1. An Introduction to the HPV Vaccine Kelly Copeland Med2 Student The Ohio State University College of Medicine

2. Objectives  Understand the basics of HPV (how its spread, what it causes)  Know the two low risk and high risk types of HPV discussed in the lecture and what each cause  Understand the difference between quadrivalent and bivalent  Know the basics of the vaccine (when it should be given, who should receive it, what it is composed of)

3. Human Papillomavirus  Non-enveloped  Double stranded DNA virus  8,000 bp genome

4. HPV- Who, When, Where  Over 200 types  Spread person to person via skin-to-skin contact  40 are considered STDs  Most Common STD  6 million people every year  Within 2 years of sexual activity 40% of women will be infected  Lifetime risk 80%

5. HPV- What  Usually not associated with symptoms  Many types cause no harm  Others cause…  Plantar warts  Genital warts  Cancer

6. Types of HPV  Low Risk HPV: cause condyloma accumunatum (genital warts); treatable; not usually linked with cancer  6  11  High Risk HPV: cause cervical dysplasia and cancer  16  18  31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 (we will not discuss these further)

7. HPV  16+18 account for >70% of cervical cancers  6+11+16+18 account for 90% genital warts  All HPV types account for 99% of cervical cancers  etiologic agent necessary for cervical cancer to develop

8. HPV- How  HPV encodes 2 proteins that aid in carcinogenic mechanism  E6: inhibits tumor suppressor p53  loss of cell cycle control, inhibition apoptosis, deregulates transcription and DNA replications, and stimulates cell immortalization  E7: destabilizes tumor suppressor pRB  accelerate DNA synthesis, disrupts cell cycle control, causes chromosomal changes and mitotic mutations

9. But… It does NOT ALWAYS cause cancer  When the virus infects the cell and replicates E6 and E7 cause dysplastic changes in cells lining the cervix  Majority of abnormal cells go away  In the case the body cannot clear these cells in ~10 to 15 years undetected and untreated dysplastic changes can become cancerous

10. HPV and associated malignancies  Cervical cancer  Oropharyngeal cancer  Anal cancer  Vaginal cancer  Vulvar cancer  Penile cancer  Non-melanoma skin cancer

11. HPV Summary  HPV is a virus transmitted person to person by skin to skin contact  There are over 200 types where 40 are considered STDs  HPV is the most common STD  HPV can have no symptoms and cause no harm or it may cause plantar warts, genital warts, and in some cases cancer  HPV encodes proteins E6 and E7 that inhibit tumor suppressors and are responsible for carcinogenic changes  There are low risk and high risk types of HPV

12. HPV Summary  High risk types 16 and 18 cause >70% cervical cancer  Low risk types 6 and 11 and high risk types 16 and 18 cause 90% of genital warts  HPV is the etiologic agent of cervical cancer  HPV is associated with other malignancies

13. Cervical Cancer Epidemiology  Second most common cause of cancer related deaths in women  510,000 cases and 288,000 deaths worldwide  11,300 case and 4,000 deaths in US  11 women die each day  Most common in women ages 30-55 (rare in teens)  Incidence and mortality is 50% higher in AA

14. Types of Cervical Cancer  Squamous cell carcinoma  Squamous epithelium on outer surface of cervix  Strong association to type 16 HPV  Adenocarcinoma  Adenomatous gland cells higher in the cervix called the endocervical canal  more difficult to detect  higher risk of delayed diagnosis  Strong association to type 18 HPV

15. Histological Location of adenocarcinoma and squamous cell carcinoma of the cervix Adenocarcinoma Squamous cell carcinoma Endocervical canal

16. Cervical Cancer Screening  ~10-15 year pre-invasive phase of dysplasia gives ideal opportunity for screening  Cervical cytology (Pap Smear)  Exfoliate cells from cervix  Examine with microscope  Difficult to detect adenocarcinomas, quick progressing or early stage lesions  Molecular HPV testing has recently been added to the screening algorithm

17. Cervical cytology

18. Cervical Cancer prevention  As mentioned before screening for pre-cancerous is an important part of prevention/detection of cervical cancer  BUT prior to 2005 condoms were considered the best prevention of HPV and subsequently cervical cancer  UNTIL June 2005……

19. HPV Vaccine  June 2005 FDA approved first HPV vaccine (quadrivalent)  October 2009 FDA approved second HPV vaccine (bivalent)

20. HPV Vaccine- What  Non-infectious  Contain no viral DNA  Consist of viral capsid protein L1 that assembles into a virus like particle (VLP)  VLP elicits type specific Ab response from patient for future protection

