Vaginal immune mediators ramp up after first sexual intercourse

From the Hladik and Roxby labs, Vaccine and Infectious Disease Division

Adolescent girls and young women are at high risk of sexually transmitted infections, including HIV. The Joint United Nations Programme on HIV/AIDS estimates that in some countries, girls and women aged 15-24 account for 80% of new HIV infections. The period spanning months immediately after first-time penile-vaginal sexual intercourse is associated with higher incidences of STIs and bacterial vaginosis compared to later in life. However, the reasons for this vulnerability have remained unclear. Beyond the challenges of gathering data from this population undergoing dynamic life events, it is difficult to differentiate immune changes that occur as consequences of STIs and those that occur independently of them. Sean Hughes, a research scientist in Dr. Florian Hladik’s lab in the Vaccine and Infectious Disease Division at the Fred Hutch and the Department of Obstetrics and Gynecology at the University of Washington, led a recent study published in eLife, which examined changes in cervicovaginal immune mediators after first-time sexual intercourse in a cohort of adolescent girls and young women in Kenya.

To investigate this question, the authors measured the concentrations of 20 immune mediators in samples of cervicovaginal lavages from Kenyan girls and women aged 16-20. These samples were collected in the months before and after first penile-vaginal sexual intercourse as part of the Kenya Girls Study, a previous longitudinal project led by Dr. Alison Roxby, the co-senior author of this paper. The researchers compared concentrations of the immune mediators in the pre- and post-first sex samples using mixed effect models.

The authors found that immune mediator concentrations were higher in post-first sex samples compared to pre-first sex samples. Lead author Sean Hughes says that a key takeaway from the study is showing that “cytokine and immune mediator concentrations rise dramatically in the vagina after young women start to have sexual intercourse. Further, it shows that the increase is not a sudden change; instead, the concentrations increase continuously over time for at least a year, doubling after about 5 months.”

Immune mediator concentrations increase in the time period following first penile-vaginal intercourse.
Immune mediator concentrations increase in the time period following first penile-vaginal intercourse. Image taken from original eLife article

In addition to analyzing the samples from the Kenya Girls Study, the authors performed a systematic review of previously published studies to identify datasets that they could use for meta-analysis. They identified two eligible studies: one from Belgium, and another from the US. Hughes explains, “We combined the results of our study with the results of two other similar studies. The similarity of the results of all three studies increases our confidence in our findings. It’s especially nice for something like CCL4, which had non-significant (p > 0.05) results in both of the studies where it was measured, but because those two studies had very similar results, it comes out as significant in the meta-analysis.”

This study identified an association between first penile-vaginal sexual intercourse and increases in cervicovaginal immune mediators in adolescent girls and young women from three populations. This observation is an important first step in understanding the biological mechanisms behind this association, and ultimately, protecting this population against STIs during this window of high vulnerability. The team is already considering additional questions that arise from this study. Hughes says, “The first and most important question is the role of the increased cytokine levels: do they help prevent sexually transmitted infections? Are they a sign of the immune system maturing at a site that is now being exposed to more foreign antigens? Do they increase HIV risk by recruiting CD4s to the site? Additionally, a wide range of cytokines increased in concentration: pro-inflammatory, anti-inflammatory, chemokines, etc. Why are they all moving in tandem despite their differing functions? Another question is how long after first sexual intercourse the cytokines continue to increase in concentration. Presumably, vaginal cytokine concentrations eventually plateau, rather than increasing for the rest of the woman’s life, but we don’t know if that’s the case. We have samples collected later after first sex, so we can follow the same women up to several years after they have sexual intercourse for the first time.”

In addition to this paper, Hughes simultaneously led another study published in BMC Medicine, which looked at effects of the menstrual cycle on concentrations of cervicovaginal immune mediators. The authors conducted a systemic review of the literature and performed meta-analysis on 31 studies. They found that many immune mediators, including antibodies and chemokines, were lower in the luteal (post-ovulation) phase of the menstrual cycle. Together, the two studies provide the important insight that the concentrations of immune mediators are not static, but fluctuate throughout a person’s lifetime in response to specific triggers.

This work was supported by the National Institutes of Health and the Center for AIDS Research (CFAR) of the University of Washington/Fred Hutchinson Cancer Center (eLife study); the University of Washington Royalty Research Fund, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Human Development, and CFAR (BMC Medicine study).

The Fred Hutchinson/University of Washington Cancer Consortium members Drs. Anna Wald and Florian Hladik contributed to this work.

Hughes SM, Levy CN, Calienes FL, Martinez KA, Selke S, Tapia K, Chohan BH, Oluoch L, Kiptinness C, Wald A, Ghosh M, Hardy L, Ngure K, Mugo NR, Hladik F, and Roxby AC. 2022. Starting to have sexual intercourse is associated with increases in cervicovaginal immune mediators in young women: a prospective study and meta-analysis. eLife. 11:e78565.

Hughes SM, Levy CN, Katz R, Lokken EM, Anahtar MN, Hall MB, Bradley F, Castle PE, Cortez V, Doncel GF, Fichorova R, Fidel PL Jr, Fowke KR, Francis SC, Ghosh M, Hwang LY, Jais M, Jespers V, Joag V, Kaul R, Kyongo J, Lahey T, Li H, Makinde J, McKinnon LR, Moscicki AB, Novak RM, Patel MV, Sriprasert I, Thurman AR, Yegorov S, Mugo NR, Roxby AC, Micks E, Hladik F, and The Consortium for Assessing Immunity Across the Menstrual Cycle. 2022. Changes in concentrations of cervicovaginal immune mediators across the menstrual cycle: a systematic review and meta-analysis of individual patient data. BMC Medicine. 20(1):353.