1. EPIDEMIOLOGY OF INFNT DENGUE CASES ILLUMINATES SEROTYPE- SPECIFICITY IN THE INTERACTION BETWEEN IMMUNITY AND DISEASE AND CHANGES IN TRANSMISSION DYNAMICS

2. INTRODUCTION The research on dengue disease was carried out in Bangkok in Thailand. The age group used was children under the age of 1 year, since infant cases have fairly uniform antibodies titers across serotypes and thus avoids the uncertainty of timing and also time period that infants are at high is of infection with severe outcome is short. The other countries that are epidermis to dengue disease are Vietnam, Indonesia and Philippines. Dengue disease is caused by DENV flavivirus (DENV-2 and DENV-4).

3. INTRO CONT Infants borne to dengue-immune mothers gain dengue antibodies which decreases over the first year and it become susceptible to dengue infection. This study also considers the interaction between antibody titre and disease. In this case, dengue case data from Queen Sirikit National Institute of child health, was investigated between 1973-2012. The relationship between antibody levels and disease outcomes was also investigated and compared to other ages and immunity groups. They too studies on the changes in dengue case numbers and mean age of severe infant cases over time.

4. MATERIALS AND METHODS Material 1.Public Health samples- Colllected during passive surveillance of hospitalized dengue cases from 1973-2012. 2.Clinical blood samples- Acute and convalescent blood samples from clinically suspected dengue inpatient at Queen Sirikit National Institute of Child Health (QSNICH) were tested for evidence of DENV infection at Armed Forces Research Institute of Medical Sciences (AFRIMS). Methods a)Viral isolation- used for testing acute blood samples. b)Hemi-nested reverse transcriptase polymerase chain Reaction (RY-PCR) also used for testing acute convalescent blood samples.

5. Methods cont c) Dengue serological assay- used for testing acute convalescent blood samples. d) Dengue hemagglutination inhibition assay- used for testing primary infection serologically. e) enzyme-linked immunosorbent assay (ELISA) was used to capture dengue IgM/IgG. Statistical analysis The cases were grouped into 3 groups: a)Primary cases- aged less than 1year old and were refered to as infant primary cases. b)Primary cases aged more than 1 year (>1yr) non infant primary cases. c)Post-primary cases of all ages and only 40 of 21090 were post primary cases below 1 year of age.

6. Methods cont The results of each group were calculated as per the proportion of cases that were in each serotype and for each serotype, the proportion of cases that were in each group. Using Pearson correlations, the correlation between the annual numbers of cases in each group for each serotype was assessed. Mean ages for cases of each serotype was calculated in infant primary cases over all years and mean age for all serotypes for each year. Generalized linear models was used to assess trends over time and relationship between annual mean age and annual proportion of all cases in infants and analysis performed.

7. RESULTS The serotype distribution in infant in primary case is similar to post- primary cases in non-infants. DENV-1 causes many cases of about 35% in both primary infants and post-primary non-infants while DENV-2 has about 31% cases. DENV-1 cause primary non-infant cases of 57% and 5% by DENV-2. DENV-3 have a slight difference of 22% and 27% in primary infants and post-primary cases respectively, and this represent 37% of primary non-infant cases. DENV-4 have few cases of 12% post-primary, 4% of infant primary and 1% primary non-infant cases.

8. Results cont

9. DISCUSSION The serotype distribution of hospitalized dengue cases in different immune groups depends majorly on immune status. Few primary cases of DENV-2 and DENV-4 has been shown in Thailand where infants exposed to such serotypes represents the exposure of dengue naïve individuals over 1 year. The findings can be interpreted in 2 mutual ways: 1.DENV-2 and DENV-4 were less likely to cause disease to immunocompromised individuals compared to DENV-1 and 3. 2.DENV-2 and DENV-4 were more likely to cause disease in an enhanced post-primary infection than DENV-1 and DENV-3.

10. DISCUSSION CONT These results suggested that the 1 st way is the most likely explanation, with the correlation between the annul case number in each group, being lower for DENV-2 and DENV-4, than for DENV-1 and 3, suggesting the significance of immunity in the population. These difference may also explain the contradictory results between infant DHF and increased levels of enhancing activity in sera for DENV-2 but not DENV-3. Its also suggests the under representation of DENV-4 in infant primary cases compared to the secondary cases. Difference between serotypes should be considered in vaccination trials for both immune and non-immune individuals.

11. Discussions cont Observed differences in the mean age in infants by serotypes ( highest in DENV-1 and 3 followed by DENV-2 then DENV-4) could be due to 2 non-mutual reasons: 1.High force of infection for the serotypes with lower mean age. Suggesting high force of infection for DENV-2 and DENV4 compared to DENV-1 and DENV-3. 2.Differential waning of the antibody titers by serotype leading to potential enhancement occurring at different ages for different serotypes.

12. Discussion cont The small but significant increase in mean age of infant cases over time (especially 1990-2007) is consistent with the increase in mean age of dengue seen in the general population of Thailand. This could have been due to reduction in the force of infection. Both trends are consistent with a decrease in FOI during this period. After 2007 however,a decrease in the mean age of infant cases and an increase in the proportion of cases in infants was observed, suggesting an increase in FOI during this period. A change in the mean age of infants over time and by serotypes was also shown. The study suggest that infants can act as sentinel population for understanding population level of transmission together by being informative about immune-mediated pathogenesis.

13. CONCLUSION

14. GENERAL GROUP OPINION In infants DENV-2 and DENV-4 cause disease in presence of dengue antibody