Rotavirus vaccine - Rotateq- Does Valency Matter North Zone Pedicon oct 2018 - talk taken in the holy city of amritsar as a part of the First NZ pedicon for IAP. Discussed the differences and benefits of Rotavirus vaccines that are available in India including Rotateq, Rotarix, Rotavac Rotasure and Rotasiil

1. Dr. Gaurav Gupta, Mohali.
for Punjab Pedicon, 7th Oct, 2018.

2. Conflict of Interest
Receive grants from various vaccine
manufacturers

3. Scope
 Potential benefits & shortcomings of currently
available RV Vaccines
 Early administration
 TAKE theory – are more doses better?
 Real world effectiveness data
 Data about individual serotypes
 Grading

4. Presently Available RV Vaccines
 RV 5
 RV 1
 116 E
 BRV-PV

5. Presently Available RV Vaccines
 RV 5 – Rotateq – MSD
 RV 1
 116 E
 BRV-PV

6. Presently Available RV Vaccines
 RV 5 – Rotateq – MSD
 RV 1 – Rotarix - GSK
 116 E
 BRV-PV

7. Presently Available RV Vaccines
 RV 5 – Rotateq – MSD
 RV 1 – Rotarix - GSK
 116 E – Rotavac - Bharat Bt/ Rotasure – Abbott
 BRV-PV

8. Presently Available RV Vaccines
 RV 5 – Rotateq – MSD
 RV 1 – Rotarix - GSK
 116 E – Rotavac - Bharat Bt/ Rotasure – Abbott
 BRV-PV - Rotasiil - SII

9. Presently Available RV Vaccines
 RV 5 – Rotateq – MSD (G1-4, P8)
 RV 1 – Rotarix - GSK
 116 E – Rotavac - Bharat Bt/ Rotasure – Abbott
 BRV-PV - Rotasiil - SII

10. Presently Available RV Vaccines
 RV 5 – Rotateq – MSD (G1-4, P8)
 RV 1 – Rotarix - GSK (G1,P8)
 116 E – Rotavac - Bharat Bt/ Rotasure – Abbott
 BRV-PV - Rotasiil - SII

11. Presently Available RV Vaccines
 RV 5 – Rotateq – MSD (G1-4, P8)
 RV 1 – Rotarix - GSK (G1,P8)
 116 E – Rotavac - Bharat Bt/ Rotasure – Abbott (G9,P11)
 BRV-PV - Rotasiil - SII

12. Presently Available RV Vaccines
 RV 5 – Rotateq – MSD (G1-4, P8)
 RV 1 – Rotarix – GSK (G1,P8)
 116 E – Rotavac - Bharat Bt/ Rotasure – Abbott (G9,P11)
 BRV-PV - Rotasiil – SII (G1-4,G9)

13. Presently Available RV Vaccines
 RV 5 – Rotateq – MSD (G1-4, P8)
 RV 1 – Rotarix – GSK (G1,P8)
 116 E – Rotavac - Bharat Bt/ Rotasure – Abbott (G9,P11)
 BRV-PV - Rotasiil – SII (G1-4,G9)

14. Indian RV vaccines – 116E & BRV-PV
 Indian Clinical efficacy data available
 Around 7,000 Indian children in each case – not
powered enough for s/e like intussusception
(1-2/ 1,000; 1-2/10,000; 1-2/1,00,000)
 Long – term data limited,
 International data limited

15. Imported RV vaccines – RV5 & RV1
 Huge International data of real world effectiveness
 Safety well established
 Long term data available
 Only have Indian immunogenicity trials
 No regulatory need
 Huge International Data
 High immunogenicity in India

