Most HPV vaccine clinical trials do not collect direct data about clinical outcomes, like cancer or precancer, for young adolescents, because it is unethical to collect samples from the cervix of vaccinated girls who are sexually naïve and because precancerous lesions do not appear for years after the HPV infection has occurred. Also, since treatment is offered as precancers develop, progression to cervical cancer is rare even in those not vaccinated and requires a very long time for follow-up. Therefore, immunological bridging is used to infer efficacy against cervical and anal cancer. Efficacy is also inferred for the younger age group because immunogenicity (antibody responses) is non-inferior to that seen in older age groups.
Immunogenicity
Although there is no known correlate of protection (ie, an established antibody level required for protection against HPV-related disease), HPV vaccines generate excellent antibody responses in most recipients.
HPV4
Immunisation with three doses of HPV4 vaccine produces antibody responses against HPV16, HPV18, HPV6 and HPV11 in more than 99percent of vaccine recipients. The peak antibody titres following three doses of HPV vaccine are greater than that following natural infection.
A Cochrane systematic review found the immunogenicity of two- and three-dose HPV vaccination schedules in young females to be comparable.[45] Two doses of HPV4 are more immunogenic in recipients aged between 9 and under 15 years than in older groups aged over 15 years and comparable to three doses in older recipients (those over 15 years).[46] In young females, two doses have been found to be non-inferior to three doses for at least 21 months after vaccination, particularly when the interval between doses is at least six months.[47,48] The immunogenicity of three doses of HPV4 vaccine has been established to be robust and long-lasting.[49,50,51] Anamnestic responses have been demonstrated out to at least 8.5 years.[51]
Differences in seroconversion rates and antibody titres were seen in immunocompromised individuals. The immune response to HPV4 among immunocompromised children appears adequate,[52,53] although antibody titres were lower than those in healthy children of the same age groups.[52] Seroconversion among HIV-infected individuals has been demonstrated to be robust and higher among those with lower HIV loads or on antiretroviral therapy.[54,55,56]
While some immunosuppression regimes can attenuate the immune response to HPV4, patients with autoimmune diseases generally appear to respond well to the vaccine.[57] In contrast, adult solid organ transplant recipients produce suboptimal responses to HPV4.[58]
HPV9
The immunogenicity of HPV9 vaccine was initially assessed in women aged 16–26 years.[59] Antibody responses generated by the HPV9 were non-inferior to HPV4 against HPV types 6, 11, 16 and 18; and in girls and boys aged 9–15 years.[60] Antibody responses to all nine vaccine HPV types in girls and boys aged 9–15 years and men aged 16–26 years were non-inferior to women aged 16–26 years.[61,62]
Men who have sex with men appear to produce lower antibody titres than heterosexual men (although seroconversion rates to all nine vaccine types were greater than 99percent in both groups).[61] This lower antibody response is possibly due to greater exposure to the virus, highlighting the importance of vaccination at a young age.
The immunogenicity of two doses of HPV9 in girls and boys aged 9–14 years was non-inferior to three doses in women aged 16–26 years, the age group in which efficacy was demonstrated.[63]
Efficacy
HPV-related cancers
HPV4 and HPV9 vaccines offer similar protection against cervical, vagin*l and vulval precancerous lesions or cancer in women vaccinated at 15–26 years.[45] Protection is greatest among young women not initially infected with HPV 16/18 prior to vaccination (vaccine efficacy of 95percent [95% CI: 83–99] against vagin*l and vulval lesions).[64]
HPV9 efficacy was studied in women aged 16–26 years and compared with HPV4.[59] HPV9 prevented cervical, vulvar and vagin*l disease and persistent infection related to HPV types 31, 33, 45, 52 and 58 (the five additional serotypes in HPV9). The antibody response and incidence of disease related to HPV types 6, 11, 16 and 18 were similar in the two vaccine groups.
