שנת סיום: 2021
כותרת עבודת הדוקטורט: Sex Differences in Infectious Diseases and the Association between Sex Hormones and the Immune Response to Pertussis Vaccine in Pregnant and non-Pregnant Women
מנחים: פרופ' מנפרד גרין
Background
The importance of evaluating sex differences in disease and role of sex hormones in the modulation of the immune system is an increasing area of interest in the understanding of the mechanisms of infectious diseases. Sex differences in the incidence rates for various infectious diseases have long been reported (1-4). However, for most diseases, the direction and magnitude of the sex differences at different ages and consistency over different countries and time periods have not been systematically evaluated. The mechanisms are not clear. Behavioral differences can explain some of the differences, but there is evidence that genetic factors and sex hormones are likely to play a part (5).Sex differences have been observed in the response to some vaccines and it has been postulated that sex hormones may play a part (6-8). Since pregnancy is associated with tremendous changes in concentrations of sex hormones such as estradiol, estriol, progesterone and prolactin, these hormonal changes may impact on the immune response to vaccines given during pregnancy.There were two main aims of the studies in this dissertation.The first was to determine the magnitude and consistency of the male to female incidence rate ratios for different infectious diseases over different countries and time periods.The second aim was to assess the immune response to pertussis vaccine during pregnancy compared with non-pregnant women, together with their sex hormone status.
Methods
In part 1, meta-analytic methods were used to assess sex differences in the male to female incidence rate ratios for five diseases – viral meningitis, pertussis, shigellosis, salmonellosis and rotavirus disease. Age and sex-specific national data were obtained for 6-27 years for five to nine countries. The male to female incidence rate ratios (IRR) were computed for each country and age group. For each age group, meta-analytic methods were used to combine the incidence rate ratios over countries and time periods. Heterogeneity was assessed using Q statistics and I2 and the appropriate model used. In order to explore associations of the IRRs with age-group, country and time period, meta-regression analyses were performed . To evaluate the effect of individual county and reported years on the incidence rate ratio, we performed leave-one-out sensitivity analysis and recomputed the pooled IRRs.In part 2, in order to determine the impact of pregnancy and sex hormones on the response to pertussis vaccine, two cross-sectional studies were carried out – one on pregnant women before the delivery and the other on non-pregnant women. Blood samples were drawn – in the pregnant women 4-24 hours before delivery and in the non-pregnant women at the time of immunization and 45-50 days later. The blood samples were assayed for anti-pertussis antibodies and sex hormones. The t-test was used to compare the two groups in post-immunization log transformed (geometric mean concentrations, GMC) pertussis antibody levels. Multiple regression analysis was carried out to assess the association between pertussis antibodies following immunization and estrogen and progesterone in each group, controlling for age, BMI and smoking status.
Results
First part. The male to female incidence rate ratio varied over age groups and for different diseases. We found stable estimates of the extent of the excess male incidence rates in majority of diseases. In the age groups <1, 1-4, 5-9 and 10-14, there was a remarkably consistent excess morbidity in males over countries and time for viral meningitis, salmonellosis, shigellosis and rotaviral enteritis. Unlike these diseases, pertussis incidence rates by age group in nine countries over a period of six to 27 years revealed stable and higher pertussis incidence rates in females than in males in all age groups from infancy to older adults.Second part. Pregnant women who were vaccinated against pertussis toxin developed significantly lower IgG levels. Younger age of non-pregnant females and lower levels of estrogen were associated with higher antibody levels. In pregnant females group there was a strong association between the antibody levels and estrogen and progesterone levels.