This document provides information on Rotavirus gastroenteritis (RVGE) and rotavirus vaccines in India, with a focus on vaccine 116E. It discusses how RVGE is a major cause of childhood diarrhea and mortality in India. It summarizes clinical trial results showing the 116E vaccine is effective at preventing severe RVGE, has a good safety profile with no increased risk of intussusception compared to other vaccines, and provides broad protection against circulating rotavirus strains in India. Phase 3 and 4 trials demonstrated 116E is well-tolerated and effective in preventing severe RVGE in Indian children when administered in a 3-dose schedule.

1. RVGE & Vaccines – Indian Data
Dr. Gaurav Gupta,
Practising Pediatrician, Charak Clinics,
Mohali.

2. That can't be right. I read the news all the time. I read about plane crashes and freak
accidents. Where is the news about these half-million kids dying?'

3. Scope
• RVGE in India
• Indian Data on vaccines
• 116E vaccine
• Comparing vaccines

4. ROTAVIRUS GASTROENTERITIS & VACCINATION 4
4
Source: Mehendale S et al. Expanded Indian National Rotavirus Surveillance Network in the Context of Rotavirus Vaccine Introduction. Indian Pediatr. 2016
Jul 8;53(7):575-81.

5. Rotavirus is associated with 40% of
hospitalization for diarrhea
Source: Kang G et al. Multicenter, hospital-based surveillance of rotavirus disease and strains among indian children aged <5 years. J Infect Dis. 2009 Nov 1;200 Suppl
1:S147-53.

6. Health Care costs due to Rotavirus
Infections
India spends Rs. 2.8 - 3.7 billion annually
Source: J. E. Tate et al. Disease and economic burden of rotavirus diarrhea in India/Vaccine 27 S (2009) F18–F24

7. Vaccine effectiveness
With current immunization coverage and vaccine efficacy,
– 686,277 outpatient visits,
– 291,756 hospitalizations
– 26,985 deaths
can be prevented annually in India
7
Source: John J et al. Rotavirus gastroenteritis in India, 2011-2013: revised estimates of disease burden and potential impact of vaccines. Vaccine. 2014 Aug 11;32 Suppl 1:A5-
9.
3 preventable deaths in the time we finish this
session
33 hospitalizations in the time we finish this
session

8. Proportion of Rotavirus Positive cases
by age
Source: Kang G et al. Multicenter, hospital-based surveillance of rotavirus disease and strains among indian children aged <5 years. J Infect Dis. 2009 Nov 1;200 Suppl
1:S147-53.

9. Source: Satarupa Mullicka, Paulami Mandala ; Vaccine 32S (2014) A20–A28 Hospital based surveillance and genetic characterization of rotavirusstrains in children (<5
years) with acute gastroenteritis in Kolkata,India, revealed resurgence of G9 and G2 genotypes during 2011–2013
G9
39%
G2
39%
G1
16%
G12
6%
Hospitalized children1
G9
23%
G2
41%
G1
26%
G12
10%
OPD cases1
G9 & G12 rising across India & are important cause of Hospitalization in children
Vaccine needs to have strong heterotrophic protection
Hospital based Surveillance for Rotavirus Serodiversity

10. Rotavirus Strain Diversity in India
Diversity within India
continuously shifting
though the yrs & in each
region (N, S, E & W)
Source: Kang G, Desai R, Arora R, Chitamabar S, Naik TN, Krishnan T, Deshpande J, Gupte MD, Venkatasubramaniam S, Gentsch JR, Parashar UD; Indian Rotavirus Strain
Surveillance Network,Mathew A, Anita Sr, Ramani S, Sowmynarayanan TV, Moses PD, Agarwal I, Simon A, Bose A, Arora R, Chhabra P, Fadnis P,Bhatt J, Shetty SJ, Saxena
VK, Mathur M, Jadhav A, Roy S, Mukherjee A, Singh NB.Diversity of circulating rotavirus strains in children hospitalized with diarrhea in India, 2005-2009. Vaccine. 2013 Jun
12;31(27):2879-83.

