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From Peyton Rous to the HPV : A Journey of Discovery and Progress H. Cody Meissner, MD

Peyton Rous began his famous are particularly remarkable experiments in 1909 at the Rockefeller accomplishments because neither Institute, demonstrating that a sarcoma B nor HPV can be on the chest of a Plymouth Rock hen cultured by conventional methods. that had been brought to him by a farmer from Long Island, New York, More than 120 types of HPV are fi could be transplanted to other recognized and classi ed by sequences chickens. Because cell-free tumor on an outer surface (L1) of the extracts resulted in transmission of the virus. Most HPVs infect cutaneous sarcoma to other hens, he postulated epithelial cells, whereas some HPVs the agent must be a small transmissible infect the mucosal basal epithelium. fi agent, possibly a virus.1 The concept HPVs that infect mucosa are classi ed that a virus might cause cancer was as nononcogenic (low risk) or fi outside the prevailing concepts of the oncogenic (high risk), de ned by their ability to cause precancerous lesions of Tufts Medical Center, School of Medicine, Tufts University, time, and his postulate languished Boston, Massachusetts for years. the cervix (cervical intraepithelial neoplasia), anogenital cells, or Opinions expressed in these commentaries are In 1964, Epstein et al2 described the oropharyngeal cells. with those of the author and not necessarily those of the first identified DNA tumor virus a high-risk type is a necessary American Academy of Pediatrics or its Committees. in cell lines obtained from African requirement for , but DOI: https://doi.org/10.1542/peds.2019-2345 children suffering from Burkitt infection is not sufficient by itself to Accepted for publication Aug 8, 2019 lymphoma, demonstrating the human cause cancer, on the basis of the Address correspondence to H. Cody Meissner, MD, oncogenic potential of this virus (later observation that most infected women Tufts University School of Medicine, 800 Washington named the Epstein-Barr virus). By resolve their HPV infection and do not St, Boston, MA 02111. E-mail: cmeissner@ 1981, virus had been linked develop cervical cancer. tuftsmedicalcenter.org to , and PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, a plasma-derived The HPV disease burden in the United 1098-4275). was licensed as the first anticancer States is large, with an estimated 79 Copyright © 2019 by the American Academy of vaccine.3 In 1983, papillomavirus DNA million persons infected and an Pediatrics was isolated from human cervical estimated 14 million new HPV FINANCIAL DISCLOSURE: The author has indicated cancer tissue, and today, human occurring annually. he has no financial relationships relevant to this article to disclose. papillomavirus (HPV) is recognized to Adolescents and young adults 15 cause essentially all cervical cancers.4 through 24 years of age acquire FUNDING: No external funding. The US Food and Drug Administration approximately half of these new POTENTIAL CONFLICT OF INTEREST: The author has licensed the first HPV vaccine in 2006. infections. Estimates by the Centers for indicated he has no potential conflicts of interest to Disease Control and Prevention disclose. Wherever vaccination campaigns indicate that ∼33 600 cancers are COMPANION PAPERS: Companions to this article can against these 2 vaccine-preventable caused by HPV each year in the United be found online at www.pediatrics.org/cgi/doi/10. tumor (hepatitis B, HPV) have States, with 20 200 cancers in women 1542/peds.2019-1791 and www.pediatrics.org/cgi/ been established, the rates of liver (mostly cervical) and 13 400 in men doi/10.1542/peds.2019-1808. cancer caused by hepatitis B and the (mostly oropharyngeal). Approximately precancerous cervical lesions of HPV 90% of these cancers could be To cite: Meissner HC. From Peyton Rous to the have been reduced dramatically. prevented by routine administration of HPV Vaccine: A Journey of Discovery and Progress. Pediatrics. 2019;144(6):e20192345 Development and availability of these 2 the 9-valent human papillomavirus

