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 Primary
Stool/ serum
48.5% /-
74% / 72%
Detection in reinfection
Stool/ serum
46.3% /-
36% / 83%
Age of infection (≤6
months)
56%
34%
Primary symptomatic
30%
47%
Vellore
Mexico
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
6/12/24/36
56/81/96/99%
34/67/96/-
RVGE by age
6/12/24/36
20/36/43/48
NA
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%
serotypes
Vellore
Mexico
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%
2nd and 0% 3rd were
moderate to severe
Pathogens
ROTA
NORO
Giardia
Mixed
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 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
Why poor protection from natural infection?
 Earlier infection, interference with maternal antibodiestransplacental/ 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 perspectives
Possible, 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 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 !!
THANK YOU