LJUBLJANA, SLOVENIA – There is good news and bad news about human papillomavirus (HPV) vaccination as a means of preventing cervical cancer.
The bad news is the HPV vaccines are projected to be in short supply, unable to meet global demand until at least 2024. The good news is that – in one study, for 11 years and counting – which would effectively double the existing supply, Aimee R. Kreimer, PhD, said at the annual meeting of the European Society for Paediatric Infectious Diseases.
These data come from post hoc analyses of major phase 3 randomized controlled trials of bivalent HPV vaccine in Costa Rica and quadrivalent vaccine in India. However, these secondary analyses aren’t considered rock solid evidence because the subjects who got a single dose weren’t randomized to that strategy, they simply for one reason or another didn’t receive the recommended additional dose or doses.
“I don’t know if these studies are enough, so several studies have been launched over the past couple of years with an eye toward generating the quality of data that would be sufficient to motivate policy change, if in fact one dose is proven to be effective,” said Dr. Kreimer, a senior scientist at the National Cancer Institute in Bethesda, Md.
The first of these formal randomized, controlled trials – a delayed second-dose study in 9- to 11-year-old U.S. boys and girls – is due to be completed next year. Four other trials ongoing in Africa and Costa Rica, all in females, are expected to report findings in 2022-2025.
Dr. Kreimer is first author of a soon-to-be-published 11-year update from the phase 3 Costa Rica HPV Vaccine Trial, which was launched prior to licensure of the GlaxoSmithKline bivalent HPV vaccine. Previous analyses showed that at both 4 and 7 years of follow-up, a single dose of the vaccine was as effective as two or three in preventing infection with HPV types 16 and 18, which are covered by the vaccine.
“Now the research question has transitioned to, ‘Will one dose be sufficiently durable?’ she explained.
The answer from this study is yes. At 11 years since receipt of the bivalent HPV vaccine, there was no difference in terms of prevalent HPV 16/18 infection between the one-, two-, and three-dose groups. To address the issue of possible selection bias in this post hoc nonrandomized comparison, Dr. Kreimer and her coinvestigators looked at rates of infection with HPV 31 and 45, which aren’t covered by the vaccine. The rates were similar regardless of the number of vaccine doses received 11 years earlier, indicating women in all three dosing groups are at similar risk for acquiring HPV infection, thus bolstering the legitimacy of the conclusion that one dose provides effective long-term protection.
Intriguingly, HPV serum antibody levels in the single-dose group have remained stable for 11 years at a level that’s only about one-quarter of that associated with three doses of the vaccine, albeit an order of magnitude greater than the level induced by natural immunity.
“This really challenges the dogma of the HPV vaccine,” according to Dr. Kreimer. “It suggests that inferior [HPV] antibodies do not necessarily mean inferior protection.”
The explanation for this phenomenon appears to be that HPV subunit vaccine mimics the shell of authentic virions so well that the immune system sees it as dangerous and mounts long-term antibody production. Also, cervical infection by HPV is a relatively slow process, allowing time for vaccine-induced antibodies to interrupt it, she said.
In contrast to the encouraging findings from this post hoc analysis and another from a phase 3 trial of quadrivalent vaccine in India, numerous phase 4 vaccine effectiveness monitoring studies have shown markedly lower vaccine effectiveness for one dose of HPV vaccine. Dr. Kreimer cautioned that this is a flawed conclusion attributable to a methodologic artifact whereby the investigators have lumped together single-dose recipients who were 17 years old or more at the time with those who were younger.
“The problem is that many people who are aged 17-18 years already have HPV infection, so when they are vaccinated it shows up as a vaccine failure. That’s not correct. These are prophylactic HPV vaccines. They’re not meant to help clear an infection,” she noted.
Stepping back, Dr. Kreimer observed that cervical cancer “is really a story of inequality.” Indeed, 90% of cervical cancers occur in low-income countries, where HPV vaccination uptake remains very low even more than a decade after licensure. When modelers project out in the future, they estimate that at current HPV vaccination levels in Sub-Saharan Africa, which has the highest cervical cancer rates in the world, it would take more than 100 years to achieve the World Health Organization goal of eliminating the malignancy.
Asked by an audience member how low a single-dose vaccine effectiveness level she considers acceptable to help reach the goal of eliminating cervical cancer in developing countries, Dr. Kreimer cautioned against the tendency to let ‘perfect’ become the enemy of ‘good.’
“I’ll remind everyone that, in this moment, very few of the target girls in the lower– and upper-lower–income countries are getting any vaccination. So I don’t think it’s a question of whether we should be going from two to one dose, I think it’s really a question of, for those who are at zero doses, how do we get them one dose? And with the HPV vaccine, we’ve even seen suggestions of herd immunity if we have 50% uptake,” she replied.
Dr. Kreimer reported having no financial conflicts regarding her presentation.