Myths and Realities about HPV Vaccination

Rachel N. Caskey, MD, MaPP

The Advisory Committee for Immunization Practices (ACIP), which is part of the CDC, is an appointed committee responsible for developing written recommendations for the routine administration of vaccines, including ages for vaccination, dosing regimen, precautions, and contraindications. To fulfill their objectives, the ACIP meets 3 times a year to ensure that timely responses to evolving issues are possible, including vaccine approvals and data on experiences with existing vaccines. The ACIP recommends universal HPV vaccination for females using the quadrivalent (HPV4) or bivalent (HPV2) vaccine. The targeted age for vaccination is 11 to 12 years, although the vaccine can be given as early as age 9 and up through 26 years of age. Following the FDA approval of the HPV4 biologics license supplement in October 2009 to include prevention of genital warts caused by HPV 6 and 11 in males 9 through 26 years of age, the ACIP supported permissive use of the vaccine for males in this age group, with the target age group 11 to 12 years of age.

HPV Vaccine Coverage: The Reality

National data on vaccination coverage among adolescents aged 13 to 17 years indicate that HPV vaccination rates in girls are lower than those achieved with other adolescent vaccines.¹ At the time data were collected in 2009, 44.4% of girls aged 13 to 17 years had initiated HPV vaccination (ie, they had received at least one dose). Slightly more than one-fourth (26.7%) had completed the 3-dose HPV vaccination series. Vaccination rates for other vaccines for this age group were much higher. For example, rates for vaccination with at least 2 doses of the measles mumps rubella (MMR) vaccine were 89.1%, and vaccination rates for at least 3 doses of the hepatitis B vaccine were 89.9%. HPV vaccination rates are therefore suboptimal.

Myths and HPV Vaccination Adverse Events

After initial licensing of the HPV4 vaccine was approved in 2006, safety of the HPV vaccine received significant attention from the public news media. In 2008, for example, The Dallas Morning News highlighted the story of a teenaged girl who developed epilepsy after receiving the HPV vaccine.² Compelling language early in the story refers to the similarity of this case to “5,000 reports filed by the public through a national database that monitors the safety of vaccines after they are licensed.” Concerned parents can be easily convinced of the vaccine’s dangers after reading this and similar stories. In addition to general articles in the lay press, some high profile individuals are propagating unwarranted concern or skepticism about vaccines in general, including the HPV vaccine, in every information outlet available, ranging from books to internet to popular talk shows.

Another concern that influences HPV vaccination in the United States is reflected by the Family Research Council’s stance that “Giving HPV vaccine to young women could be potentially harmful because they may see it as a license to engage in premarital sex.”³ However, numerous studies have shown that teenagers are not more likely to have sex or more sexual partners when condoms or emergency contraception are available in high schools.^4-7 By analogy, it can be assumed that vaccinating girls and boys against HPV will not result in higher rates of sexual activity.

Realities of the HPV Vaccine Adverse Events

Adverse events associated with the HPV vaccine include reports of teenage girls fainting after receiving the vaccine. This was not observed during prelicensure clinical trials, which is attributed to the protocol requirement that subjects remain sitting for 30 minutes after receiving the vaccine. Adolescents frequently have more labile syncope, postural hypotension, and vasovagal responses. They also tend to have poor, inadequate diets, and if they have blood drawn or receive any vaccine in a nutritionally-deprived condition they are more likely to faint if they become immediately ambulatory. If the adolescent sits for at least 15 minutes after receiving any vaccine or blood draw, the likelihood of fainting is significantly decreased. The ACIP and AAP recommend that all children wait 15 minutes after immunization,^8,9 and an HPV4 label change was approved in 2009, adding syncope to the warnings and precautions section of the prescribing information, also with the recommendation to observe patients for 15 minutes after immunization.¹⁰ The October 2007 ACIP meeting report noted that 89% of previously reported syncopal events occurred within 15 minutes of vaccination, and that approximately one-third of syncope reports from 1990 through 2004 occurred in persons 10 to 18 years of age.

