# Presentation: 151946

## Quadrivalent HPV Vaccine Efficacy and Provisional Recommendations Lauri Markowitz, MDDSTDP, NCHHSTP, CDC

## Licensed & 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? |

## Quadrivalent HPV Vaccine

- 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

## Quadrivalent HPV Vaccine Clinical Development Program

| 

Efficacy Trials* | 

“Bridging” Immunogenicity
Safety Trials  |
| --- | --- |
| 
females 
16-26 yrs | 
females 
9-15 yrs  |
|  |  |

## Quadrivalent HPV Vaccine FDA Licensure – June 8, 2006

- Indicated in girls and women 9-26 years of age for the prevention of the following diseases caused by HPV types 6, 11, 16, and 18:
- Cervical cancer
- Genital warts (condyloma acuminata)
- Cervical, vaginal and vulvar precancerous or dysplastic lesions

## Quadrivalent HPV Vaccine Additional Clinical Development: results expected in next few years

-  Efficacy trials in males
-  Efficacy in females older than 26 years
-  Long term follow-up

## Efficacy for Prevention of Clinical HPV Disease Due to HPV 6/11/16/18*

| 
Endpoint | Vaccine
N   Cases | Placebo
N   Cases | 
   Efficacy | 
(95% CI) |
| --- | --- | --- | --- | --- |
| 
HPV 16/18
related CIN2/3 or AIS | 
8487   0  | 
   53 | 
  100 | 
(93,100) |
| 
HPV 6/11/16/18
related CIN | 
7858   4 | 
   83 | 
  95 | 
(87, 99) |
| 
HPV 6/11/16/18
related Genital warts | 
7897   1
 | 
7899   91 | 
  99 | 
(94,100) |

- *Integrated dataset; results in the Per-Protocol Populations

## Populations in Quadrivalent HPV Vaccine Trials among Females 16-26 years of age

|  | Seronegative | Seropositive |
| --- | --- | --- |
| PCR (-) | Prophylactic efficacy in HPV-naïve women
(Per protocol population) | Low recurrence rate 
High efficacy  |
| PCR (+) | 
No evidence of efficacy | 
No evidence of efficacy |

## Time to Detection of HPV 16/18 CIN 2/3 or AIS, All Participants 16-26 years of age

**Phase II and III Database for GARDASIL****®**** and HPV 16 Vaccine**

- v501p5p7p13p15c2w  Apr. 28, 2006

## Antibody Titers by Age at Enrollment Anti-HPV 6 GMTs (Quadrivalent HPV vaccine)

**Immunogenicity Bridge**

**Antibody Titers by Age at Enrollment ****Anti-HPV 6 GMTs (Quadrivalent HPV vaccine)**

**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**

- Merck, unpublished data, ACIP presentation by Eliav Barr, February 2006

## Anti-HPV 16 GMTs Through 5 Years

**Protocol 007**

- 0

- 7

- 12

- 18

- 24

- 30

- 36

- 54

- 60

- 10

- 100

- 1000

- 10000

- GMT
-  (Log Scale)

- Time Since Vaccination 1 (Months)

- *

- *

- *

- Vaccination

**GARDASIL**

- 

- Placebo (Sero (+) and PCR (-)

-                 to HPV 16 at Day 1)

**Notes:**
To supplement the efficacy results of the study that I just showed, I present a graphic of anti-HPV 16 GMTs over time. The X-axis provides time, and the stars denote vaccination.  The white line represents the subset of placebo recipients who were anti-HPV 16 seropositive at Day 1. So this line provides a reference for the durability of natural anti-HPV 16 over a 5 year period. As you can see, the levels are generally stable.
Now, lets look at vaccine induced anti-HPV 16. We see that after an initial decline of about 1-log-fold early in the follow-up, anti-HPV levels are stable for the next 3.5 years. 

##  Quadrivalent HPV VaccineSummary

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

## Quadrivalent HPV VaccineSummary

- >99% seroconversion rates in 9-26 year-olds
- Antibody titers substantially higher than after natural infection; highest in those vaccinated at younger ages
- Antibody titers decline over time after 3rd injection, but plateau by 24 months

## Recommendations

- Routine vaccination
- Catch-up vaccination
- Special situations
- Precautions and contraindications

## Routine Vaccination Provisional Recommendation 

- 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
* *

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

- Routine
- Prevalent infection, targeting ‘high risk’ groups not possible
- Modeling shows greater impact
- 11-12 years
- Vaccination prior to sexual debut
- Implementation advantages; consistent with young adolescent health care visit
- High antibody titers after vaccination at this age
- Data through 5 years show no evidence of waning immunity; ongoing studies will monitor duration of protection

##  Females 13-26 Years Provisional Recommendation 

- Vaccination is 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 

- Females not yet sexually active can be expected to have the full benefit of vaccination
- Sexually active females may not have full benefit of vaccine because they may have been infected with vaccine HPV types, however:
- Only a small percentage are likely to have been infected with all four vaccine HPV types
- For those already infected with _>_1 vaccine HPV types, vaccine would provide protection against disease caused by the other vaccine HPV types
- Therefore, although overall vaccine effectiveness would be lower, most females will still derive benefit from
-    vaccination

## Special Situations

- Equivocal or abnormal Pap test
- Positive HPV test
- Genital warts
- Immunosuppression
- Lactating women

## Vaccination during Pregnancy Provisional Recommendation 

- Initiation of the vaccine series should be delayed until after completion of the pregnancy
- If a woman is found to be pregnant after initiating the vaccination series, completion should be delayed until after the pregnancy
- If a vaccine dose has been administered during pregnancy, there is no indication for intervention

## Precautions and Contraindications

- Moderate or severe acute illnesses:  should be deferred until after the illness improves
- History of immediate hypersensitivity or severe allergic reaction to yeast or to any vaccine component: contraindication

## Cervical Cancer Screening

- Cervical cancer screening – no change
- 30% of cervical cancers caused by HPV types not in the quadrivalent HPV vaccine
- Vaccinated females could subsequently be infected with non-vaccine HPV types
- Sexually active females could have been infected prior to vaccination
- Decision to vaccinate should not be based on Pap testing, HPV DNA testing or HPV serologic testing
- Providers should education women about the importance of cervical cancer screening