The HPV Vaccine: Then and Now

Linda Brookes, MSc

Disclosures

August 01, 2016

In This Article

Human Papillomavirus Vaccination: Why is Coverage So Low in the United States?

The human papillomavirus (HPV) is the most common sexually transmitted infection in the United States.[1] The Centers for Disease Control and Prevention (CDC) has confirmed that at least half of all sexually active men and women will acquire HPV in their lifetime.[2] The latest figures indicate that about 79 million Americans are currently infected with HPV, and about 14 million people are newly infected each year.[3] HPV is associated with almost all cases of cervical and anal cancers, approximately 70% of vaginal, vulvar, and oropharyngeal cancers, and 60% of penile cancers.[4] From 2008 to 2012, about 38,793 new cases of HPV-related cancers were diagnosed annually, which is a 16% increase over the 33,369 cases diagnosed from 2004 to 2008.[5]

Three Vaccines With Different Availabilities

Three HPV vaccines have become available since 2006, and all are currently licensed in the United States. The first vaccine to be introduced was the quadrivalent (four-valent) vaccine Gardasil® (Merck), known in Europe as Silgard, which protects against HPV types 6, 11, 16, and 18. HPV 16 and 18, the two most common "high-risk" genotypes, cause approximately 70% of all cervical cancers. HPV 6 and 11, two "low-risk" genotypes, cause 90% of anogenital warts (condylomata). First approved in 2006 for girls and women 9 to 26 years of age, Gardasil approval was extended to boys of the same age in 2010.[6] A bivalent (two-valent) vaccine, Cervarix® (GlaxoSmithKline), which protects against HPV types 16 and 18, was approved in 2010 for use in girls and women 9 to 25 years of age, but not in boys.[7] Since the introduction of the HPV vaccines, several studies have demonstrated that both the two- and four-valent versions protect against HPV-associated disease and infection caused by the HPV types targeted by each vaccine.[8–11] In addition, each vaccine shows a moderate degree of cross-protection against some non-targeted HPV types.[8–12]

In 2014, a nine-valent vaccine, Gardasil® 9 (Merck), was approved in the United States.[13] In addition to HPV types 6, 11, 16, and 18, Gardasil 9 protects against HPV types 31, 33, 45, 52, and 58, which account for about 15% of cervical cancers.[14] Gardasil 9 has since been approved in Australia, Canada, and Europe. After Gardasil 9 was launched in the United States, practitioners began switching from the four-valent to the nine-valent vaccine, explains Lauri Markowitz, MD, from the National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention at the CDC, during an interview with Medscape.

"The nine-valent vaccine is very similar to the four-valent, and is not perceived as a totally different vaccine," she says. CDC data show that about 10 million doses of Gardasil 9 have been distributed in the United States since its introduction. Merck previously announced that after US Food and Drug Administration (FDA) approval of Gardasil 9, the four-valent Gardasil would gradually be retired.[15] "We plan to stop taking orders for Gardasil 4 by the end of 2016," a Merck spokesperson tells Medscape. "Outside the United States, the transition process will vary by country, but we will maintain availability of Gardasil until countries make a full transition to Gardasil 9." The CDC's Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination with any of the three currently available HPV vaccines for girls and women 11 to 26 years of age and for boys and men 12 to 21, if they have not previously been vaccinated.[14] [Editor's note: The CDC provides additional information on the use of nine-valent vaccine in individuals who started and/or completed the HPV vaccine series with bivalent or quadrivalent vaccine.]

Dosing Schedules Changing

The FDA has approved a three-dose schedule for all three HPV vaccines, with the second dose administered 1 to 2 months after the first dose and the third dose administered 6 months after the first dose. In Europe, a two-dose schedule for children 9 to 13 years of age—at 0 and 6 months—was approved for Cervarix in 2013[16] and for Gardasil in 2014[17] on the basis of clinical trial data showing immunogenicity and safety comparable to the three-dose schedule.[18,19,20,21] The two-dose schedule for both vaccines was endorsed in 2014 by the World Health Organization (WHO).[21] This past April, a two-dose schedule for Gardasil 9 was approved in Europe for girls and boys 9-14 years of age.[22] No data have been submitted to the FDA to support a two-dose schedule for either Cervarix or Gardasil, so it has not been approved in the United States. However, the FDA is currently reviewing primary immunogenicity analyses of a two-dose schedule for Gardasil 9.[15] Administration of a two-dose series of nine-valent HPV vaccine in girls and boys 9-14 years of age, with the second dose given 6 or 12 months after the first dose, generates antibody responses that are noninferior to the three-dose regimen in young women 16-26 years of age (specifically, the anti-HPV 6/11/16/18/31/33/45/52/58 antibody), according to a recent clinical trial.[15] The CDC recently reviewed studies of HPV vaccines comparing three-dose with two-dose schedules.

At the recent ACIP meeting, potential wording for recommendations for the two-dose schedule was discussed; it will be voted on at a future meeting, according to Dr Markowitz. She and her colleagues recently examined different hypothetical scenarios of duration of protection and found that two-dose schedules are likely much more cost-efficient even if they don’t protect for quite as long as a three-dose schedule.[23]

A recent study suggested that a two-dose schedule would result in a small percentage of additional teens being considered fully vaccinated. The impact of a two-dose vaccine schedule on vaccine uptake is not known.[24] Cases have also been made for single-doses of the four- and two-valent vaccines.[25,26]

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