HPV Vaccine

Have it or Leave it??

1-Case:

Our 22 year-old patient wonders if she should get the vaccine?

2-PICO format Problem: HPV vaccine, efficiency? Side

effects? Intervention: HPV vaccination Comparison: clinical trials with placebo

group Outcome:

Short termeffective against HPV caused anogenital diseases and cervix,vaginal,vulvar, oropharyngeal Ca.

Long term ??? New vaccine!

3- Literature Search

Papillomaviruses are double-stranded DNA viruses that constitute the Papillomavirus genus of the Papillomaviridae family. These viruses are highly species specific; human papillomaviruses (HPV) infect only humans. There are more than 100 types of HPV, which can be subdivided into cutaneous or mucosal categories based upon their tissue tropism.

 Human papillomavirus is a sexually transmitted pathogen that causes anogenital disease in males and females. Persistent viral infection with high-risk human papillomavirus (HPV) genotypes causes virtually all cancers of the cervix. The same HPV genotypes (or "types") that cause cancer of the cervix also cause most cases of anal cancer and significant proportion of oropharyngeal cancer in men and women, a significant proportion of vulvar and vaginal cancer in women, and significant proportion of penile cancer.

Two vaccines have been developed against HPV infection; one is a quadrivalent vaccine (Gardasil) and the other is a bivalent vaccine (Cervarix). The United States Food and Drug Administration approved Gardasil in 2006 and Cervarix in 2009 for the prevention of HPV-related diseases.

Cost of HPV Vaccine?

As july 2012,price of either vaccine is about 130$ per dose (3 doses totally)

GARDASIL® [Human Papillomavirus Quadrivalent (Types

6, 11, 16, and 18) Vaccine, Recombinant] Suspension for intramuscular injection Initial U.S. Approval: 2006CERVARIX [Human Papillomavirus Bivalent

(Types 16 and 18) Vaccine, Recombinant] Suspension for Intramuscular Injection Initial U.S. Approval: 2009

The worldwide prevalence of HPV infection among females is approximately 10 percent. The highest regional prevalence is in Africa, where 22 percent of women have evidence of HPV infection. Worldwide, the most serious HPV infections are caused by high-risk types HPV 16 and 18, both of which are preventable by vaccination.

Clinical trial data have demonstrated efficacy against acquisition of vaccine-associated HPV types with declines in incident and persistent HPV infections and decreasing rates of cervical and anal squamous intraepithelial lesions.

VACCINE DEVELOPMENT  The HPV L1 major capsid protein, when recombinantly

expressed alone, can self-assemble into virus-like particles (VLPs) for each HPV type. The HPV L1 VLPs do not contain the HPV viral genome or any other genetic material and therefore are rendered non-infectious and non-carcinogenic. Preclinical research demonstrated that L1 is highly immunogenic with and without an adjuvant.

The proof-of-concept vaccine trial with HPV 16 VLP demonstrated that HPV 16 infection could be effectively prevented. In follow-up studies of this population, women were nearly completely protected against HPV 16 up to 8.5 years after HPV 16 vaccination.

Two vaccines were subsequently developed and tested in phase III efficacy trials for use:

An HPV vaccine that targets HPV 6, 11, 16, and 18 (quadrivalent HPV 6/11/16/18 VLP vaccine) (Gardasil; Merck & Co, Inc, Whitehouse Station, New Jersey)

An HPV vaccine that targets HPV 16 and 18 (bivalent HPV 16/18 VLP vaccine) (Cervarix; GlaxoSmithKline, Rixensart, Belgium)

GARDASIL

Gardasil has been evaluated in two large, randomized clinical trials named FUTURE (Females United To Unilaterally Reduce Endo/ectocervical disease) II and I.

The FUTURE II trial — In a phase III, multi-national prospective, double-blind, placebo-controlled trial

(FUTURE II), more than 12,000 women, aged 15 to 26 years (mean age of 20 years), were randomly assigned to receive a three-dose regimen of vaccine or placebo. The majority of the study participants were from Europe (65 percent) and Latin America (26 percent). Women with greater than four lifetime sexual partners or a history of abnormal cytology were excluded from the study. Evidence of past or current infections with HPV 16 and/or HPV 18 (as measured by serology and DNA detection in cervical specimens) was found in approximately one-fourth of the women in the vaccine and placebo arms (23 and 28 percent, respectively) through one month follow-up after vaccination.

The primary efficacy analysis (According-To-Protocol [ATP] analysis) was performed in those subjects who did not have evidence of either HPV 16 or 18 infection (by HPV DNA or HPV serological testing) through one month after the third dose of vaccine; these patients were referred to as "HPV-naive" as per protocol. The primary composite end point was the development of CIN 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV 16 or HPV 18 among the "HPV-naive" women. After a mean follow-up of three years, the following results were demonstrated:

Vaccine efficacy, for the prevention of the primary composite end point, was 98 percent in study participants who were "HPV-naive".

