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• A test-negative case-control study examined an effectiveness of pertussis vaccine. • 4 doses of vaccine provided a high effectiveness in subjects under 6 years of age. • Vaccine effectiveness declines with time passed since the fourth dose. • 4 doses of pertussis vaccine have no preventive effect for school-aged children. 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. 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. 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). 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. [ABSTRACT FROM AUTHOR]

Abstract While the basic definition of vaccination-associated acute disseminated encephalomyelitis (ADEM) is relatively clear and easily understandable, it is often difficult to diagnose ADEM based on clinical findings alone. ADEM is actually a heterogeneous clinical syndrome that can be approximately characterized by encephalomyelitis with multiple inflammatory demyelination, autoimmune causes, and relationship with a preceding infection or vaccination. The differential diagnosis of ADEM should exclude the possibility of infectious or other autoimmune encephalitis. The occurrence of vaccination-associated ADEM is influenced by several factors including the health and ethnic status of the vaccinated individual, vaccine components, and environment. Cases suspected of vaccination-associated ADEM should be analyzed cautiously from multi-disciplinary perspectives. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Freeze dried, cell culture-derived Japanese encephalitis vaccine (Inactivated) (JEBIK®V) is approved for a three-dose primary immunization followed by a one-dose booster immunization in Japan. We conducted a multicenter, double-blinded, randomized controlled trial of the safety and immunogenicity of the vaccine in 370 healthy children who received three doses of 5, 2.5 or 1.25μg of virus protein per 0.5mL formulation subcutaneously. Children received two doses of test vaccine 7–28 days apart followed by a dose 6–12 months after the second vaccination. The three-dose regimen showed a good safety profile with no serious vaccine-related adverse events. Fever and reactions at the injection site were common adverse reactions at each dose of vaccine. The seroconversion rates were 100%, 99.2% and 95.0% after two doses in the 5, 2.5 and 1.25μg groups, respectively, and 100.0% after three doses in all groups. The geometric mean titers were high for all three formulations after the second and third doses, with a very clear dose–response relationship. These results indicate that JEBIK®V is likely to be a useful vaccine. [Copyright &y& Elsevier]

Abstract: The incidence of reported cases with pertussis has increased in young adults in Japan and the lack of additional booster immunizations containing pertussis components is suspected to be one of the causal reasons. Instead of DT immunization at 11–12 years of age, safety and immunogenicity were investigated using 0.2ml and 0.5ml of DTaP. 176 subjects in DTaP 0.5ml, 178 in DTaP 0.2ml, and 197 in DT 0.1ml groups were enrolled in clinical trial. The relative risk of local reactions in the DTaP 0.2ml group compared to the DT 0.1ml group was 1.13 (95% CI: 0.97–1.30), and that of the DTaP 0.5ml to the DT 0.1ml group was 1.34 (95% CI: 1.18–1.53). The relative risks of local pain and heat were 1.62 (95% CI: 1.33–1.98) and 1.59 (95% CI: 1.19–2.13), respectively, in the DTaP 0.5ml group compared to the DT 0.1ml group. Sero-positive rates against PT and FHA were 54% and 82% before immunization and increased to >95% for both after vaccination with no significant difference in GMT. Instead of the scheduled DT program, 0.2ml of DTaP was acceptable and demonstrated efficient immunogenicity. [ABSTRACT FROM AUTHOR]

• In Japan, Prenatal DTaP vaccination lacks required safety information. • Pertussis seroprevalence is approximately 70% among pregnant Japanese women. • Maternal antibody titers in early pregnancy reflect infant antibody titers. • Preconception DTaP vaccination is one way to obtain maternal immunity. • A national survey to evaluate the safety information of prenatal DTaP is necessary. An increasing number of countries have been introducing acellular pertussis vaccination during pregnancy for the prevention of neonatal pertussis. In response to the fact that infantile pertussis cases of 0–5 months age groups remained unchanged despite the universal vaccination program, prenatal pertussis vaccination has been a rising issue in Japan. Hence, we investigated the seroprevalence of pertussis, diphtheria, and tetanus antibodies in Japanese pregnant women and neonates, and evaluated the necessity of diphtheria-tetanus-acellular pertussis (DTaP) vaccination during the preconception or prenatal period. Maternal PT-IgG (EIA) and FHA-IgG (EIA) for the first trimester, within 1 week after delivery, and cord blood were collected, along with colostrum pertussis-IgA (ELISA), diphtheria-IgG (EIA), tetanus-IgG (EIA), and blood samples from the first trimester. The maternal seroprevalence of PT-IgG and FHA-IgG was 69 % and 75 %, respectively. All tested participants were positive for diphtheria-IgG and tetanus-IgG (100 %). First trimester PT-IgG/FHA-IgG antibody titers were significantly associated with cord blood PT-IgG/FHA-IgG titers (P < 0.001). We found that pertussis seroprevalence among pregnant Japanese women was approximately 70 %. The antibody seropositivity rate of pertussis was lower than that of diphtheria and tetanus. Fetal acquired passive immunity against pertussis is higher when the level of maternal antibody in the first trimester is sufficient. At least 30 % of study population did not reach to the threshold value to provide sufficient pertussis immunity for the neonates and themselves. The acellular pertussis vaccine (DTaP) approved in Japan lacks safety information for pregnancy, hence, a solution for prompt administration of prenatal acellular pertussis vaccination might be introducing DTaP in the preconception period. [ABSTRACT FROM AUTHOR]

