Oseltamivir use and severe abnormal behavior in Japanese children and adolescents with influenza: Is a self-controlled case series study applicable?

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 Tmax (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 Tmax. 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.

Effectiveness of an influenza A (H1N1) 2009 monovalent vaccine among Japanese pregnant women: a prospective observational study assessing antibody efficacy.

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.

Immunogenicity of a monovalent 2009 influenza A (H1N1) vaccine among pregnant women: lowered antibody response by prior seasonal vaccination.

BACKGROUND: Pregnant women are a high-risk group for influenza-associated complications and hospitalizations. METHODS: To examine the immunogenicity of a monovalent 2009 influenza A (H1N1) vaccine among pregnant women, a prospective cohort study was performed at 2 medical institutes of obstetrics in Japan. One hundred fifty subjects received 2 subcutaneous doses of vaccine 3 weeks apart. The hemagglutination inhibition antibody titer was measured in serum samples collected at 3 time points: before vaccination, 3 weeks after the first dose, and 4 weeks after the second dose. RESULTS: The first dose of vaccine induced a ≥ 10-fold rise in the average level of antibody. The seroresponse rate (≥4-fold rise) was 91%, and the seroprotection rate (postvaccination titer ≥ 1:40) was 89%. The second dose of vaccine conferred little additional induction of antibodies. Similar immune responses were observed irrespective of body mass index before pregnancy, trimester, or age at vaccination. However, lesser immune response was shown in subjects who had received the 2009-2010 seasonal influenza vaccine before the H1N1 vaccination. CONCLUSIONS: A single dose of vaccine induced an adequately protective level of immunity in pregnant women. The potential interference with seasonal vaccination requires a more thorough investigation to prepare for future influenza pandemics.