News & Views — HPV: Notes from IPVC2023

In mid-April, we had the opportunity to meet with colleagues and partners in Washington, D.C., at the 35th International Papillomavirus Conference & Basic, Clinical and Public Health Scientific Workshops (IPVC 2023). This conference is unique in that the sole focus is papillomaviruses, and attendees range from bench scientists to public health officials to frontline caregivers. The beauty of this model is that even though the conference has tracks for basic science, clinical science and public health, attendees don’t need to “stay in their own lane.” They can move back and forth between lectures, catching up on the latest animal models and then learning about cervical cancer screening barriers in low- and middle-income countries all in the same day.

The Vaccine Education Center (VEC) team was there as part of the “One Less Worry” campaign’s partner pavilion. The “One Less Worry” campaign is a program of the International Papillomavirus Society that seeks to educate about and improve global understanding of human papillomavirus (HPV) risks and prevention.

Here are some takeaways from the conference that we thought might be of interest to our readers.

HPV biology

Often the questions that we receive in the VEC stem from confusion and a lack of understanding of HPV infections. Some of the points made during this conference served as a reminder about the complexities of HPV infection, making the confusion among laypersons understandable.

Possible outcomes of infection

When a person is infected with HPV, one of two things can happen:

1. The virus is managed by our immune system — This means HPV is no longer in the body; however, this can take months to happen, during which time the virus is replicating and our immune system is trying to overcome it. In this scenario, a person will test negative for HPV because the virus is no longer present.
2. The virus persists — If our immune system doesn’t completely manage the infection, two scenarios can occur:
   1. The virus continues to replicate, and it is not controlled by the immune system — This can go on for years, leading to cellular changes and potentially cancer. In this scenario, a person will test positive for the virus.
   2. The virus continues to replicate, but it is controlled by the immune system — In this scenario, the immune system never quite gets the upper hand, so the virus doesn’t clear from the body, but as long as the immune system continues battling the infection, the virus stays in check. Cellular changes will not occur if this is the case, and the person will test negative for HPV during this period. If the immune system comes to a point where it no longer keeps the virus in check, the person will test positive for HPV, and if the immune system does not regain control, eventually cellular changes and cancer could occur.

Persistence versus clearance

Persistence is described as having HPV-positive tests in two or more consecutive samples. However, because, as described above, HPV can continue to replicate but not be detectable, clearance is more difficult to define. As such, from a clinical standpoint, clearance means the individual has tested negative for HPV. It does not mean, however, that the virus is no longer infecting the person.

Intermittent detection

Because clearance means the virus has not been detected in samples, but it can still be causing infection, it is not surprising that the virus could be detected intermittently. When studies have evaluated several samples from the same individual over time, they have confirmed this to be the case. Likewise, when a series of samples have been taken from the same individual, studies have confirmed that often people are infected with multiple types of HPV at the same time.

This paper by Brown and colleagues from 2005 demonstrates these points.

Most common types vary around the globe

HPV16 is most commonly isolated from HPV-caused cancerous tumors, regardless of the location of the cancer (cervix, vulva, vagina, anus, penis, oropharynx, oral cavity or larynx).

However, while HPV16 is the most common cause of cervical cancer around the globe, the other predominant types of HPV vary somewhat by geographic region. Globally, HPV18 is the second most common type of HPV isolated from invasive cervical cancers, but it is not always the second most common type isolated from cytologically normal samples. Except for HPV35, which accounts for 2% to 5% of cervical cancers in Africa, the other common types are contained in the nonavalent HPV vaccine, Gardasil^®9. In addition to types 16 and 18, other common types found in cervical cancer samples, and Gardasil-9, include 45, 31, 33, 52 and 58. The other two types of HPV covered by the vaccine, types 6 and 11, do not cause cancer. These so-called “low risk” types are the most common causes of genital warts.

Median clearance times vary

Low-risk types of HPV tend to clear more quickly than high-risk types; however, the median period of positivity is several months, even for those that resolve more quickly. In a 2013 study by Jaisamrarn and colleagues, HPV16 and HPV31 were the least likely to clear. Median months to clearance ranged from about eight months for non-cancerous types to about 17 months for HPV16. A meta-analysis by Rositch and colleagues, also published in 2013, similarly found that about half of HPV infections last six to 12 months.

Transmission versus reactivation

Sometimes a positive HPV test leads to questions about when the infection was acquired. Studies have shown that both new partners and total number of lifetime partners are associated with HPV positive tests. However, as Rositch and colleagues showed in a 2012 evaluation of 35- to 60-year-old women, only 13% to 27% of samples with detectable HPV DNA could be attributed to a new partner, suggesting that infections often linger for years. In the same study, 72% of the individuals with DNA-positive samples reported having five or more lifetime partners.

