaccine Epidemiology Research Group created by the MHLW to probe how the virus strains for the seasonal influenza vaccine should be selected in Japan. In this context, a symposium, entitled "Issues of the Present Seasonal Influenza Vaccines and Future Prospects", was held as part of the 22nd Annual Meeting of the Japanese Society for Vaccinology in 2018, and subjects related to the influenza vaccine viruses were discussed among relevant administrators, manufacturers, and researchers. This report summarizes the presentations given at that symposium in order to convey the present scheme of vaccine virus selection, the evaluation of the resulting vaccines, and the efforts at new vaccine formulation in Japan. Notably, from March 2022, the MHLW has launched a discussion of the merits of the seasonal influenza vaccines produced by foreign manufacturers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Takao Hozawa is an employee of Denka Co., Ltd. in Tokyo, Japan. All other authors declare that they are free of competing interests.’, (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: In the era of childhood pneumococcal conjugate vaccine (PCV) immunization, especially 13-valent pneumococcal conjugate vaccine (PCV13) immunization, serotype replacement of Streptococcus pneumoniae and herd immunity in adults have been reported worldwide. Therefore, continuous evaluation of the effectiveness of the pneumococcal vaccine in adults is crucial because vaccine effectiveness may change owing to these factors. The purpose of this study was to evaluate the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) against all-cause pneumonia and pneumococcal pneumonia in older individuals with community-acquired pneumonia (CAP) after the introduction of childhood PCV13 in Japan, a topic that has remained largely unexplored., Methods: We evaluated pneumococcal vaccine effectiveness in this multicenter, matched case-control study conducted in hospitals and clinics. Cases included patients (aged ≥ 65 years) newly diagnosed with CAP between October 2016 and September 2019. A maximum of five non-pneumonia control patients matched for sex, school grade, date of outpatient visit, and medical institution were selected for each case. Conditional logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of pneumococcal vaccines for the occurrence of all-cause CAP and pneumococcal CAP., Results: The analysis included 740 individuals (142 patients and 598 controls). The median age of participants was 75 years (men: 54%). The adjusted OR for pneumococcal vaccination against all-cause CAP was 1.31 (95% CI: 0.84-2.06), while that for PPSV23 vaccination in the previous 5 years was 1.33 (95% CI: 0.85-2.09). The adjusted OR for PPSV23 vaccination in the previous 5 years against pneumococcal CAP was 0.93 (95% CI: 0.35-2.50)., Conclusions: This study was unable to demonstrate the effectiveness of PPSV23 against all-cause and pneumococcal pneumonia after the introduction of childhood PCV13 in Japan. Nonetheless, additional studies are needed to validate these results., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Although several assays are used to measure anti-receptor-binding domain (RBD) antibodies induced after severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccination, the assays are not fully comparable in practice. This study evaluated the immunogenicity of the BNT162b2 mRNA vaccine in healthy adults using two immunoassays., Methods: This prospective cohort study included SARS-CoV-2-naïve adults, predominantly healthcare workers, aged 20-64 years, who received two BNT162b2 vaccine doses between March and May 2021. Blood samples were collected before the first vaccination (S0), before the second vaccination (S1), 4 weeks after the second vaccination (S2), and 6 months after the second vaccination (S3). anti-RBD antibodies were measured using the Architect SARS-CoV-2 IgG II Quant (Abbott Laboratory) and Elecsys anti-SARS-CoV-2 S (Roche Diagnostics) assays., Results: Among the 385 participants, the geometric mean antibody titers (GMTs) on the Architect assay (AU/mL) were 7.5, 693, 7007, and 1030 for S0, S1, S2, and S3, respectively. The corresponding GMTs on the Elecsys assay (U/mL) were 0.40, 24, 928, and 659, respectively. The GMT ratio (S3/S2) was 0.15 on the Architect and 0.71 on the Elecsys assay. The correlation between antibody titers measured with the two assays were strong at all time points after vaccination (Spearman's correlation coefficient: 0.74 to 0.86, P < 0.01 for all). GMT was significantly lower in the older age group after vaccination (P < 0.01), with no significant differences according to sex. Seroprotection (≥5458 AU/mL on the Architect assay and ≥ 753 U/mL on the Elecsys) at each time point was 0 %, 1 %, 67 %, and 1 % on the Architect assay and 0 %, 1 %, 62 %, and 43 % on the Elecsys, respectively., Conclusions: Two BNT162b2 vaccine doses resulted in adequate anti-RBD antibody response, which varied by age. As the two assays showed different kinetics, the results of single immunoassays should be interpreted with caution., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In Japan, a monovalent mumps vaccine is provided on a voluntary basis. Due to public concerns over post-vaccination aseptic meningitis, the vaccination coverage is not high enough. The present study investigated the incidence of adverse events, including aseptic meningitis, after Torii strain-derived mumps vaccination., Methods: This retrospective, observational study used data collected by a vaccine manufacturer regarding adverse events following mumps vaccinations at medical institutions between 1992 and 2018. In addition, the number of Torii strain-derived mumps vaccines shipped each year was obtained. The incidence (per 100,000 doses) and 95% confidence intervals (CIs) were calculated for all adverse events and each adverse event, categorized as aseptic meningitis, encephalitis, mumps, mumps complications, and others., Results: During the study period, 8,262,121 mumps vaccine doses were shipped, and 688 subjects reported adverse events. The incidence for all adverse events (per 100,000 doses) was 8.33, and the incidence was 4.19 for aseptic meningitis, 0.33 for encephalitis, 0.80 for mumps, 0.25 for mumps complications, and 3.78 for others. The incidence of aseptic meningitis (per 100,000 doses) was 7.90 (95% CI: 5.61-10.18) between 1998 and 2000 but declined by half, to 3.91 (2.46-5.36), between 2001 and 2003. The most recent incidence (per 100,000 doses) of aseptic meningitis, for the period 2016 to 2018, was 2.78 (1.94-3.62)., Conclusion: The incidence of post-vaccination aseptic meningitis has declined significantly since 2001, and the incidence has remained stable at fewer than 3 cases per 100,000 doses since 2010. Multiple factors might have contributed to the decline in aseptic meningitis incidence, including (i) lowered misclassification of aseptic meningitis resulting from echovirus infection; (ii) changes in the vaccine manufacturing process in 2000; and (iii) publication in 2008 of the recommendation for vaccination of children at 1 year of age., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yoshio Hirota reports financial support was provided by The Ministry of Health, Labor and Welfare, Japan. Takashi Nakano reports a relationship with Takeda Pharmaceutical Co Ltd that includes: speaking and lecture fees. Takashi Nakano reports a relationship with Daiichi Sankyo Co., Ltd that includes: speaking and lecture fees., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: The Japanese national immunization program recommends that children receive 4 doses of acellular pertussis vaccine between 3 months and 2 years of age. Nevertheless, the number of pertussis cases is increasing in elementary school children aged 6-12 years. Therefore, a test-negative case-control study was conducted to assess the effectiveness of the pertussis vaccine program., Methods: Subjects included children aged ≥3 months who visited a collaborating hospital due to pertussis-specific cough between October 2017 and November 2019. All subjects underwent diagnostic tests for pertussis, and those diagnosed as positive were regarded as cases. Subjects diagnosed as pertussis-negative were classified as controls. Vaccination history was collected using a questionnaire administered to parents with reference to immunization records. Logistic regression models were employed to calculate the odds ratio (OR) and 95% confidence interval for laboratory-confirmed pertussis., Results: Of 187 recruited subjects (120 cases and 67 controls), questionnaire responses were obtained for 145 subjects (95 cases and 50 controls). Compared with unvaccinated subjects, the vaccine effectiveness (VE) of 4 doses was 70% among all subjects and reached to 90% with marginal significance among subjects under 6 years of age. However, among school-aged subjects, the VE was not suggestive of protection against pertussis (VE: 8%). For vaccinees given 4 doses, the OR for developing pertussis increased significantly with longer duration since the fourth dose (compared with <4.5 years, OR of 6.0-8.2 years = 5.74; OR of ≥8.3 years = 3.88; P for trend by duration < 0.01)., Conclusion: Effectiveness of administering 4 doses of pertussis vaccine during infancy decreases with time passed since the fourth dose. This regimen does not protect school-aged children against pertussis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: For the 2017-18 influenza season, A/Saitama/103/2014 (CEXP-002) (Saitama strain) was antigenically more similar to prior circulating strains than A/Hong Kong/4801/2014 (X-263) (Hong Kong strain) in a ferret model and was selected as the A(H3N2) vaccine virus strain in Japan. However, the Saitama strain grew poorly, and the Japanese government switched to the Hong Kong strain, raising public concerns of poor effectiveness. To enhance understanding of the correlation between antigenicity in experimental models and immunogenicity, as a surrogate measure of vaccine effectiveness, in the human population, we compared the immunogenicity of specially-prepared single dose monovalent influenza A(H3N2) vaccines containing the Saitama or the Hong Kong strain., Methods: A randomized controlled trial of 100 healthy adults aged 20-64 years (n = 50/group) was conducted. Virus neutralization assay was performed on sera from days 0 (pre-vaccination) and 21 (post-vaccination). Geometric mean titer (GMT), mean fold rise (MFR), seroconversion proportion (SCP), and seroprotection proportion (SPP) were calculated for vaccine strains and a representative circulating A(H3N2) virus strain (A/Osaka/188/2017)., Results: For the Hong Kong strain, post-vaccination GMT was significantly higher in the Hong Kong vaccine recipients (1:546 vs 1:260, p < 0.01), but MFR, SCP, and SPP were similar for both vaccine groups. For the Saitama strain, post-vaccination GMT (1:116 vs 1:61, p = 0.01) and SPP (86% vs 68%, p = 0.03) were significantly higher in the Hong Kong vaccine recipients, but MFR and SCP were similar for both vaccine groups. Against A/Osaka/188/2017, post-vaccination GMT and MFR were similar in both vaccine groups, but SCP (32% vs 4%, p < 0.01) and SPP (28% vs. 6%, p < 0.01) were significantly higher in the Hong Kong vaccine recipients., Conclusion: The Hong Kong vaccine induced better or equivalent immunogenicity in comparison to the Saitama vaccine. Our trial showed that antigenic similarity in experimental models does not necessarily correlate with immunogenicity in the human population., Clinical Trial Registration: UMIN000029293., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘TK has received a reward for advisor tasks from The Biken Foundation from April 2016 to March 2018. The other authors have nothing to declare’., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Immunogenicity studies on pandemic influenza vaccine are necessary to inform rapid development and implementation of a vaccine during a pandemic. Thus, strategies for immunogenicity assessment are required., Objective: To identify essential factors to consider when evaluating the immunogenicity of pandemic influenza vaccines using the experience in Japan with the influenza A(H1N1)pdm09 vaccine., Methods: We conducted a search of observational studies using PubMed and IchushiWeb. Search terms included "influenza vaccine AND (immunogenicity OR immune response) AND Japan AND (2009 OR pdm09) NOT review," and was limited to studies conducted in humans., Results: A total of 33 articles were identified, of which 16 articles met the inclusion criteria. Immunogenicity of the commercially available influenza A(H1N1)pdm09 vaccine satisfied the international criteria for influenza vaccine immunogenicity in all study populations. The most remarkable immune response was observed in junior high school students, while the lowest immune response was observed in hematological malignancy patients. Similar to immunogenicity studies on seasonal influenza vaccines, factors such as patient background (e.g., age, underlying condition, pre-vaccination titer, body mass index, etc.) and study procedure (e.g., concurrent measurement of pre- and post-vaccination antibody titer, effects of infection during the study period) may have affected the assessment of immunogenicity to the influenza A(H1N1)pdm09 vaccine. In addition, prior vaccination with the seasonal influenza vaccine may inhibit antibody induction by the influenza A(H1N1)pdm09 vaccine., Conclusions: This review discusses factors and strategies that must be considered and addressed during immunogenicity assessments of pandemic influenza vaccines, which may provide useful information for future influenza pandemics., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Influenza vaccines minimize the risk of influenza-related morbidity, complication, and death in elderly people. Although evaluating vaccine effectiveness (VE) is important for promoting immunization programs and coping with influenza epidemics, it is difficult to evaluate its effectiveness in Japan, where no frameworks to use large databases, such as a vaccination registry and health maintenance organization datasets, are available. Therefore, another analytic epidemiological investigations to evaluate VE in Japan are required. Herein, we describe the basic principles of a cohort study, which might be the most comprehensive, but expensive, study design. It is particularly important to be aware of the potential bias and confounding factors that should be minimized in the study design and analysis. We focus on "laboratory-confirmed influenza" and "influenza-like illness", and discuss why it is important to follow up with equal intensity, and how to control for bias; problems that often arise in population-based observational cohort studies., (Copyright © 2017. Published by Elsevier Ltd.)

