Protective effect of Natural ROTA virus infection

A.J.Chitkara

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)

VELLORE (Gladstone et al)

MEXICO ( Velazquez et al)

Time Period 2002-2006 1987-1990

Number of children 452, 83% (373 – 99.5% follow up)

200 (77% follow up)

Child months 13937 3699

Surveillance: visits/stool Twice weekly/ every 2 wks & GE

Weekly/ weekly & GE

Rota detection ELISA & PCR ELISA

Serology IgG & IgA IgG & IgA

Infections detected 1103, 48% stool & 76 % serum

316, 57% stool & 77% serum

Primary/ reinfection 30 % / 70% 52% / 48%

Detection in PrimaryStool/ serum 48.5% /- 74% / 72%

Detection in reinfectionStool/ serum 46.3% /- 36% / 83%

Age of infection (≤6 months)

56% 34%

Primary symptomatic 30% 47%

Vellore Mexico

Incidence:InfectionDiarrhoea

0.99 (0.94-1.05) /child/yr0.25 (0.22-0.29) /child/yr

1/child/yr0.3/child/yr

Infections by age6/12/24/36 56/81/96/99% 34/67/96/-

RVGE by age6/12/24/36 20/36/43/48 NA

serotypes G1P8 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%

Vellore Mexico

Documented Infections/ GE (%)12345 or more

8.8 / 29.927.3 / 28.136.5 / 18.215.5 / 1811.3 / 25.8

52/4732/2513/323/20

Severity (Vesikari score)1-10 Mild11-15 moderate16-20 severe

27 %34.5 %67.4 %

28% primary & 19% 2nd and 0% 3rd were moderate to severe

PathogensROTANOROGiardiaMixed

36%15.2%8.5%8%10.3%

NA

Vellore Mexico

Protection 79% for mod/severe GE after 3 infections

100% for mod/severe GE after 2 infections

Any GE (≥ 2) 71% 83%

Mild RVGE 72% 75%

Moderate RVGE 57% 100

Severe RVGE 57% 100

Asymptomatic infection 2/3

33/46% 62/74%

GE in seroconverted 22%

Homotypic protection ?? documented

Conclusions (Gladstone et al NEJM 2011)

Early age of infection 56% by 6 monthsFrequent re-infectionsHigh viral diversityLower rate of protection from any severity

RVGE after natural infectionNo evidence of homotypic protectionModification of rotavirus vaccination

strategies: dose/ frequency

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 ??

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

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)

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)

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)

Implications For ROTA vaccines

Lower protection after natural RV infection demonstrated yet 80% protection after 3 infections.

Oral vaccines have suboptimal efficacy in developing countriesEfficacy 50-55% in African & Asian countries

High burden of disease may justify use of the existing vaccines

Rethinking: strategy/ vaccinesMore number of doses !!

THANK YOU