RotaTeq® Post Marketing Surveillance
and Effectiveness Data
Dr Swashraya Shah
MSD India
24 Dec 2011
Contents
• RotaTeq® Post licensure Safety Data:
− US
− Australia
− Indian Data of spontaneous reports till date
• RotaTeq® Post licensure Effectiveness Data:
− US
− Australia
− Nicaragua
RotaTeq: Post-Marketing Surveillance
• US
• Vaccine Safety Datalink (VSD) and Vaccine Adverse
Events Report: Feb 06 – Sep 07
• Vaccine Safety Datalink: May 06 – May 08
• Summary report of meeting of ACIP (Data from 20062010)
• Australia (July 07 – Dec 08)
Vaccine Safety
Datalink (VSD)
• Large federally funded
collaboration
• Investigates Vaccine AEs at 8
managed care organizations
• Sites in VSD contribute
electronic Data on
immunizations, ICD-9 diagnosis
codes (inpatient, ED, OPD) and
demographics
• It includes data for about:
Vaccine AE Reporting
System (VAERS)
• National passive surveillance
system
• Managed jointly by FDA and
CDC
• Receives reports of AEs after
vaccination from various sources
including HCPs, state and local
immunization programs, vaccine
recipients and manufacturers
• 8.8 million people annually
• Annual birth cohort of about
95000.
1. Haber et al. Postlicensure Monitoring of Intussusception After RotaTeq Vaccination in the United States,
February 1, 2006, to September 25, 2007. Pediatrics 2008;121;1206-1212, 2. Belongia E A et al. Real-Time
Surveillance to Assess Risk of Intussusception and Other Adverse Events After Pentavalent, Bovine-Derived
Rotavirus Vaccine. Pediatr Infect Dis J 2010;29: 1–5)
US Feb 06 to Sep 07 – VAERS data1
•
•
•
•
Assessed Post RotaTeq® IS reports using data from VSD and VAERS.
Observed versus expected Rate Ratios determined using vaccine dose
distribution data and VSD background IS rates.
VAERS : Post RotaTeq®:
• 1901 AE reports, 160 (8.4%) confirmed IS reports.
• 47 (29% of total IS) within 1-21 days, 27 (17%) within 1-7 days. (For
Rotashield >60% IS cases were within 1-7 days)
Expected cases were calculated from the VSD background rate of IS:
Within 1-21 d
Within 7 d
•
•
Observed
47
27
Expected
151
50
Observed rate was not elevated above age adjusted background rate of IS
within 1-21 day or within 1-7 day.
Observed/expected RRs were similar when stratified according to dose or age
group.
Haber et al. Postlicensure Monitoring of Intussusception After RotaTeq Vaccination in the United States,
February 1, 2006, to September 25, 2007. Pediatrics 2008;121;1206-1212
US Feb 06 to Sep 07 – VSD data1
• Between May 21, 2006 to Sep 25, 2007, total of 111521 doses of
RotaTeq® administered.
• IS Cases:
RotaTeq®
Non RotaTeq®
recipients
recipients
IS cases
3/111521
9 / 186722
Relative Risk: 0.84 (95% CI: 0.14 – 3.92)
• Data from VSD and VAERS do not indicated that RotaTeq is
associated with IS. Observed/expected RRs were similar when
stratified according to dose or age group
Haber et al. Postlicensure Monitoring of Intussusception After RotaTeq Vaccination in the United States,
February 1, 2006, to September 25, 2007. Pediatrics 2008;121;1206-1212
US Surveillance using prospective cohort
design May 2006 – May 2008
• This study used data from VSD. Participating VSD sites generated
weekly data files with immunization data, inpatient and outpatient
diagnosis codes (ICD-9 codes)
• Included the RotaTeq® Exposed population : children from 4- 48 weeks
who received RotaTeq® between May 06 and May 08.
• 2,07,621 doses administered (42% were first doses), Largest post
licensure study of RotaTeq vaccine safety.
• Observed frequencies of AEs compared with prelicensure (Background)
incidence rate.
• Cases of IS identified based upon electronic diagnosis codes. IS case
Confirmed by medical record review.
Belongia E A et al. Real-Time Surveillance to Assess Risk of Intussusception and Other Adverse Events
After Pentavalent, Bovine-Derived Rotavirus Vaccine. Pediatr Infect Dis J 2010;29: 1–5)
Results:US Surveillance (May 06 – May 08)
• Total 5 children had ICD - 9 codes for IS. 2 were confirmed of IS by
medical record review.
• Observed incidence (Computerized diagnosis code for IS: 5 and cases
expected based on historical rates: 6.75)
• Only 2 validated cases of IS occurred after more than 2,00,000 doses
and neither occurred after first dose. Both cases were diagnosed more
than 14 days after vaccination.
• There was no statistically significant elevated risk following first dose,
second dose or third dose of RotaTeq®
• By the end of surveillance period, there was no evidence that RotaTeq®
was associated with increased risk for any other prespecified adverse
events like meningitis/encephalitis, seizures, myocarditis or gram
negative sepsis.