In Japan, the Vaccine Epidemiology Research Group created by the Ministry of Health, Labour and Welfare has played an important role in demonstrating the solid scientific basis for vaccine efficacy and safety since 2002. Members of the group, including epidemiologists, clinicians and microbiologists, have been conducting collaborative studies on vaccines for influenza, pertussis, rotavirus gastroenteritis, polio and pneumonia. So far, the group has achieved several works and contributed to the national vaccination program, including research on the immunogenicity of low doses of influenza vaccine among young children, the immunogenicity and effectiveness of the 2009 influenza pandemic vaccine among various risk groups, the interchangeability of live/inactivated polio vaccines, the health impact of influenza on pregnant women, and the monitoring of influenza vaccine effectiveness using case-control studies with a test-negative design. As part of the 18th Annual Meeting of the Japanese Society of Vaccinology, these accomplishments were featured in the Vaccine Epidemiology Symposium. This report summarizes the recent epidemiological studies on vaccine in Japan as a prologue to the next six papers collected from the symposium., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Since the 1990s, self-controlled designs including self-controlled case series (SCCS) studies have been occasionally used in post-marketing evaluation of drug or vaccine safety. An SCCS study was tentatively applied to evaluate the relationship between oseltamivir use and abnormal behavior Type A (serious abnormal behavior potentially leading to an accident or harm to another person) in influenza patients., Methods: From the original prospective cohort study with approximately 10,000 Japanese children and adolescents with influenza (aged <18years), 28 subjects (mean age: 7.3years) who developed abnormal behavior Type A after the first visit to the collaborating hospitals/clinics were analyzed. We hypothesized four combination patterns of the effect period (i.e., the period that effect of oseltamivir on occurrence of abnormal behavior Type A is likely) and the control period. Mantel-Haenszel rate ratio (M-H RR) and its 95% confidence interval (CI) were calculated as the relative risk estimate., Results: Among 28 subjects in the SCCS study, 24 subjects (86%) were administered oseltamivir and 4 subjects (14%) were not. Abnormal behavior Type A was more likely to occur in the effect period than the control period in every pattern (M-H RR: 1.90-29.1). We observed the highest estimate when the effect period was set between the initial intake of oseltamivir and T max (M-H RR: 29.1, 95% CI: 4.21-201)., Conclusion: Abnormal behavior Type A was more likely to develop up to approximately 30 times during the period between the initial intake of oseltamivir and T max . However, this period overlapped with the early period of influenza where high fever was observed. Since useful approaches to control the influence of the natural disease course of influenza were not available in this study, we could not deny the possibility that abnormal behavior was induced by influenza itself. The SCCS study was not an optimal method to evaluate the relationship between oseltamivir use and abnormal behavior., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