Summary: Recently, the incidence of reported pertussis cases of adults has dramatically increased in Japan. In the present study, we analyzed seven Bordetella pertussis isolates recovered from adults in Japan using pulsed-field gel electrophoresis (PFGE) and sequencing of their antigenic and virulence-associated proteins, compared with those from children. PFGE analysis demonstrated that the adult strains were closely related to the child strains (78–100% genetic similarity). On the other hand, the genotyping revealed that 71% (5/7) of the adult strains and 47% (25/53) of the child strains had the same combination of antigenic/virulence-associated allelic variants (ptxS1B/prn1/fim2-1/fim3A/fhaB1/tcfA2) as the Japanese vaccine strain Tohama, respectively. In comparison to the child strains, there was no apparent antigenic and genetic shift in the adult strains. Our result suggests that (i) there is no B. pertussis circulating strain specific to adults and (ii) the antigenic/virulence-associated proteins are unrelated to the rise in adult pertussis incidence in Japan. [Copyright &y& Elsevier]

Abstract: Vaccinations for children with allergic diseases often need to be postponed or terminated because of the presumed risk of an immediate-type allergic reaction such as anaphylaxis. A new skin test protocol for predicting allergic reactions using the vaccine itself and the following stepwise vaccination method were developed and tested. Intradermal tests using 1:10 and 1:100 diluted measles vaccine indicated that the former was superior to the latter because a positive reaction against 1:10 diluted vaccine was found in 28.6% of 49 patients with severe allergic diseases including bronchial asthma, atopic dermatitis, food allergies and allergies to two or more allergens with high levels of IgE, as compared with the reaction against 1:100 diluted vaccine in 10.2% of the patients. Patients negative for 1:10 skin tests were safe from the following full-dose vaccine shots. Three patients showed very strong local reactions against measles vaccine, and avoided receiving the following full-dose shot. Positive reactions to skin tests of 1:10 diluted vaccine were found in 11 patients, who were given stepwise vaccinations. Three patients had adverse reactions, and two of them had been negative for 1:100 skin tests. In the case of influenza vaccine, skin tests were again more sensitive to 1:10 than to 1:100 diluted vaccine, because 3 out of 14 patients with positive reactions showed immediate-type adverse reactions against the following stepwise vaccinations, and 1 of them was negative for the 1:100 skin test. Moreover, the results of the skin prick test (undiluted vaccine) and the intradermal skin test (1:10 diluted vaccine) indicated that the latter was more useful in both cases of measles (54 patients) and influenza vaccine (69 patients). Overall, the skin test using 1:10 diluted vaccine was the more suitable for predicting an immediate-type reaction to measles and influenza vaccinations. Patients having negative 1:10 skin tests can be expected to show no adverse reactions to the remaining injections and even the positive subjects will complete the course of vaccine doses by the stepwise method. [Copyright &y& Elsevier]

