Effectiveness of HPV Vaccination Heralded Despite Criticism of Studies

Becky McCall

January 23, 2020

A flurry of comments about the HPV vaccine have emerged this week, which is Cervical Cancer Prevention Week. Obviously timed to coincide with it, the Journal of the Royal Society of Medicine published a critical appraisal of published phase 2 and 3 efficacy trials which questioned measurement of efficacy and vaccine success claims for cervical cancer prevention in women. But experts have been critical of the paper, and have warned that it could be misintepreted. 
 
Also this week Public Health England (PHE) reported that HPV16 and 18 infection rates are below 2% in 16 to 18-year-old women (data drawn from 2014-2018), and the prevalence of HPV6 and 11, which cause 90% of genital warts – has halved. Even so, cervical cancer remains the most common cancer in women under 35, killing about 850 women a year in the UK. 

Methodological Problems 

The study highlighting trial uncertainties was led by Claire Rees, MSc, of Queen Mary University, London. It was published in the 22nd January edition of the Journal of the Royal Society of Medicine.

"This review has revealed many methodological problems with the phase 2 and 3 efficacy trials of HPV vaccination leading to uncertainty regarding understanding its efficacy," writes Rees with her co-authors from Newcastle University.

"Trials may have overestimated efficacy by combining high-grade cervical disease with low-grade cervical changes that occur more frequently but often resolve spontaneously without progressing," said Rees in a press release accompanying the publication. "We found insufficient data to clearly conclude that HPV vaccine prevents the higher-grade abnormal cell changes that can eventually develop into cervical cancer."

Experts have been reacting to the findings through the Science Media Centre.

Margaret Stanley, emeritus professor of epithelial biology, University of Cambridge, took issue with the critical appraisal. She highlighted that the analysis of clinical trials from many years ago had been superseded by real-world evidence of HPV vaccination effectiveness.

Findings from other countries concurred with those from England, she said, for example Australia, Demark, Sweden, and Scotland, where more than 70% vaccination coverage had been achieved, together with the implementation of good screening programs.

"These countries have reported big falls in cervical pre-cancers in the vaccinated groups. Scotland is probably the best example from the UK, and last year [a study found] that girls vaccinated in Scotland aged 13-14 in 2008/9, who subsequently underwent cervical smear testing aged 20, showed an 86% reduction in CIN3 [cervical intraepithelial neoplasia grade 3] - severely abnormal cells found on the surface of the cervix, compared to those who were unvaccinated," she explained. 

"Such a dramatic reduction is hard to attribute to statistical chatter," asserted Stanley.

However, Jonathan Ball, professor of molecular virology, University of Nottingham, highlighted that the study raises some important points. "HPV vaccination isn't the absolute panacea for cervical cancer prevention, for example in cases where HPV infection isn't the cause. We still need to understand more fully the long-term benefits and efficacy of HPV vaccination and ensure that adequate cancer screening is available to all."

Sophia Lowes, Cancer Research UK's health information manager, said via email: "We're aware of these limitations of the trials on the HPV vaccination, but all the evidence we have so far suggests the vaccine is safe and effective. Results from clinical trials are encouraging and show the vaccine protects against the virus and abnormal cell changes in the cervix… we expect to see a significant drop in cases of cervical cancer over the coming years."

Methodological Flaws in HPV Efficacy Trials

The study led by Claire Rees assessed 12 published phase 2 and 3 randomised controlled efficacy trials of HPV vaccines - brands named Cervarix and Gardasil. The review lists multiple methodological flaws.

In their paper, the study authors note that 'it is still uncertain whether human papillomavirus (HPV) vaccination prevents cervical cancer as trials were not designed to detect this outcome, which takes decades to develop'. Instead, the trials, show evidence that vaccination prevents CIN1; however, 'this is not a clinically important outcome (no treatment is given),' they write.

They add that the use of composite and distant surrogate outcomes, including CIN1 makes it impossible to determine effects on clinically significant outcomes. 'High efficacy against CIN1+ does not necessarily mean high efficacy against CIN3+, which occurs much less frequently. There are too few data to clearly conclude that HPV vaccine prevents CIN3+,' they write. 

Nor did the trial populations reflect vaccination target groups due to differences in age and restrictive trial inclusion criteria, they add.