Vaccine efficacy remained high (95 percent) in those HPV-negative participants who did not receive all doses of vaccine according to protocol, suggesting some flexibility in the timing of the vaccine schedule.

Seroconversion rates at 24 months among 1512 vaccinated women in the immunogenicity sub-study were 96, 97, 99, and 68 percent for HPV types 6, 11, 16, and 18, respectively.

Importantly, the vaccine efficacy for the composite endpoint in the intention-to-treat (ITT) analysis, which included participants with baseline or incident HPV infection by one month after the last dose of vaccine, was significantly lower (44 percent) than in the according-to-protocol (ATP) analysis. Vaccine efficacy for CIN 2 or 3 disease due to all HPV types was also low (17 percent) in the overall population of women who had undergone randomization. These results suggest limited cross-reactivity of protection and the importance of early vaccination before infection

The vaccine was well tolerated; women who received the vaccine were more likely to have an injection site event (eg, erythema, pain, pruritus, and/or swelling) than women receiving the placebo.

The FUTURE 1 trial — A similarly designed phase III placebo-controlled trial was conducted in 5455 women aged 16 to 24 years to assess the efficacy of quadrivalent vaccine to prevent HPV-related anogenital disease

(FUTURE I) . The majority of the study participants were from Latin America (41 percent) or North America (29 percent). Women with greater than four lifetime sexual partners or a history of any genital warts or abnormal cytology were excluded from the study. Evidence of past or current infection with one or more of the vaccine genotypes (HPV 6, 11, 16 and/or 18) as measured by serology and DNA detection in cervical specimens was found among women in the vaccine and placebo arms (38 and 42 percent, respectively) through one month follow-up after vaccination.

The primary aim of the trial was to determine vaccine efficacy in reducing the combined endpoint of incidence of anogenital warts, vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VAIN) grades 1 to 3 or cancer associated with HPV 6, 11, 16, or 18.

A secondary aim was to observe whether the administration of vaccine reduced the combined incidence of CIN grades 1 to 3, adenocarcinoma in situ, or cancer associated with vaccine-type HPV. After a mean follow-up of three years, the following results were demonstrated:

The vaccine was 100 percent effective in preventing anogenital disease in women who were "HPV-naive" (ie, no cases were identified in the vaccine group versus 60 cases in the placebo group).

Vaccine efficacy was 100 percent in preventing CIN grades 1 to 3 or adenocarcinoma in situ caused by the vaccine-type HPVs in those women who were "HPV-naive" (ie, no cases were diagnosed in the vaccine group, whereas 65 cases were diagnosed in placebo group).

The vaccine was well tolerated. However, women who received the vaccine were 10 percent more likely to experience an injection site event (erythema, pain, pruritus, and/or swelling) and 3 percent more likely to experience an injection-related event (eg, fever) than women receiving the placebo.

As noted in the FUTURE II trial, vaccine efficacy in preventing cervical disease among the intention-to-treat group, which included participants with baseline HPV infection prior to vaccination, was lower (55 percent) compared with the according-to-protocol analysis in FUTURE I. Vaccine efficacy against lesions associated with any HPV genotype for all cervical lesions was 20 percent.

Prevention of subsequent disease   A post-hoc subgroup analysis of pooled data from

the two FUTURE trials evaluated the effect of the quadrivalent HPV vaccine on rates of HPV-related disease in women who developed genital disease despite vaccination. Among women who underwent cervical surgery for HPV-related disease, the incidence of subsequent CIN grade 2 or worse related to any HPV type was lower in the 474 who had received the vaccine compared with the 592 placebo recipients (1.1 versus 3.1 cases per 100 person years).

Among women who had been treated for genital warts, or vaginal or vulvar intraepithelial neoplasia, vaccine recipients had lower rates of subsequent genital warts but the same rates of vulvar, vaginal, or CIN grade 2 or worse as placebo recipients.

This study had several notable limitations. The mean follow-up was short (1.2 years), and there were few overall events. Furthermore, the retrospective analysis could not ensure that all events were new episodes as opposed to residual disease. Nevertheless, these results suggest that the vaccine may reduce the risk of subsequent HPV-related cervical disease in women with a history of CIN grade 2 or worse. Although the study demonstrated efficacy, there are no data on the population effectiveness

Post-approval safety  The Centers for Disease Control and Prevention

(CDC) conducted a review of the adverse events following immunization (AEFI) for Gardasil between June 1, 2006 and December 1, 2008. There were 12,424 reports of AEFIs following Gardasil distribution, or 53.9 reports per 100,000 doses distributed. The proportion of AEFI per vaccine dose was similar to those observed for other vaccines, but there was an increased reporting of syncope and venous thromboembolic events.