Highlights • An active surveillance through a phased introduction of the Hib vaccine in Japan was studied. • Hib disease incidence decreased significantly after vaccine introduction. • Hif and non-typeable H. influenzae were isolated from a few cases. • Serotype replacement was not observed after the introduction of the Hib vaccine. • Continuous capsular typing and strain identification surveillance is important. Abstract Background Haemophilus influenzae type b (Hib) vaccine was introduced as a voluntary vaccine in December 2008 and was included in the national routine immunization program in April 2013 in Japan. Currently, no nationwide data are available to evaluate the effectiveness of Hib vaccine in Japan. Methods To evaluate the effectiveness of Hib vaccine in Japan, nationwide active population-based surveillance of culture-proven invasive infections caused by H. influenzae in children was performed in 2008–2017 in 10 prefectures in Japan (covering approximately 23% of the total Japanese population). Clinical data were recorded on a standardized case report form. Capsular type and antimicrobial susceptibility of the H. influenzae isolates were examined. The incidence rate ratio (IRR) and its confidence interval (CI) were calculated to compare data from 5 years before and that from after the introduction of the national routine Hib vaccine immunization program. Results During the 10-year study period, 566 invasive H. influenzae disease cases including 336 meningitis cases were identified. The average number of invasive H. influenzae disease cases among children <5 years of age during 2013–2017 decreased by 93% (IRR: 0.07, 95%CI 0.05–0.10, p < 0.001) compared with those occurring during 2008–2012. Hib strains have not been isolated from invasive H. influenzae disease cases since 2014; however, non-typeable H. influenzae and H. influenzae type f isolates have been noted as causes of invasive H. influenzae diseases among children <5 years in the post-Hib vaccine era. Conclusions After the governmental subsidization of the Hib vaccine, invasive Hib disease cases decreased dramatically in the study population, as per our surveillance. Continuous surveillance is necessary to monitor the effectiveness of Hib vaccine and for detecting any emerging invasive capsular types. [ABSTRACT FROM AUTHOR]

Although anaphylaxis is an extremely rare vaccine-associated adverse event, it occurred in young children following administration of the 2011/12 seasonal split influenza vaccine, which contained 2-phenoxyethanol as the preservative. These children had high levels of IgE antibodies against influenza vaccine components. We herein investigated why these children were sensitized. One hundred and seventeen series of serum samples were obtained immediately before, and one month after the first and second immunizations with the HA split vaccine of 2011/12. Forty-two sequential serum samples were collected in the acute and convalescent phases (2 and 4 weeks) after natural infection with H1N1 Pdm in 2009. IgE antibodies developed following the vaccination of young children with seasonal split vaccines, whereas no significant IgE response was observed following natural infection with H1N1 Pdm 2009. The prevalence of IgE antibodies was not influenced by outbreaks of H1N1 Pdm. Repeated immunization with the HA split vaccine induced IgE sensitization against the influenza vaccine irrespective of the H1N1, H3N2, or B influenza subtypes. The reasons why anaphylaxis only occurred in recipients of the influenza vaccine containing 2-phenoxyethanol are still being investigated, and the size distribution of antigen particles may have shifted to a slightly larger size. Since the fundamental reason was IgE sensitization, current split formulation for the seasonal influenza vaccine needs to be reconsidered to prevent the induction of IgE sensitization. [ABSTRACT FROM AUTHOR]

Background In Japan, the seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2010. PCV13 has replaced PCV7 since November 2013. Methods The effectiveness of PCV7 in protecting against invasive pneumococcal disease (IPD) in children aged <5 years was evaluated in a nationwide active population-based surveillance of IPD in 2008–2013 in 10 prefectures in Japan. Results 1181 cases were identified; 711 pneumococcal strains were analyzed for serotyping and antimicrobial resistance. Compared with the baseline IPD incidence (25.0 per 100,000), a 98% decline in IPD caused by PCV7 serotypes was found after the introduction of PCV7. This was partially offset by an increased incidence of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes, resulting in a 57% decline in overall IPD incidence. Absolute increases in the incidence rates of IPD caused by PCV13 minus PCV7 and non-PCV13 serotypes were 2.1 and 2.8 per 100,000 during the study period, respectively. The proportion of meropenem-nonsusceptible strains, especially with serotypes 19A and 15A, increased significantly after PCV7 introduction. Conclusions Our data confirmed a 98% decline in IPD incidence caused by PCV7 serotypes in children aged <5 years and serotype replacement after PCV7 introduction. This shows the importance of continuing surveillance of serotypes responsible for IPD and their antimicrobial resistance in Japan. [ABSTRACT FROM AUTHOR]

Severe local swelling has been regarded as a serious safety problem for the booster immunisations of diphtheria tetanus acellular pertussis combined (DTaP) vaccine and DT combined toxoids (DT-td). We attempted to search for the factor of DTaP vaccines possibly contributing to the enhanced local reaction by using the mouse hind paw swelling reaction. Mice were immunised intramuscularly with DTaP vaccine twice at 1-month interval and were challenged their hind paw with one of the antigens of DTaP vaccine 2 weeks later. D-td was shown to elicit the strongest swelling among the vaccine antigens. No causal relationship was found between the swelling and the level of immunoglobulin G (IgG) or IgE in mice. Residual pertussis toxin (PT) activity of DTaP vaccines for immunisation was shown to play a role in the enhanced sensitisation of mice to the D-td-related hind paw swelling. [Copyright &y& Elsevier]