1. Safety of Quadrivalent Human Papillomavirus (HPV4) Vaccine: What Providers Should Know
National Immunization Conference
March 28, 2012
Julianne Gee, MPH
Immunization Safety Office
Centers for Disease Control and Prevention
Today I will be providing an overview of the safety of Quadrivalent Human Papillomavirus Vaccine, or HPV4.
For those who were at the October ACIP meeting, this talk is very similar to what was presented at that meeting.

2. Presentation Outline Describe sources of HPV4 safety data
Review of US surveillance HPV4 safety data
Review findings from a recent Vaccine Safety Datalink (VSD) study
Review findings from 2011 Institute of Medicine’s report of adverse events and vaccines
In this presentation, I will describe the sources of HPV4 safety data
Review findings from prelicensure trials, US surveillance efforts, and describe select manufacturer postlicensure commitments.
I’ll review findings from a recent VSD study
Lastly, I will present relevant conclusions surrounding HPV vaccine from the recent IOM report

3. Sources of Safety Data for HPV4
Pre-licensure trials
Post-licensure safety monitoring and evaluation
US Vaccine Safety Surveillance Systems:
Passive :
Vaccine Adverse Event Reporting System (VAERS)
Active:
Vaccine Safety Datalink (VSD) Rapid Cycle Analysis
Studies: VSD
Manufacturer post-marketing commitments*
The sources of safety data for HPV4 include pre-licensure trials conducted by the manufacturer
The Post licensure safety data sources include our US govt sponsored safety surveillance systems which are comprised of the vaccine adverse event reporting system (VAERS) and the Vaccine safety datalink Rapid Cycle Analysis.
In addition, there are multiple manufacturer post marketing commitments, which has been described in the Bonani et al paper published in Vaccine 2010
* Bonani P, et al. A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD. Vaccine 2010

4. HPV4 Pre-licensure Studies*
Entire study population: 29,323
Girls and women (9-45 yrs)
Boys and men (9-26 yrs)
Frequent non-serious adverse events:
Injection site pain, fever, nausea, dizziness, syncope
Serious systemic adverse events (SSAEs):
Most frequent SSAEs reported in any study arm:
Headache, gastroenteritis, appendicitis, pelvic inflammatory disease,
urinary tract infection, pneumonia, pulmonary embolism, bronchospasm, asthma
0.04% SSAEs considered to be vaccine-related
40 deaths: events reported consistent with events in healthy adolescent and adult populations
Among the multiple pre licensure studies, the entire study population included 29,323 males and females
The most frequently reported serious systemic adverse events (SSAEs ) in any study group are listed on this slide
0.04% of the SSAEs were judged to be vaccine related by the study investigator.
Across the clinical studies there were 40 deaths reported. The events reported were consistent with events expected in healthy adolescents and adult populations.
Based on the findings from these studies FDA licensed HPV 4 in June 2006 for females 9-26yrs
* FDA, Product approval-prescribing information [package insert]

5. Vaccine Adverse Event Reporting System (VAERS)
National post-licensure passive surveillance system
Co-managed by CDC and FDA
Early warning system for vaccine safety surveillance
Monitors for known adverse events (AEs)
Detects signals for previously unrecognized or rare AEs
Generates hypotheses for further study
Limitations
Reporting biases
Incomplete data
Lack of availability of denominator data
Not designed to assess for causality
Briefly, for those who are not familiar with VAERS, its a national passive surveillance system for vaccine adverse events. Jointly operated by the CDC and FDA.
It serves as an early warning system for vaccine safety surveillance
Because VAERS is a voluntary and passive surveillance system it does face some limitations. Most importantly, VAERS is not designed to assess causality between an adverse event and a vaccine.
- It is subject to reporting biases
- data are sometimes incomplete, missing critical pieces of information
- it does not provide denominator data