CIN in general is likely to have been over-diagnosed in the trials because cervical cytology was conducted at intervals of 6-12 months rather than at the normal screening interval of 36 months. 'This means that the trials may have overestimated the efficacy of the vaccine as some of the lesions would have regressed spontaneously.'

Rees and colleagues also found fault with conclusions drawn from trials that diagnosed persistent infection on the basis of frequent testing (less than 6 months). 'There is uncertainty as to whether detected infections would clear or persist and lead to cervical changes.'

Reflecting on the Rees study to Medscape UK via email, Maurie Markman, chief clinical officer, Cancer Treatment Centers of America, Philadelphia, US, cautioned that unfortunately the paper may be misinterpreted. He noted that there has been a documented, unequivocal reduction in the prevalence of HPV 16 and HPV 18 infections following vaccination and that these HPV types are known to be responsible for approximately 70% of cervical cancer worldwide.  "Since it is well-recognised that it will likely take at least a decade, and perhaps much longer, after persistent infection occurs for cervical cancer to develop it may be many years before an actual reduction in the incidence of invasive cervical cancer is demonstrated."

But he asserted that based on all existing data, "there is simply no reason to believe that this will not be the very positive end result of a rigorous HPV vaccination strategy".    

Public Health England Data Show Record Low Levels of HPV Infection

The data released by PHE this week paints a more positive picture. Cancer-causing HPV16 and 18 infections are now extremely uncommon in young sexually active women in England, following the introduction of HPV vaccination for year 9 girls in 2008, says PHE in a press release.

In a sample of more than 600 young women tested in 2018, no HPV16 or 18 infections were detected, representing a dramatic reduction from a decade earlier, when over 15% of young sexually active women were found to have these infections.

PHE claim that these reductions are a result of high HPV vaccine uptake. Eleven million doses have been given to young women in England, with 83.9% coverage in year 9 girls, they say.

Seeing this as evidence of the success of the immunisation programme, Dr Vanessa Saliba, consultant epidemiologist, PHE, remarked in a news release: "With millions of young women protected by HPV vaccination, we expect to see big reductions in cervical cancer in years to come and the introduction of the boys' programme will accelerate this progress."

More Sensitive Cancer Screening Test: NHS England

Both vaccination and screening play key roles in reducing the burden of cervical cancer, and aimed at further improving the incidence of cervical cancer, NHS England this week announced use of a more sensitive cervical screening test, rolled out as part of the NHS Long Term Plan.

The new and more sensitive test now looks for traces of high-risk HPV, which causes nearly all cases of cervical cancer. According to a press release from NHS England, the new test means that any sign of infection will be spotted at an earlier stage before it could potentially develop into cancer. With 2500 new cases of cervical cancer in England every year, research says that a quarter of these cases could be prevented with use of the new test.

Professor Peter Johnson is national clinical director for cancer at NHS England. He pointed out that "… there is no doubt this new way of testing will save lives. Combined with the success of the HPV vaccine for both boys and girls, we hope that cervical cancer can be eliminated altogether by the NHS in England." Johnson added that cervical cancer often causes no symptoms during the early stages of the disease, which is why it is "especially important that people attend their tests and that those who are eligible get vaccinated against HPV".

Tackling Cervical Cancer: Vaccination and Screening

Adding to the plethora of HPV/cervical cancer related findings this week, Cancer Research UK published figures showing that despite cervical cancer rates in Britain halving between the late 1980s and mid-2000s progress has since been 'stalling and stagnating'.

Thousands of cervical cancers have been prevented since the national screening programme was introduced in 1988 but the latest data show a steep (54%) rise in rates among 25- to 29-year-olds, suggesting these potentially life-saving interventions do not always reach the people who need them.

Latest figures show less than three-quarters of women invited for cervical screening take it up, and this falls even further in younger age groups and more deprived regions. Cancer Research UK is working to unpick why people do not attend cervical screening and identifying the barriers.

Published in the 22nd January edition of the Journal of the Royal Society of Medicine.

COI: Professor Stanley  is a consultant for both GSK and Merck Sharp & Dohme Limited.

Dr Ball and Dr Markman have declared no conflicts of interest.

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