16. 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

17. 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

18. Rotavirus Vaccines in India
Vaccine Valency Rotavirus
strains
Country of
Manufacture
No. of
doses
Dosing
schedule
Regulatory
approval
RotaTeq Pentavalent
vaccine
G1-G4,P8 Pennsylvania,
USA
3 6, 10, 14 weeks Yes
116E Monovalent
vaccine
G9P11 India 3 6, 10, 14 weeks Yes
BRV-PV Pentavalent
vaccine
G1-G4, G9 India 3 6, 10, 14 weeks Yes
3 Dose Rotavirus Vaccines:
2 Dose Rotavirus Vaccines:
Company Valency Rotavirus
strains
Country No. of
doses
Dosing
schedule
Regulatory
approval
RV1 Monovalent
vaccine
G1 Belgium,UK 2 10, 14 weeks Yes

19. Early Vaccination at 6 weeks for
Rotavirus – WHO & IAP-ACVIP
Position
WHO Recommendations
1:
• WHO continues to recommend that the first dose of rotavirus vaccine be
administered as soon as possible after 6 weeks of age, along with diphtheria-
tetanus-pertussis (DTP) vaccination, to ensure induction of protection prior to
natural rotavirus infection.
IAP-ACVIP Recommendations
2,3:
RV5 RV1 – RIX4414
6 weeks Dose - 1
10 weeks Dose - 2 Dose - 1
14 weeks Dose - 3 Dose - 2
• As per IAP 2016 recommendations, RV1 administered at 6 & 10 weeks is less immunogenic than RV1 given
at 10 & 14 weeks3.
• Hence, IAP-ACVIP recommends RV1 at 10 & 14 weeks in order to achieve a better immune response3.
1. WHO Position Paper on Rotavirus Vaccines. WER. No. 5, 2013, 88, 49–64
2. Vipin M Vashistha et al. Indian Academy of Pediatrics (IAP) Recommended Immunization Schedule for Children Aged 0 through 18 years – India, 2014 and Updates on Immunization. Indian
Pediatrics. VOLUME 51__OCTOBER 15, 2014.
3. Vipin Vashistha et al. Indian Academy of Pediatrics (IAP) Recommended Immunization Schedule for Children Aged 0 through 18 years – India, 2016 and Updates on Immunization. Indian
Pediatrics. Aug 26 2016 [E-pub. Ahead of print]. P. 35.
Indian NIP : 3 Dose RV
Vaccine

20. RV Serotypes change as per time, region and
setting hence the need for broad protection
Natural
Infection Study:
Gladstone et al1
(2002-2006)
Indian
Rotavirus Strain
Surveillance
Network2
(2005-2009)
RVGE Outpatient
Burden study3
(2011-2012)
* All values expressed as %
1. Gladstone B P et al. N Engl J Med 2011;365 (4):337-46. 2. Kang G et al. Vaccine 31 (2013) 2879-2883. 3. Gajanan S. Namjoshi et al. Rotavirus
gastroenteritis among children less than 5 years of age in private outpatient setting in urban India. Vaccines 32S (2014) A36-A44.
G1P(8), 15.9 G2P(4), 13.6
G10P(11), 8.7
Others, 61.8
G1, 25
G2, 21
G9, 13
Others, 41
G1P(8), 32.1
G2P(4), 27.5
G2P(6), 7.33
Others, 33.1

21. Training for rotavirus vaccine introduction | 201221 |
What should you do in this scenario?
10 weeks = Rota1 and Penta1
35 weeks = ?
Module 3: Rotavirus vaccine eligibility
1

22. Training for rotavirus vaccine introduction | 201222 |
What should you do in this scenario?
32 wk PT baby
17 weeks = ?
Module 3: Rotavirus vaccine eligibility
2

