Rotateq presentation for Small Group Meet,

1. Rotavirus: Dilemma of Developing Countries
Rotavirus Vaccine: Recent Updates from
 IAPCOI Consensus Recommendations and
 WHO Position Paper
Facilitator: Dr Gaurav Gupta
28th June 2013

2. What’ s this talk going to be about ?
• Rationale of RV vaccine
– Morbidity & Mortality in India
– Relevance to Pvt Practitioners
• Differences between Rotarix & Rotateq
– 3 doses v/s 2 doses
– Cross Protection – Heterotypic v/s homotypic immunity (in Indian
context)
– Human v/s Bovine strain immunogenicity
• Safety concerns with RV vaccines
• Latest WHO & IAP Guidelines
• CME

4. My
pediatric
cohort
High socio-
economic
status.
High level of
sanitation
and
hygiene.
East and
Prompt
Access to
health care
facilities.
Disease is not
VERY severe in
them.
NO WORRIES AT ALL?
Well
Nourished,
less chance
of nutrient
deficiency
Robust
Immunity
Then why did developed
world e.g. US start with
rotavirus vaccine

5. Rationale for Rotavirus Vaccination as a public health measure for
prevention of rotavirus disease in U.S.1
1
Rates of rotavirus illness
among children in
industrialized and less
developed countries were
similar,
indicating that clean water
supplies and good hygiene
have little effect on virus
transmission;
Therefore, further
improvements in hygiene
in the United States were
unlikely to have a
substantial impact on
disease prevention
2
In the US, a high level of
rotavirus morbidity
continued in the
prevaccine era despite
available therapies.
e.g. Rate of
hospitalizations for
gastroenteritis in young
children declined only
modestly during
1979−1995 despite the
widespread availability of
oral rehydration solutions
in the treatment of
dehydrating
gastroenteritis
3
Studies of natural rotavirus
infection: indicated that
initial infection protects
against subsequent severe
gastroenteritis, (although
subsequent asymptomatic
infections and mild disease
still might occur)
Therefore, vaccination
early in life, which mimics
a child’s first natural
infection, should prevent
the majority of cases of
severe rotavirus disease
and their sequelae
1. Morbidity and Mortality Weekly Report. February 6, 2009 / Vol. 58 / No. RR-2
EVEN “DEVELOPED
WORLD “ HAS
CHOSEN
ROTAVIRUS
VACCINATION

10. RV protection after natural infection
a) Indian and Mexico study
Setting Velazquez et al1
Community setting in
outskirts of Mexico.
Year of study 1987 - 1990
Enrollment and
sample size
200 Newborns
betwn Oct 1987 – Oct 1988
Follow up Birth cohort F/u 2 years.
3699 (77%) child months followup.
Visits, stool
samples
1/week, 1/week + Diarrhea
Testing for Rota G typing
Blood sample First wk and every 4 months
Primary
Infections
52% (i.e. remaining were
reinfections)
Infections by 6
months of age
34%
Protective Efficacy for
Mod. to Sev. Diarrhea
100 % after two infections.
1. Velazquez et al. Rotavirus Infection In Infants As Protection Against Subsequent Infections. N Engl J Med 1996;335:1022-8. 2. Gladstone et al. Protective Effect of Natural
Rotavirus Infection in an Indian Birth Cohort. N Engl J Med 2011;365:337-46.
Gladstone et al2
Community setting in
three areas of Vellore, India.
2002 - 2006
452 Newborns
betwn Mar 2002 – August 2003
Birth cohort F/u 3 years.
13340 child-months (99.5%) follow up. 373
children completing study
2/week, 1 in 2 weeks + Diarrhea
G and P typing
At birth/first week and every six mth
RESULTS
33.6% (i.e.remaining were
reinfections)
53%
79% after three infections