11. QUIZ
What all is TRUE about RVGE?
1. Diarrhea precedes Vomiting
2. 1/3 children can have fever above 102 F
3. Foul-smelling green / brown stools
4. Blood in stools
5. Average duration of LM is 10-14 days

12. QUIZ
What all is TRUE about RVGE?
1. Diarrhea precedes Vomiting
2. 1/3 children can have fever above 102 F
3. Foul-smelling green / brown stools
4. Blood in stools
5. Average duration of LM is 10-14 days

13. QUIZ
Rotavirus vaccines available in India
• RV 1 =
• RV 5 =
• 116E =
• BRV-PV =

14. QUIZ
Rotavirus vaccines available in India
• RV 1 = Rotarix
• RV 5 = Rotateq
• 116E = Rotavac / Rotasure
• BRV-PV = Rotasiil

15. What is 116E?
In the mid-1980s, neonates born at the AIIMS (New Delhi)
were commonly infected with a rotavirus strain before
hospital discharge that was later encoded 116E.
Source: 1. Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet.
2014 Jun 21;383(9935):2136-43.
These infants remained asymptomatic and experienced 46%
fewer episodes of rotavirus diarrhea than babies who were
not neonatally infected

16. Why 116E?
Source: 1. Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet.
2014 Jun 21;383(9935):2136-43. 2. Aiyar J, Bhan MK, Bhandari N, Kumar R, Raj P, Sazawal S. Rotavirus specific antibody response in saliva of infants with rotavirus diarrhea. J
Infect Dis 1990; 162:1383–4.
Because rotaviruses do not commonly infect infants in the first few
months of life, this strain was unique in that it grew in the presence of
trans-placental antibodies from the mother.2
Heterotypic protection across a broad array of commonly circulating
rotavirus genotypes in India strongly suggests that 116E will provide
protection throughout India and in other regions of the world.1

17. Clinical data
116E

18. 116E: Dose escalation study
Conclusion
• 3 administrations of vaccine doses of 1x104 ffu and 1x105 ffu were safe
• 1x105 ffu dose of 116E demonstrated a robust immune response after 3
administrations
Source: Bhandari N et al. A dose-escalation safety and immunogenicity study of live attenuated oral rotavirus vaccine 116E in infants: a randomized, double-blind, placebo-
controlled trial. J Infect Dis. 2009 Aug 1;200(3):421-9.

19. Vaccine
(n=4354)
Placebo
(n=2187)
Vaccine efficacy
Severe RVGE 1% 3% 56.4%
Very Severe RVGE
<1% <1% 49.8%
Severe RVGE
needing
hospitalization
1% 3% 56.4%
Phase III clinical study: Efficacy at 1
year
Source: Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet. 2014
Jun 21;383(9935):2136-43.

20. Vaccine (4354) Placebo (2187) Vaccine efficacy
Severe RVGE 93(2%) 102(5%) 55%
Very Severe RVGE 12 (<1%) 14(<1%) 57.2%
Severe RVGE
needing
hospitalization
92 (2%) 102(5%) 55.6%
RVGE of any
severity
406 (9%) 310(14%) 36.4%
Source: Nita Bhandari et all; Vaccine 32S(2014) A110-A116; Efficacy of monovalent human bovine rotavirus vaccines in Indian children in 2nd year of life
Phase III clinical study: Efficacy at 2
year

21. Heterotypic protection
Protection offered by
this vaccine during the
first 2 years of life is
against the array of
commonly circulating
genotypes
This suggests that the vaccine could offer significant protection in varying geographical
settings and over time.
Source: Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life. Vaccine. 2014 Aug 11;32 Suppl 1:A110-6.
Vaccine
(N=4354)
Placebo
(N=2187)
Vaccine
efficacy%
All 93 102 55.1%
G1P[8] 40 34 42.0%
G2P[8] 26 35 63.4%
G12P[6] 8 13 69.7%
G12P[8] 5 8 69.2%
Others 8 12 67.2%

22. ROTAVIRUS GASTROENTERITIS & VACCINATION 23
P H A S E I I I C L I N I C A L S T U D Y 1 1 6 E : C O N C L U S I O N
Efficacy
Safety
116E efficacious in
• Prevention of severe RVGE, RVGE of any severity &
severe GE of any etiology
• Reduces hospitalizations & supervised rehydration
therapy
• Offers broad protection against most commonly
circulating rotavirus genotypes in India
116E rotavirus vaccine is well tolerated in Indian
infants
Monovalent human-bovine (116E) rotavirus vaccine is
well-tolerated and immunogenic
Source: Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled
trial. Lancet. 2014 Jun 21;383(9935):2136-43.