21. HPV Vaccine- How  Insert L1 gene into yeast genome  Yeast transcribes and translates L1 gene to create recombinant L1 capsid protein  5 recombinant L1 capsid proteins combine to create a pentamer  72 pentamers self assemble to create non-infectious VLP

22. Assembly of VLPs

23. Quadrivalent vs Bivalent  Quadrivalent: contains L1/VLPs for 4 types of HPV  Types 6,11,16 and 18  93-100% effective against preventing precancers caused by 16 and 18  99% effective against genital warts caused by 6 and 11  Used to prevent cervical, vulvar, vaginal precancers and dysplastic lesions as well as genital warts  Bivalent: contains L1/VLPs for 2 types of HPV  Types 16 and 18  93-100% effective against preventing cervical precancers caused by 16 and 18  Used for prevention of cervical cancer, precancers, and dysplastic lesions associated with HPV types 16 and 18

24. HPV Vaccine- Who  Both vaccines are prophylactic  intended to prevent HPV rather than treat it  Should be given prior to exposure or in this case preferably prior to the onset of sexual activity  Can and should be given to women who have already had sex, genital warts, abnormal screening tests, or prior HPV infections but assume it only protects against HPV types not already acquired

25. HPV vaccine- when  Females ages 11-12  As young as 9  Catch up unvaccinated 13-26  No preference of vaccine (quad or bi)  Males ages 11-12: Prevent genital warts, anal cancer, and transmission  As young as 9  Catch up unvaccinated 13-21  Quadrivalent  MSM and immunocompromised can receive the vaccine through age 26

26. Vaccination Schedule  Both require 3 doses  First: time of patient choosing (recommend 11-12 yo)  Second: 2 months after first  Third: 6 months after first Must be 12 weeks after second Must be 24 weeks after first  Interruptions ≠restart regimen

27. Schedule Interruption Guidelines  If interrupted after first dose…  Second dose should be given as soon as possible  Third dose should be given 12 weeks after second  If interrupted after second dose…  Third dose should be given as soon as possible assuming it has been 12 and 24 weeks past second and first doses respectively

28. Are they interchangeable?  Recommended that the same type be used for all three doses but…  If uncertainty about which was previously used OR  If the one previously used is unavailable  Either can be used to complete or continue the regimen  BUT… it can only be assumed patient is protected against 16 and 18  IF… quadrivalent was given for part of the regimen there may be some protection against 6 and 11

29. Vaccine Contraindications  Pregnant women  If discovered after first dose… delay second and third until pregnancy completed  No intervention necessary  No evidence of adverse outcomes of pregnancy or fetus but limited data  Patient allergic to yeast  Patient allergic to other vaccine component

30. Side Effects of Quadrivalent  Pain  Redness  Swelling at injection site  Fever within 5 days of infection  Headache  Serious but rare: bronchospasm, asthma, hypersensitivity, gastroenteritis, HA with hypertension  0.2% discontinued vaccine due to side effects

31. Side Effects of Bivalent  More local side effects than quadrivalent  Pain  Redness  Swelling  Fatigue  Headache  Myalgia (muscle aches)

32. Vaccine Safety  Both vaccines associated with syncope (fainting) though not significantly more than other vaccines  Recommended that the patient is seated during vaccination and for 15 minute observation period to decrease the risk of injury from fainting

33. Vaccine Safety  Both vaccines are shown to be extremely safe as long as the proper contraindications are followed

34. Vaccine Cost  ~$120 per dose or $360 per regimen  Most large insurance plans cover the cost of recommended vaccines  There are federal health programs that will help children and teens get the vaccine who are underinsured, Medicaid eligible, American Indian or Alaskan natives  Vaccines for Children (VFC)

35. Patient Education  HPV vaccine may not fully protect everyone and does not protect against all types of HPV or prevent all cases of cervical cancer or genital warts, which means….  Patients need to understand that regular screening tests are still necessary AND  Patients should still protect themselves against other types of HPV as well as other STDs

36. What your patients need to know  Risk  Screening  Prevention  These are the essentials in helping your patient make an informed decision about their own care

37. The Controversy  Intended to insure that when the decision is made to become sexually active they are protected  Not to interfere with thoughts on premarital sex  In fact it is a great opportunity to begin sexual education in both patients and parents  Another school of thought for parents resistant to have the sexual education discussion with their children is to approach it as all other childhood vaccines  You are getting it to prevent getting sick