Introduction
Human papillomavirus (HPV) is one of the most common sexually transmitted infections worldwide. Most sexually active individuals are infected at least once in their lifetime (1,2). HPV is responsible for approximately 4–5% of all cancers globally and for >95% of cervical cancer cases (2–4). In 2019, HPV caused an estimated ~620,000 cancer cases in women and ~70,000 in men (5). Over 200 HPV types have been identified, of which about 12–14 are classified as high-risk. HPV-16 and HPV-18 together cause about 70% of cervical cancer cases (4,6,7). Prevalence peaks in the late teens and twenties and declines with age (1). Common clinical outcomes include anogenital warts, precancerous lesions, and cancer.
This literature review summarizes the history, pathogenesis, and prevention of HPV with a focus on the development and impact of HPV vaccination.
History and Origin of HPV
HPV-related genital and cutaneous warts have been recognized since ancient times. Hippocrates described genital warts as early as 400 BC, and papillomavirus-like lesions have been depicted in historical art and myths (8). In the 19th century, physicians observed a higher incidence of cervical cancer among sexually active women, but the viral etiology was not understood (5).
In the 1970s, Harald zur Hausen hypothesized that HPV caused cervical cancer. In the 1980s, his group identified HPV-16 and HPV-18, confirming this link (3,5–7,9). Papillomaviruses infect a wide range of vertebrates. Molecular evidence suggests PV lineages originated ~424 million years ago, long before humans, with subsequent host-virus co-evolution leading to human-specific HPV types (10).
Etiopathogenesis
HPV spreads through direct skin-to-skin or mucosal contact, including sexual contact, and can also be transmitted perinatally. It can remain infectious for at least several days on contaminated surfaces and is notably resistant to some disinfectants. Ethyl and isopropyl alcohol are not fully effective against native virions. Inactivation is achieved with hypochlorite, hydrogen peroxide systems, peracetic acid, and UV-C irradiation (5).
HPV infects basal epithelial cells via microabrasions. The L1 protein binds to laminin-332 in the basement membrane and undergoes conformational change, interacting with heparan sulfate proteoglycans and cyclophilin B, exposing the L2 protein. After L2 cleavage by furin, the virus binds annexin A2 and enters the cell. Viral DNA then traffics via the Golgi to the nucleus. E1 and E2 genes initiate replication; E5, E6, and E7 proteins promote proliferation, inhibit apoptosis, and suppress immunity. Persistent infection can lead to viral DNA integration into host DNA—a hallmark of HPV-associated cancers. Most infections clear naturally without causing disease (5).
Treatments for Anogenital Warts
Early interventions targeted wart lesions rather than the virus. Treatments reduce visible lesions but do not eradicate HPV, so recurrence is common (11).
- Topical agents: Podophyllin resin and podophyllotoxin are cytodestructive. Podophyllotoxin 0.5% clears about 70% of warts (12). Salicylic acid, trichloroacetic acid, and dichloroacetic acid can also be used. Trichloroacetic acid is typically provider-applied and achieves clearance rates of up to 83%. Imiquimod cream is another commonly used immune response modifier.
- Cytostatics: Bleomycin (33–92% clearance) and 5-fluorouracil (39–77% clearance, with high recurrence rates).
- Surgical therapies: Cryotherapy, CO₂ laser ablation, photodynamic therapy, and surgical excision are effective for selected cases.
Treatments for Cervical Cancer
The choice of treatment depends on the cancer stage (11):
- Surgery (e.g., radical hysterectomy) is used for early-stage disease.
- Concurrent chemoradiation (cisplatin-based) is the standard for locally advanced disease.
- Radiation therapy (external or brachytherapy) and systemic chemotherapy may be used alone or in combination in advanced stages.
Vaccine Development, Promotion, and Policies
In the late 1980s, Ian Frazer and Jian Zhou developed virus-like particles (VLPs) by expressing the L1 protein, laying the foundation for HPV vaccines.
- Gardasil (quadrivalent: HPV 6/11/16/18) was first licensed in 2006.
- Cervarix (bivalent: HPV 16/18) followed in 2009.
- Gardasil 9 (nonavalent: HPV 6/11/16/18/31/33/45/52/58) was approved in 2014.
These vaccines show >90% efficacy against vaccine-type infections and high-grade lesions (5).
Canadian Experience
School-based HPV immunization for girls began between 2007–2009 and expanded to boys between 2013–2017.
- A Institut national de santé publique du Québec study reported vaccine-type (6/11/16/18) HPV prevalence of 1.5% in vaccinated vs 11.0% in unvaccinated individuals (13).
- In Alberta, vaccinated women had significantly reduced risk of cervical abnormalities—28% lower for abnormal cytology, 26% for low-grade, and 52% for high-grade lesions (14).
New Vaccines
- Cecolin (bivalent 16/18) – WHO prequalified in 2021 (China).
- Walvax 9-valent HPV vaccine – approved in China in 2024.
- Cervavac – licensed in India in 2022.
Therapeutic vaccines and RNA vaccines remain under clinical and preclinical investigation (5).
Conclusion
Before HPV vaccination, cervical cancer caused significant global mortality. While treatments addressed disease manifestations, vaccination provided the first primary prevention tool against HPV-associated cancers. Alongside Hepatitis B vaccine, the HPV vaccine is among the first vaccines proven to prevent cancer.
If countries achieve World Health Organization’s 90-70-90 targets—90% vaccination coverage, 70% screening, 90% treatment of precancer—cervical cancer could be eliminated as a public-health problem within this century. Continued global vaccination and improved therapeutic options will be crucial to achieving this goal.
References
6. Illah O, Olaitan A. Updates on HPV Vaccination. Diagnostics. 2023 Jan 9;13(2):243.
9. Frazer IH. The HPV Vaccine Story. ACS Pharmacol Transl Sci. 2019 Jun 14;2(3):210–2.
10. Willemsen A, Bravo IG. Origin and evolution of papillomavirus (onco)genes and genomes.