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Cervicovaginal Microbiomes of HPV-Infected Women Lead To Potential Pre-Cancer Marker

NEW YORK – A team of researchers from the US, Costa Rica, and France has identified potential microbial markers of cervical pre-cancer progression or clearance in women with high-risk human papillomavirus (HPV) infections.

"This study demonstrates that features of the cervicovaginal microbiome are associated with [high-risk HPV] progression in a prospective longitudinal cohort," corresponding author Robert Burk, a researcher at Albert Einstein College of Medicine, and his colleagues wrote.

Members of the Costa Rica HPV Vaccine Trial Group used targeted 16S ribosomal RNA gene sequencing and fungal ITS1 internal transcribed spacer sequencing to profile microbial and fungal community members, respectively, in cervicovaginal samples collected over two clinic visits from 273 women with high-risk HPV infections.

The results, published in PLOS Pathogens on Thursday, suggested that cervical pre-cancer progression coincided with a rise in Gardnerella representation and enhanced microbial diversity.

"The results of our study suggest a novel association between the effect of Gardnerella and disruption of [cervicovaginal microbiome] homeostasis that can influence the pathway of [high-risk HPV] infection progression to cervical pre-cancer," the authors reported.

While most cervical HPV infections clear over the course of a few months, the team explained, women with persistent HPV infections are at enhanced risk of developing cervical cancer or pre-cancerous lesions.

"Despite being the most common sexually transmitted infection and the causal agent of cervical cancer," the authors noted, "it is still not clear why only a small proportion of high-risk HPV infections progress to cervical cancer."

To explore potential microbiome contributions to such progression, the researchers profiled cervicovaginal samples from 273 women between the ages of 18 and 25 years who had been enrolled in a Phase III clinical trial, including 266 participants tested again after an average of one-and-a-half years.

Using 16S and fungal ITS1 sequences found in the cervicovaginal samples at each time point — together with HPV infection clearance, persistence, or progression to cervical neoplasia grade 2 (CIN2+) or grade 3 (CIN3+) lesions — the team relied on advanced epidemiological modeling and other analysis to uncover the proposed Gardnerella biomarker.

That microbe appeared to be more common in women with infections that progressed to pre-cancerous CIN2+ lesions, as was enhanced microbial diversity, the researchers reported. Their follow-up experiments suggested that rising Gardnerella in microbiomes of at-risk patients reflected increased cervicovaginal diversity driven by pre-cancerous progression.

"We present data that Gardnerella is in fact associated with CIN2+ lesions, but rather than directly causing the CIN2+ lesion, appears to induce a higher diversity [in the cervicovaginal microbiome] over time … which in turn mediates the observed effect of Gardnerella in [high-risk HPV] disease progression," the authors wrote.