To evaluate influenza disease burden among pregnant women, an epidemiological study using the self-control method was conducted. Study subjects were 12,838 pregnant women who visited collaborating maternity hospitals and clinics in Osaka Prefecture, Japan, before the 2013/14 influenza season. As a study outcome, hospitalization due to respiratory illnesses between the 2010/11 and 2013/14 seasons was collected from each study subject through a baseline survey at the time of recruitment and a second survey after the 2013/14 season. The hospitalization rates during pregnancy and non-pregnancy periods was calculated separately. To compare the hospitalization rate during pregnancy with that during non-pregnancy within the same single study subject, Mantel-Haenzel rate ratios (RR MH ) were calculated. During the four seasons examined in this study, nine and 17 subjects were hospitalized due to respiratory illnesses during pregnancy and non-pregnancy periods, respectively. The hospitalization rate was 2.54 per 10,000 woman-months during pregnancy and 1.08 per 10,000 woman-months during non-pregnancy. The RR MH for the hospitalization rate during pregnancy compared with that during non-pregnancy was 4.30 (95% confidence interval, 1.96-9.41). Our results suggest that during the influenza season, pregnant women have a higher risk than non-pregnant women for hospitalization due to respiratory illnesses. The self-control method appears to be an appropriate epidemiological method for evaluating the disease burden of influenza among pregnant women., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

