For HPV Vaccine to Have Optimal Impact, ‘Provider Hesitancy’ Must Be Overcome


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Honoring National Cancer Institute researchers Douglas R. Lowy, MD, and John T. Schiller, PhD, with the Lasker-DeBakey Clinical Medical Research Award for advances in technology that enabled the development of human papillomavirus (HPV) vaccines to prevent cervical cancer and other tumors caused by HPV, the Lasker Foundation noted the two scientists “took a bold but calculated approach toward a major public health problem whose solution required them to vault formidable hurdles.”1 As Dr. Lowy, Acting Director of the National Cancer Institute (NCI) and Chief of the Laboratory of Cellular Oncology, explained in an interview with The ASCO Post, the vaulted hurdles involved vaccine development and production issues, but a formidable barrier remains—“provider -hesitancy” to discuss HPV vaccine with young patients and their parents and encourage use of the vaccine at an early age.

John T. Schiller, PhD

John T. Schiller, PhD

The Centers for Disease Control and Prevention (CDC) “has identified what it refers to as ‘provider hesitancy’ on the part of primary care providers and pediatricians—the people who ordinarily are giving childhood and adolescent vaccines,” Dr. Lowy said. “There is a reluctance to talk about the HPV vaccine, its availability, and that it is recommended for young adolescents.” Whatever can be done by government agencies, medical societies, media, and other health-care professionals including oncologists “to get the word out to primary care providers would be especially useful,” Dr. Lowy stressed. 

Can Prevent Cancer at Multiple Sites

“Virtually 100% of cervical cancer cases are attributable to HPV infection,” Dr. Lowy explained. By protecting against infection by the most common types of high-risk HPV—types 16 and 18—as well as some other types, HPV vaccines can prevent almost all cases of cervical cancer. The vaccine can also prevent 50% to 90% of cancers that arise in the vagina and vulva in women, cancer of the penis in men, and cancers of the anus and oropharynx in men and women, depending on the cancer and the setting, Dr. Lowy added. 

“The HPV vaccine is generally talked about as a vaccine that can prevent cervical cancer,” Dr. Lowy said. “That is largely because cervical cancer worldwide is by far the most important HPV-associated cancer,” accounting for about 90% of deaths attributed to HPV infection. 


There is a reluctance to talk about the HPV vaccine, its availability, and that it is recommended for young adolescents. [Efforts] to get the word out to primary care providers would be especially useful.
— Douglas R. Lowy, MD

“But in the United States, where we have had high-quality cervical cancer screening for many years, the incidence and mortality rates of cervical cancer have gone down substantially, and there are as many noncervical cancers as there are cervical cancers in the United States that are caused by HPV infections. This vaccine is given systemically, so there is no inherent reason to think that it is less protective against the development of precancer and cancer at these other sites than it is at the cervix,” Dr. Lowy noted. 

“Certainly, the studies leading to U.S. Food and Drug Administration (FDA) approvals of the vaccine for the anogenital diseases have shown similar high rates of protection,” Dr. Lowy said. 

“There is only one study that demonstrates protection in the oropharynx,” he continued. “That was conducted by the NCI among women in Costa Rica, and it was a post hoc analysis…. It just looked at the carriage rates of HPV-16 and HPV-18 in the mouth, and there was more than a 90% difference between the carriage rates in the control group and the vaccinated group,” Dr. Lowy explained. “But there is no FDA-approved indication for oropharyngeal cancers, primarily because there is no premalignant lesion, as there is at the anogenital sites. FDA approvals for the HPV vaccine are based on reducing dysplasia rather than reducing the incidence of infection, although they also do that.”

Two and Three Doses

The CDC recommends routine HPV vaccination for girls and boys aged 11 and 12, although vaccination can be started as young as 9 years old. “Ideally, adolescents should be vaccinated before they are exposed to HPV. However, people who have already been infected with one or more HPV types can still get protection from other HPV types in the vaccine,” according to the CDC.2 

In addition, vaccination is recommended for females aged 13 through 26 years and males aged 13 through 21 years “who were not adequately vaccinated when they were younger,” the CDC advises. “Vaccination is also recommended for gay, bisexual, and other men who have sex with men, transgender people, and persons with certain immunocompromising conditions [aged 22 through 26 years] who were not adequately vaccinated when they were younger.” 

