1. Post-Licensure Safety Data: Monitoring Two Human Papillomavirus (HPV) Vaccine Products: Gardasil® (HPV4) and CervarixTM (HPV2)
Barbara A. Slade, MD
Julianne Gee, MPH
Immunization Safety Office
DHQP/NCEZID/OID/CDC

2. Vaccine Adverse Event Reporting System (VAERS)
National post-licensure passive surveillance system for reporting vaccine adverse events
Co-managed by CDC and FDA
Early warning system for vaccine safety surveillance
Monitors for known adverse events (AEs)
Detects signals for previously unrecognized/rare AEs
Generates hypotheses for further study
Limitations
Risk of underreporting and other reporting biases
Incomplete data
Lack of availability of denominator data
Cannot assess causality
Briefly, for those who are not familiar with VAERS, as I mentioned it s a national passive surveillance system for vaccine adverse events. Jointly operated by the CDC and FDA.
The system accepts reports from physicians, other health care providers, and the public
It serves as an early warning system for vaccine safety surveillance in which is allows for:
- Signal detection
Previously unrecognized and/or rare adverse events
-Monitoring known adverse events
It is a voluntary, passive surveillance system and therefore faces some limitations.
- there are reporting biases s
- data are sometimes incomplete, missing critical pieces of information
- it does not provide denominator data
- and we cannot assess causality using VAERS

3. Review of HPV4 Reports to VAERS
Aggregate summaries of VAERS reports were evaluated for reporting patterns and potential “signal” identification
Reports of select serious adverse events (SAEs)*, including deaths and other medically important conditions were reviewed in detail
* VAERS defines serious adverse events as those involving death, hospitalization, life-threatening illness, persistent or significant disability/incapacity, or certain other medically important conditions

4. Aggregate Summary of HPV4 AEs Reported to VAERS, June ‘06----Dec ‘09
Outcome
Doses Distributed
30 million
Total # VAERS HPV4 Reports
15,672
# Serious VAERS HPV4 Reports
(% of total reports)
1,208 (7.7%)
# (%) Most Frequently Reported
Syncope, Syncope Vasovagal
2592 (16.5%)
Dizziness
2451 (15.6%)
Nausea
1611 (10.3%)
Headache
1501 (9.6%)
Injection site reactions
1554 (9.9%)
Syncope: 2,592 reports
Serious reports: 158
Head injuries (Fractures, dental injuries, contusions, lacerations, intercranial hemorrages)
Reported increase in syncope for all adolescent vaccines

5. Select HPV4 Serious Adverse Event (SAE) Reports, confirmed by medical review
26 deaths
No clustering by cause of death, by time since vaccination, or by age
57 thromboembolic events*
41/57 (72%) had known risk factor(s)
29 had history of estrogen-containing birth control measures
11/24 (46%) of cases tested for genetic coagulation mutation tested positive
Increased reporting rates compared to females of the same age range who received other vaccines
Pulmonary embolus, deep venous thrombosis, cerebral venous sinus thrombosis, cerebral vascular accident
50 deaths, 81 thromboemboli
* pulmonary embolus, deep venous thrombosis, cerebral venous sinus thrombosis, cerebral vascular accident

6. Select HPV4 Serious Adverse Event (SAE) Reports, confirmed by medical review
18 cases of Guillain Barre Syndrome
met Brighton case definition*
12 cases of pancreatitis
All confirmed cases had known risk factors**
2 cases of a juvenile ALS-like disorder
Autopsy: destruction of anterior horn cells in spinal cord
Rapidly progressive course
57 GBS, 19 pancreatitis, 5 ALS-like *
**gallstones, alcohol, increased lipids, Coxsackie infection, estrogen use, obesity, ulcerative colitis, post colectomy

7. Vaccine Safety Datalink (VSD) Project
Collaboration: CDC and 8 Managed Care Organizations (MCOs) in the US
Annual population > 9.2 million
Advantages of VSD for vaccine safety research
Large, well-defined population
Computerized, linkable administrative data files
Powerful tool for controlled population-based studies 7

8. VSD: HPV4 Rapid Cycle Analysis
FOR INTERNAL VSD DISCUSSION ONLY
VSD: HPV4 Rapid Cycle Analysis
Objective: Identify associations between HPV4 and a pre-specified list of adverse outcomes in females age 9-26 years
Weekly analyses conducted using sequential statistical methodologies
Outcomes monitored:
GBS
Stroke
Venous Thromboembolism (VTE)
Appendicitis
Seizures
Syncope
Allergic Reactions
Anaphylaxis