6. Summary of HPV4 VAERS US Reports
Published Post-licensure Safety
Surveillance *
Updated Post-Licensure Safety Surveillance
Reporting Dates
6/1/06-12/31/08
6/1/06-9/15/2011
Doses Distributed
23,051,336
~40 million doses**
Total VAERS reports
12,424
20,096
Serious (%)±
6.2%
7.2%
Specific AEs assessed
Injection site reactions, syncope, headache, hypersensitivity, Guillain Barré Syndrome (GBS), transverse myelitis, motor neuron disease, venous thromboembolic events (VTE), pancreatitis, autoimmune disorders, pregnancy , death
Continued monitoring, including assessment of specified AEs
Assessment
Safety profile consistent with pre-licensure data, with exception of VTE and syncope
No new adverse event concerns or clinical patterns identified
In August 2009, VAERS published a 2 yr summary surveillance report in JAMA
The authors concluded that the safety profile of HPV4 among females was consistent with pre-licensure data, with the exception of Venous thromboembolism and syncope.
We have continued monitoring HPV4 reports among females and males and in the third column we present an update of the data through
There have been approx 20K reports received to VAERS in which 7% are considered serious.
To date, no new adverse event concerns have been identified nor any new clinical patterns.
*Slade B, Leidel L, Vellozzi C, et al. JAMA. Post-licensure Safety Surveillance for Quadrivalent Human Papillomavirus Recombinant Vaccine ; 302(7):
** Permission granted by manufacturer to present dose information
±Serious defined as an event resulting in Death, Life-threatening illness, Hospitalization, Prolongation of existing hospitalization, Persistent or significant disability

7. Summary of VAERS HPV4 Reports June 1, 2006 - September 15, 2011
Characteristics
All (N,%)
Female (N,%)
Male (N,%)
Total reports*
20,096
19,075 (94.9%)
569 (2.8%)
Median Age (Range)**
17 yrs (0-82)
14 yrs (0-77)
Age group (years)
<9
109 (0.5)
77 (0.4)
27 (4.7)
9-10
289 (1.4)
270 (1.4)
16 (2.8)
11-12
2158 (10.7)
1994 (10.4)
149 (26.2)
13-18
8774 (43.7)
8443 (44.3)
285 (50.1)
19-26
5061 (25.2)
4997 (26.2)
40 (7.0)
>26
427 (2.1)
401 (2.1)
23 (4.0)
Unknown
3278 (16.3)
2893 (15.2)
29 (5.1)
This slide represents characteristics those who had a reported AE following HPV4
As you can see the majority of the total reports received to vaers through Sept 15th are female. Later in this presentation, I will provide a more focused summary of male reports.
The median age of all reports received was 17 in which almost 44% of these reports were among 13-18yr olds.
* Unknown gender= 452 (2.2%)
** Includes reports in children < 1 yr

8. Summary of VAERS HPV4 Reports June 1, 2006 - September 15, 2011
Characteristics
All (N, %)
Female (N, %)
Male (N,%)
Total reports*
20,096
19,075 (94.9%)
569 (2.8%)
Serious**- fatal
71 (0.3)
57 (0.3)
3 (0.5)
- non-fatal
1,456 (7.2)
1,415 (7.4)
30 (5.2)
Non-serious
18,569 (92.4)
17,603 (92.2)
530 (94.2)
Reported by- Manufacturer
12,378 (61.6)
11,866 (62.2)
135 (23.7)
- Provider
4,152 (20.6)
3,839 (20.1)
288 (50.6)
Received HPV4 only
15,201 (78.6)
14,550 (76.2)
251 (44.1)
Median onset interval from vaccination to adverse event (range)±
0 days (0-1,977)
0 days (0-1,977)
0 days (0-433)
The characteristics of the types of reports we have received include are listed in this slide.:
- There have been a total of 1,527 serious reports.
Approximately 62% of total reports were received by the manufacturer.
78.6% of all VAERS reports received HPV4 only
The median onset interval from vaccination to AE was 0 days.
* Unknown gender= 452 (2.2%)
** Serious defined as an event resulting in Death, Life-threatening illness, Hospitalization, Prolongation of existing hospitalization, Persistent or significant disability
± Day 0 = Day of vaccination