When using a case-control study design to examine vaccine effectiveness, both the selection of control subjects and the consideration of potential confounders must be the important issues to ensure accurate results. In this report, we described our experience from a case-control study conducted to evaluate the effectiveness of acellular pertussis vaccine combined with diphtheria-tetanus toxoids (DTaP vaccine). Newly diagnosed pertussis cases and age- and sex-matched friend-controls were enrolled, and the history of DTaP vaccination was compared between groups. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of vaccination for development of pertussis. After adjustment for potential confounders, four doses of DTaP vaccination showed a lower OR for pediatrician-diagnosed pertussis (OR=0.11, 95% CI, 0.01-0.99). In addition, the decreasing OR of four doses vaccination was more pronounced for laboratory-confirmed pertussis (OR=0.07, 95%CI, 0.01-0.82). Besides, positive association with pertussis was observed in subjects with a history of steroid treatment (OR=5.67) and those with a recent contact with a lasting cough (OR=4.12). When using a case-control study to evaluate the effectiveness of vaccines, particularly those for uncommon infectious diseases such as pertussis, the use of friend-controls may be optimal due to the fact that they shared a similar experience for exposure to the pathogen as the cases. In addition, to assess vaccine effectiveness as accurately as possible, the effects of confounding should be adequately controlled with a matching or analysis technique., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Based on the unique characteristics of influenza, the concept of "monitoring" influenza vaccine effectiveness (VE) across the seasons using the same observational study design has been developed. In recent years, there has been a growing number of influenza VE reports using the test-negative design, which can minimize both misclassification of diseases and confounding by health care-seeking behavior. Although the test-negative designs offer considerable advantages, there are some concerns that widespread use of the test-negative design without knowledge of the basic principles of epidemiology could produce invalid findings. In this article, we briefly review the basic concepts of the test-negative design with respect to classic study design such as cohort studies or case-control studies. We also mention selection bias, which may be of concern in some countries where rapid diagnostic testing is frequently used in routine clinical practices, as in Japan., (Copyright © 2017. Published by Elsevier Ltd.)