23. BRV-PV & 116E Phase 3 Efficacy, Immunogenicity & Safety Trials [Snapshot]
(Not head to head comparison trials)
1. Isanka et al. Efficacy of a Low-Cost, Heat-Stable Oral Rotavirus Vaccine in Niger. N Engl J Med 2017;376:1121-30.
2. Kulkarni 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). https://doi.org/10.1016/j.vaccine.2017.09.014.
3. Zade et al. Bovine Rotavirus Pentavalent Vaccine Development in India. Vaccine 32S (2014) A124-A128.
4. 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. The Journal of Infectious Diseases 2009; 200:421–9.
5. Bhandari N et al. Efficacy of a Monovalent Human-Bovine (116E) Rotavirus Vaccine in Indian Infants: A Randomized Double Blind Placebo Controlled Trial. Lancet. 2014; 383 (9935): 2136–43.
6. Lokeshwar et al. Immunogenicity and safety of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine (PRV) in Indian infants. Human Vaccines & Immunotherapeutics 9:1, 178–182; January 2013; c 2013.
7. Narang et al. Immunogenicity, reactogenicity and safety of human rotavirus vaccine (RIX4414) in Indian infants. Human Vaccines 5:6, 414-419; June 2009
8. Bhandari N et al. Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian children in the second year of life . Vaccines 32S (2014) A110-A116.
BRV-PV
(India data)
116E
(India data)
RV5
(India data)
RV1
(India data)
Efficacy
(< 2 years)
SRVGE
(VS>11)
1 year Efficacy data
not published
56.4% [PPP] 5
VSRVGE
(VS>15)
1 year Efficacy data
not published
49.8% [PPP] 5
Efficacy
(at 2 years)
SRVGE
(VS>11)
39.5% [PPP] 2 55.1% [PPP] 8
VSRVGE
(VS>16)
54.7% [PPP] 2 57.2% [PPP] 8
Immunogeni
city
60% - Phase 2b3
33.6% - Phase 32
89.7% - Phase 2a4
39.9% - Phase 35
83% [India] 6 58% [India] 7
Serotype
specific
Efficacy
Overall efficacy
against
G1,G2,G3,G9,G12 =
38.9%1
[ -ve CI G3,G9,G12]
Negative CI values for
G1P[8], G12P[8] &
G9P[4] 5,8
55.6-93.3%
[G1,G2,G3,G
4,P[1] 6
Safety
12 cases of GE 7 days
post vaccination (V=7,
P=5) 2
20 cases of G9P[11] GE seen
after dose 1 & 2 cases post dose
2 of II6E RV vaccine. All cases
were mild or moderate by VS5
Tolerable
safety profile6
Tolerable safety
profile7

24. ‘TAKE’ Theory
Disclaimer: Immunological mechanisms in protection from RVGE after natural infection or vaccination are not exactly known. The
forthcoming slides are to elaborate the concept proposed by an expert about the mechanism of action of multivalent rotavirus vaccine.
Multivalency might be helpful in better “Take” of
Rotavirus Vaccines

25. Multivalent vaccine probably works
by mechanism of multiple hits
• A concept proposed by Dr Timo Vesikari.
• Explains why Multivalent vaccines give successive robust
immune response and efficacy as per the number of doses
(BOOSTING) And
• Monovalent vaccines may not have adequate boosting effect.

26. Multivalent Rotavirus Vaccine with Multiple
Doses: Immunological Advantage
• Multiple serotypes in the vaccine:
• May allow repeated doses (three altogether) to ‘TAKE’ and
build solid cross-protective immunity, probably based on a
high(er) level of serum IgA antibodies against VP6 group
antigen.
Vesikari Timo. Clin Microbiol Infect 2012; 18 (Suppl. 5): 57–63.

27. Benefits of ‘TAKE’
• Higher IgA response to VP6 = more GMT = ?
longer protection
• Protection against strains having different VP6
serotypes (Eg. G2,P4 – Brazilian Data)

