rotavirus vaccine presentation rotateq 28 june 2013
DESCRIPTION
Rotateq presentation for Small Group Meet,TRANSCRIPT
Rotavirus: Dilemma of Developing Countries
Rotavirus Vaccine: Recent Updates from IAPCOI Consensus Recommendations and WHO Position Paper
Facilitator: Dr Gaurav Gupta28th June 2013
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
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
Rationale for Rotavirus Vaccination as a public health measure for prevention of rotavirus disease in U.S.1
1Rates 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
2In 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
3Studies 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
Burden of Disease
WHY THESE CHANGES:• WHO has revised global diarrhea estimates• Differences in Rota Detection rates in Pre 2000
studies and post 2000/2005 studies• Improvement in sanitation and hygiene: Large
effect on bacterial and parasitic diarrhea and less effect on RV diarrhea
a) Rotavirus disease mortality world wide
2004 200850%
55%
60%
65%
70%
75%
80%
85%
90%
95%
100%
71
63
29
37
RV Mortality 2004 vs 2008
Other causes RV
1. The Journal of Infectious Diseases 2009; S9–15 2. The Lancet Infectious Diseases, Volume 12, Issue 2, Pages 136 - 141, February 2012
SANITATION AND HYGIENE: NO MUCH IMPACT ON ROTAVIRUS DISEASE
RV protection after natural infectiona) 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
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
1 2 30
20
40
60
80
100
120
38
62
7473 75
99
87
100
Asymptomatic Infection Mild Diarrhea
Moderate to Severe Diarrhea
1 2 30
20
40
60
80
100
120
2433
4644
7279
18
57
79
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)
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 weeksNo Concomitant OPV
Seroconversion was 58.3%,after 2nd dose.
RV52 Safety and Immunogenicity. 3 dose schedule, starting at 6 weeksConcomitant 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
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
Global Distribution of Rotavirus Serotypes1
G1P[8]65%
G3P[8]3%
G4P[8]9%
G9P[6]1%G9P[8]
3%
Other7%
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.
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
Rotavirus Disease Burden In India
122,000-153,000
457,000-884,000
2 million
Estimated annual number and risk of death, hospitalization, and outpatientvisits 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
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 witha 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.
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
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.
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
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
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, 49–64Indian Pediatrics . Volume 49. JULY 16, 2012
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
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
The potential for decreasing the burden of rotavirus disease, including mortality, is greatest in:
• Mexico • Africa • Brazil • India
The potential for decreasing the burden of rotavirus disease, including mortality, is greatest in:
• Mexico • Africa • Brazil • India
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
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
Which of the following is a contraindication to rotavirus vaccination in infants and small children?
• Hirschspung disease • HIV • Malabsorption syndrome • Severe combined immunodeficiency syndrome
Which of the following is a contraindication to rotavirus vaccination in infants and small children?
• Hirschspung disease • HIV • Malabsorption syndrome • Severe combined immunodeficiency syndrome
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
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
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
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
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
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
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 ?