1. Protective effect of Natural ROTA virus infection A.J.Chitkara

2. Acknowledgement  Dr. Gagan deep Kang (co-author)  Prof. N.K.Arora (Director, INCLEN)  Prof. Piyush Gupta & Dr Dheeraj Shah (editors – Indian Pediatrics)  Dr. Umesh Parashar (CDC USA)  Rodrigo Deantonio Suarez (GSK biologicals)

3. VELLORE (Gladstone et al) MEXICO ( Velazquez et al) Time Period2002-20061987-1990 Number of children452, 83% (373 – 99.5% follow up) 200 (77% follow up) Child months139373699 Surveillance: visits/stoolTwice weekly/ every 2 wks & GE Weekly/ weekly & GE Rota detectionELISA & PCRELISA SerologyIgG & IgA Infections detected1103, 48% stool & 76 % serum 316, 57% stool & 77% serum Primary/ reinfection30 % / 70%52% / 48% Detection in Primary Stool/ serum48.5% /-74% / 72% Detection in reinfection Stool/ serum46.3% /-36% / 83% Age of infection (≤6 months) 56%34% Primary symptomatic30%47%

4. VelloreMexico Incidence: Infection Diarrhoea 0.99 (0.94-1.05) /child/yr 0.25 (0.22-0.29) /child/yr 1/child/yr 0.3/child/yr Infections by age 6/12/24/3656/81/96/99%34/67/96/- RVGE by age 6/12/24/3620/36/43/48NA serotypesG1P8 14%, G2P4 11.5%, G10P11 7.4%, G9P8 6.5%, G1P4 4.6%, G1P6 1.2%, G10P4 1.2%, G9P4 1% G3 35%, G1 20%, G2 15%, G4 6%

5. VelloreMexico Documented Infections/ GE (%) 1 2 3 4 5 or more 8.8 / 29.9 27.3 / 28.1 36.5 / 18.2 15.5 / 18 11.3 / 25.8 52/47 32/25 13/32 3/20 Severity (Vesikari score) 1-10 Mild 11-15 moderate 16-20 severe 27 % 34.5 % 67.4 % 28% primary & 19% 2 nd and 0% 3 rd were moderate to severe Pathogens ROTA NORO Giardia Mixed 36% 15.2% 8.5% 8% 10.3% NA

6. VelloreMexico Protection79% for mod/severe GE after 3 infections 100% for mod/severe GE after 2 infections Any GE (≥ 2)71%83% Mild RVGE72%75% Moderate RVGE57%100 Severe RVGE57%100 Asymptomatic infection 2/3 33/46%62/74% GE in seroconverted22% Homotypic protection??documented

7. Conclusions (Gladstone et al NEJM 2011)  Early age of infection 56% by 6 months  Frequent re-infections  High viral diversity  Lower rate of protection from any severity RVGE after natural infection  No evidence of homotypic protection  Modification of rotavirus vaccination strategies: dose/ frequency

8. Why poor protection from natural infection?  Earlier infection, interference with maternal antibodies- transplacental/ breast milk IgA  Is immunogenicity related to quantum of inoculation ?  majority of primary asymptomatic, may be less immunogenic  Does that mean symptomatic RV would offer more protection?  39% of primary RVGE & 19% of primary RV infection have a subsequent symptomatic rotavirus infection (Kang 2011)  No difference for protection between symptomatic/ asymptomatic infection (Velazquez 1996)  High prevalence of breast feeding (98% initiated & median duration 12 months) can not fully explain as breast fed children also had RVGE. No subgroup comparison available for BF/top fed  Other host factors ??

9.  Is this study done in the poorest SE strata representing 30% of Indian heterogeneous population applicable to the other SE strata?  Different perspectives  Possible, but no data available

10. Interpretation of Data in Table 3 “ Table 3 has very limited significance as it is based on small number of subject (44, 25, and 41 in each strain). The number of homotypic rotaviral infections or diarrhea are too small (mostly less than 1%) within each group for any valid interpretation. The results (P values) are not going to reach significance level because of this problem. It does not mean that there is no homotypic protection but only means that the data could not show any such evidence. This is most likely because of a very small number of subjects rather than actual lack of protection. Overall, we should not try to interpret too much from this table.” Editor’s Indian Pediatrics (personal communication)

11. Interpretation of Table 3  “From statistical point of view, analysis in Table 3 is adequate. The author’s used rate ratios ( a variant for relative risk) indicated for cohort studies to determine differences among rotavirus sero and genotyped incidence rates. Results need to be interpreted with caution as the numbers are small and the study was not powered to indicate differences among rotavirus types, but some trends are observed most of them with no statistical significance.”  Rodrigo Deantonio Suarez (personal communication)

12. Interpretation of Table 3 PLEASE REMEMBER THAT PROTECTION FROM HOMOTYPIC AND HETEROTYPIC INFECTION CAN ONLY BE DETERMINED BY STUDIES WHERE AT LEAST ONE INITIAL AND THEN ONE DIARRHOEAL SAMPLES WERE GENOTYPED AND A LOT OF INFECTIONS DETERMINED ONLY BY SEROLOGY THEREFORE HAVE TO BE EXCLUDED.WE SHOW THAT RATE RATIOS FOR SUBSEQUENT INFECTIONS DO NOT DIFFER BASED ON THE INITIAL INFECTING GENOTYPE, AND THEREFORE TAKEN TOGETHER WITH OUT WHOLE DATASET THERE IS NO EVIDENCE FOR EXCLUSIVELY HOMOTYPIC PROTECTION. THERE IS EXCELLENT CORROBORATION OF THIS FINDING FROM PUBLISHED VACCINE STUDIES THAT SHOW WITH THE GSK VACCINE THAT PROTECTION IS AGAINST ALL GENOTYPES. Gagandeep Kang (personal communication)

13. Implications For ROTA vaccines  Lower protection after natural RV infection demonstrated yet 80% protection after 3 infections.  Oral vaccines have suboptimal efficacy in developing countries  Efficacy 50-55% in African & Asian countries  High burden of disease may justify use of the existing vaccines  Rethinking: strategy/ vaccines  More number of doses !!

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