Belongia E A et al. Real-Time Surveillance to Assess Risk of Intussusception and Other Adverse Events
After Pentavalent, Bovine-Derived Rotavirus Vaccine. Pediatr Infect Dis J 2010;29: 1–5)
Updated Data from CDC
(Discussed in Oct 27, 2010 Meeting of ACIP)
• A large post-marketing study of IS following RotaTeq® which includes
over 850,000 total doses.
• Surveillance conducted for IS using two windows: 30-day and 7-day. At
8 VSD Sites
• Cohort:
– Exposed population : children who received any dose of RotaTeq® with or
without other vaccines from age 4 to 34 weeks.
– Concurrent comparison group : received any vaccine besides RotaTeq®
from age 4 to 34 weeks.
• Data from May 2006 to May 2010.
• Probably the largest active surveillance study of IS and RotaTeq® in the
US.
From Summary Report of ACIP meeting in Oct 2010 accessed on 23 Dec 2011 at
http://www.cdc.gov/vaccines/recs/acip/downloads/min-archive/min-oct10.pdf
Updated Data from CDC
(Discussed in Oct 27, 2010 Meeting of ACIP)
• IS Cases
− 31 cases of IS out of 850,000 RotaTeq® doses.
− 19 cases In the comparison group, out of 405,000 comparison visits.
− Within 7 days: Only 2 cases after first dose (first dose : 3,32,000) While in
comparator group there were 4 cases.
• Summary:
– The US post marketing experience in VSD provides no evidence that
RotaTeq® is associated with an increased risk for IS in either the 30-day or
7-day window.
From Summary Report of ACIP meeting in Oct 2010 accessed on 23 Dec 2011 at
http://www.cdc.gov/vaccines/recs/acip/downloads/min-archive/min-oct10.pdf
PMS NIP Australia
• Safety of rotavirus vaccines, with
respect to a possible association with
intussusception, was assessed in
four states using two concurrent
active surveillance mechanisms
• During the first 18 months following
the introduction of rotavirus vaccines
into the NIP in Australia
• Actively sought all cases of
confirmed intussusception in infants
<24 months of age from 1st July
The numberof doses administered of either RotaTeq or Rotarix
2007 to 31st December 2008 and
vaccine during the period 1st July 2007 and 30th December 2008.
– Light grey – states using Rotarix in the NIP.(only W.Australia &
determined their rotavirus vaccine
NSW included in analyses)
− Dark grey – states using RotaTeq in the National Immunization
status.
Program.(only Victoria/S Australia included for analyses).
Buttery J P et al. Intussusception following rotavirus vaccine administration: Post-marketing surveillance in the National
Immunization Program in Australia. Vaccine 29 (2011) 3061–3066
Results of Australian study
• Relative risk of IS in infants 1 to < 9 months of age:
− 1–7 days:
► RotaTeq® RR = 1.15, (95CI: 0.37,2.68)
► Rotarix® RR = 1.58, (95% CI: 0.51,3.69)
− 1–21 days:
► RotaTeq® RR = 0.77 (95% CI 0.37,1.41)
► Rotarix®RR = 1.37, (95% CI 0.73, 2.34)
• Is there more risk with particular vaccine:
• It is not possible to make any comparison of the increased risk
following these two vaccinations due the small number of
intussusception cases which limits the precision of these estimates.
Buttery J P et al. Intussusception following rotavirus vaccine administration: Post-marketing
surveillance in the National Immunization Program in Australia. Vaccine 29 (2011) 3061–3066
India Spontaneous reports of AEs after
RotaTeq® vaccination
Date of receipt of AE
report
Adverse Event Term
Suspect Drug
Reporters
Causality
24-May-11
Diarrhea with blood streaks
RotaTeq®
Yes
24-May-11
Abnormal movement of limbs, Voice
chocking, Cyanosis, Screaming,
Crying
RotaTeq®
Yes
16-Aug-11
Intussusceptions
RotaTeq®
No
27-Sep-11
Intussusceptions
RotaTeq®
No
No report of any SAE after receipt of RotaTeq®
Different Methods / systems that evaluated
Post licensure effectiveness of RotaTeq®
 NREVSS: National Respiratory and Enteric Virus Surveillance
System:
Is a laboratory-based system that monitors temporal and geographic
patterns associated with the detection of respiratory and enteric viruses
including rotavirus
 New Vaccines Surveillance Network:
It evaluates the impact of new vaccines and vaccine policies through a
network of 7 sites in the U.S. Conducts population-based inpatient and
enhanced outpatient surveillance for vaccine-preventable disease
outcomes, applied epidemiologic and health service research, and
investigator-initiated studies to achieve the goals of the network.