We conducted a case-control study to elucidate associations between pneumonia in elderly individuals and 23-valent pneumococcal polysaccharide vaccine (PPSV23) and seasonal influenza vaccine (influenza vaccine). Here, we examined selection of controls in our study using an analytic epidemiology approach. The study period was from October 1, 2009 through September 30, 2014. Cases comprised ≥65-year-old patients newly diagnosed with pneumonia. For every case with pneumonia, two patients with other diseases (one respiratory medicine, one non-respiratory medicine) who were sex-, age-, visit date- and visit hospital-matched were selected as controls. Odds ratios (ORs) and 95% confidence intervals (CIs) of vaccination for pneumonia were calculated using conditional logistic regression model. Similar analyses were also conducted based on the clinical department of controls. Analysis was conducted in 234 cases and 438 controls. Effectiveness of pneumococcal vaccination or influenza vaccination against pneumonia was not detected. Proportions of either vaccination in controls were greater among respiratory medicine (pneumococcal vaccine, 38%; influenza vaccine, 55%) than among non-respiratory medicine (23%; 48%). Analysis using controls restricted to respiratory medicine showed marginally significant effectiveness of pneumococcal vaccination (OR, 0.59; 95%CI, 0.34-1.03; P=0.064) and influenza vaccination (0.64; 0.40-1.04; 0.072). However, this effectiveness might have been overestimated by selection bias of controls, as pneumonia cases are not necessarily respiratory medicine patients. In the analysis using controls restricted to non-respiratory medicine, OR of pneumococcal vaccination for pneumonia was close to 1, presumably because the proportion of pneumococcal vaccination was higher in cases than in controls. Because pneumococcal vaccine was not routinely administered during the study period, differences in recommendations of vaccination by physician in different clinical departments might have greatly affected vaccination proportions. When we select controls, we should consider the background factors (underlying diseases, clinical department, etc.) which affect physicians' recommendation of vaccination., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In order to assess factors associated with reactogenicity of trivalent inactivated influenza vaccine (IIV3) among young children, data on 1538 vaccinees aged 0-5 years in a previous vaccine effectiveness study were analyzed. The most frequent reaction was redness (19%), followed by induration, swelling, itching, and pain (6-12%); there were no serious adverse events. For some local reactions, multivariate analyses indicated associations of younger age, preschool attendance, presence of siblings, and allergy with lower risk, and use of thinner needles with higher risk. Most notably, administration of one or more IIV3 vaccines during the previous 3 seasons was positively associated with each local reaction (adjusted odds ratios: 3.6-5.4). For subjects aged ≥3 years, prior successive annual vaccinations were associated with substantially increased local reactions, with clear dose-response relationships (P for trend: <0.001 for each); for example, an 9.8-fold greater risk of swelling following three successive annual vaccinations before the study season., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In 2008, the number of pertussis cases increased substantially among Japanese adolescents, despite high coverage with acellular pertussis vaccine (DTaP). This study examined the effectiveness of DTaP vaccine in the routine immunization program in Japan. Between April 2009 and October 2012, we conducted a multicenter, case-control study, and compared the history of DTaP vaccination between 55 newly diagnosed pertussis cases and 90 age- and sex-matched controls. DTaP vaccine history was obtained by a self-administered questionnaire completed by their parents or guardians. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) of vaccination for development of pertussis. DTaP vaccination of ≥1 dose revealed a significantly lower OR for pertussis (OR=0.20, 95%CI, 0.04-0.97), and the OR of complete vaccination (4 doses) was 0.22 (0.04-1.05). Even after limiting subjects to those whose vaccination status could be confirmed by the immunization records, the negative associations were observed. The decreasing ORs of 4-dose vaccinees remained, even among subjects who had received the fourth dose ≥9.2 years earlier (OR=0.11, 95%CI, 0.01-1.02). In conclusion, DTaP vaccination had a preventive effect for pertussis. Effectiveness was observed even 9 or more years after the final dose., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In order to estimate the effectiveness of an influenza A (H1N1) 2009 monovalent vaccine among pregnant women, we prospectively observed 135 Japanese pregnant women who received an influenza A (H1N1) 2009 monovalent vaccine during November 2009. We calculated an index of "antibody efficacy", in which the medical visits for respiratory illnesses were compared between those with and without post-vaccination hemagglutination inhibition (HI) titer ≥1:40. The product of antibody efficacy and achievement rate is theoretically equivalent to the vaccine effectiveness. Among all subjects, an inverse but non-significant relationship during the epidemic period was observed between post-vaccination HI titer ≥1:40 and medical visits for respiratory illnesses. After stratification by trimester at recruitment, a significant inverse association during the epidemic period was found among subjects in the first or second trimester (antibody efficacy: 91%, vaccine effectiveness: 79%). The influenza A (H1N1) 2009 monovalent vaccine administered in the first or second trimester reduced medical visits for respiratory illnesses among Japanese pregnant women., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Subjects with severe motor and intellectual disability (SMID) are considered to be debilitated and at high risk of influenza infection. However, the safety and immunogenicity of pandemic H1N1 (pH1N1) vaccine in these subjects have not been reported. We measured the hemagglutination inhibition antibody titer and calculated the geometric mean titer ratio (GMTR), seroprotection rate, and seroconversion rate in 104 subjects with SMID (mean age±standard deviation 40.1±12.9 years), and in 179 healthcare workers (40.7±10.4 years) in a long-term care facility. Antibody responses after the first dose of pH1N1 vaccine among workers were greater than the European Medicines Evaluation Agency criteria and US Food and Drug Administration (FDA) criteria: the seroprotection rate was 79.9% (95% confidence interval (CI) 73.3-85.5), the seroconversion rate was 77.9% (95%CI: 70.8-84.0), and GMTR was 7.3 (95%CI: 6.9-7.8). Responses among subjects with SMID were lower than the FDA criteria: the seroprotection rate was 56.3% (95%CI: 46.2-66.1), the seroconversion rate was 54.1% (95%CI: 43.7-64.2), and GMTR was 5.4 (95%CI: 4.9-5.9). Any additional antibody response induced by the second dose of vaccine among subjects with SMID was limited. Multivariate analysis indicated that subjects with SMID had a significantly lower seroprotection rate (odds ratio (OR) 0.37, 95%CI: 0.20-0.66) and seroconversion rate (OR 0.34, 95%CI: 0.20-0.59) than healthcare workers. No serious adverse reaction was reported in either group. These results indicate that a single dose of pH1N1 vaccine does not induce sufficient immunity among subjects with SMID, and a second dose is likely to be ineffective because of diminished immunogenicity. Further study is required to determine if vaccination over consecutive influenza seasons can improve immunogenicity in subjects with SMID., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Influenza vaccination efficacy was evaluated in 114 institutionalized elderly people in 2002/03. Strain A/H3N2 was isolated; 44 and 8 subjects had sudden-onset fever (> or = 37.8 degrees C) and kit-diagnosed influenza, respectively. Odds ratios adjusted for age, sex, comorbidity, and vaccine strain (OR(adj)) were determined using multiple logistic regression. Seroprotected patients (haemagglutination-inhibition antibody titre > or = 1:40) had lower incidence of fever (OR(adj), 0.35; 95% confidence interval [CI], 0.09-1.28) and kit-diagnosed influenza (OR(adj), 0.35; 95% CI, 0.03-4.64) than patients without seroprotection (antibody efficacy, approximately 65%). Seroprotective levels of vaccination-induced antibodies probably prevent influenza among the institutionalized elderly, although statistical significance could not be confirmed owing to the sample size., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The aim of the present study was to investigate the influenza vaccine effectiveness among young children in Japan. Study subjects were recruited from 43 pediatric clinics. Influenza-like illness (ILI) was defined as an acute febrile illness with respiratory symptoms; ILI with a fever of > or =39 degrees C was considered to be severe ILI (SILI). The adjusted OR of vaccination significantly decreased to 0.75 for SILI. Influenza vaccination for young children had a protective effect on the occurrences of SILI. This study also indicated that three key tools (case surveillance with equal scrutiny, confining observation to the peak epidemic period, and adoption of strict criteria for ILI) could minimize outcome misclassification and thus provide adequate methodology for monitoring vaccine effectiveness without laboratory confirmation.