If it turns out that one dose is sufficient, this would both reduce the cost of vaccination and be much simpler to give.
— Douglas R. Lowy, MD

Dr. Lowy explained, “Once you reach a certain age, you have had most of your lifetime exposures, although people who are adults continue to be exposed. The 26-year-old cutoff is generally a question of cost-effectiveness. The trials were done initially in women in that age range and then in men.” 

There have also been controlled trials among women between the ages of 25 and 45 or 55, he noted, and while efficacy was shown, the FDA has not approved vaccination for individuals in those age ranges. However, the European Medicines Agency (EMA) has approved the vaccine for women over age 25 or 26.

In a 2016 update of the HPV vaccine dosing schedule for -Gardasil, the CDC’s Advisory Committee on Immunization Practices recommended two doses, given at least 6 to 12 months apart for those starting the vaccine series before their 15th birthday. Those just starting to receive the HPV vaccine at age 15 or older should get three doses, with the second dose given 1 to 2 months after the first, and the third dose 6 months after the first dose. 

Three HPV Vaccines

Three HPV vaccines are currently approved by the FDA—Gardasil (quadrivalent), Gardasil 9 (9-valent), and Cervarix (bivalent). All three protect against HPV-16 and HPV-18. Gardasil also provides protection against HPV types 6 and 11, and Gardasil 9 also protects against HPV types 6, 11, 31, 33, 45, 52, and 58. 

Gardasil 9 is the most widely available of these vaccines in the United States. “The others are fine vaccines, but GlaxoSmithKline stopped selling Cervarix in the Unites States a couple of years ago, and Gardasil 4 is essentially being phased out for sale in the United States by Merck, which makes Gardasil 9,” Dr. Lowy said.

“Gardasil 9 was the first of the three vaccines for which the drug company applied to the FDA for a label change, that is, to give only two doses to young adolescents. The FDA approved that change last fall, and the Advisory Committee on Immunization Practices (ACIP) strongly endorsed it,” Dr. Lowy stated. Cervarix and Gardasil 4 were approved for two doses in Europe several years ago, Dr. Lowy said, but not in the United States. “That was simply because the sponsors asked the EMA for approval, but did not ask the FDA, and the FDA can’t give approval if they are not asked.” 

For Males and Females 

When the first HPV vaccine (Gardasil) was approved in this country in 2006, it was recommended only for girls and young women. “In 2009, the FDA approved Gardasil for boys, but just for the prevention of genital warts. In 2011, the approval was extended to the prevention of anal cancer for boys. Therefore, it wasn’t until 5 years after the introduction of the vaccine that it was approved for boys for a cancer indication,” Dr. Lowy said. 

Since 2011, the ACIP has made the same recommendation for vaccination for boys as it does for girls, for similar reasons, he continued. “It is to protect the vaccinee, so he or she is much less likely to acquire infection, and thereby to develop genital warts or cancer, and secondly, to contribute to herd immunity against the HPV types present in the vaccine.”

For Cancer Patients, Too

A recently published study in the Journal of Clinical Oncology among 982 cancer survivors aged 9 to 26 at 1 to 5 years after completion of therapy found that their HPV vaccine initiation rates were significantly lower than others their age.3 “Predictors of noninitiation included lack of provider recommendation,” the authors reported. 

NCI Chiefs Win 2017 Lasker-DeBakey Award

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While young cancer survivors don’t represent a large enough population for their low HPV vaccination rate to be considered a major public health problem, “certainly as -individuals, they deserve the best preventive care they can receive,” Dr. Lowy commented. “We know that frequently, patients who are treated for one cancer may be at increased risk of developing another cancer, and so under those circumstances, it is reasonable to consider HPV vaccination,” he added. 

“The vaccine is useful for preventing the acquisition of HPV infection, but once you have an infection, the vaccine does not alter the natural history. It does not help patients get rid of HPV,” Dr. Lowy noted. The vaccine could, however, protect against infection by other HPV types.

Opportunity for Improvement

“Since the HPV vaccine was introduced for females in 2006 and for males in 2011, coverage has increased gradually among females and more rapidly among males,” according to a recent report about vaccination coverage in the United States among adolescents aged 13 to 17.4 During 2015 to 2016, the percentage of adolescents aged 13 to 17 receiving one or more doses of HPV vaccine increased from 56.1% to 60.4%. “In 2016, 43.4% of adolescents (49.5% of females; 37.5% of males) were up to date with the HPV vaccination series,” the study found.