11. RV protection after natural infection
1. Velazquez et al. Rotavirus Infection In Infants As Protection Against Subsequent Infections. N Engl J Med 1996;335:1022-8. 2. Gladstone et al. Protective Effect of Natural
Rotavirus Infection in an Indian Birth Cohort. N Engl J Med 2011;365:337-46.
b) Results from Mexican & Vellore Cohort
38
62
7473 75
99
87
100
0
20
40
60
80
100
120
1 2 3
Asymptomatic Infection
Mild Diarrhea
Moderate to Severe Diarrhea
24
33
4644
72
79
18
57
79
0
20
40
60
80
100
120
1 2 3
In general, in Vellore Cohort, the efficacy of natural infection in protecting against
subsequent outcomes was less as compared to Mexico cohort
(The two cohorts were from different settings and this graph is for presentation purpose only)

12. 3. Rotavirus vaccine efficacy
e) Indian Immunogenicity Data
1. Human Vaccines 5:6, 414-419; June 2009. 2. Human Vaccines & Immunotherapeutics 9:1, 178–182; January 2013; 3. The Journal
of Infectious Diseases 2009; 200:421–9, 4. Indian Pediatrics . Volume 49. JULY 16, 2012
Vaccine Setting Results
RV11 Safety and Immunogenicity.
2 dose schedule, Starting at 8-10 weeks
No Concomitant OPV
Seroconversion was 58.3%,after
2nd dose.
RV52 Safety and Immunogenicity.
3 dose schedule, starting at 6 weeks
Concomitant OPV administered
Seroconversion was 82.35%
after 3rd dose
116 E3 Safety and Immunogenicity, Dose Escalation study.
3 dose schedule. Vaccine or placebo received at 8-12-
16 weeks.
No Concomitant OPV.
1 X 105 FFU 116E
(Phase III trial conducted with higher dose and 3 dose schedule)4
Seroconversion was 89.7% after
3rd dose

13. 3. Rotavirus vaccine efficacy
WHO
• There is currently insufficient evidence to make a
general recommendation on the need for a third
dose of RV1 in the primary series.
• Further adequately powered studies would be
helpful to explore whether additional doses have a
favourable risk/benefit ratio in high mortality
settings and whether partial vaccination is also
efficacious against severe rotavirus diarrhoea.
WHO Position Paper Jan 2013. WER No. 5, 2013, 88, 49–64

15. Global Distribution of Rotavirus Serotypes1
G1P[8]
65%
G3P[8]
3%
G4P[8]
9%
G9P[6]
1%G9P[8]
3%
Other
7%
G2P[4]
12%
Other=untypeable and rare G-P combinations.
1. Santos N, Hoshino Y. Rev Med Virol. 2005;15:29–56. Reproduced by permission of John Wiley & Sons Limited.

16. Rotavirus Strains Diversity in India
G2 P[4], 25.7%
G12 P[4][6][8],
6.5%
G9 P[8], 8.5%
G1 P[8], 22.1%
Unique features: Diversity of rotavirus strains & mixed infections. Need for vaccines formulated
against a broad range of strains.2
It is found that the predominant Rota Virus strain (type) in cities varied from year to year and
from city to city. 3
1. The Journal of Infectious Diseases 2009; 200:S147–53. 2. Indian J. Med Res 118, Aug 2003, Pg 59-67 3. Journal of Clinical Microbiology. Oct 2001, Pg 3524-3529.
IRSN Data

19. Rotavirus Disease Burden In India
122,000-153,000
457,000-884,000
2 million
Estimated annual number and risk of death, hospitalization, and outpatient
visits due to rotavirus diarrhea in children <5 years of age in India.
Adapted from: J. E. Tate et al. Disease and economic burden of rotavirus diarrhea in India/Vaccine 27 S (2009) F18–F24
EVENTSRISK
1 in every 177-196 children
1 in every 31-59 children
1 in every 13 children
Deaths
Hospitalizations
Outpatient Visits

21. 21

22. 4. Serodiversity
c) Serotype-wise efficacy in Phase III CT of RV1 Vaccines1
Efficacy of RV1 against Severe RVGE
according to clinical case definition (%)
Vaccine (N = 9009) Placebo Group (N =
8858):
G1P(8) 91.8
G3P[8], G4P[8], 9P[8] 87.3
G2P[4] 41.0
Efficacy against severe rotavirus
gastroenteritis with
a score of ≥11 on the Vesikari scale (%)
Vaccine Group (N = 9009)
Placebo Group (N = 8858):
G1P(8) 90.8
G3P[8], G4P[8], G9P[8] 86.9
G2P[4] 45.4
41
87.3
91.8
90.8
86.9
45.4
1. Palacio R et al. N Engl J Med 2006;354:11-22.

