Understanding the cervical microbiome: a promising frontier in HPV treatment

By Tarun Sai LomteReviewed by Danielle Ellis, B.Sc.Apr 26 2023

A recent feature published in the Proceedings of the National Academy of Sciences (PNAS) provided emerging insights into microflora associated with human papillomavirus (HPV) infections.

Background

Four in every five females will contract HPV infection in their life. Around 90% of infections will subside within two years, while doctors have no cure for the remaining 10% of infections the immune system fails to clear. Merck introduced Gardasil in 2006, the only HPV vaccine in the United States (US).

The latest version of this vaccine can protect against two non-cancerous genital warts and seven high-risk HPV types. However, there are over 100 lower-risk types the vaccine cannot protect against. Vaccine uptake can eradicate HPV but is modest in the US. By 2019, around 54% of boys and girls aged 13-17 had completed their vaccination regimen.

The World Health Organization (WHO) estimates show that only 12% of females and 4% of males are fully vaccinated worldwide, partly because the vaccine is inaccessible in many regions. Moreover, the vaccine cannot eliminate the virus from infected females. Reassuringly, infections can be treated, preventing their progression to cancer.

Emerging evidence points to the links between cervical bacteria, the immune system, and outcomes of HPV diagnosis. Cervical bacteria can fight off HPV, while others can help the virus attack damaged/weakened epithelial cells. Research is underway for microflora-supporting topical solutions to prevent HPV infections from persisting. One such solution is a gel containing food molecules for healthy bacteria growth.

Microflora

The cervix harbors an ecosystem of bacteria, including Lactobacillus, Gardnerella, and Mycoplasma. Healthy vaginal flora is dominated by Lactobacillus. Compositional shifts to a mix of many species can lead to uncomfortable symptoms diagnosed as bacterial vaginosis (BV), which can increase the risk of some sexually transmitted infections (STIs), including HPV.

In 2020, researchers investigated how cervical/vaginal flora alterations cause persistent HPV infection using data from a vaccine trial. The study analyzed microbial communities of females receiving placebos and observed that they grouped into four types – two were dominated by Lactobacillus, one by Gardnerella, and the other by different species.

Females with Gardnerella-dominant microbiomes were more likely to have progressive HPV leading to precancers than others. The presence of specific BV-related species correlated with an increased risk of progressive HPV. A follow-up study evaluated gynecological swabs and found that interleukin-1β (IL-1β) was consistently elevated.

Females with elevated IL-1β were more likely to have persistent HPV. This suggests that inflammation due to an unhealthy microbiome allows the virus to linger. Inflammation from BV or abrasions from sexual activity damage epithelial cells, allowing the virus to invade basal cells. Prolonged cellular multiplication can lead to precancerous dysplasia and cancer.

Treatment

Research suggests L. crispatus is typically enriched in healthy vaginal flora, with a protective effect, secreting proteins and lactic acid to lower vaginal pH, resulting in an inhospitable environment for abnormal cervicovaginal species. By contrast, L. iners secretes compounds that disrupt mucus/epithelial layers, allowing the pathogens to invade. This species is often associated with BV when predominant in the cervicovaginal environment.

One researcher suggests eliminating harmful bacterial species in females with early-stage HPV infection and repopulating the flora by administering an L. crispatus probiotic. Gynecologists already employ a similar practice for recurrent urinary tract infections and yeast infections. Papilocare is a cervical gel that forms a defensive film and microenvironment on the cervix and repairs damaged epithelia.

It contains a patented oligosaccharide (Bioecolia), which is a prebiotic and the preferred source of food for Lactobacillus. In addition, several topical treatments to support vaginal/cervical microbiota are under development. Understanding the interactions between bacteria and viruses on the cervix will open avenues to explore the relationships between other microbes, cancers, and viruses.