9. Most Frequently Reported Terms for Non-serious and Serious Reports Following HPV4 in VAERS
Non-serious (N=18,569)
Serious (N=1,527)
MedDRA Preferred Terms* %
Syncope
14.5
Headache
25.0
Dizziness
13.7
Nausea
18.6
9.3
Fatigue
17.4
8.3
16.8
Injection site pain
7.0
Vomiting
14.7
Drug exposure during pregnancy
6.8
Pyrexia
6.3
Computerized tomogram normal
13.0
Loss of consciousness
5.9
12.6
Urticaria
4.9
Asthenia
11.7
Pain in extremity
Pain
11.6
On this slide you can see the most frequently reported terms for all non-serious and serious reports.
* As coded using the MedDRA preferred terms, more than one code may be assigned to a single event

10. : VAERS Serious Reports of Syncope Following HPV4*
Total number of serious reports: 202
Injuries resulting from syncopal event:
Fractures (nose, skull, maxillary)
Dental injuries
Contusions
Concussions
Intracranial hemorrhages (subdural hematoma, subarachnoid hemorrhage)
No reports of death resulting from injury following a vasovagal syncopal event
Dispropotional reporting of syncope was identified in the 2009 VAERS review of HPV4 published in JAMA.
Since Sept 15th of 2011, syncope continues to be one of the most common terms identified in both non-serious and serious reports. There have been 202 serious reports of syncope. Injuries that have resulted from a syncopal event include those listed on this slide.
There have been no reports of death received by VAERS from injury resulting from a vasovagal syncopal event.
* Unverified reports coded as syncope or syncope vasovagal

11. VAERS Reports of Anaphylaxis
Total number of reports: 43*
All female
Serious reports: 20
Median age (range): 17 years (11-27)
Median onset from vaccination to event: 0 days (0-10)
Confirmed anaphylaxis: 12
All treated and recovered
No confirmed deaths due to anaphylaxis
In our review of anaphylaxis reports to VAERS, we found 43 reports in which they were all female and 20 were considered serious. The median age was 17 yrs and the median onset from vaccination to event was 0 days.
There were 12 reports in which we were able to confirm a n anaphylaxis diagnosis
(by either MD diagnosis, or Brighton criteria level 1-3)
All were treated and recovered.
There were no confirmed deaths due to anaphylaxis.
***
-7 were reported as serious either due to “life threatening” being checked off or report by MFR
of these 3 had HPV alone and 1 did not have this information documented
-all were treated and recovered
Of the remainder 32:
3 were hearsay reports
2 had symptoms that ranged from 3 days – 20 days after the vaccination date
3 had multitude of symptoms but doctors found difficult to come up with a diagnosis
The remainder ( 24) did not have enough on the report to establish a diagnosis of anaphylaxis
*Reports coded with MedDRA terms: anaphylactic shock, anaphylactic reaction,
anaphylactoid shock, anaphylactoid reaction

12. VAERS: Reports of Death Following HPV4
Total Death Reports
N= 70
Verified*
N= 34
Unconfirmed
N= 36
We have had a total of 71 reports of death to VAERS, of which 34 have been verified by autopsy, death certificate or confirmation by medical provider
Among the 37 unconfirmed reports of death, the majority have been considered hearsay—meaning we have no specific knowledge about a patient or event therefore unable to confirm the death. This included reports from people in which they have read about a possible HPV death on a website , newspaper or magazine.
"Other" are current death reports "under investigation".
Female
N= 32
Male
N=2
Hearsay**
N=32
Other**
N=4
*Deaths verified by autopsy, death certificate, or provider confirmation
** Hearsay: Reports with no identifying information for follow-up. Other: Under investigation

13. VAERS Verified Reports of Death (N=34)
Characteristic
Female
32(94%)
Median age (range)
17 yrs (10-37)
Median days vaccination to death
15 days (2-745)
HPV dose closest to death
Dose 1 15
Dose 2 8
Dose 3 11
Concomitant vaccinations
Received HPV4 only
Received concomitant vaccination 13
Not documented 6
Among the 34 verified death reports:
32 were female
The median age was 17 yrs and median days from vaccination to death was 15 days
Among these death reports, 15 received dose 1, 8 reports were following dose 2, and 11 were following dose 3
15 of the death reports received HPV4 only
13 received concomitant vaccination