Adverse events that have also been attributed to the HPV4 vaccine include headaches, low-grade fevers, and injection site reactions manifested as a sore arm.¹¹ None of the sensational adverse events propagated on the Internet and other public media sources have been causally linked to this vaccine. The prescribing information for both vaccines describes deaths that occurred across all clinical studies, with the conclusion that “the events reported were consistent with events expected in healthy adolescent and adult populations” and “causes of death among subjects were consistent with those reported in adolescent and adult female populations.”^10,12 The clinical database of more than 20,000 male and female vaccine recipients demonstrates no difference in the death rates between placebo and vaccine recipients.¹¹

Vaccine Adverse Event Surveillance in the United States

Other adverse events linked in the press to the HPV vaccine include Guillain-Barré syndrome, blood clots, seizures, sudden death, and birth defects. Data on these events are acquired in the United States by a national passive surveillance program, the Vaccine Adverse Event Reporting System (VAERS).¹³ VAERS was created in 1990 as part of the National Childhood Vaccine Injury Act, which requires health care providers and vaccine manufacturers to report all adverse events that occur following vaccination. VAERS also accepts reports from the public on adverse events associated with any vaccine. Reports can be submitted not only by the patient who experienced the event, but also by anyone who acquires information about an event by any means. The burden of validating the accuracy and validity of reports is, therefore, immense.

Approximately 30,000 reports are filed with VAERS annually, of which approximately 13% are classified as serious; that is, they involve a disability, hospitalization, life-threatening situation, or death. VAERS reports are unfiltered and lack a denominator. Therefore, the information can be used to generate hypotheses, but it cannot be used to test a hypothesis. For example, in one VAERS report a medical assistant reported that a patient told the physician that the daughter of her neighbor was vaccinated with 1 dose of HPV4 vaccine and subsequently became paralyzed. Unknown medical attention was sought, the outcome is unknown, and a product complaint was not involved. This is a hearsay report in the absence of an identifiable patient, and attempts are being made to verify the existence of a patient fitting this scenario of events. Records like this are common, and many adverse events are unsubstantiated. The policy of accepting anonymous adverse event reports from anyone is subject to additional biases. For example, a study that examined the reporting source in the VAERS database found that in 2002, 87% of VAERS reports that were related to thimerosol and 35% of those related to autism were filed in connection with litigation.¹⁴ Lawyers are able to manipulate the system to show increases in vaccine-related adverse events that are based on litigation, not health research.

There are 2 other complementary sources of vaccine safety information in the United States, both of which are part of the CDC: the Vaccine Safety DataLink (VSD) project and the Clinical Immunization Safety Assessment (CISA) Network.^15,16 The VSD project was established in 1990 as a collaborative effort between the CDC and 8 managed care organizations to fulfill the following objectives:

• Conduct population-based research on immunization safety questions
• Evaluate immunization safety hypotheses that arise from medical literature, passive surveillance systems, adjustments to immunization schedules, and introduction of new vaccines
• Guide national immunization policy decisions
• Partner with health care providers, public health officials, and others to ensure that the public has the best available information regarding the risks and benefits of immunization

The CISA Network was established in 2001 as a collaboration between the CDC, 6 medical research centers, and America’s Health Insurance Plans. The CISA mission is:

• To conduct clinical research about vaccine adverse events and the role of individual variation
• To provide clinicians with vaccine-based counsel, and empower individuals to make informed immunization decisions
• To assist domestic and global vaccine safety policy makers in the recommendation of exclusion criteria for at-risk individuals
• To enhance public confidence in sustaining immunization benefits for all populations

Accessing Adolescents for Vaccination

The ACIP recommends targeting those 11 to 12 years of age for the HPV vaccine. This age coincides with the schedule for other routine immunizations, including Tdap (tetanus, diphtheria, pertussis) and meningococcal conjugate vaccines (MCVs). In addition, as children enter their teenage years, the likelihood that they will make a primary health care visit, which is currently the most common venue for vaccine administration, decreases substantially (Figure 1).¹⁷ However, only slightly more than one-half of children 11 and 12 years of age interface with a primary health care visit in a calendar year.

