# Presentation: 655930

## Human Papillomavirus (HPV) Vaccine The findings and conclusions in this presentation have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or policy.June 6, 2006NVACLauri Markowitz, MDDSTD/NCHHSTPCenters for Disease Control and Prevention

## Candidate Prophylactic HPV  Vaccines 

| 

Vaccine/
Manufacturer | 

HPV Types | 

FDA Filing | 

FDA Decision | 

ACIP Vote |
| --- | --- | --- | --- | --- |
| 
Quadrivalent
Merck
 | 
6/11/16/18 | 
Dec 2005 | 
June 
2006 | 
June
 2006? |
| Bivalent
GSK
 | 16/18 | Dec 2006? | 2007? | 2007? |

## Outline

- Background on HPV and cervical cancer
- HPV vaccine
- Acceptability
- Proposed recommendations

## Background Human Papillomavirus

- Non enveloped DNA virus
- >100 different types
- ~40 types are sexually transmitted
- “Low-risk” types (6,11, 42, 43, 44...)
- “High-risk” types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58....)

## >100 HPV types

- Cutaneous

- (~60 types)

- “Common”

- warts

- (hands/feet)

- Mucosal

- (~40 types)

- “high-risk”

- types
- (16,18)

- “low-risk”

- types
-  (6,11)

-  low grade cervical            	abnormalities
-  high grade abnormalities/
-   cancer precursors
-  anogenital cancers

-  low grade cervical 		abnormalities
-  genital warts
-  respiratory papillomas

## Genital HPV Infection	

- HPV is the most common sexually transmitted infection in the US
- First infection is usually acquired soon after sexual debut. Infection with multiple types common
- Infection is usually transient and not associated with symptoms – 90% of infections clear within 2 years
- Persistent HPV infection is cause of cervical cancer as well as other anogenital cancers

**Notes:**
Several lines of evidence have converged to identify HPV as the cause of cervical cancer.  

## Natural History of HPV Infection and Cervical Cancer

**  ****Initial**
** ****HPV**
** ****infection**

**CLEARED HPV INFECTION**

-    **CIN* 1**

**Persistent**
**infection**

**CIN* 2/3**

**  ****CANCER**

-     Up to 20 years

-            1 year

- Up to 5 years

***cervical intraepithelial neoplasia**

## Age-Adjusted Invasive Cancer Incidence Rates, Among Women, U. S.,  2000

- United States Cancer Statistics: 2000 Incidence; NPCR

**Notes:**
This slide uses data from cancer surveillance showing the age adjusted 
incidence rates of various cancers.  As you can see, breast cancer has the 
highest incidence among women. Cervical cancer is the 11th most common cancer 
among women in the U.S.

## Cervical Cancer Mortality Rates U.S., 1946-1984

**Source: Program for Improving Clinical Pap Smear Programs and Management, Office of Population Affairs, DHHS, 1987.**

## HPV-Related Disease Burden, U.S.

- Cervical cancer: 9,710 cases & 3,700 deaths (2006 estimate)
-      70% caused by types 16,18
- Pap tests:  50 million; 2.8 million abnormal
- Genital warts: .5 to 1million
-       90% caused by types 6,11
- Recurrent respiratory papillomatosis (rare)
-       90% caused by types 6,11
- Other anogenital cancers: (anal, penile, vaginal, vulvar)

## Percentage of Adolescents Who Have Had Vaginal Sex, by Gender and Age National Survey of Family Growth (NSFG), 2002

- Mosher et al., 2005; Vital and Health Statistics: No. 362

**26**

**40**

**49**

**70**

**77**

**25**

**37**

**46**

**62**

**69**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**15**

**16**

**17**

**18**

**19**

**Age**

**Females **

**Males **

## High Risk HPV Prevalence, by AgeSentinel Surveillance, U.S.2003-2004 (N=5555)

- CDC, unpublished data

## Cumulative Incidence of HPV Infection among Female College Students, by Time Since Sexual Debut

- Winer et al. Am J Epidemiol 2003;157

**4 years, > 50%**

## HPV Prevalence                                    Population Estimates, U.S.

- 20 million people are infected
- 15% of persons age 15-49 currently infected
- 6.2 million new infections each year
- > 50% of sexually active men & women acquire genital HPV infection