9. VSD: HPV4 Rapid Cycle Analysis
Monitored for ~ 3 years:
August 6, 2006 – October 4, 2009
Total HPV4 doses administered
Youth (9-17 yrs): 419,942
Adults (18-26 yrs): 186,616
Total utilization by dose:
Dose 1: 45.1%
Dose 2: 32.4%
Dose 3: 22.4% 9

10. VSD: HPV4 Rapid Cycle Analysis (RCA)
Conducting final analyses
Finish manuscript
Long-term surveillance for VTE, Stroke, and GBS
Monitor outcomes until 1 million doses administered 10

11. Summary of HPV2 VAERS Adverse Event Reports
264 VAERS reports
2 from US; 262 foreign* reports
263 Cervarix alone
259 females; 4 males
Age ranges
6—17 yo: 184 (70%)
18—29 yo: 32 (12%)
No reports in VSD to date
I case with other vaccines: HepA, Tdap, varicella
*Foreign reports = reports submitted from foreign countries

12. Summary of HPV2 (Cervarix) VAERS Adverse Event Reports
Outcome
Number (% of Total Reports)
Total # VAERS Reports
264
# (%) Most Frequently Reported
Dizziness
50 (19%)
Headache
40 (15%)
Malaise
35 (13%)
Syncope
28 (11%)
Dyspnea
23 (9%)
Pyrexia
22 (8%)

13. Summary of HPV2 (Cervarix) VAERS Serious Adverse Event (SAE) Reports
Outcome
Number
(% of Total Reports)
# Serious VAERS Reports
(% of total reports)
94 (36%)
Grouping of SAEs
Deaths 3
Life-threatening Illnesses 20
Hospitalizations 54
Permanent disabilities 17
Foreign reports do not contain enough information to do detailed medical review.

14. Comparative Data on Safety of HPV2 and HPV4 Vaccines in Healthy Women Aged 18--45 years*
Percentage of women reporting specific solicited local symptoms at least once within 7 days after any vaccine dose
Symptom
CervarixTM
(n=524)
Gardasil®
Pain
93%
72%
Redness
44%
26%
Swelling
36.5%
22%
The incidence of solicited symptoms was generally higher after Cervarix™, injection site reactions being most common. However, compliance rates with the three-dose schedules were similarly high (= 84%) for both vaccines.
11 clinical trial of 30,000
Most frequent local rxn: injection site pain
Clinical trials: generally safe and tolerable
ASO4-adjuvanted vaccine
*Einstein MH et al. Human Vaccines 2009;5(10):

15. Comparative Data on Safety of HPV2 and HPV4 Vaccines in Healthy Women Aged 18--45 years*
Percentage of women reporting specific solicited general symptoms at least once within 7 days after any vaccine dose
Symptom
CervarixTM (n=526)
Gardasil® (n=526)
Arthralgia
21.7%
15.4%
Fatigue
49.8%
39.8%
Fever
14.4%
11.0%
Gastrointestinal
32.7%
26.5%
Headache
47.5%
41.9%
Myalgia
27.6%
19.6%
Rash
4.8%
3.4%
Urticaria
4.9%
4.0%
The incidence of solicited symptoms was generally higher after Cervarix™, injection site reactions being most common. However, compliance rates with the three-dose schedules were similarly high (= 84%) for both vaccines.
*Einstein MH et al. Human Vaccines 2009;5(10):

16. Summary: Vaccine Safety of HPV Vaccines
VAERS reports for HPV4 similar to findings reported in JAMA 2009 article.
VSD RCA completing Rapid Cycle Analyses for HPV4.
Inadequate use of HPV2 vaccine in the US to identify the types of rare SAEs seen with post-licensure safety assessment.
Post-licensure monitoring of both HPV4 and HPV2 is continuing in both VAERS and VSD.
* compared to females of the same age range who received other vaccines

17. HPV Vaccine and General Vaccine Safety References
Reports of Adverse Events Following Gardasil ® (on the CDC vaccine safety web site):
Gardasil ® Package Insert:
CervarixTM Package Insert:
VAERS information:
VAERS public search tool:   
CDC. Syncope after Vaccination. MMWR 2008;57(17):
Slade BA et al. Human Papillomavirus Recombinant Vaccine Postlicensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine. JAMA 2009;302(7):

