Peyton Rous began his famous experiments in 1909 at the Rockefeller Institute, demonstrating that a sarcoma on the chest of a Plymouth Rock hen that had been brought to him by a farmer from Long Island, New York, could be transplanted to other chickens. Because cell-free tumor extracts resulted in transmission of the sarcoma to other hens, he postulated the agent must be a small transmissible agent, possibly a virus.1 The concept that a virus might cause cancer was outside the prevailing concepts of the time, and his postulate languished for years.
In 1964, Epstein et al2 described the first identified human DNA tumor virus in cell lines obtained from African children suffering from Burkitt lymphoma, demonstrating the human oncogenic potential of this virus (later named the Epstein-Barr virus). By 1981, hepatitis B virus had been linked to hepatocellular carcinoma, and a plasma-derived hepatitis B vaccine was licensed as the first anticancer vaccine.3 In 1983, papillomavirus DNA was isolated from human cervical cancer tissue, and today, human papillomavirus (HPV) is recognized to cause essentially all cervical cancers.4 The US Food and Drug Administration licensed the first HPV vaccine in 2006.
Wherever vaccination campaigns against these 2 vaccine-preventable tumor viruses (hepatitis B, HPV) have been established, the rates of liver cancer caused by hepatitis B and the precancerous cervical lesions of HPV have been reduced dramatically. Development and availability of these 2 vaccines are particularly remarkable accomplishments because neither hepatitis B virus nor HPV can be cultured by conventional methods.
More than 120 types of HPV are recognized and classified by sequences on an outer surface protein (L1) of the virus. Most HPVs infect cutaneous epithelial cells, whereas some HPVs infect the mucosal basal epithelium. HPVs that infect mucosa are classified as nononcogenic (low risk) or oncogenic (high risk), defined by their ability to cause precancerous lesions of the cervix (cervical intraepithelial neoplasia), anogenital cells, or oropharyngeal cells. Infection with a high-risk type is a necessary requirement for cervical cancer, but infection is not sufficient by itself to cause cancer, on the basis of the observation that most infected women resolve their HPV infection and do not develop cervical cancer.
The HPV disease burden in the United States is large, with an estimated 79 million persons infected and an estimated 14 million new HPV infections occurring annually. Adolescents and young adults 15 through 24 years of age acquire approximately half of these new infections. Estimates by the Centers for Disease Control and Prevention indicate that ∼33 600 cancers are caused by HPV each year in the United States, with 20 200 cancers in women (mostly cervical) and 13 400 in men (mostly oropharyngeal). Approximately 90% of these cancers could be prevented by routine administration of the 9-valent human papillomavirus vaccine (9vHPV) (Gardasil 9; Merck) early in life.5
A common feature of tumor viruses is a latent phase when replication and release of infectious viral particles from an infected cell are markedly reduced. A latent infection is thought to allow the virus to hide from immune detection because expression of viral proteins would stimulate an immune response that would eliminate the virus. In the case of HPV, viral DNA can persist in a latent phase within the cell as naked nucleic acid, and protein expression is limited to a small number of viral proteins, some of which have oncogenic potential. One theory as to why viral oncogenic proteins exist at all is because HPV replication requires the enzymes involved in host cell replication. When a virus shifts from a latent phase to active replication, viral proteins are expressed to induce host cell replication, but if cell replication becomes uncontrolled, a tumor results. This theory has been offered as an explanation for the interval of several decades between HPV infection that commonly occurs in the late teenage years or early twenties and the development of cervical cancer decades later. It also explains why the HPV vaccine is only prophylactic and is not protective if infection occurs before vaccination.
For many generations, people have wished for a vaccine that would offer protection against cancer. Curiously, such a vaccine is now readily available but reluctance to administer or to accept the vaccine has kept HPV immunization rates far below those of other routinely recommended vaccines. For each year that HPV vaccination rates remain low, thousands of preventable HPV-associated cancers will occur in men and women.
A theoretical concern that has contributed to HPV vaccine hesitancy relates to vaccine safety. Two articles in this issue of Pediatrics address HPV vaccine safety. In the report from the Vaccine Adverse Events Reporting System, researchers analyze reports from a 3-year period during which 28 million 9vHPV doses were distributed.6 In the second report from the Vaccine Safety Datalink, authors describe surveillance for prespecified adverse events after administration of >830 000 9vHPV doses.7 In both reports, the authors conclude that the postlicensure safety profile of the 9vHPV is consistent with data from the prelicensure trials and that no new safety concerns have been identified.
The time has come for all vaccine administrators and parents to understand that the availability of the 9vHPV is one end of a remarkable journey of discovery and progress to develop a safe and effective vaccine to prevent suffering and death from a common cancer. The HPV vaccine adds to the legacy of immunization as one of the most effective public health interventions for disease prevention and improvement of the health of humankind. Deferral of HPV vaccination because of questions regarding safety can no longer be defended as a reasonable option.
Opinions expressed in these commentaries are those of the author and not necessarily those of the American Academy of Pediatrics or its Committees.
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POTENTIAL CONFLICT OF INTEREST: The author has indicated he has no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The author has indicated he has no financial relationships relevant to this article to disclose.