23. ROTAVIRUS GASTROENTERITIS & VACCINATION 24
P H A S E 4 T R I A L
Source: Ella R et al. A Phase 4, multicentre, randomized, single-blind clinical trial to evaluate the immunogenicity of the live, attenuated, oral rotavirus vaccine (116E),
ROTAVAC®, administered simultaneously with or without the buffering agent in healthy infants in India. Hum Vaccin Immunother. 2018 Jul 3;14(7):1791-1799.

24. • 3 groups
– Group I (n=300) received 116E with 5 minutes prior administration of 2.5 ml of
buffer (same as in Phase III study)
– Group II (n=300) received 116E without buffer
– Group III (n=300) received 116E immediately mixed with 2.5 ml of buffer prior
administration
• All subjects received concomitant EPI childhood vaccines along with 3 doses of 116E
during the study
• Study took place at 15 sites across India
Non inferiority trial
Phase IV, multi-center, randomized, single-blind, study to evaluate the
immunogenicity, reactogenicity & safety of the live attenuated rotavirus vaccine
116e when administered simultaneously with or without the buffering agent
Source: Data on file

25. Conclusions
• No significant difference in seroconversion/seroprotection in all 3 groups
at day 0 & day 84
• Similarly, there was no significant difference in GMT’s in all 3 groups at day
0 & day 84
• 116E without buffer is non-inferior to 116E with buffer, either given before
or simultaneously
• No significant difference in all adverse events & severe adverse events
between groups
Non inferiority trial
Source: Data on file

26. Intussusception
116E vs Other Rotavirus vaccines

27. Phase III clinical study: Safety
• 6 cases of intussusception in the vaccine group and 2 in the placebo
group, all of which happened after the third dose.
• Serious adverse events: Observed at the same rates in 2 groups.
Source: Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial. Lancet. 2014
Jun 21;383(9935):2136-43.

28. Intussusception with 116E
• Difference between cases of intussusception reported in the
treatment arms (vaccine vs. placebo) are not statistically significant
(94/100,000 child-years vs 71/100,000 child-years)
• None of the intussusception cases required surgical intervention
• First to use broad screening criteria and intense and active
surveillance for intussusception
Source: John J et al. Active surveillance for intussusception in a phase III efficacy trial of an oral monovalent rotavirus vaccine in India. Vaccine. 2014 Aug 11;32 Suppl 1:A104-
9)

29. 116e Vaccine Safety
• Multicenter, hospital-based, active surveillance study at 27 hospitals in India
• From April 2016 to June 2019, a total of 970 infants with intussusception were
enrolled
• 589 infants who were 28 to 365 days of age were included in the self-controlled
case-series analysis
• No increase in intussusception risk was found in the case–control analysis
31
Source: Reddy SN et al. Intussusception after Rotavirus Vaccine Introduction in India. N Engl J Med. 2020 Nov 12;383(20):1932-1940
Conclusion: 116e is not associated with intussusception in Indian
infants

30. Vaccine Study
design
Risk Interval Risk
measure
Risk
estimate
116 E Case-control 112 days Relative risk 1.41
RV1 Australia Case control 1-7 days Relative Risk 1.05
RV5 Australia Case Control 1-7 days Relative Risk 1.33
RV5 USA Self
controlled
1-7 days Relative risk 1.8
116 E Case-control 112 days Odds Ratio 1.34
RV1 Brazil Case control 1-7 days Odds Ratio 1.9
RV1 Mexico Case control 1-7 days Odds Ratio 1.1
RV1 Australia Case control 1-7 days Odds Ratio 2.44
RV5 Australia Case control 1-7 days Odds Ratio 2.53
Buttery JP, Danchin MH, Lee KJ, et al. Intussusception following rotavirus vaccine administration: post-marketing surveillance in the National Immunization Program in Australia. Vaccine
2011;29:3061-6. Carlin JB, Macartney K, Lee KJ, et al. Intussusception risk and disease prevention associated with rotavirus vaccines in Australia's national immunisation program. Clinical
infectious diseases : an official publication of the Infectious Diseases Society of America 2013. . Shui IM, Baggs J, Patel M, et al. Risk of intussusception following administration of a
pentavalent rotavirus vaccine in US infants. JAMA : the journal of the American Medical Association 2012;307:598-60
Intussusception data of Rota virus
vaccines
No additional risk of intussusception with 116E vaccine vs other vaccines