18. Thank You

19. Additional Slides

20. Age Distribution of HPV4 AEs Reported to VAERS: June ‘06 – Dec ‘09

21. Select HPV4 Serious Adverse Event (SAE) Reports, June ‘06—Dec ‘09
Total No. of SAEs
Total No. of Confirmed SAEs*
Death 50 26
Thromboembolic Events 81 57
Guillain Barre Syndrome 18
(plus 9 pending review)
Pancreatitis 19 12
“juvenile Amyotropic Lateral Sclerosis”-like 5 2
26 deaths: No clustering by cause of death, by time since vaccination, or by age
Thromboembolic events: PE (31;alone=21;+DVT=10), DVTs (UE=10; LE=7), CVA,
GBS: 18 met Brighton case definition
12 confirmed pancreatitis all had known risk factor: Gallstones (2), Alcohol use (2), inc TG (1), Coxsackie infxn (1), estrogen use (2), obesity (3), ulcerative colitis, s/p colectomy (1)
2 ALS-like: rapidly progressive---not typical, autopsy----destruction anterior horn cells
* After medical review, removing hearsay reports, cases with no identifying information for follow-up, and cases with insufficient information.

22. Summary of HPV Adverse Event Reports
Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant = Gardasil ® = qHPV
Females: June 8, 2006—Dec. 31, 2009
Males: June 8, Oct. 15, 2009
licensed 10/16/2009
Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant = CervarixTM = bHPV
Through 4/1/10
As I mentioned, VAERS has recently published a paper in JAMA describing the reports received to VAERS from June 2006 to December 31, 2008.
The findings from this paper were generally not that different from what is seen in the safety reviews of other vaccines recommended for this age group.
The next couple of bullets describe the methods that were used in the paper.
Symptoms were assigned a medra code and classified as serious or non-serious, based on FDA’s regulatory definition of a serious adverse event.
Because no denominator is available through VAERS, the authors used the number of doses distributed in the US, during the study time period, which was 23, 051,336. This served as a denominators to assess reporting rates and proportional reporting ratios
Detailed case reviews were conducted for select serious AEs, in which the investigators from CISA played an integral role in reviewing and confirming many of the outcomes. ,m

23. Adverse Events Following HPV2 (Cervarix) Vaccine
Literature Report
Einstein MH et al. Comparison of the immunogenicity and safety of CervarixTM and Gardasil ® human papillomavirus (HpV) cervical cancer vaccines in healthy women aged 18–45 years. Human Vaccines 2009;5(10):
VAERS Reports
No reports to date in VSD
randomized, observer-blind study compared the two vaccines in a single, well-defined population of healthy women aged 18–45 years, using identical methodology for assessment of immunogenicity and safety.

24. Classification of Reporter Type to VAERS qHPV: 6/1/06----12/31/2009
Type of Reporter
Frequency
Percent
Patient/Parent
746
4.8%
Provider
2825
18%
State Health Dept.
212
1.35%
Manufacturer
9989
63.7%
Other
1896
12%
Unknown 4
0.03%

25. Summary of HPV4 AEs in Males Reported to VAERS, pre-FDA approved indication (Oct ‘09)
Total Number of VAERS Reports n = 75
1 female
34 medical errors
6 HIV positives
4 injection site reactions
7 male babies exposed in utero
2 enrolled in study, experienced AE
3 syncope
1 pulmonary embolus
Total SAEs n = 10
6 male babies exposed in utero

26. 57 thromboembolic events 18 cases of GBS 12 cases of pancreatitis
Confirmed Selected SAEs Reported to VAERS for HPV4, June ‘06---Dec ’09, cont.
26 deaths
57 thromboembolic events
18 cases of GBS
12 cases of pancreatitis
2 cases of a “juvenile ALS-like” disorder
Causes of death: Cardiac (8), PE (4)“juvenile ALS” (2); seizure disorder (2); unable to assess (no identifiers [6], hearsay [16], insuff info [1]);drugs (2); diabetic ketoacidosis (1); meningoencephalitis (1); cerebral vasculitis (1); undet (4); influ B sepsis (1); necrotizing fasciitis (1)
VTE: 81 reports
31 pulmonary emboli
8 with DVTs
11 strokes
2 SSST
24 DVTs
9 upper extremities
15 lower extremities
8 with PEs
5 manufacturer reports with no identifiers
10 hearsay reports
34 reports with HPV4 alone
28 reports serious
Most associated with known risk factors associated with VTE reports
VAERS reports do not establish a causal relationship between the vaccine and the adverse event 26

27. Age Distribution of HPV4 AEs Reported to VAERS: June ‘06 – Dec ‘09