Current Topics in Microbiology and Immunology

HPV Type Replacement After HPV Vaccination

Human papillomavirus (HPV) vaccination effectively reduces the risk of HPV-attributable cancers, including cervical, vulvar, vaginal, anal, oropharyngeal, and other head and neck cancers. Concerns for a lower-than-expected vaccine impact, as defined as an increase in the prevalence of precancer by nonvaccine types, compared to that anticipated based on attribution studies, have been raised in the postvaccination era. Three distinct and nonmutually exclusive processes-HPV type replacement, clinical unmasking, and viral unmasking-could be responsible for this apparent increase of nonvaccine types. HPV type replacement, in which nonvaccine types fill a niche left vacant after the elimination of vaccine types, is unlikely to occur due to the remarkable genetic stability of the virus and the lack of natural competition between individual HPV types. However, clinical unmasking, in which the absence of clinical interventions aimed at eliminating cervical disease caused by vaccine types permits uninterrupted progression of nonvaccine types, may occur since HPV coinfections are common. Alternatively, the observed shift could be completely erroneous due to the false discovery of type replacement via viral unmasking, a diagnostic assay artifact. In this chapter, we describe these processes and the mechanisms underlying them.

DNA Methylation in Cervical Intraepithelial Neoplasia and Cervical Cancer: Triage and Management

This chapter discusses the role of DNA methylation, an epigenetic mechanism that regulates gene expression, as a key event in cervical carcinogenesis, and highlights its potential as a biomarker for detecting cervical cancer and high-grade precancerous lesions. Methylation levels of specific genes (methylation markers) gradually increase with cervical disease severity, allowing several clinical applications. Methylation markers have been evaluated as alternative triage tools for high-risk (hr) human papillomavirus (HPV)-positive women, including those with borderline or mildly abnormal cytology results, and for use in specific populations such as women living with HIV. Methylation testing often outperforms traditional cytology-based triage methods and offers long-term reassurance against cervical cancer when the result is negative. Additionally, methylation markers have shown prognostic potential in predicting the natural course of high-grade precancerous lesions, as well as a promising performance for the detection of recurrent disease. While ongoing research focuses on validating methylation testing in self-collected samples, low-resource settings, and HPV-vaccinated populations, current evidence supports its potential to enhance early detection, risk stratification, and post-treatment monitoring in cervical cancer prevention and care.

Human Papillomavirus Screening: Design and Targeting of Human Papillomavirus Genotypes

In 2018, there were globally about 350,000 deaths from cervical cancer, despite the fact that the disease can be prevented by screening and in spite of the fact that highly effective human papillomavirus (HPV) tests became available some 25 years ago. WHO recommended HPV as the primary choice for cervical screening in 2014 (WHO 2014). In this chapter, I will outline the major evidence base behind HPV-based screening, discuss some of the major bottlenecks that has hampered the use of HPV-based screening for prevention of cervical cancer, and point out recent developments that may overcome these bottlenecks, in particular how targeting of screening to the most oncogenic HPV genotypes can be used to optimize sensitivity, specificity, and feasibility of HPV screening.

Cofactors in Human Papillomavirus Carcinogenesis

Human papillomavirus (HPV) infection is the necessary cause of cervical cancer (CC) and other HPV-related malignancies, yet by itself is not sufficient for malignant progression. A myriad of co-factors influences the risk that an HPV infection persists and progress to precancerous lesions and invasive disease. Understanding these cofactors is crucial for risk stratification and informing comprehensive preventive strategies-complementing HPV vaccination and screening-to further reduce the incidence of cervical and other HPV-associated cancers.This chapter reviews the epidemiological and mechanistic evidence for key cofactors in HPV-driven carcinogenesis. The most established cofactors-including tobacco smoking, immunosuppression (particularly HIV infection), long-term use of oral contraceptives, high parity, and coinfection with other sexually transmitted infections-have consistently been associated with increased risk of HPV persistence and disease progression. We discuss their prevalence, magnitude of risk, and biological plausibility. Emerging and less established cofactors, such as the cervical microbiome, nutritional status and diet, and host genetic polymorphisms, which may modulate immune responses to HPV or the propensity for viral persistence are also explored.

Microbiome, Human Papillomavirus and Cervical Carcinogenesis

The microbiome describes the collection of genes derived from microorganisms that live in body systems. After the discovery of Lactobacilli as important for vaginal health, the vaginal microbiome was initially binarily classified into healthy or bacterial vaginosis (BV), before being further explored using 16S sequencing and the development of community state types (CST) by Ravel et al. There are a plethora of studies describing the vaginal microbiome composition in relation to cervical disease outcomes, more specifically human papillomavirus infection and persistence, cervical preinvasive and invasive disease. While there is some conflicting evidence, the general consensus is that Lactobacillus spp., in particular Lactobacillus crispatus or CST I, is associated with healthy status, and BV, CST IV and Lactobacillus depletion are associated with cervical intraepithelial neoplasia. What constitutes a 'normal' vaginal microbiome is not clear; in Ravel's study, around a quarter of women had CST I, and a quarter had CST IV. Although directionality is not established, mechanistic studies suggest immunomodulation and support biological plausibility. More recently, prebiotics and probiotics have been studied and there is some emerging evidence that this may be associated with increased clearance of cytological abnormalities. Important future work includes larger longitudinal studies, patient-derived organoids to examine causality and mechanistic insights, and development and trial of novel therapeutic treatments.