31. Clinical data
116E vs Other Rotavirus vaccines

32. Efficacy of Rota vaccines (Asia)
34
Vaccine
Number of
doses
Outcome measures Sites Efficacy after 1 yr Efficacy after 2 yrs
RV51 3 Severe rotavirus GE (Vesikari >11)
Bangladesh,
Vietnam
51% 45.5%
RV12 2
Severe acute rotavirus diarrhoea
(Vesikari score ≥ 11)
Matlab,
Bangladesh
48% 25.8%
116E3 3 Severe rotavirus GE (Vesikari >11)
Multiple sites in
India
56.3% 48.9%
BRV-PV4 3 Severe rotavirus GE (Vesikari ≥11)
Multiple sites in
India
36% 39.5%
Efficacy of 116E vaccine shows consistent
high levels of efficacy
Sources: 1) Zaman K et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in Asia: a randomised,
double-blind, placebo-controlled trial. Lancet. 2010; 376(9741):615-23.
2) Zaman K et al. Effectiveness of a live oral human rotavirus vaccine after programmatic introduction in Bangladesh: A cluster-randomized trial. PLoS Med. 2017;
14(4):e1002282.
3) Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life. Vaccine. 2014; 32 Suppl 1:A110-6.
4) Kulkarni PS et al. A randomized Phase III clinical trial to assess the efficacy of a bovine-human reassortant pentavalent rotavirus vaccine in Indian infants. Vaccine.
2017 Oct 27;35(45):6228-6237.

33. Proprietary and confidential — do not distribute
Rotavirus Vaccine Efficacies
RV1 RV5
116E BRV-PV
36
Source: Raju B, Parikh RP, Vetter VV, Kolhapure S. Epidemiology of rotavirus gastroenteritis and need of high rotavirus vaccine coverage with early
completion of vaccination schedule for protection against rotavirus diarrhea in India: A narrative review. Indian J Public Health. 2019 Jul-Sep;63(3):243-
250.

34. Proprietary and confidential — do not distribute
37
R O T A V I R U S V A C C I N E S C O M P A R I S O N
PARAMETERS 116E RV1 RV5 BRV-PV
Indian Data Yes1
No efficacy data
Immunogenicity
data present
No efficacy data
Immunogenicity
data present
Yes4
Seroconversion
Rate
89.7% (4-fold rise
in RV IgA titer)5
58.3% (anti-
rotavirus IgA conc.
≥20 U/ml in
infants negative for
anti-RV IgA prior
to vaccination)6
83% (3-fold rise in
serum anti
rotavirus IgA
antibodies)7
33.6% (percentage
of subjects with ≥3-
fold increase in
rotavirus IgA titres
at Day 28 (±7 days)
post dose 3 with
respect to baseline
values)4
Vaccine efficacy 1
Yrs (Severe RVGE)
56.4%1 No data published No data published 36%4
Vaccine Efficacy 2
Yrs (Severe RVGE)
55.1%8 No data published No data published 39.5%4
Heterotypic
Protection
Present1 Present9 Not documented Not documented
Maternal Antibody
interference
116E overcomes the
interference from
maternal antibody10
Present11 Present11
No data published

