Transcript Slide 1

A Tale of Two Vaccine Safety Concerns
-Rotashield
(Original Rotavirus Vaccine)
-Thimerosal
American Medical Writers Association Meeting
October 11, 2007
Walter A. Orenstein, M.D.
Professor of Medicine and Pediatrics
Director, Emory Vaccine Policy and Development
Associate Director, Emory Vaccine Center
From: MMWR 2006; 55 (RR-12) 1-13
Rhesus Rotavirus Vaccine†
 Licensed in 1998
 Contained 4 vaccine viruses (RRV-TV)
– 1 derived from a virus isolated in Rhesus
monkeys
– 3 reassortant viruses with 1 human gene
and 10 rhesus genes
 3 doses, 50-60% effective against all
disease, 80-90% against severe disease
From: Clark HF, et al. Chapter 51, Rotavirus Vaccines, Vaccines 4th edition,
eds. Plotkin SA and Orenstein WA, 2004 pp 1327-1345
Prelicensure Evaluation of
RRV-TV
 11,000 children evaluated
 Adverse events 15% fever attributable
to vaccine, 3-5 days post dose 1, 2%
post dose 2
 Intussusception noted in 5 of 11,000
vaccinees, 1 of 4500 placebo recipients
(difference not significant)
 ACIP and AAP warned intussusception
might be an adverse event and
encouraged reporting
From: Clark HF, et al. Chapter 51, Rotavirus Vaccines, Vaccines 4th edition,
eds. Plotkin SA and Orenstein WA, 2004 pp 1327-1345
Intussusception and RRV-TV†
 9/1/98 – 7/7/99 – 15 cases reported
 13/15 after dose 1
 12/15 within 1 week of any dose
 11/15 onset 3 – 5 days post vaccination
Preliminary studies in one HMO and one
State suggested an increased risk
although the numbers were too small to
reach significance
CDC recommends postponing
vaccination until more data available
† MMWR 1999; 48:577-81
From: Murphy TV, et al. N Engl J Med 2001; 344(8):564-573
From: Kramarz P, et al. Pediatr Infect Dis J 2001; 20(4):410-416
Withdrawing of Rotavirus
Vaccine Recommendation†
 ACIP votes on October 22, 1998 to
withdraw recommendation for routine
use
† MMWR 1999; 48:1007
Summary of Deliberations on
Intussusception - I
 Possibility of intussusception noted in
pre-licensure trials. Physicians warned
of possible adverse events and
encouraged to report
 Reports of 15 cases were unusual –
clustered 3 – 5 days post dose 1
 Preliminary data in HMO and one State
also raised concerns
 CDC recommended stopping
vaccination until more data were
available
Summary of Deliberations on
Intussusception - II
 Extensive studies conducted which
confirmed causal association
 Recommendation withdrawn
 Standards for evaluating new rotavirus
vaccines changed
 Current vaccine evaluated in 72,325
infants to detect intussusception
Exposure to Mercury from Vaccines
in US Infants (<6months) at the
Time of Review
Pediatrics 2001; 107: 1147-1154
Government Actions on
Thimerosal† - I
 Significant safety margin in mercury
exposure limits
 Exposure for ethyl mercury in vaccines
could exceed limits for methyl mercury
for EPA but not ATSDR or FDA
 No known harms from thimerosal in
vaccines
 Known harms from failure to vaccinate
† MMWR 1999; 48:563-564
Government Actions on
Thimerosal† - II
 Remove thimerosal-containing
vaccines as soon as possible
 Continue to vaccinate with any
available vaccine
 Potentially alter the hepatitis B
schedule
† MMWR 1999; 48:563-564
California Estimated Prevalence of
Autism and Estimated Mercury
Exposure in Vaccines
From Stehr-Green P et al. Am J Prev Med 2003; 25:101-106
Thimerosal and Autism
Characteristic findings in Autism and in Mercury Poisoning †
Autism
Mercurism
Motor
Stereotypies
Ataxia, dysarthria
Vision
No abnormality
Constricted visual fields
Speech
Delay, echolalia
Dysarthria
Sensory
Hyper-responsiveness
Peripheral Neuropathy
Socially aloof,
insistence on sameness
Toxic psychosis; in mild
cases, non-specific
depression anxiety
Large
Small
Psychiatric
Head size
† Nelson KB, Bauman ML. Pediatrics 2003; 111: 674-679
All Mercury is Not the Same
 Mercury in any form has not been
linked to autism
 Major toxicity – methyl Hg
 Ethyl mercury – shorter ½ life
– Less associated with neurotoxicity
Epidemiologic Studies of
Autism and Vaccines
Ecologic
– Compare secular trends over time with trends in
vaccine coverage rates, thimerosal exposure, etc.
– Weakest kind of study
Case-Control
– Select cases, determine vaccine and/or thimerosal
exposure
– Select controls and compare exposures in cases
and controls
– Measure odds ratio which approximates relative risk
Cohort
– Compares rates of autism in children exposed and
not exposed to vaccines
– Can look for a dose-response effect
– Measure relative risk
Selected Strengths and
Weaknesses of
Epidemiologic Studies
Strengths
– Measure disease in human populations
– Measure under conditions of actual
product use
– Best able to detect relationships if factor
of concern accounts for large proportion
of total cases
Weaknesses
– Potential for biases in case ascertainment,
case definition, and confounding
Figure 2. Birth cohort prevalence rates and ethyl mercury exposure. Dotted lines take
Into account the additional ethyl mercury exposure because of mass vaccination
Campaign against meningitis.
From: Fombonne E, et al. Pediatrics 2006; 118:e139-e150
Rate Ratio of Autism and Autism
Spectrum Disorders (ASD) by
Exposure to Thimerosal in Vaccines†
Thimerosal
in vaccines
PersonYears
No
Autism
Other ASD
1,660,159
303
1.00
1.00
169,920
18
1.01
0.95
(0.6-1.71)
(0.66-1.37)
447,973
33
0.70
1.20
(0.46-1.09)
(0.92-1.56)
602,113
53
0.96
1.13
(0.63-1.47)
(0.84-1.51)
Trend
0.98
1.03
per 25µg
(0.90-1.06)
(0.98-1.09)
None
1 dose
(25µg Hg)
2 doses
(75µg Hg)
3 doses
(125µg Hg)
†JAMA
2003; 290: 1763-1766
Schedule 5 weeks, 9 weeks, 10 months, in Denmark
Criteria for Evaluating the Quality
of Cohort Studies of Autism and
Thimerosal Exposure†
 Cohort inclusion/exclusion criteria precisely