- Cates, STD 1999; Weinstock, Perspectives on Sexual and
- Reproductive Health 2004; Koutsky Am J Med 1997

## Candidate HPV VLP Vaccines

- HPV L1  major capsid protein of the virus is antigen used for immunization
- Expression of L1 protein uses recombinant technology
- L1 proteins self-assemble into virus-like particles (VLP)

- HPV VLP

## Candidate HPV VLP Vaccines 

| 

Vaccine/
Manufacturer | 

HPV Types | 

Schedule |  | 

Adjuvant | 

Target Groups |
| --- | --- | --- | --- | --- | --- |
| 
Quadrivalent
Merck
 | 
6/11/16/18 | 
0,1,6 mos | 
Alum |  | 
females & males |
| Bivalent
GSK
 | 16/18 | 0,1,6 mos | Alum
and MPL(ASO4)
  |  | females |

## HPV Vaccine Initial Clinical Development Programs

| 

Vaccine/
Manufacturer | 

Efficacy Trials* | 

Adolescent Immunogenicity
Safety Trials  |
| --- | --- | --- |
| 
Quadrivalent
Merck
 | 
females 
16-26 yrs | 
females and males
9-15 yrs  |
| Bivalent
GSK

 | females 
15-25 yrs | females
10-14 yrs 
 |

- *endpoints include CIN 2/3 or AIS

## HPV Vaccine Additional Clinical Development

| 

Vaccine/
Manufacturer | 

Efficacy in
Females >26  | 

Long Term Follow-up  | 

Efficacy in Men |
| --- | --- | --- | --- |
| 
Quadrivalent
Merck
 | 
X | 
X | 
X

 |
| 
Bivalent
GSK
 | 
X | 
X
 | 

 |

## HPV Vaccine Phase II TrialsPrevention of Persistent Infection

**Manufacturer**
_**Vaccine **_**	****	**_**Vaccine**_**  ****	**_**Placebo**_**   ****	**_**VE (95% CI)**_**   ****	**
- 				_N _    _cases_	_N _    _cases_
**Merck **
** **  HPV 16            	768    0		765    41    	100%  (90,100)
**GSK**
-   HPV 16/18 	  	366    0 	355    16 	100%  (77,100)
-   Koutsky et al.  NEJM 2002, 347
-   Harper et al. Lancet 2004, 364

## Efficacy - Phase III TrialQuadrivalent HPV Vaccine HPV 16/18 Related Cervical Cancer Precursors 

**Mean 17 Months of Follow-Up in Per Protocol Population**

| Endpoint | Vaccine(N=5301) | Placebo (N=5258) | Efficacy | (97.5% CI) |
| --- | --- | --- | --- | --- |
| HPV 16/18 related 
CIN 2/3 or AIS | 0 | 21 | 100% | (76,100) |

- Merck, unpublished data, ACIP presentation, February 2006

## Efficacy - Phase III TrialQuadrivalent HPV Vaccine HPV 6/11/16/18 Related External Genital Lesions 

**Mean 20 Months of Follow-Up** **in the** **Per Protocol Population**
***External genital lesions includes genital warts, VIN, VaIN**

| Endpoint | Vaccine (N = 2261) | Placebo (N = 2279) |    Efficacy | (97.5% CI) |
| --- | --- | --- | --- | --- |
| HPV 6/11/16/18 EGL* | 0 | 40 | 100% | (88,100) |

- Merck, unpublished data, ACIP presentation, February 2006

## Populations in Quadrivalent HPV Vaccine Phase III Clinical Trials

| Day 1 | Seronegative | Seropositive |
| --- | --- | --- |
| PCR (-) | Prophylactic efficacy in HPV-naïve women
(Per protocol population) | Prevention of recurrence of infection? |
| PCR (+) | 
Post exposure prophylaxis in women with early infection? | 
Treatment of chronic HPV infection? |