 Hospital Discharge Data from different states and Hospitals
Rotavirus Test Results from NREVSS*
Includes 2009-2010 season
Before RotaTeq® Introduction
(2000 – 2006 Median)
After RotaTeq® Introduction
(2007 – 2008 Season)
NREVSS=National Respiratory and Enteric Viruses Surveillance System
Tate et al Pediatrics 2009; Tate et al PIDJ Jan 2011
Decreased
seasonal
peak &
delayed
occurrence
New Vaccine Surveillance Network (2006-2010):Number of
Acute Gastroenteritis (AGE) and Rotavirus-confirmed
Hospitalizations, Age <3 Yrs
250
Number of cases
211
200
194
168
147
150
107
100
51 %
51%
RV+
RV+
101
52
%
52%
RV+
RV+
101
6%
RV+
50
26 %
RV+
44
9
0
4%
RV+
2006
2007
2008
4
2009
2010
Payne D et al PAS, 2009 and unpublished data; Presented by Cortese M. ACIP June 2010
Total AGE
Rotavirus +
Reduction in AGE Hospitalizations in US after RV
Vaccine Introduction
 Using 100% hospital discharge data from 18 states, accounting for 49% of the
US population, authors calculated acute gastroenteritis hospitalization rates
for children aged <5 years by rotavirus season during pre-RV5 rotavirus
seasons from 2000 through 2006 with those during the post-RV5 2007 and
2008 seasons.
16% reduction
45% reduction in 2008 season
Curns AT, et al. Reduction in Acute Gastroenteritis Hospitalizations among US Children After Introduction of Rotavirus Vaccine: Analysis of Hospital Discharge
Data from 18 US States The Journal of Infectious Diseases 2010; 201(11):1617–1624
Reduction in AGE Hospitalizations in US after RV
Vaccine Introduction
Herd
Immunity ?
Substantial decreases in AGE
Hosp rates noted among
age groups
that were too young or too old
to be vaccinated with RV5.
Source: Curns AT, et al. Reduction in Acute Gastroenteritis Hospitalizations among US Children After Introduction of Rotavirus
Vaccine: Analysis of Hospital Discharge Data from 18 US States The Journal of Infectious Diseases 2010; 201(11):1617–1624
SOUTH AUSTRALIA HOSPITALIZATION DATA
RotaTeq®
Introduced
in South
Australia
NIP in July
2007
Age specific RVGE and ACGE Hospitalization rates per 100000 children: Pre and Post
Rotavirus Vaccine Introduction
At 2 year period post vaccine introduction (compared to 2 yrs prior) and in
age group < 6 yrs:
Admissions for RVGE to SA hospitals: reduced by 83% (955 vs 165)
Admissions for ACGE to SA hospitals: reduced by 48% (4153 vs 2142)
Clarke M. F. et al. Direct and indirect impact on rotavirus positive and all-cause gastroenteritis hospitalisations in South Australian children following
the introduction of rotavirus vaccination. Vaccine 29 (2011) 4663– 4667
Nicaragua: Serotype Specific Effectiveness Data
 2006: Merck-Nicaraguan Ministry of Health RotaTeq
partnership implemented. Between 2006 and 2009, 1.3
million RV5 dosages supplied.
 A matched case-control study for the effectiveness of
RV5 was conducted (Controls were hospital/community
controls).
This 3-year demonstration
project suggested a
significant positive public
health impact of RV5 on
children at risk for RGE in
Nicaragua,
Mast T. et al. Case-control Study of the Effectiveness of Vaccination With Pentavalent
Rotavirus Vaccine in NicaraguaThe Pediatric Infectious Disease Journal • Volume 30,
Number 11, November 2011
Nicaragua was the first
GAVI-eligible country to
introduce rotavirus
vaccine.
Projected Effectiveness of RotaTeq in 6 Asian
Countries1
Background
• In case it is not always feasible to conduct clinical trials in every
country, results from previously conducted studies can help to predict
disease reduction in other countries.
• This analysis used a previously validated mathematical efficacy
projection model, which was developed to project the efficacy of a live
attenuated rotavirus vaccine in India.
• The Model was validated by using data from a phase II clinical trial with
known rotavirus serotype distribution.2
1.Khoury et al. Projecting the effectiveness of RotaTeq® against rotavirus-related hospitalizations and deaths in six Asian
countries. Human Vaccines 7:5, 506-510
2.Salinas et al.Evaluation of safety,immunogenecity & efficacy of an attenuated rotavirus vaccine,RIX-4414:a randomised
placebo control trial in latin american infants.PIDJ 2005;24(9):807-16
Projected Effectiveness of RotaTeq® in 6
asian countries
Khoury et al. Projecting the effectiveness of RotaTeq® against rotavirus-related hospitalizations and
deaths in six Asian countries. Human Vaccines 7:5, 506-510;
Projected annual reduction in RGE related
deaths
Khoury et al. Projecting the effectiveness of RotaTeq® against rotavirus-related hospitalizations and
deaths in six Asian countries. Human Vaccines 7:5, 506-510;
Indian RV Immunogenicity & Safety Study
Serum Anti-rotavirus IgA Responses
GMTs of serum anti-rotavirus IgA
Time points
N
Units
95% CI
Pre dose 1
102
3.81
(2.74 , 5.29)
Post dose 3
102
79.95
(55.23 , 115.73)
% of subjects with ≥3 fold rise = 82.4% (75 , 90%)
Bhave S. Presented PGHNNC Conference,PGI Chandigarh Oct 2010
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