14. VAERS Verified Reports of Death
Reported causes of death after clinical review with median onset interval:
Neurological: 7 (seizures [5]; ALS [2])
53 days (13-745)
Cardiac: 7 (arrhythmia [3]; myocarditis [3]; congenital)
9 days (2-25)
Pulmonary embolism: 4
14.5 days (13-181)
Infectious: 5 (Group A Strep [2]; N. meningitidis, MRSA; HIV-CNS vasculitis)
29 (4-117)
Other non-infectious: 4 (suicide; type 1 DM DKA; drug overdose; polymyositis)
35 (2-594)
Undetermined cause of death: 7
17 (2-121)
No patterns in verified death events
This slide illustrates the reported causes of death among those verified deaths..
After clinical review:
7 were classified as neurological deaths, 7 cardiac deaths, 4 PEs, 5 were classified as infectious, 4 were other non-infectious, and 7 were unexplained cause of death in which for many of these reports even upon autopsy a specific COD could not be determined.
* Median onset interval from vaccination to death (range)

15. Summary of HPV4 VAERS Reports: Males
Total VAERS reports: 569*
Pre-licensure reports (6/1/06-10/15/09): 65
Post-licensure reports (10/16/09-9/15/11): 504
Serious Reports: 33 (5.8%)
HPV4 given alone: 44%
Median age (range) 14 yrs (0-77)
Median onset interval from vaccination to event (range): 0 days (0-433)
Because the committee will be voting on routine HPV4 vaccine recommendation for males, we wanted to provide you with an in-depth review of male reports following HPV4 in VAERS.
There has been a total of 569 reports; 504 male reports were received since the vaccine was licensed in 10/09
33 serious reports,
44% of reports HPV4 given alone (n=202)
Median age (range): 14 yrs (0-41 yrs)
Median onset interval (range): 0 days (0-433 days)
* Reports from June 1, 2006-Sept 15, 2011

16. Most Frequently Reported Terms for Non-serious and Serious Reports Among Males Following HPV4 in VAERS
Non-serious (N=536)
Serious (N=33)
MedDRA Preferred Terms* %
Dizziness
18.8
Pyrexia
27.3
Syncope
15.3
White blood cell count increased
24.2
Injection site erythema
10.0
Nausea
Pallor
9.0
Pain in extremity
21.2
8.4
Blood glucose increased
7.7
Dyspnea
18.2
Headache
7.6
Cough
Wrong drug administered
7.4
Muscular weakness
Injection site swelling
7.2
Abdominal pain
Fall
6.3
Chest pain
On this slide you can see the most frequently reported terms for non-serious and serious reports among males following HPV4
* As coded using the MedDRA preferred terms (PT), More than one code may be assigned to a single event

17. HPV4 Male Serious Reports
Total male serious reports: 33
3 deaths: 2 verified; 1 hearsay
1 female incorrectly coded as male
Serious non-fatal reported categories (n=29)
Neurological: 9 (Guillain Barré syndrome [4]; seizures [2]; altered mental status; transverse myelitis; acute dystonic reaction)
Immune/Allergic: 4 (Stevens-Johnson syndrome; allergic reaction [2], serum sickness)
Cardiac: 2 (myocarditis; pericarditis)
Gastrointestinal: 4 (acute pancreatitis [2]; appendicitis; colon cancer)
Infectious: 2 (cellulitis; diarrhea)
Other: 8 (syncope/presyncope [3]; pulmonary embolism; osteitis pubis; DM type 1; sickle cell disease; spontaneous pneumothorax)
There have been 33 serious male HPV4 reports, of which 3 have been death reports, one incorrectly coded as a male, and 29 are serious.