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Higher rates of adolescent vaccine coverage may be possible by using venues outside the doctor’s office, which can include school- or church-based immunization and implementing other nontraditional vaccine delivery strategies such as walk-in clinics in retail establishments, which may be necessary if universal vaccination of adolescents is to be achieved. In addition, a recent study by the Working Group on Complementary Settings evaluated the qualifications of other health care settings and their interest in providing adolescent vaccination services.¹⁸ The site’s ability to meet the 7 National Vaccine Advisory Committee (NVAC) quality standards was included as part of the evaluation. Possible constraints of alternative sites, even those that are also health care settings, include lack of capability for proper storage and management of vaccination supplies and for accurate patient screening, including assessment of contraindications. Other obstacles that must be overcome in any nontraditional setting include lack of access to immunization information systems, transmitting data to primary care physicians, and other issues related to collecting and reporting data. In some locales these obstacles have been avoided, and their programs may serve as a model for other sites. For example, a largely successful school-based influenza immunization program was implemented in Carroll County, Maryland in 2005.¹⁹

In conclusion, the HPV4 vaccine has been the target of spurious media attacks since it was approved for use in 2006. Passively acquired adverse event surveillance data can be used to formulate discrete hypotheses for testing in well-designed research in response to possible safety issues. The safety of the HPV4 vaccine is supported by data from this postlicensure surveillance, which resulted in placing additional emphasis on the importance of enforcing a 15-minute wait after immunization to avoid fainting episodes. Between June 1, 2006 and December 31, 2008, more than 20 million doses of the quadrivalent vaccine were distributed in the United States, with proven safety. However, vaccine coverage remains low, and providing immunization in nontraditional settings may be required to achieve adequate coverage.

References

1. Centers for Disease Control and Prevention. National, state, and local area vaccination coverage among adolescents aged 13-17 years—United States, 2009. MMWR Morb Mortal Wkly Rep. 2010;59(32):1018-1023.
2. Meyers J. HPV vaccine’s suspected side effects cause concern. The Dallas Morning News. June 6, 2008. http://www.dallasnews.com/sharedcontent/dws/news/localnews/stories/DN-vaccine_06met.ART.North.Edition1.46ef875.html. Accessed January 10, 2011.
3. Maher B. Family Research Council opposes vaccine that could stop spread of HPV. July 2005. http://www.thefreelibrary.com/Family+Research+Council+opposes+vaccine+that+could+stop+spread+of+HPV-a0134625957. Accessed March 29, 2011.
4. Schuster MA, Bell RM, Berry SH, Kanouse DE. Impact of a high school condom availability program on sexual attitudes and behaviors. Fam Plann Perspect. 1998;30(2):67-72, 88.
5. Blake SM, Ledsky R, Goodenow C, Sawyer R, Lohrmann D, Windsor R. Condom availability programs in Massachusetts high schools: relationships with condom use and sexual behavior. Am J Public Health. 2003;93(6):955-962.
6. Raine TR, Harper CC, Rocca CH, et al. Direct access to emergency contraception through pharmacies and effect on unintended pregnancy and STIs: a randomized controlled trial. JAMA. 2005;293(1):54-62.
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8. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices. Record of the proceedings. October 24-25, 2007. http://www.cdc.gov/vaccines/recs/acip/downloads/min-archive/min-oct07.pdf. Accessed January 15, 2011.
9. American Academy of Pediatrics. Vaccine administration. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:9-12.
10. Gardasil [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2010.
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12. Cervarix [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010.
13. Vaccine Adverse Event Reporting System (VAERS). http://vaers.hhs.gov/index. Accessed January 15, 2011.
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15. Vaccine Safety Datalink (VSD) Project. http://www.cdc.gov/vaccinesafety/activities/vsd.html. Accessed January 13, 2011.
16. Clinical Immunization Safety Assessment (CISA) Network. http://www.cdc.gov/vaccinesafety/activities/cisa.html. Accessed January 13, 2011.
17. Albertin C, et al. Adolescent health care utilization across the United States: who may be reached for immunization? Paper presented at: Pediatric Academic Societies Meeting; April 29, 2006; San Francisco, CA.
18. Schaffer SJ, Fontanesi J, Rickert D, et al; Working Group on Complementary Settings. How effectively can health care settings beyond the traditional medical home provide vaccines to adolescents? Pediatrics. 2008;121 (suppl 1):S35-S45.
19. Davis MM, King JC Jr, Moag L, Cummings G, Magder LS. Countywide school-based influenza immunization: direct and indirect impact on student absenteeism. Pediatrics. 2008;122(1):e260-e265.