28. Immunogenicity Data of RV1 and RV5
from some countries
RV1 GMC (geometric mean
Concentration), (95% CL)
% Seroconversion, (95%
CL)
Study location by u 5mr (under 5
Mortality Rate)
Finland 375 (329, 427) 89 (86, 91) Low u5MR
Taiwan 106 (67, 166) 86 (70, 95) Low u5MR
Vietnam 77 (55, 109) 63 (54, 72) Medium u5MR
Bangladesh 47 (30, 72) 57 (44, 68) High u5MR
India 49 (36, 67) 58 (49, 67) High u5MR
Serum rotavirus IgA antibody concentrations 1–2 months after dose 2 for RV1; seroconversion defined as GMC >20 U/mL after RV1
RV5 GMT (Geometric mean titre),
(95% CL)
% Seroconversion (95%
CL)
Study location by u 5mr (under 5
Mortality Rate)
US & Finland 338 (266, 429) 95 (91, 98) Low u5MR
Taiwan 306 (185, 504) 94 (83, 99) Low u5MR
Vietnam 159 (107, 235) 97 (90, 100) Medium u5MR
Bangladesh 29 (19, 46) 78 (66, 88) High U5mr
India 80 (55, 116) 82 High u5MR
Serum rotavirus IgA antibody concentrations 1–2 months after dose 3 for RotaTeq; seroconversion defined as >3-fold rise in GMT titers
after RotaTeq.
The studies were not head to head studies, accordingly comparison of both vaccines is not appropriate
Manish Patel et al. A Systematic Review of Anti-Rotavirus Serum IgA Antibody Titer as a Potential Correlate of Rotavirus Vaccine Efficacy. The Journal of Infectious Diseases
2013;208:284–94.
Authors’ Comments:
• Pooled 2 year efficacy was significantly higher in trials where IgA GMC or
GMT exceeded 90 compared to those with rotavirus IgA GMC or GMT
below 90.
• IgA titers <90 were associated with lower efficacy and waning during the
second year after vaccination.

29. Training for rotavirus vaccine introduction | 201229 |
What should you do in this scenario?
Module 4: Rotavirus vaccine eligibility

30. Training for rotavirus vaccine introduction | 201230 |
How to administer the vaccine?
1
3 4
2
Module 4: Rotavirus vaccine eligibility

31. • Accidentally frozen RV vaccine – what to do?
• Accidentally RV vaccine given IM – does it
count?
• Unknown RV vaccine given – how to proceed?

32. Rotavirus Efficacy and Safety Trial
(REST)1
• Multicentre, in 11 countries on 3 continents
(Europe, US, Latin America/Caribbean), from
2001 to 2004
• Randomised, double-blind controlled,
RotaTeq vs placebo
• 70,301 infants enrolled/68,038 received
at least 1 dose of RotaTeq or placebo
• Age at enrollment: children 6 to 12 weeks
• Oral, 3-dose regimen, every 4–10 weeks
1. Vesikari T, et al. N Engl J Med. 2006;354:23–33.

33. Introduction of RotaTeq in GAVI-Eligible Countries
Nicaragua
Oct 2006
Rwanda May 2012 The Gambia
Aug 2013
Burkina Faso
Oct 2013
Mali
Jan 2014
Cote d’Ivoire
Sao Tome
2016
• In same year as US licensure (2006)
Merck-Nicaragua MoH partnership
implemented
• 1.3 million doses donated over 3 yrs
• 3 dose vaccine effectiveness after 2
years of follow-up (2007-9) against
severe rota (≥11) was 85% (66,93) in
those <1 year
• Hospitalizations for diarrhea in <1 year
olds decreased by 51% in 2014
• Diarrhea hospitalizations declined
among older children not vaccinated,
suggesting indirect protection
Lancet Global
Health 2016
PIDJ 2011

34. RotaTeq in NIP in Rwanda (Reduction in RV Hospitalizations)_20161
RV5 introduced in NIP in 2012:
• In May, 2012, Rwanda became the first low-income African country to introduce
pentavalent rotavirus vaccine into its routine national immunization programme.
• This study provides the first evidence of the effect of pentavalent rotavirus vaccine on
the severe all-cause and rotavirus diarrhea disease burden in sub-Saharan Africa after
introduction of the vaccine into the routine childhood immunization programme.
1. Fidele Ngabo, Jacqueline E Tate et al. Effect of pentavalent rotavirus vaccine introduction on hospital admissions for diarrhoea and rotavirus in children in
Rwanda: a time-series analysis. Lancet Glob Health 2016; 4: e129–36.
Key Findings:
1. Post NIP – RV admissions fell by 61-70%
2. Greatest effect was in age eligible children.
3. Decrease in children outside vaccination age (indicative of indirect protection
through reduced virus transmission).
4. Overall VE = 75% (95 CI).

