HPV vaccination: a success story but with more work still more to do
HPV vaccination: a success story but with more work still more to do
- There are currently three licensed HPV vaccines that are highly effective
- HPV vaccination programmes should be gender neutral and include older women in addition to younger cohorts
- Vaccination after treatment could address recurrence of cervical cancer but the mechanism is not yet fully understood
Dr Jorma Paavonen, Professor Emeritus, University of Helsinki, Finland, gave a short history of HPV vaccination and outlined key challenges at this year’s the European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 2019, Amsterdam, the Netherlands.
The link between HPV and cervical cancer was discovered in 1982 and the first vaccine was approved in 2006.
At present three prophylactic HPV vaccines are licensed: the tetravalent vaccine Gardasil®, based on virus-like particle (VLP) antigens for HPV types 6, 11, 16 and 18; the bivalent vaccine Cervarix®, based on VLP antigens for HPV types 16 and 18; and a non-valent vaccine Gardasil®9, based on VLP antigens for types 6, 11, 16, 18, 31, 33, 45, 52 and 58.
HPV is implicated in cancers of the cervix, anus, vagina, penis, vulva, oropharynx and oral cavity.
“The development of HPV vaccines has been a major success story,” Dr Paavonen said. “But although many European countries have implemented HPV vaccine programmes... coverage is still surprisingly low. That is a major problem.”
“It’s unacceptable that there are 60,000 cases of cervical cancer in Europe and 25,000 deaths,” he added. The age-standardised incidence rate for cervical cancer is 4.3 per 100,000 women in Finland versus 29 per 100,000 women in Romania.
Dr Paavonen said that the HPV screening and vaccination programme in Finland was a good model for demonstrating herd effect and near elimination of high-risk HPV. Rates of cervical cancer dropped by 80% in 1989 due to screening alone.
The Finnish vaccination programme started in November 2013. This nationwide school-based programme mainly targeted 11 to 12-year-old girls with two doses of bivalent vaccine; although the programme was conducted in schools, coverage rates vary a lot in different regions.
Despite Finland’s organised HPV screening and vaccination programme, cervical cancer incidence is now increasing in Finland and other European countries. Negative media attention related to the adverse effects of the vaccine are partly to blame, Dr Paavonen explained.
A Finnish public health campaign to combat these negative perceptions has gone some way to addressing the decline in HPV vaccination.
Should the HPV vaccine be gender neutral?
“It is not ethical, fair or socially responsible to have a public health policy that forces men to rely on herd immunity which will not be reach for decades,” said Dr Paavonen, quoting Dr Margaret Stanley.
A community randomised trial in Finland investigated what the best vaccination strategy for HPV should be. This study vaccinated 20,514 females and 11,661 males in secondary schools in 2007-2010. Participants were randomised to the gender-neutral HPV 16/18 vaccine (arm A), HPV vaccination of girls and HBV vaccination of boys (arm B), and gender-neutral HBV vaccine (arm C).
During 2010-2014, 11,396 samples were collected from 13,545 18.5-year-old attendees. Vaccine efficacy and protective efficacy (PE) were calculated. (PE was calculated as coverage rate-weighted mean of vaccine efficacy + herd effect.)
HPV16/18/45 and 31/33/35 vaccine efficacy varied between 86-94% and 30-66%, respectively. Only the gender-neutral vaccination provided significant herd effect against HPV18 (61%) and HPV31 (72%) in the 1995 birth cohort. Increased herd effect against HPV33 (39%) and HPV35 (42%) were also observed.
High vaccine efficacy against HPV16/18/45 and, gender-neutral vaccination-enforced, herd effect against HPV18/31/33/35 by the bivalent vaccine rapidly provides comparable overall protective effectiveness against six oncogenic HPV types: 16/18/31/33/35/45.
These data strongly supported a gender-neutral vaccination strategy when vaccination coverage is low or moderate. The authors calculated that, due to the significant herd effect of the gender-neutral vaccination strategy, high-risk HPVs could be eliminated in 25 years.
Gender-neutral broad-spectrum HPV vaccination programmes have now been adopted by 16 countries in Europe.
Should older women be vaccinated?
Although HPV risk is greatest in younger women, those older than 25 remain at risk. The phase III, double-blind, randomised, controlled VIVIANE study enrolled 4,407 participants. The study concluded that in women older than 25 years, the HPV 16/18 vaccine continues to protect against infections, cytological abnormalities, and lesions associated with HPV 16/18 and CIN1+ irrespective of HPV type, and infection with non-vaccine types HPV 31 and HPV 45 over 7 years of follow-up.
One way to approach HPV vaccination in older women is the HPV-FASTER strategy. This was developed to address the disconnect between HPV screening and vaccination by combining both strategies. It proposes to offer to screen women after or at vaccination in women aged 30 and above. High-risk HPV-positive women are likely to have persistent infection and need careful follow-up.
Could treatment then vaccination be an effective strategy to combat cancer recurrence?
The recurrence rate for women diagnosed with cervical pre-cancer is high: over 10 years, almost one in five treated diseases recur. The SPERANZA trial investigated the efficacy of vaccination directly after loop electrosurgical excision procedure (LEEP) for CIN2+ (cervical intraepithelial neoplasia grade 2 or greater).
In this study, Ghelardi et al (2018) enrolled 536 participants; 248 had HPV vaccination and follow-up and 276 received follow-up only. In each group, 174 and 176 patients were suitable for statistical analysis, respectively. In the vaccinated group, only two patients had a clinical disease relapse versus 11 in the follow-up only group, which translated as a vaccine efficacy of 81.2% (95% CI 34.3-95.7%).
“The vaccine efficacy was strikingly high; it was almost difficult to believe if this was true or not,” Dr Paavonen told the audience. “How can this work? The vaccine is prophylactic, not therapeutic.”
“There are several explanations. One is that perhaps it boosts the immune response against the residual disease. Or perhaps it has a booster effect against auto-inoculation from another genital site; it may prevent a new infection; or perhaps it prevents reactivation of latent infection.”
The field of HPV vaccine research continues to evolve, despite the availability of three effective vaccines.
Based on Paavonen J. HPV vaccines: lights and shadows (symposium S0483). Presented on Saturday 13 April 2019.
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