## Anti-HPV 16 GMTs Through 3.5 Years Postdose 3

**HPV 16 L1 VLP Vaccine**

**Placebo recipients previously infected with HPV 16**

**Anti-HPV 16 GMTs Through 3.5 Years Postdose 3**

- Mao et al. Obstetrics and Gynecology 2006,107

## Anti-HPV 6 Antibody Titers after 3 Doses by Age at Enrollment (Quadrivalent HPV vaccine)

**Immunogenicity Bridge**

**Anti-HPV 6 Antibody Titers after 3 Doses ****by Age at Enrollment** (Quadrivalent HPV vaccine)

|  | Number of Subjects Evaluable (n)  |  |  |  |  |  |  |  |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| Age | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 |
| n | 68 | 129 | 166 | 141 | 166 | 148 | 109 | 85 | 137 | 440 | 511 | 624 | 576 | 564 | 400 |

**9**

**10**

**11**

**12**

**13**

**14**

**15**

**16**

**17**

**18**

**19**

**20**

**21**

**22**

**23**

**Age at Enrollment (Years)**

- 500

- 700

- 900

- 1100

- 1300

- 1500

- 1600

**Serum GMT with 95% CI, mMU/mL**

**Efficacy Program**

##  Quadrivalent HPV VaccineSummary

- High efficacy in 16 to 26 year-old females who are naïve to the respective vaccine HPV types
- HPV 16,18 related CIN 2/3
- HPV 6,11,16,18 related CIN
- HPV 6,11,16,18 related external genital lesions
- Efficacy data available through 5 years; duration of protection and need for booster unknown
- No evidence of therapeutic efficacy
- Safe; side effects mainly local reactions

## Quadrivalent HPV VaccineSummary

- >99% seroconversion rates in 9-26 year-olds
- Antibody titers decline over time after 3rd injection, but plateau by 18 months
- Antibody titers substantially higher than after natural infection; highest in those vaccinated at younger ages
- No serologic correlate of immunity

## HPV Vaccineand Cervical Cancer Screening

- Even with 100% coverage, current generation HPV vaccines will not eliminate need for cervical cancer screening in the US
- Types other than HPV 16 and 18 cause ~30% of cervical cancers

## Pediatricians’ Intention to Recommend HPV Vaccine for Female and Male Patients, by Age

- Kahn J et al. Journal of Adolescent Health 2005

**Notes:**
This shows data from a provider survey of AAP pediatricians.  Providers were asked about their intention to vaccination males and females at different ages.  Concern about parent reluctance to accept vaccination was sited as one concern. Newspaper media coverage cite as barrier
Parents may be less likely to vaccinate children; Pediatricians may be less likely to recommend;

## Potential Unintended Consequences of HPV Vaccine

- Increase in sexual risk unlikely
- Research shows generally low levels of HPV knowledge
- Multiple influences on adolescent sexual behavior
- Fear of STD not apparent major motivation for abstinence
- No evidence of behavioral disinhibition in other similar fields

## Family Research Council and HPV Vaccines

- FRC welcomes the news that vaccines are in development for preventing...HPV
- Media reports suggesting that FRC opposes all development or distribution of such vaccines are false
- While we welcome medical advances such as an HPV vaccine, it remains clear that practicing abstinence until marriage and fidelity within marriage is the single best way of preventing the full range of STD....
- _[www.frc.org](http://www.frc.org/)__  _Press release, 10/18/05

## Advisory Committee on Immunization Practices (ACIP)

- Provides guidance to Secretary, HHS and Director, CDC on vaccine preventable diseases in the US
- Develops recommendations and publishes written guidance for use of vaccines
- Makes recommendations for the Vaccines for Children (VFC) Program

## ACIP HPV Vaccine WorkgroupFDA Licensure Assumptions

- Quadrivalent HPV 6,11,16,18 vaccine will be licensed for use in females 9-26 years of age in mid 2006
- Quadrivalent HPV vaccine may be licensed for use in males at a later date
- Bivalent HPV 16,18 vaccine will be licensed for use in females at a later date

## Vaccines and Related Biological Products Advisory Committee May 18, 2006

- Do the data from studies 005, 007, 013, and 015 support the efficacy of Gardasil for the prevention of HPV 16/18 related  cervical cancer, cervical AIS, and CIN 2/3 or worse in females 16-26 years of age?
- Do the data from studies 007, 013, and 015 support the efficacy of Gardasil for the prevention of HPV 6/11/16/18 related VIN 2/3 and VaIN 2/3 in females 16-26 years of age?
- Do the data from studies 007, 013, and 015 support the efficacy of Gardasil for the prevention of HPV 6/11/16/18 related condyloma acuminata, VIN 1 and VaIN 1?
- Do the immunogenicity data support bridging of the younger female population (9-15 years of age) to the efficacy population (females 16-26 years of age)?
- Do the safety data from studies 007, 013, 015, 016 and 018 support the safety of Gardasil for use in females 9-26 years of age?