Protection against CIN 2/3 or adenocarcinoma in situ is widely accepted as a surrogate for protection against invasive cancer, since study participants who develop these precancerous lesions require treatment to prevent progression to invasive cancer. Bivalent and quadrivalent HPV vaccines have been shown to be highly effective in preventing these HPV16- and HPV18-related precancerous lesions in females.[1,65] In the pivotal efficacy trial in women aged 15–26 years, HPV4 vaccine efficacy for the prevention of precancerous lesions related to HPV16 or HPV18 was 98percent (95% CI: 86–100) in the per-protocol susceptible population.[66]
A phase III clinical trial among Asian and Latin American women found population-specific vaccine efficacy to be more than 96percent against any grade of cervical, vulvar and vagin*l disease and more than 93percent efficacy against six-month persistent HPV infection.[67]
Studies in males, including men who have sex with men, have shown that HPV4 vaccine is efficacious against anal HPV infection and associated precancerous lesions.[9,68,69] HPV4 protects men vaccinated between ages 16–26 years against genital warts or external genital lesions compared with unvaccinated dummy controls.[45]
Effectiveness
A 2016 systematic review of published literature summarised the global experiences with HPV4 from 1 January 2007 to 29 February 2016.[70] It assessed the global effect of HPV4 vaccine on HPV infection, genital warts and cervical abnormalities based on 57publications across nine countries. The greatest impact was seen in countries with high vaccine uptake and among girls vaccinated prior to HPV exposure. Maximal reductions of around 90percent were reported for vaccine-type HPV infections (6, 11, 16, 18) and genital wart cases.
For women vaccinated before the age of 20 years, the risk of CIN2+ was significantly lower than in unvaccinated women (effectiveness of at least one dose is 58–77 percent).[71,72,73]
Duration of protection
As vaccination programmes have only been in place for little over a decade, the duration of protection is not yet fully known. Follow-up studies 8–10 years after HPV vaccination have shown no waning of protection.[1] Long-term studies are ongoing to determine the duration of efficacy for all HPV vaccines.
Herd immunity and population impact
In January 2019, WHO began considering a global strategy to eliminate cervical cancer and established clear targets to 2030. This is only achievable with high vaccination coverage and access to regular screening for all women.[74,75]
Australia saw a reduction in the prevalence of vaccine-type HPV infections (6, 11, 16, 18) in unvaccinated young men after the introduction of the vaccine to young women, supporting the role of herd immunity.[76,77,78] There was also a significant decrease in the prevalence of vaccine-type HPV infections in unvaccinated women (aged 25 years or younger).[79] Vaccination of females has provided herd immunity against oropharyngeal HPV16 prevalence in unvaccinated males in the UK.[80]
In a study of sexual health clinic data in Melbourne, the researchers noted the near disappearance of genital warts in women and heterosexual men aged under 21 years.[78] In addition, the data indicated that the basic reproductive rate (seesection1.2.1) had fallen below one. This reduction in cases occurred without any corresponding reduction in women aged over 30 years, men who have sex with men and non-residents. Similar trends were noted in the data from the Australian genital warts national surveillance network.
Eleven years after the introduction of HPV4 vaccine in the US, HPV4 types declined by 81percent in vaccinated women and 40percent in unvaccinated women. As well as direct protection from HPV9 vaccine, potential cross-protection from HPV4 was also observed in vaccinated women with a 71percent decline in prevalence of the additional, genetically related HPV9 types.[4]
Previous exposure to HPV
While efficacy is unclear, there are no safety concerns in offering vaccination to women who have had HPV-related disease and would like to use the vaccine to reduce the risk of further disease.
A retrospective analysis of the HPV4 vaccine’s pivotal efficacy trial data (Future I and Future II) studied a group of women who were vaccinated before they had their first treatment for HPV-related disease.[81] This showed a reduction in subsequent HPV‑related disease in vaccinated women aged 15–26 years who had received treatment for cervical, vulvar or vagin*l disease during the trial. The study showed a 46.2percent reduction (95% CI: 22.5–63.2) after cervical surgery of any HPV-related disease and 35.2percent reduction (95% CI: 18.8–51.8) after diagnosis of genital warts or vagin*l or vulvar disease.
In contrast, a systematic review found that there was no evidence that HPV vaccines were effective in preventing vaccine-type HPV-associated precancer in pre-exposed women. This review explored efficacy against CIN3+ precancers in women with evidence of prior vaccine-type HPV exposure in three randomised controlled trials and two post-trial cohort studies.[82] Despite these findings, it was concluded that longer-term benefits in preventing re-infection could not be excluded (ie, the vaccine is not therapeutic but may prevent future infection, emphasising the importance of vaccination prior to sexual debut).