23. Rotavirus Strains Diversity in India
G2 P[4], 25.7%
G12 P[4][6][8],
6.5%
G9 P[8], 8.5%
G1 P[8], 22.1%
1. The Journal of Infectious Diseases 2009; 200:S147–53. 2. Indian J. Med Res 118, Aug 2003, Pg 59-67 3. Journal of Clinical Microbiology. Oct 2001, Pg 3524-3529.
IRSN Data

24. 4. Serodiversity
d) Serotype-wise efficacy in Phase III CT of RV51
Clinical Efficacy of RV5 against RVGE of Any
Severity. (%)
Vaccine (N = 2834) Placebo (N = 2839):
G1 74.9
G2 63.4
G3 82.7
G4 48.1
G9 65.4
Reduction in number of hospitalizations and
ED visits (%): Vaccine (N = 34,035)
Placebo (N = 34,003)
G1 95.1
G2 87.6
G3 93.4
G4 89.1,
G9 100.0
G12 100.0
74.9
63.4
82.7
48.1
65.4
95.1
87.6
93.4
89.1
100
100 1. Vesikari T. et al. N Engl J Med 2006;354:23-33.

26. As humans are the natural hosts for these strains, it has been
suggested that
– The immune responses they stimulate in infected
humans, even after growth in cell culture, may be
greater and more consistent than those elicited after
administration of animal strains.
WHO Immunological Basis of Immunization. Module 21 Rotavirus
• Not all vaccines derived from human rotavirus strains elicit
greater immune responses, or protection in immunized
subjects than found after immunization with animal strains
(Flores et al., 1990; Vesikari et al., 1991b).
• A reassortment vaccine (human + bovine) like RV5 may
actually enhance the immunogenicity to RV surface antigens
VP4 & VP7. (Vaccines, Plotkin. 6th Edition, 2013)
a) Human Vs Human bovine reassortment vaccine

27. After a primary, natural rotavirus infection, infants develop virus-
specific neutralizing antibodies in serum directed against the
infecting G type at levels greater than those directed against
other G types.
Protection against rotavirus disease in adults challenged with a
virulent human rotavirus strain G1P1A(8) co-related with
antibodies directed against homotypic VP4 and VP 7.
This may explain in part, why heterotypic protection after
administration of vaccines such as WC3, RRV, Rotarix is
inconsistent.
Inconsistent Heterotypic Protection of Rotavirus Vaccines:
Plotkins textbook 6th ed.
Clarke H F, Offit P A, Parashar U D. Rotavirus Vaccines. In: Plotkin SA, Orenstein WA, Offit PA eds. Vaccines. 6th ed. Chapter 30. Philadelphia, PA: Saunders
Elsevier 2012

30. WHO
• Rotavirus vaccines should be included in all national
immunization programmes and considered a priority, particularly
in countries with high RVGE-associated fatality rates, such as in
south and south-eastern Asia and sub-Saharan Africa.
• Though RV Vaccines efficacy is less, it has huge impact.
IAPCOI
• still believes that in developing countries with high rotavirus
disease incidence, even moderate to low vaccine efficacy
translates into significant numbers of severe rotavirus
gastroenteritis cases prevented and into significant public health
impact.
c. WHO and IAPCOI
Rotavirus vaccines WHO position paper – January 2013. WER No. 5, 2013, 88, 49–64
Indian Pediatrics . Volume 49. JULY 16, 2012