35. RotaTeq: – Data on G9 & G12
(Ref: RotaTeq Product Insert MSDIN 11/16)

36. RotaTeq Data on G9 & G12
Key highlights:
1. 1 year efficacy against SRVGE for G9 = 74.1%1.
2. 3 year efficacy against SRVGE for G9 = 98.2%1.
3. Vaccine Effectiveness (VE) against G12 = 78%1.
4. VE persists for 7 years which is statistically significant (3
years for RV1) 2.
1. RotaTeq PI. MSDIN 11/16.
2. Payne et al. Long-term Consistency in Rotavirus Vaccine Protection: RV5 and RV1 Vaccine Effectiveness in US Children, 2012–2013. Clinical Infectious Diseases®
2015;61(12):1792–9

37. THREE Contraindications for RV vaccine

38. • H/o anaphylaxis
• SCID
• H/o Intussusception
THREE Contraindications for RV vaccine

39. ACIP: Moving from Evidence to
Recommendation
Pentavalent Rotavirus Vaccine gets Category A recommendation
Overall evidence type
Overall evidence type across all critical
outcomes
1
Values and preferences (assume a set of values for each outcome considered)
OUTCOME VALUES AND PREFERENCES
Rotavirus diarrhea Relatively lower value
Severe rotavirus diarrhea High value
Hospitalization for rotavirus diarrhea High value
Intussusception High value
Other serious adverse events High value
Cost effectiveness Relatively lower value
Draft recommendation
We recommend vaccination of infants with three doses of rotavirus vaccine.
Recommendation category Category A
Ahmed F. U.S. Advisory Committee on Immunization Practices Handbook for Developing Evidence-based Recommendations. Version 1.2. Atlanta, GA: Centers for
Disease Control and Prevention (CDC); 2013. Available from http://www.cdc.gov/vaccines/acip/recs/GRADE/about-grade.html#resources
RotaTeq:
Type 1 GRADE A recommendation

40. WHO Grading of Scientific Evidence:
Higher score for RV5 in preventing severe rotavirus
diarhhoea in High Mortality Countries
What is the effect of
RV1 compared to
placebo for preventing
severe rotavirus
diarrhoea in high-
mortality countries?
What is the effect of
RV5 compared to
placebo for preventing
severe rotavirus
diarrhoea in high-
mortality countries?
What is the effect of
RV1 compared to
placebo for preventing
severe all cause
diarrhoea in high-
mortality countries?
What is the effect of
RV5 compared to
placebo for preventing
severe all cause
diarrhoea in high-
mortality countries?
Final numerical rating of
quality of evidence
3* 4 3* 4
Statement on quality of
evidence
Further research is likely
to change the estimate
of effect
Further research is very
unlikely to change our
confidence in the
estimate of effect
Further research is likely
to change the estimate
of effect.
Further research is very
unlikely to change our
confidence in the
estimate of effect
Conclusion We are moderately
confident that use of
RV1 in high mortality
countries reduces the
rate of severe rotavirus
diarrhoea
We are confident that
use of RV5 in high
mortality countries
reduces the rate of
severe rotavirus
diarrhoea
We are moderately
confident that use of
RV1 in high mortality
countries reduces the
rate of severe all-cause
diarrhoea
We are confident that
use of RV5 in high
mortality countries
reduces the rate of
severe all-cause
diarrhoea
* Downgraded due to indirectness as trials were conducted in Malawi and South Africa: generalization to high--‐mortality countries is difficult.
http://www.who.int/immunization/documents/positionpapers/en/ . Accessed 7th Jan 2018.

41. To Summarize
• RV vaccines are being used in more than half
the countries of the world
• Wherever introduced, they have measurable
impact
• Early use of RV Vaccines will reduce U5MR
significantly
• Multivalent vaccines have shown good long
term efficacy & safety across the world

42. Acknowledgements: Dr. Puneet Kalra, MSD
Missed something ?
Check www.slideshare.com/gauravg
More queries ?
docgaurav@gmail.com