18. VAERS Verified Male Reports of Death
Myocarditis
Age: 10 yrs
Days from vaccination to death: 9 days
Received other vaccines on same day
Meningococcal, Hepatitis A, Tdap, HPV4 (Dose 1)
No past medical history
Obstructive congenital subaortic membrane
Age: 15 yrs
Days from vaccination to death: 25 days
Received only HPV4, Dose 1
Past medical history: asthma; cardiac disorder O

19. Vaccine Safety Datalink (VSD)
Collaboration between CDC and 10 managed care organizations
Data from ~9.8 million members captured annually (~3% of US population)
Group Health Cooperative
Northwest Kaiser Permanente
HealthPartners
Harvard Pilgrim
Marshfield Clinic
No. CA Kaiser Permanente
The next portion of this talk will be to briefly describe the Vaccine Safety Datalink, rapid cycle analysis for HPV4 among females and findings.
The Vaccine Safety Datalink, or VSD, is a collaboration between CDC and 10managed care organizations. It was established in 1990 to address gaps in vaccine safety,
Using automated data sources that already exist as part of the participating health plans infrastructure, the VSD collects medical and vaccination data on more than 9.8 million members annually (3% of the US population)
Kaiser Permanente Colorado
So. CA Kaiser Permanente
Kaiser Permanente Georgia
CDC
Kaiser
Permanente Hawaii

20. Rapid Cycle Analysis (RCA)
Alternative to traditional post-licensure vaccine safety study methods, which generally take years to complete
Basics of RCA vaccine safety monitoring:
Tests specific hypotheses with well-defined outcomes
Each week, evaluate the number of events in vaccinated persons
Compare to the expected number of events based on a comparison group
Historical or concurrent
Weekly analyses with statistical adjustment for multiple looks
RCA is not intended to be ‘final answer’
Potential associations (“signals”) need further study to determine whether signals are real or spurious
Our project developed a monitoring system for newly licensed vaccines called the Rapid Cycle Analysis.
The basics of RCA are listed on this slide.
Rapid cycle is not intended to be the final answer. Its a signal detection method for pre-specified events and potential associations or signals do arise. When they do, we take steps to investigate the potential signal appropriately
****
This monitoring system tests specific hypotheses with well defined outcomes and relatively short defined risk windows.
The outcomes of interest are initially based on findings from pre-licensure trials and the literature. One of the strengths of VSD/RCA is that during the course of monitoring, we have the ability to add outcomes of concern to ongoing RCAs that have been identified by VAERS or other sources
Each week, we evaluate the number of events in vaccine persons and compare it to the number of expected events, based on a comparison group—which is historical or concurrent
Using sequential analyses methodologies, we adjust statistically for multiple looks
Lieu TA, et al. Real-time vaccine safety surveillance for the early detection of adverse events. Med Care Oct;45:S89-95.

21. VSD HPV4 Rapid Cycle Analysis Results
VSD active surveillance confirmed no significant risk for any of the pre-specified adverse events after vaccination
GBS, seizures, syncope, appendicitis, stroke, VTE, and other allergic reactions
Additional study is needed for a possible non-statistical association between HPV4 and VTE
All confirmed cases had other risk factors for VTE
No increase in rate of anaphylaxis following HPV4 as compared to previous VSD studies
Our paper was recently published online in Vaccine and the main findings from this analysis included:
- We found no significant risk for any of the pre-specified adverse events following HPV4 vaccination.
We did, however, find a possible non-statistically significant association between HPV4 and VTE and further study is ongoing
With regards to anaphylaxis, we found no increase in the rate of anaphylaxis following HPV4 as compared to previous VSD studies
* Gee J, et al. Monitoring the Safety of Quadrivalent Human Papillomavirus Vaccine: Findings from the Vaccine Safety Datalink Vaccine. Oct

22. VSD HPV4 Vaccine Monitoring and Evaluation: Next Steps
Long-term surveillance of GBS and stroke
Currently ongoing
VTE self-controlled case series analysis
RCA of HPV4 in males
The next steps for VSD with regards to the safety of HPV4 include long-term surveillance of GBS and stroke since the RCA had limited power to assess associations between HPV4 and these very rare adverse events occuring in this particular age group
We are currently conducting a self-controlled case series analysis looking at VTE and all vaccinations, with a focused analysis on HPV4 and VTE. Using this design, we can control for confounding such as OCP use, smoking, and other risk factors for VTE.
The VSD has not yet initiated a RCA in males for HPV4. We are awaiting sufficient uptake among this population.