The fundamental issue in assessing influenza vaccine efficacy is to observe all study subjects with equal intensity throughout the surveillance period. The case definition can be adopted within the scope of the budget and the logistics of the study; however, there is no doubt that culture-proven influenza is currently the best outcome index. More pronounced vaccine efficacy can be detected if stricter case definition criteria are applied and/or if observations are confined to the peak epidemic period. Patients identified through passive case-finding in clinics do not properly represent all influenza cases that occur in the study subjects. Almost all non-randomized studies which have so far been conducted by Japanese clinicians do not take confounders into consideration. Even though laboratory-confirmed influenza is identified, vaccine efficacy should primarily be estimated based on the presence of any influenzal illness, since efficacy calculated by virus type or subtype often results in loss of statistical power. The results from post hoc subgroup analysis may not offer a solid base for assessing vaccine efficacy and should be cautiously interpreted.

In 1976, influenza mass vaccination among schoolchildren was started under the Preventive Vaccination Law, which was intended to control epidemics in the community. However, in the late 1980s, questions about this policy and vaccine efficacy arose, and a campaign against vaccination began. In 1994, influenza was excluded from the target diseases list in the Preventive Vaccination Law, without considering the immunization policy with respect to the common indications in high-risk groups. In 2001, the Law was again amended, specifying target groups, such as the elderly aged 65 or over, for influenza vaccination. In the 2005--2006 season, vaccine coverage among the elderly reached 52%. This shows that the need for vaccination has gradually become understood. However, the anti-vaccination campaign, which claims that the influenza vaccine has no efficacy, is still active. Vaccine efficacy studies that were not properly conducted are also being reported. In 2002, the Ministry of Health, Labor, and Welfare organized a research group on vaccine efficacy consisting of epidemiologists. The present symposium, as part of the 9th Annual Meeting of the Japanese Society for Vaccinology in 2005, was planned to further introduce epidemiological concepts useful in studying influenza vaccine efficacy.

Selection bias is of critical concern in the study of influenza vaccine effectiveness when using an observational study design. This bias is attributable to the inherently different characteristics between vaccinees and non-vaccinees. The differences, which are related both to vaccination and signs of clinical disease as an outcome, may lead to erroneous estimation of the effectiveness. In this report, we describe how selection bias among elderly nursing home residents may lead to a spurious interpretation of the protective effect of influenza vaccine. Our results should be a lesson in the importance of regarding selection bias when assessing influenza vaccine effectiveness.