**Committee members voted (13/13) yes to all  **

## ACIP HPV Vaccine WorkgroupProposed Recommendations (2/06) Routine Vaccination 

-    *ACIP recommends routine vaccination of females 11-12 years of age with three doses of quadrivalent HPV vaccine. The vaccination series can be started as young as 9 years* of age at the discretion of the physician. *
* *Presented at February 2006 ACIP meeting
**depends on FDA indication** ** *

## Rationale: Routine Vaccination of Females at 11-12 Years

- Routine
- Prevalent infection, targeting ‘high risk’ groups not possible
- Modeling shows more impact
- 11-12 years
- More females vaccinated prior to sexual debut than at older ages
- Implementation advantages; consistent with young adolescent health care visit
- Although duration of protection not known, no evidence of waning immunity; ongoing studies will monitor duration

##  ACIP HPV Vaccine WorkgroupProposed Recommendations Vaccination of Females 13-26 years 

- 	*Vaccination is also recommended for females 13-26 years of age who have not been previously vaccinated. Ideally vaccine should be administered before onset of sexual activity, but females who are sexually active should still be vaccinated. *

## Rationale: Vaccination of Females 13-26 years 

- Older females not yet sexually active can be expected to have the full benefit of vaccination
- Studies evaluating type-specific prevalence in the US indicate a small percentage of sexually active females have been infected with all HPV vaccine types
- Infection with one HPV type does not appear to adversely impact the protection afforded by the vaccine against other vaccine HPV types
- Overall vaccine effectiveness would be lower when administered to a population of females who are sexually active; most females will derive benefit from vaccination

## Summary

- Two HPV vaccines are in development; FDA approval for the quadrivalent HPV vaccine may be in June 2006
- If licensed, ACIP will consider recommendations for quadrivalent vaccine at the June 29-30 meeting
- Vaccines have high efficacy for prevention of HPV infection, cervical cancer precursor lesions, external genital lesions in females
- Recommendations need to take into consideration multiple factors, including epidemiology, acceptability, impact and cost effectiveness
- Vaccine would be most efficacious administered to young adolescent females

## Cumulative probability of Incident HPV type 6, 11, 16, 18 Infection 24 months after sexual initiation, Women

| HPV Type |   Cumulative Incidence at 24 months  

          %                             (95% CI) |  |
| --- | --- | --- |
| 6 | 7.5 | (7.0, 12.6) |
| 11 | 0.9 | (0.3, 2.3) |
| 16 | 10.4 | (7.8, 13.8) |
| 18 | 4.1 | (2.6, 6.4) |

- Cumulative probability of Incident HPV type 6, 11, 16, 18 Infection **24 months after sexual initiation, Women**

- Winer et al.  Am J Epidemiol 2003;157

## Two types of Cost Effectiveness Models in HPV Vaccine Literature

- Markov models
- model natural history of HPV infection
- Dynamic models
- model transmission of HPV + natural history of HPV infection

## Models and cost-effectiveness of HPV vaccine in the U.S. Vaccination of females against types 16/18 at 12 years compared with cervical cancer screening alone

- Markov Models				Cost/QALY
- Goldie et al. 				   $24,300
- Sanders & Taira 			   $22,800
- Kulasingam and Myers 	                      n/a
- Dynamic Models
- Taira et al. (2004) 			   $14,600
- Elbasha*  (with HPV 6/11 benefits)		<$0

- Goldie SJ, et al. Journal of the National Cancer Institute 2004;96:604-15.
- Sanders GD, Taira AV. Emerging Infectious Diseases 2003;9:37-48.
- Kulasingam SL, Myers ER. JAMA 2003;290:781-89.
- Taira AV et al.  Emerging Infectious Diseases 2004;19,1915-23
- *unpublished