CERVARIX

Cervarix is a bivalent vaccine that targets HPV genotypes 16 and 18, which are associated with the majority of cervical cancers and precancerous lesions (CIN2/3) found worldwide; unlike Gardasil it does not target HPV 6 and 11. Cervarix has been evaluated in one large, randomized clinical trial named PATRICIA (Papilloma trial against cancer in young adults) and an autonomous US National Cancer Institute (NCI)-sponsored trial in Costa Rica.

In PATRICIA, a phase III, multi-national prospective, double-blind, placebo-controlled trial, more than 18,000 women, aged 15 to 25 years (mean age of 20 years), were randomly assigned to receive a three-dose regimen of vaccine or a control hepatitis A vaccine.

The majority of the study participants were from Europe (38 percent) and Asia Pacific (33 percent). Women with greater than six lifetime sexual partners or a history of colposcopy were excluded from the study. Approximately 26 percent of women in both arms had current or evidence of past infections by HPV 16 and HPV 18 (as measured by serology and DNA detection in cervical specimens through one month follow-up following vaccination).

The primary efficacy analysis (According-To-Protocol [ATP] analysis) was performed in those subjects who did not have evidence of either HPV 16 or 18 infections (by HPV DNA or HPV serological testing) at enrollment and were HPV 16 and 18 DNA-negative at six months. The primary composite end point was the development of CIN 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV 16 or HPV 18. After a mean follow-up of three years, the following results were demonstrated:

Vaccine efficacy for the prevention of the primary composite end point of CIN2, CIN3, adenocarcinoma in situ, or cancer was 93 percent.

Vaccine efficacies for the prevention of incidentally-detected 6-month and 12-month persistent infections by HPV 16/18 were 94 percent and 91 percent, respectively.

The vaccine was well tolerated and there were no differences in the serious adverse events by study arm.

Importantly, the vaccine efficacy in preventing CIN2 or more severe lesions in the intention-to-treat (ITT) analysis, which included participants with baseline or incident HPV infection by one month after the last dose of vaccine, was significantly lower (53 percent) than in the according-to-protocol analysis noted above. Vaccine efficacy for CIN2 or more severe disease due to all HPV types was also significantly lower (30 percent) in the overall population of women who had undergone randomization.

Therapeutic Effects?

There was no evidence that HPV vaccination altered the course of vaccine-type HPV infections present before or at the administration of the first dose of vaccine in the NCI trial. These data reinforce the use of HPV vaccine to prevent infection rather than as a therapeutic intervention to treat preexisting HPV infection and related diseases.

Postlicencure Safety

(AEFI: adverse events following immunization)

Most Common Adverse Effects The most frequently

reported AEFIs included syncope (n = 1847, 15% of

reports), dizziness (n = 1763,14%), nausea (n = 1170, 9%), headache (n = 957, 8%)

and injection site reactions (n =

926, 7.5%).

Themost frequent serious symptom/MedDRA preferred-term codes included

159 reports of headache (21%),119 nausea (16%), 113 dizziness (15%), 102 vomiting (13%), 102 pyrexia (13%), 102 fatigue (13%),and 98 syncope (13%).

Medically important serious events;

8 reports of anaphylactic reaction (1%), 9 deep vein thrombosis (1.2%), 31 GBS (4%), 25 hypersensitivity (2.5%), 10 transverse myelitis (1.3%), 6 pancreatitis (0.8%), 14 pulmonary embolism (1.8%), 23 death (3%), 68 convulsion (8.8%), 30 urticaria (3.9%) and 9 autoimmune disorder (1.2%).

Human Papilloma Virus Vaccine and Primary Ovarian Failure:Another Facet of the Autoimmune/Inflammatory SyndromeInduced by AdjuvantsSerena Colafrancesco1,2, Carlo Perricone1,2, Lucija Tomljenovic1,3, Yehuda Shoenfeld1,4

Problem:Post-vaccination autoimmune phenomena are a major facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and differentvaccines, including HPV, have been identified as possible causes.

Method of studyThe medical history of three young women who presented with secondary amenorrhea following HPV vaccination was collected. Data regarding type of vaccine, number of vaccination, personal, clinical and serological features, as well as response to treatments were analyzed.

ResultsAll three patients developed secondary amenorrhea following HPV vaccinations, which did not resolve upon treatment with hormone replacement therapies. In all three cases sexual development was normal and genetic screen revealed no pertinent abnormalities (i.e., Turner’s syndrome, Fragile X test were all negative). Serological evaluations showed low levels of estradiol and increased FSH and LH and in two cases, specific auto-antibodies were detected (antiovarian and anti thyroid), suggesting that the HPV vaccine triggered an autoimmune response. Pelvic ultrasound did not reveal any abnormalities in any of the three cases. All three patients experienced a range of common non-specific post-vaccine symptoms including nausea, headache, sleep disturbances, arthralgia and a range of cognitive and psychiatric disturbances. According to these clinical features, a diagnosis of primary ovarian failure (POF) was determined.