This study, done during the 2002--2003 season among children <6 years of age to investigate influenza vaccine effectiveness and confounding factors, involved 2913 children (1512 vaccinees, 1401 non-vaccinees) recruited from 54 paediatric clinics. Between December 2002 and April 2003, parents reported their children's maximum body temperatures weekly. Influenza-like illness (ILI) was defined as an acute febrile illness (> or =38.0 degrees C) during the peak epidemic period. Adjusted odds ratios (ORs) for ILI were obtained using a logistic regression model. In analysis for total subjects, the ORs were significantly decreased for vaccinees (OR: 0.76, 95% CI: 0.66-0.88) and significantly increased for younger age groups, including children aged 2.0-3.9 years (1.42, 1.18-1.72) and those < 2.0 years (2.02,1.61-2.54), compared to those between 4.0 and 5.9 years. ORs were significantly increased for children who visited a physician within the last 6 months for a cold (1.27, 1.08-1.50), attended preschool (1.72, 1.45-2.04), and had > or =3 siblings (1.42, 1.15-1.74). These confounding factors are suggested to be considered in estimating vaccine effectiveness among young children. In subgroup analysis by age groups, significantly decreased ORs were seen in 2.0-3.9-year-old (0.59, 0.47-0.74) and 4.0-5.9-year-old (0.75, 0.58-0.98) vaccinees; no significant vaccine effectiveness was detected for those < 2.0 years (1.07, 0.80-1.44). Thus, among very young children vaccine effectiveness could not be demonstrated.

In 1979, Maebashi City discontinued influenza mass vaccination immediately after a case of vaccine-related convulsion occurred. A research group of the Maebashi City Medical Association studied the effects of mass vaccination on influenza activity in two cities without mass vaccination programs and three cities with mass vaccination programs (Maebashi Study). Due to possible issues of validity arising from the non-randomized design of the study, the authors of the Maebashi Study reserved discussion on the vaccine efficacy that they calculated from the attack rates among the non-vaccinees and vaccinees. Instead, they compared the overall attack rates in Maebashi and among the twice-vaccinees in the cities with mass vaccination programs. The authors limited their discussion to the fact that influenza activity in Maebashi was not materially different from that in cities with mass vaccination programs. Anti-vaccination activists misconstrued this to mean that the absence of a correlation between attack rate and vaccine coverage implies that influenza vaccine has no efficacy. This is a good example of the "ecological fallacy", which refers to the fact that a relationship between two variables at the population level does not necessarily imply the same relationship at an individual level.

To construct a framework for monitoring the effectiveness of influenza vaccine, we retrospectively surveyed elderly (> or = 65 years old) people living in rural areas of Kyoto prefecture, Japan, using a self-administered questionnaire, for their influenza-related symptoms during the peak influenza season of 2003-2004. A total of 2301 elderly individuals responded, of whom 1533 (66.6%) had been vaccinated. The odds ratio (OR) of vaccination for fever of > or = 38 degrees C, adjusted for sex, age and underlying conditions, was 0.77 (95% confidence interval (CI), 0.40-1.47), and the OR for a diagnosis of influenza in clinics was 0.81 (95% CI, 0.41-1.57). These findings suggested that the vaccine was 20% effective, although this effectiveness was not statistically significant.

This study was carried out to investigate the effectiveness of influenza vaccine among 2913 children (1512 vaccinees and 1401 nonvaccinees) under 6 years of age during the 2002-2003 season. Study subjects were recruited from 54 paediatric clinics, located in eight areas in Japan. Maximum body temperatures were obtained weekly from parents between 2002 December 16 and 2003 April 13. Influenza-like illness (ILI) was defined as an acute febrile illness (> or =38.0 degrees C) during the peak epidemic period in each study area. The vaccine antigens included were A/New Caledonia/20/99(H1N1), A/Panama/2007/99(H3N2) and B/Shandong/7/97. Vaccine effectiveness was analyzed by comparing the frequencies of ILI between vaccinees and nonvaccinees. The adjusted odds ratio (OR) and its 95% confidence interval (95% CI) were calculated by the proportional odds model using logistic regression with three-level outcome variables (<38.0/38.0-38.9/> or =39.0 degrees C). A significantly decreased OR of vaccination was observed (OR: 0.76; 95% CI: 0.66-0.88), corresponding to a vaccine effectiveness (1-OR) of 24% (95% CI: 12%-34%). When the analysis was confined to those aged > or =2 years, a more pronounced OR (0.67, 0.56-0.79) was obtained with a vaccine effectiveness of 33% (21%-44%). On the other hand, no significant vaccine effectiveness was detected among very young children; the ORs were 1.84 (0.81-4.19) for those <1 year of age and 0.99 (0.72-1.36) for those 1.0-1.9 years of age and 1.07 (0.80-1.44) when these two age groups were combined. Thus, among very young children vaccine effectiveness could not be demonstrated.

The immune response and serum nutritional status of 153 elderly residents of nursing homes (mean age 84.4 years) and 95 health care workers (mean age 36.8 years) were assessed before and after immunization with trivalent split-virus influenza vaccine. Postvaccination titers of hemagglutination inhibition (HAI) antibody to A/H1N1 and B among the elderly were lower than those among workers, but the seroconversion rates (greater than or equal to a four-fold rise) for A/H1N1 and A/H3N2 were unexpectedly higher among the elderly than among workers. However, the difference in the seroconversion rate for either strain between workers and the elderly disappeared after adjusting for the prevaccination HAI titer. Among all subjects, lower age and higher serum concentrations of total protein, albumin, Vitamin E and folate were associated with an intact immune response (postvaccination HAI titers >/=40 for at least one strain). In an age-adjusted analysis limited to the elderly, however, only Vitamin E showed a significant association with the immune response. These results suggested that Vitamin E may play an important role in maintaining the immune response, especially among the elderly.