34. In which one of these patients should you not recommend receiving a
first dose of rotavirus vaccine?
• A 10-week-old boy born HIV positive
• A 16-week-old adopted girl from unknown parentage
• A 12-week-old premature stable boy in the neonatal intensive care unit
• A 13-week-old girl who is breastfeeding

35. In which one of these patients should you not recommend receiving a
first dose of rotavirus vaccine?
• A 10-week-old boy born HIV positive
• A 16-week-old adopted girl from unknown parentage
• A 12-week-old premature stable boy in the neonatal intensive care unit
• A 13-week-old girl who is breastfeeding

37. The potential for decreasing the burden of rotavirus disease, including
mortality, is greatest in:
• Mexico
• Africa
• Brazil
• India

38. The potential for decreasing the burden of rotavirus disease, including
mortality, is greatest in:
• Mexico
• Africa
• Brazil
• India

39. Which of the following children should be given a first dose of rotavirus
vaccine?
• A full-term 5-week-old infant
• A full-term 33-week-old infant
• A full-term 16-week-old infant
• A preterm 8-week-old infant

40. Which of the following children should be given a first dose of rotavirus
vaccine?
• A full-term 5-week-old infant
• A full-term 33-week-old infant
• A full-term 16-week-old infant
• A preterm 8-week-old infant

41. Which of the following is a contraindication to rotavirus vaccination in
infants and small children?
• Hirschspung disease
• HIV
• Malabsorption syndrome
• Severe combined immunodeficiency syndrome

42. Which of the following is a contraindication to rotavirus vaccination in
infants and small children?
• Hirschspung disease
• HIV
• Malabsorption syndrome
• Severe combined immunodeficiency syndrome

43. The classic clinical triad of rotavirus gastroenteritis consists of:
• Intermittent fever, diarrhea, and abdominal pain
• Low-grade fever, vomiting, and copious, watery diarrhea
• Projectile vomiting, abdominal pain, and watery diarrhea
• Vomiting, fever greater than 102°F, and intermittent diarrhea

44. The classic clinical triad of rotavirus gastroenteritis consists of:
• Intermittent fever, diarrhea, and abdominal pain
• Low-grade fever, vomiting, and copious, watery diarrhea
• Projectile vomiting, abdominal pain, and watery diarrhea
• Vomiting, fever greater than 102°F, and intermittent diarrhea

45. According to recommendations from the IAP, at what age should the
patient have received her initial dose of rotavirus vaccine?
• Between 8 weeks and 32 weeks
• Between 6 weeks and 14 weeks, 6 days
• Between 12 weeks and 24 weeks
• Between 4 weeks and 14 weeks, 6 days

46. According to recommendations from the IAP, at what age should the
patient have received her initial dose of rotavirus vaccine?
• Between 8 weeks and 32 weeks
• Between 6 weeks and 14 weeks, 6 days
• Between 12 weeks and 24 weeks
• Between 4 weeks and 14 weeks, 6 days

47. A parent wants assurance that her son will not develop intussusception
from a rotavirus vaccine. What should you tell her?
• The benefit of preventing severe rotavirus gastroenteritis outweighs the small
potential risk for intussusception
• There is no risk for intussusception from rotavirus vaccination
• No association between RV vaccines and intussusception has been observed in
either pre- or postlicensure studies
• RotaShield® was taken off the market, but not because of an association with
intussusception

48. A parent wants assurance that her son will not develop intussusception
from a rotavirus vaccine. What should you tell her?
• The benefit of preventing severe rotavirus gastroenteritis outweighs the small
potential risk for intussusception
• There is no risk for intussusception from rotavirus vaccination
• No association between RV vaccines and intussusception has been observed in
either pre- or postlicensure studies
• RotaShield® was taken off the market, but not because of an association with
intussusception

49. FINALLY, Why are we not using more rotavirus vaccine?
• Concerns regarding RV burden in India?
• Concerns regarding RV vaccine efficacy?
• Concerns regarding LM / admission with AGE after RV vaccine?
• Cost of vaccine
• Side-effects of vaccine
• Short window period for vaccination
• Lack of patient awareness/ unable to convince parents ?