Shannon Stokley, DrPh

Shannon Stokley, DrPh

“We’re encouraged to see this finding,” said study coauthor Shannon Stokley, DrPh, of the CDC’s National Center for Immunization and Respiratory Diseases, in an article in The New York Times.5 Referring to the updated ACIP recommendation for a two-dose schedule for adolescents under 15 years old, Dr. Stokley added, “We hope to see a lot of gains with this change.”

While the study’s findings about the increase in uptake of the HPV vaccine were encouraging, the authors noted, “coverage remains 22 to 28 percentage points lower” than those for tetanus, diphtheria, and acellular pertussis vaccine (Tdap) and for one or more doses of meningococcal conjugate vaccine (MenACWY). “These gaps indicate substantial opportunity for improving HPV vaccination practices,” the authors concluded.

Moving Toward a Single Dose 

“Vaccine studies have raised the possibility that even a single dose may be able to confer long-term protection,” Drs. Lowy and Schiller wrote in a recent viewpoint article in JAMA.6

“We are about to start on a controlled trial to see if one dose given to young adolescents will be sufficient to induce long-term protection,” Dr. Lowy told The ASCO Post. “It is based on the post hoc analysis that we did in Costa Rica with an NCI trial of Cervarix. It turned out that the women who received one or two doses were as protected—they had the same vaccine efficacy—as the women who got the fully prescribed three doses,” he reported. 

“But this is not enough to change the standard of care or to change practice,” he said. “So we have embarked on a rigorous controlled trial to see whether one dose might be sufficient. There are also data from a trial in India suggesting that one dose of Gardasil may confer protection.” The new trial will test both Gardasil 9 and Cervarix, Dr. Lowy said. 

“In the United States, if it turns out that one dose is sufficient, this would both reduce the cost of vaccination and be much simpler to give,” Dr. Lowy said. “It would also be especially helpful in the developing world. Only about 3% of people in the developing world who are eligible for the vaccine have actually received it, but about 90% of cervical cancer deaths occur in the developing world. One dose would have the big advantage of being less costly and logistically far easier than even two doses.”

Vaccinations for the trial, jointly sponsored by the NCI and the Bill and Melinda Gates Foundation, are expected to start by the end of this year. The ClinicalTrials.gov identifier for the trial is NCT03180034. ■

DISCLOSURE: As part of Dr. Lowy’s U.S. government–supported research at the National Cancer Institute/National Institutes of Health, he is an inventor of technology that underlies the L1-based prophylactic virus-like particle (VLP) HPV vaccine and technology that underlies an L2-based candidate prophylactic HPV vaccine. The NIH has licensed the technology for the L1 VLP vaccine to Merck, the manufacturer of Gardasil, to GlaxoSmithKline, the manufacturer of Cervarix, and to Indian Immunologicals Ltd. The L2-based vaccine technology is the subject of a cooperative research and development agreement between the NCI, Johns Hopkins University, and Shantha Biotech, and has been licensed to Shantha, PaxVax, Acambis Inc, and GSK. U.S. Federal law entitles Dr. Lowy to a limited share of royalties the NIH receives for these technologies.

Dr. Lowy is Chief, and Dr. Schiller is Deputy Chief, of the Laboratory of Cellular Oncology at the NCI Center for Cancer Research. Dr. Lowy is also Acting Director of the NCI.

REFERENCES

1. Strauss E: 2017 Lasker-DeBakey Clinical Medical Research Award: HPV vaccines for cancer prevention. Press release, September 15, 2017.

2. Centers for Disease Control and Prevention: HPV vaccine information for clinicians. December 20, 2016. Available at www.cdc.gov. Accessed October 5, 2017.

3. Klosky JL, Hudson MM, Chen Y, et al: Human papillomavirus vaccination rates in young cancer survivors. J Clin Oncol. August 24, 2017 (early release online). 

4. Walker TY, Elam-Evans LD, Singleton JA, et al: National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years—United States, 2016. MMWR Morb Mortal Wkly Rep 66:874-882, 2017

5. Pattani A: The HPV vaccine gains ground among U.S. teenagers, The New York Times, September 22, 2017.

6. Lowy DR, Schiller JT: Preventing cancer and other diseases caused by human papillomavirus infection. JAMA 318:901-902, 2017.


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