35. Proprietary and confidential — do not distribute
38
R O T A V I R U S V A C C I N E S C O M P A R I S O N ( 2 )
PARAMETERS 116E RV1 RV5 BRV-PV
Vaccine Strain
origin
Natural; naturally
occurring
reassortant strain
G9P[11].1
Derived from the
human 89-12
strain; belongs to
G1P[8] type.2
5 live reassortant
rotaviruses isolated
from human and
bovine hosts.3
Developed from 5
Bovine (UK) X
Human Rotavirus
Reassortant
strains.4
Dose 3 dose 2 dose 3 dose 3 dose
Administration
Direct12 - No
reconstitution
required
Needs
reconstitution with
diluent2
Direct - No
reconstitution
required3
Needs
reconstitution with
buffer diluent13;
may need more
time
Source: 1. Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial.
Lancet. 2014; 383(9935):2136-43. 2. Rotarix PI. 3. Rotateq PI. 4. Kulkarni PS et al. A randomized Phase III clinical trial to assess the efficacy of a bovine-human
reassortant pentavalent rotavirus vaccine in Indian infants. Vaccine. 2017; 35(45):6228-6237. 5. Bhandari N et al. A dose-escalation safety and immunogenicity study
of live attenuated oral rotavirus vaccine 116E in infants: a randomized, double-blind, placebo-controlled trial. J Infect Dis. 2009; 200(3):421-9. 6. Narang A et al.
Immunogenicity, reactogenicity and safety of human rotavirus vaccine (RIX4414) in Indian infants. Hum Vaccin. 2009; 5(6):414-9. 7. Lokeshwar MR et al.
Immunogenicity and safety of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine (PRV) in Indian infants. Hum Vaccin Immunother. 2013
Jan;9(1):172-6. 8. Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life. Vaccine. 2014 Aug
11;32 Suppl 1: A110-6. 9. Steele AD et al. Human rotavirus vaccine Rotarix™ provides protection against diverse circulating rotavirus strains in African infants: a
randomized controlled trial. BMC Infect Dis. 2012; 12:213. 10. Appaiahgari MB et al. Transplacental rotavirus IgG interferes with immune response to live oral
rotavirus vaccine ORV-116E in Indian infants. Vaccine. 2014; 32(6):651-6. 11. Moon SS et al. Inhibitory effect of breast milk on infectivity of live oral rotavirus vaccines.
Pediatr Infect Dis J. 2010; 29(10):919-23. 12. Rotasure PI. 13. Rotasill PI.

36. Salient features: 116E vaccine
• High & consistent efficacy at 1 & 2 years
• 89.7% seroconversion
• Heterotypic protection
• First Rotavirus vaccine with efficacy data on Indian population
• Only vaccine having consistent efficacy (24%) in preventing
gastroenteritis of any cause
• WHO Prequalified vaccine
Source: The Journal of Infectious Diseases 2005; 192:S30: Roger I. Glass et al. Development of Candidate Rotavirus Vaccines Derived from Neonatal Strains in India.
2.Reference: Moon SS, et al. Differential profiles and inhibitory effect on rotavirus vaccines of nonantibody components in breast milk from mothers in developing and
developed countries. Pediatr Infect Dis J. 2013 Aug;32(8):863-70.
39

37. QUIZ
3 Contraindications for 116E vaccine

38. • H/o anaphylaxis
• SCID
• H/o Intussusception
QUIZ
3 Contraindications for 116E vaccine

39. ROTAVIRUS GASTROENTERITIS & VACCINATION 42
A G E L I M I T A T I O N F O R 1 S T & L A S T D O S E S O F
R O T A V I R U S V A C C I N E S
First dose Last dose
Minimum age 6 weeks 8 months 0 days
Rationale: Age group used in clinical trial with the goal of avoiding high
risk
period on intussusception
1st
3rd
Source: MM Parashar UD. MMWR Recomm Resp. 2009; 58:1-25. American academu of Pediatrivs. Recommended immunization schedule for perrsons aged 0-
6 yrs. http://aapredbook.aappublications.org/resources/IZSchedule0-6yrs.pdf
The recommended minimum interval between doses is 4 weeks...

40. ROTAVIRUS GASTROENTERITIS & VACCINATION 43
C U R R E N T I A P G U I D A N C E F O R I M M U N I Z A T I O N
Prevention (including immunizations) and management of
communicable diseases is considered as an “Essential Medical
service”.
• Prioritize primary vaccination series: DPT, Hep B, Hib,
OPV/IPV, Rotavirus vaccines, PCV, Influenza, Varicella
and MR/MMR.
• Avoid postponing these vaccines.
Source: IAP ACVIP Guidelines on Immunizations during COVID 19 Pandemic. Available from: https://iapindia.org/pdf/1455-FINAL-ADVISORY-
ACVIP-Guidelines-on-Immunisations-during-COVID-19-Pandemic-skd.pdf ; accessed on 5th May 2020 @ 3:00 PM.

41. ROTAVIRUS GASTROENTERITIS & VACCINATION 44
T A K E H O M E M E S S A G E
• Huge burden of RVGE with strain diversity in India
• Vaccination with heterotypic protection needed
• Native strain in vaccine with good efficacy data in Indian
children looks promising
• Prioritize rotavirus vaccine during this current crisis

42. Thanks for a patient listening!
My presentations
Acknowledgements:
www. slideshare.com/gauravg
docgaurav@gmail.com
www.youtube.com/charakclinics
Your Personal Child Specialist!
Dr Avik Mukherjee, Medical
Advisor, Abbott Vaccines
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