described
Outcome measures (diagnoses) precisely
described
Outcome measures validated at least for a sample
Methods to calculate Thimerosal exposure
described and appropriate
Basis for sample size described &/or power
discussed
Study controls for bias and confounding
Potential impact of bias on results
Other study limitations discussed
† Parker SK et al. Pediatrics 2004; 114:793-804
Methodologic Evaluation of Studies
Addressing Link of Autism and
Thimerosal†
Studies NOT supporting a
relationship
Methodologic Score
Andrews et al 2004
7/8
Heron et al 2004
Hviid et al 2003
Verstraeten et al 2003
5/8
6/8
6/8
Studies supporting a relationship
Geier and Geier 2003
0/8
Geier and Geier 2003
0/8
Geier and Geier 2003
0/8
† Parker SK et al. Pediatrics 2004; 114:793-804
Institute of Medicine
Immunization Safety Review
Vaccines and Autism†
 The Committee concludes that the evidence

favors rejection of a causal relationship between
1) thimerosal-containing vaccines and autism
and 2) MMR vaccine and autism
In the absence of experimental or human
evidence that vaccination (either the MMR
vaccine or the preservative thimerosal) affects
metabolic, developmental, immune, or other
physiological or molecular mechanisms that are
causally related to the development of autism,
the Committee concludes that the hypotheses
generated to date are theoretical only
† Immunization Safety Review Committee, Institute of Medicine,
National Academies Press, 2004
Maximum Content of Mercury in
Vaccines Children Receive Through
6 months of Age
Vaccine
1999 †
2007 ††
DTaP x 3 doses
Hib x 3 doses
Hepatitis B x 3 doses
IPV x 2 doses
PCV7 x 3 doses
Influenza x 1 dose
75 µg
75 µg
37.5 µg
0
-
<0.9 µg
0
<1.5 µg
0
0
12.5 µg
TOTAL
187.5 µg
<14.9 µg
† Ball LK et al. Pediatrics 2001; 107:1147-1154
†† www.fda.gov/cber/vaccine/thimerosal.htm, accessed 4/24/06
Children Receiving Autism
Services by Quarter, California,
2002-2006
9000
8000
7000
6000
5000
3-5 year olds
6-9 year olds
4000
3000
2000
1000
3Q
20
4Q 02
20
1Q 02
20
2Q 03
20
3Q 03
20
4Q 03
20
1Q 03
20
2Q 04
20
3Q 04
20
4Q 04
20
1Q 04
20
2Q 05
20
3Q 05
20
4Q 05
20
1Q 05
20
06
0
California Department of Developmental Services
From Wharton M via email 4/19/06
Thimerosal and Adverse
Neurologic Outcomes†






1047 children studied with standard
assessment
42 outcomes evaluated
Among girls, 2 significant associations with
better performance
Among boys, 1 significant better performance
and 2 significant negative associations
Conclusion – study does not support a link
between thimerosal and neurodevelopment
disorders
Autism was not studied
† Thompson WW, et al. N Engl J Med 2007; 357:1281-92
Comparison of Actions on Rotashield
(RRV-TV) and Thimerosal
Theoretical concerns
Signal of actual adverse
events
Signal supported by
confirmatory data
Suspend vaccination
Urge removal of
thimerosal as precaution
Comprehensive studies
Studies show harm
RRV-TV Thimerosal
No
Yes
Yes
No
Yes
No
Yes
_
No
Yes
Yes
Yes
Yes
No