The human papillomavirus: Dynamics between vaccination, viral properties and surveillance.

The human papillomavirus (HPV) is a prevalent sexually transmitted virus with over 200 known genotypes. While most HPV infections are harmless and cleared by the immune system within six to twelve months, some can persist. Low-risk types like HPV6 and HPV11 cause non-cancerous conditions such as genital warts, while high-risk types, particularly HPV16 and HPV18, are linked to various cancers, including cervical, anal, vulvar, penile, vaginal, and head-and-neck cancers. Cervical cancer, the fourth most common cancer in women globally, is primarily caused by HPV16 and HPV18, together accounting for about 70% of cases. In the Netherlands, HPV vaccination was introduced in 2009 as part of the National Immunization Program using the bivalent HPV16 and HPV18 vaccine, initially targeting girls to reduce the high burden of cervical cancer. HPV monitoring studies were established to assess the impact of vaccination on HPV-related diseases. The vaccination program has proven highly effective in reducing HPV-related diseases, although some individuals may still develop infections with HPV types against which they were vaccinated. The vaccine is also known to provide cross-protection against other non-vaccine HPV types. Despite the progress made with HPV vaccination, little is known about its effects on the molecular aspects of the virus, such as viral load and genetic variation. This thesis seeks to address this gap by investigating these aspects and assessing how vaccination affects them, as well as their influence on HPV detection platforms. Chapter 1 gives a general introduction on HPV and HPV-targeted vaccination. Chapter 2 examines how viral load affects the detection of HPV45 and HPV59, using a broad HPV-detection platform. The study suggests that the platform’s low sensitivity for detecting low viral loads, particularly in unvaccinated women, may result in an underestimation of vaccine effectiveness. Chapter 3 explores viral load reduction in vaccinated women, showing that those who received three doses had significantly lower viral loads for HPV16, HPV18, and cross-protective HPV31. This reduction correlates with decreased infection persistence, although viral load reductions did not always correspond to lower prevalence. Chapter 4 investigates genital and anal HPV infections, revealing that higher viral loads in genital infections were linked to an increased likelihood of anal infections. Vaccinated women had fewer concurrent genital-anal infections, suggesting vaccination helps prevent HPV spread within the body by reducing initial infection viral loads. Chapter 5 analyzes HPV16 genetic variation among vaccinated and unvaccinated women, showing that vaccination did not appear to affect the genetic diversity of circulating HPV16 variants. While sequencing challenges were noted due to low HPV16 viral loads in vaccinated women, the study suggests that the bivalent vaccine’s effectiveness against HPV16 remains stable. However, the limited sample size warrants further research to confirm these findings. Chapter 6 discusses the findings in a broader context, addressing their implications, limitations, and prospects for future research. Overall, this thesis highlights the importance of sensitive HPV detection methods to accurately assess vaccine effectiveness, demonstrates the vaccine’s role in reducing viral loads and infections, and shows that HPV16 genetic diversity remains stable, indicating consistent vaccine effectiveness.