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 144, number 6, December 2019:e20192345 COMMENTARY vaccine (9vHPV) (Gardasil 9; Merck) or to accept the vaccine has kept HPV regarding safety can no longer be early in life.5 immunization rates far below those defended as a reasonable option. A common feature of tumor viruses is of other routinely recommended a latent phase when replication and vaccines. For each year that HPV ABBREVIATIONS release of infectious viral particles vaccination rates remain low, thousands of preventable HPV- from an infected cell are markedly HPV: human papillomavirus associated cancers will occur in reduced. A latent infection is thought 9vHPV: 9-valent human men and women. to allow the virus to hide from papillomavirus vaccine immune detection because A theoretical concern that has expression of viral would contributed to HPV vaccine hesitancy REFERENCES stimulate an immune response that relates to vaccine safety. Two articles would eliminate the virus. In the case in this issue of Pediatrics address HPV 1. Rous P. A transmissible avian . of HPV, viral DNA can persist in vaccine safety. In the report from the (Sarcoma of the common fowl.). J Exp a latent phase within the cell as naked Vaccine Adverse Events Reporting Med. 1910;12(5):696–705 nucleic acid, and protein expression is System, researchers analyze reports 2. Epstein MA, Achong BG, Barr YM. Virus limited to a small number of viral from a 3-year period during which particles in cultured lymphoblasts from proteins, some of which have 28 million 9vHPV doses were Burkitt’s lymphoma. Lancet. 1964; oncogenic potential. One theory as to distributed.6 In the second report 1(7335):702–703 why viral oncogenic proteins exist at from the Vaccine Safety Datalink, 3. Sherlock S, Fox RA, Niazi SP, Scheuer PJ. all is because HPV replication authors describe surveillance for Chronic and primary liver- requires the involved in prespecified adverse events after cell cancer with hepatitis-associated host cell replication. When a virus administration of .830 000 9vHPV () in serum. Lancet. – shifts from a latent phase to active doses.7 In both reports, the authors 1970;1(7659):1243 1247 replication, viral proteins are conclude that the postlicensure safety 4. Dürst M, Gissmann L, Ikenberg H, zur expressed to induce host cell profile of the 9vHPV is consistent Hausen H. A papillomavirus DNA from replication, but if cell replication with data from the prelicensure trials a cervical carcinoma and its prevalence becomes uncontrolled, a tumor and that no new safety concerns have in cancer biopsy samples from different geographic regions. Proc Natl results. This theory has been offered been identified. Acad Sci USA. 1983;80(12):3812–3815 as an explanation for the interval of The time has come for all vaccine 5. Centers for Disease Control and several decades between HPV administrators and parents to infection that commonly occurs in the Prevention. HPV statistics. Available at: understand that the availability of the https://www.cdc.gov/cancer/hpv/ late teenage years or early twenties 9vHPV is one end of a remarkable statistics/cases.htm and the development of cervical journey of discovery and progress to 6. Shimabukoro TT, Su JR, Marquez PL, cancer decades later. It also explains develop a safe and effective vaccine to why the HPV vaccine is only Mba-Jonas A, Arana JE, Cano MV. Safety prevent suffering and death from of the 9-valent human papillomavirus prophylactic and is not protective if a common cancer. The HPV vaccine vaccine. Pediatrics. 2019;144(6): infection occurs before vaccination. adds to the legacy of immunization as e20191791 For many generations, people have one of the most effective public health 7. Donahue JG, Kieke BA, Lewis EM, et al. wished for a vaccine that would offer interventions for disease prevention Near real-time surveillance to assess protection against cancer. Curiously, and improvement of the health of the safety of the 9-valent human such a vaccine is now readily humankind. Deferral of HPV papillomavirus vaccine. Pediatrics. available but reluctance to administer vaccination because of questions 2019;144(6):e20191808

Downloaded from www.aappublications.org/news by guest on September 29, 2021 2 MEISSNER From Peyton Rous to the HPV Vaccine: A Journey of Discovery and Progress H. Cody Meissner Pediatrics 2019;144; DOI: 10.1542/peds.2019-2345 originally published online November 18, 2019;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/144/6/e20192345 References This article cites 6 articles, 3 of which you can access for free at: http://pediatrics.aappublications.org/content/144/6/e20192345#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Disease http://www.aappublications.org/cgi/collection/infectious_diseases_su b Vaccine/Immunization http://www.aappublications.org/cgi/collection/vaccine:immunization _sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 29, 2021 From Peyton Rous to the HPV Vaccine: A Journey of Discovery and Progress H. Cody Meissner Pediatrics 2019;144; DOI: 10.1542/peds.2019-2345 originally published online November 18, 2019;

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/144/6/e20192345

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. Pediatrics is owned, published, and trademarked by the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2019 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

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