This study expands and updates through 1995 our earlier report on influenza vaccine use in 18 developed countries. Five of the six countries with high levels of vaccine use in 1992 (> or = 130 doses/1000 population) showed little change or slight declines over the subsequent 3 years. The exception was the United States, where a new federal program for vaccination reimbursement for the elderly helped to increase vaccine distribution from 144 to 239 doses/1000 population. The six countries with medium levels of vaccine use in 1992 (76-96 doses/1000 population) increased to > or = 100 doses/1000 population by 1995. Among the six low-use countries in 1992 (< or = 65 doses/1000 population), only Finland showed substantial improvement (96 doses/1000 population) in 1995. Four new countries were added to the study. In Germany, vaccine use increased to 80 doses/1000 population in 1995, but in Ireland it remained at a low level (48 doses/1000 population). In Korea, vaccine use increased from 17 to 95 doses/ 1000 population during the period 1987-1995. In Japan, very high levels of vaccine use (approximately 280 doses/1000 population) in the early 1980s were associated with vaccination programs for school children. However, vaccine use fell precipitously when these programs were discontinued, and only 2 and 8 doses/1000 population were used in 1994 and 1995, respectively. In all 22 countries, higher levels of vaccine use were associated with vaccination reimbursement programs under national or social health insurance and were not correlated with different levels of economic development. Excluding Japan, in 1995 there was still a greater than fourfold difference between the highest and lowest levels of vaccine use among the other 21 countries in the study. Given its well established clinical effectiveness and cost-effectiveness, none of these countries has yet achieved the full benefits of its programs for influenza vaccination.

The efficacy of the influenza vaccine is often understimated, due to the dilution of the outcome by noninfluenzal illnesses. We thus explored the methodology to evaluate the effect of the inactivated influenza vaccine under the following strict conditions: an assessment of the effectiveness on clinical illness among healthy adults in a small-scale mixed epidemic during the 1991-1992 season. The vaccine antigens included were A/Yamagata/32/89 (H1N1), A/Beijing/352/89 (H3N2), and B/Bangkok/163/90. Two indices were analyzed: "vaccine efficacy", a comparison between the vaccinees and the nonvaccinees; and "antibody efficacy", a comparison between those with and those without a protective level of pre-epidemic hemagglutination-inhibition (HAI) antibody. The odds ratio (OR) and its 95% confidence interval (95% CI) was calculated by the logistic regression model. A decrease in the age-adjusted OR of vaccination was not statistically significant: 0.54 (95% CI: 0.19-1.53) corresponding to vaccine efficacy (1-OR) of 46% (-53% to 81%). Among the vaccinees, a significantly decreased OR in those with a higher titer to A/Beijing was observed: 0.14 (0.02-0.92) adjusted for the mutual effects of pre-epidemic antibodies to different vaccine antigens. The adjusted ORs thus calculated for A/Yamagata and B/Bangkok were not found to be statistically significant. The antibody efficacy (1-OR) was estimated to be 86% (8% to 98%) against illnesses related to A/Beijing-like viruses. The product of antibody efficacy (86%) and the proportion of those who achieved a protective level of antibody after vaccination (73% for A/Beijing strain) was 63%, which is theoretically equivalent to the vaccine efficacy. Thus, the antibody efficacy is considered to be an important index, while the vaccine efficacy against clinical illnesses is easily disturbed by extraneous factors in the field trials.

The immunogenicity of the trivalent split-virus influenza vaccine was investigated among 70 healthy adults (mean age: 48.5, range: 36-68). The vaccine antigens were: A/Yamagata/32/89 (H1N1); A/Beijing/352/89 (H3N2); and B/Bangkok/163/90. Regarding the entire sample, the vaccine induced a tenfold or more rise on the average in the hemagglutination inhibition (HAI) antibody to each antigen. The response rates (greater than or equal to a fourfold rise) were about 90% or more among those with a prevaccination titer < or = 1:64 (equivalent to < or = 1:16 on the Western scale; in Japan, the HAI titers are expressed by the final, and not the initial, dilution of the serum; from hereon our findings will be expressed using the Japanese scale), whereas they were 0-50% at > or = 1:128. Thus, the prevaccination titer was negatively associated with antibody induction. The achievement rates (postvaccination titer > or = 1:128) among those with a prevaccination titer < 1:16 remained at 48-68%. Regarding the analysis of variance, a significant effect on antibody induction was indicated for the prevaccination titer (P < or = 0.002), but not for age (P > or = 0.425). The interaction between the prevaccination titer and age was significant for A/Yamagata (P = 0.030), while it was also suggestive for A/Beijing (P = 0.054): as age increased, those with no preexisting antibody (< 1:16) showed greater titer rises, in contrast to the smaller rises among those with a titer > or = 1:16. Based on the attack survey conducted separately, the vaccine efficacy on influenza-like illnesses with fever < or = 37 degrees C and > or = 37.5 degrees C was calculated to be 16% (95% confidence interval: -66% to 57%) and 37% (-55% to 74%), respectively.