Two exciting considerations related to HPV

The IPVC2023 conference had an excitement in the air. Part of this was because the group had not met in person for five years, but part of it was because of scientific progress. Two of the most exciting advances related to the effectiveness of a single dose of HPV vaccine and global planning for elimination of cervical cancer.

Just one dose of HPV vaccine is sufficient for protection in some people

In 2022, the World Health Organization (WHO) indicated that HPV vaccine could be used off-label as a single dose vaccine in those 9 to 20 years of age. The first country to make the transition was Cap Verde in Africa. In the same year, the Joint Committee on Vaccination and Immunisation (JCVI) in the United Kingdom (UK) also indicated that those younger than 25 years of age in the UK could get a single dose, and in early 2023, Australia moved to a single-dose schedule. Several other countries are currently using a one-dose schedule or planning to transition to one, including several Gavi-funded country programs.

Scientific studies evaluating the potential to protect against HPV with only a single dose have been promising, and data continue to be generated:

• Long-term follow-up of clinical trial participants from a Cervarix^® trial in Costa Rica showed similar vaccine efficacy and stable serum antibody titers more than 10 years later (Kreimer and colleagues, 2018), and unpublished data presented at the conference demonstrated similar responses as long as 16 years later.
• A study by Watson-Jones and colleagues comparing bivalent and nonavalent HPV vaccines in Tanzania showed similar antibody titers after one, two or three doses of either vaccine.
• A recent study in Kenya by Barnabas and colleagues, comparing bivalent and nonavalent single-dose HPV vaccination, demonstrated 97.5% vaccine efficacy for both vaccines against HPV types 16 and 18, and the nonavalent vaccine demonstrated 88.9% vaccine efficacy when looking at the nine types included in the vaccine compared with the control group.

Elimination of cervical cancer is possible

In 2018, the Director-General of the WHO, Dr. Tedros Adhanom Ghebreyesus, stated “One woman dies of cervical cancer every two minutes … Each one is a tragedy, and we can prevent it.” With that in mind, the WHO set 2030 targets toward cervical cancer elimination. They include aiming to have:

• 90% of girls fully vaccinated against HPV by 15 years of age
• 70% of women screened by 35 years of age and again by 45 years of age
• 90% of women identified with cervical disease receiving treatment

While the thought of cervical cancer elimination garnered excitement, several speakers made the point that it will take many years to reach this goal and current efforts are lagging, particularly in resource-poor countries.

Disparities continue to exist — even among subgroups in the U.S.

By May 2020, fewer than 30% of low- to middle-income countries had national HPV vaccine programs. In some countries that do have programs, HPV vaccine supplies continue to be limited, resulting in vaccination programs only for girls. In fact, of 117 countries reporting on their HPV vaccine programs, 77 reported only immunizing girls.

However, even in countries where supply is sufficient and recommendations are inclusive, disparities remain. In the closing plenary, Dr. Douglas Lowy, Principal Deputy Director of the National Cancer Institute, reminded the audience that in the U.S., Hispanic and Black women continue to experience higher rates of cervical cancer and death compared with White women. In fact, the 2020 mortality rate was 3.2 per 100,000 for Black women and 2.5 per 100,000 for Hispanic women, compared with 2.1 per 100,000 for White women. Globally, women in many countries are at even greater risk. In the 2020 cancer statistics report, Malawi had the greatest incidence at 40.1 cases per 100,000 and 28.6 deaths per 100,000.

To see the 2020 cancer statistics, check this paper by Sung and colleagues.

In conclusion

We were excited by all that is happening related to HPV, but we also realized just how much there remains to do. At the VEC, we regularly receive questions from the public about HPV infections, transmission and vaccination, so we know people don’t always understand this virus. And we also know that some people remain concerned about HPV vaccine safety, despite its proven record of safety and efficacy. But in the U.S., as parents and healthcare providers, we are lucky. We have sufficient vaccine supplies and the other resources needed to protect our next generation from the health effects of this virus.

Won’t it be wonderful to say that our life’s work contributed to the elimination of HPV-associated cancers? We can give parents #OneLessWorry.

HPV-related resources

• Prevent-HPV.org — Questions and answers about HPV and the vaccine
• A Look at Each Vaccine: Human Papillomavirus
• HPV: What You Should Know Q&A: English | Spanish
• HPV infographic: PDF | PNG
• Talking about Vaccines with Dr. Paul Offit: HPV video series