23. VSD Study: Reported Adverse Events in Young Women Following HPV4
Mailed survey to young women after reciept of first HPV4 vaccine
899 (27%) responded
Highlighted results:
Age is an important factor influencing young women’s experiences with HPV vaccine
Knowledge and attitude of HPV and HPV vaccine
Reporting of adverse events
Included pain, brusining, swelling, and pre-sycnope
Naleway, et al. Reported Adverse Events in Young Women Following Quadivalent Human Papillomavirus Vaccination. Journal of Womens Health (In Press) 2012

24. Manufacturer HPV4 Post-Licensure Commitments
Multiple studies*
A Post-Licensure Surveillance Program for the Safety of GARDASIL™ in a Managed Care Organization Setting (Protocol 31)
The Nordic long-term follow up study (Protocol 15)
A long-term immunogenicity, safety, and effectiveness study of GARDASIL™ among adolescents who received GARDASIL™ at yrs of age (Protocol 18)
Merck is conducting multiple post-licensure studies,
Ms. Christine Velicer will be describing their recently published study—results from protocol 31
I am going to highlight findings from interim analyses that were presented by Dr. Saah from Merck in June to the ACIP for two of their long term follow-up studies—protocols 15 and 18.
* Bonani P, et al. A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD. Vaccine 2010

25. 2011 Institute of Medicine (IOM) Report on Adverse Events of Vaccines
Syncope following vaccination:
IOM concluded that data convincingly support a causal relationship between injection of a vaccine and syncope
Anaphylaxis following HPV4:
IOM concluded that the weight of published evidence favored an acceptance of a causal relationship between HPV vaccine and anaphylaxis*
The IOM recently published a report on adverse events following vaccination.
Relevant findings for this presentation include:
The IOM conducted that data convincingly supported a casual relationship between injection of a vaccine and syncope.
For HPV4: the only outcome to be causally related to the vaccine was anaphylaxis in which the IOM concluded that the weight of published evidence favored an acceptance of a causal relationship *

26. Post-Vaccination Syncope
VAERS :
Majority of syncope occurs within 15 min of vaccination
VSD: Rates of syncope on day 0 following Td, Tdap, varicella, meningococcal or HPV vaccination among yrs:*
HPV4 Package insert: listed as a warning/precaution
ACIP recommends:
Providers should consider observation of patients for 15 minutes after vaccine administration**
Gender
Rate per 10,000 vaccinations
Male
12.5
Female
17.9
Both
15.3
Because of the recognized occurrence of post vaccination syncope, we wanted to highlight a few things to the committee:
Multiple reviews have found that the majority of syncope occurs within 15 minutes following vaccination
VSD conducted an analysis of syncope rates on day 0 following adolescent vaccination among 9-26 yrs and found that females have a higher rate than males
Specifically for HPV4, the package insert lists syncope as a warning stating that syncope has been reported following vaccination with HPV4
ACIP recommends that providers should consider observing patients 15 min after vaccine administration.
* Unpublished rates from one VSD site using electronic data only,
** Kroger AT, et al. General Recommendations on Immunization, Recommendations of ACIP. MMWR 2011

27. Summary Monitoring and evaluation are ongoing for HPV4
VAERS continues reviewing reports following HPV4
No new adverse event concerns or clinical patterns identified
VSD rapid cycle analysis confirmed no significant risk for any of the pre-specified adverse events after vaccination for two age groups (9-17yrs and yrs)
Further evaluation of VTE and HPV4 is ongoing
Providers should consider observation of patients 15 minutes after vaccine administration
In summary, monitoring and evaluation are ongoing for HPV4 from multiple sources

28. Acknowledgements
Immunization Safety Office Jorge Arana Karen Broder Jonathan Duffy Theresa Harrington Zanie Leroy Paige Lewis Pedro Moro Claudia Vellozzi Eric Weintraub DSTDP Eileen Dunne Lauri Markowitz FDA David Martin Michael Nguyen Andrea Sutherland