Conclusion We documented here the evidence of the

potential of the HPV vaccine to trigger a life-disabling autoimmune condition. The increasing number of similar reports of post HPV vaccine-linked autoimmunity and the uncertainty of long-term clinical benefits of HPV vaccination are a matter of public health that warrants further rigorous inquiry.

HPV Vaccine in Pregnancy

Both HPV vaccines do not include living viruses. According to FDA, Gardasil is situated in B category. In FUTURE 11 research, we follow pregnant women in two groups, which are vaccinated and placebo. Results show that vaccination does not cause any anomaly to pregnant women in both groups.

Can pregnant women get the vaccine? Yes, studies show that HPV vaccines do not cause

problems for babies born to women who were vaccinated while pregnant, but more research is still needed. A pregnant woman should not get any doses of either HPV vaccine until her pregnancy is completed.In conclusıon, The vaccines are not recommended for pregnant women.

HPV Vaccine and Men First of all, the vaccine was originary promoted as a

way to prevent cervical cancer. Boys do not have a cervix, so why should they be suspected to a girl’s vaccine? There are some good science based reasons:

1- Boys can transmit the virus to female sex partner later in life, leading to cervical cancer in women

2-More importantly, boys can also be directly harmed by viruse. It can cause genital warts, cancer of head and neck(tongue,tonsil.throat),anal and penile cancer,respiratory papillamatosis and giant condylama of Bushke and Lowenstein. Especially gay and bisexual men, men with weakened immune system, more likely develop those HPV related disease.

Is there a test for HPV in men? Currently, there is no HPV test

recommended for men. Men can check any abnormalities for his penis, scrotum or around the anus. Men should see his doctor if he finds warts, blisters, sores, ulcers, white patches or other abnormal areas on his penis.

Are there ways for men to reduce risk of getting HPV?One way is using Condom. The only sure way to prevent HPV

is not to have sexual contact. HPV vaccination CDC recommends the HPV vaccine for all boys ages 11 or

12, for males through age of 21 For gay and bisexual men For men wıth compromised immune system including HIV Vaccine is safe for all men through age 26 but it is most

effective when given at a younger ages,before a fırst sexual contact.

In the NEW YORK TIMES,DR William Schaffner was quatedat as saying:

“This is cancer. A vaccine against cancer was the dream of our youth. I made sure my daughter got the vaccine.If I had sons, Iwould vaccinate them too.

HPV Vaccine Application In World

HPV Vaccine in Turkey  In Turkey, incidence and mortality of cervical cancer and

other HPV related disease is lower than the world. The new and comprehensive studies are needed in order to define that cost effectivitiy analyse of HPV vaccine and immunisation, distribution of HPV genotypes, approach and support of population to the vaccine. According to present knowledge about HPV vaccine; cost of vaccination, dose number, need of special approach for target group, unclear situation in duration of efficacy and need of booster dose a dignified approach must be needed. It is seen as screening improvements have a high priority, that is essential under every condition and beside national specific studies should be conducted, developments about HPV vaccine and experiences of countries must be followed.

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BenefitsHarm

5-Follow up

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References: Labadie, J., Postlicensure safety evaluation of human papilloma virus

vaccines. International Journal of Risk & Safety in Medicine. 23 (2011). 103–112

Colafrancesco, S.,Perricone, C., Tomljenovic, L., Shoenfeld, Y., Human Papilloma Virus Vaccine and Primary Ovarian Failure: Another Facet of the Autoimmune/Inflammatory Syndrome Induced by Adjuvants. American Journal of Reproductive Immunology. 70 (2013). 309–316

Artuk, C., Overview of Current Humman Papilloma Virus (HPV) Vaccination. TAF Prev Med Bull 2013;12(3):327-334

Palefsky, J. M. (2013) Epidemiology of human papillomavirus infections. Retrieved from

http://www.uptodate.com/contents/epidemiology-of-human-papillomavirus-infections

Castle, P. E. , Cox J. T. , Palefsky, J. M. (2013) Recommendations for the use of human papillomavirus vaccines. Retrieved from http://www.uptodate.com/contents/recommendations-for-the-use-of-human-papillomavirus-vaccines

References Castle, P. E. , Cox J. T. , Palefsky, J. M. (2013) 2013) .

Clinical trials of human papillomavirus vaccines. Retrived from http://www.uptodate.com/clinical-trials-of-

human-papillomavirus-vaccines www.publichealth.gc.ca

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