HPV16 mutant E6/E7 construct is protective in mouse model.

BACKGROUND: Human papillomavirus type 16 (HPV-16) infection is strongly associated with considerable parts of cervical, neck, and head cancers. Performed investigations have had moderate clinical success, so research to reach an efficient vaccine has been of great interest. In the present study, the immunization potential of a newly designed HPV-16 construct was evaluated in a mouse model. RESULTS: Initially, a construct containing HPV-16 mutant (m) E6/E7 fusion gene was designed and antigen produced in two platforms (i.e., DNA vaccine and recombinant protein). Subsequently, the immunogenicity of these platforms was investigated in five mice) C57BL/6 (groups based on several administration strategies. Three mice groups were immunized recombinant protein, DNA vaccine, and a combination of them, and two other groups were negative controls. The peripheral blood mononuclear cells (PBMCs) proliferation, Interleukin-5 (IL-5) and interferon-γ (IFN-γ) cytokines, IgG1 and IgG2a antibody levels were measured. After two weeks, TC-1 tumor cells were injected into all mice groups, and subsequently further analysis of tumor growth and metastasis and mice survival were performed according to the schedule. Overall, the results obtained from in vitro immunology and tumor cells challenging assays indicated the potential of the mE6/E7 construct as an HPV16 therapeutic vaccine candidate. The results demonstrated a significant increase in IFN-γ cytokine (P value < 0.05) in the Protein/Protein (D) and DNA/Protein (E) groups. This finding was in agreement with in vivo assays. Control groups show a 10.5-fold increase (P value < 0.001) and (C) DNA/DNA group shows a 2.5-fold increase (P value < 0.01) in tumor growth compared to D and E groups. Also, a significant increase in survival of D and E (P value < 0.001) and C (P value < 0.01) groups were observed. CONCLUSIONS: So, according to the findings, the recombinant protein could induce stronger protection compared to the DNA vaccine form. Protein/Protein and DNA/Protein are promising administration strategies for presenting this construct to develop an HPV-16 therapeutic vaccine candidate.

Human papillomavirus (HPV) vaccination in a privately funded program in Ghana: A qualitative case study.

HPV vaccination is one of the safest and most effective interventions against HPV-related cancers. From 2013 to 2018, HPV vaccination was piloted in Ghana in preparation for a national program. Yet, at the time of this study, there was no publicly funded HPV vaccination program in Ghana. We explored an existing privately funded HPV vaccination program in Ghana to identify challenges and gaps and to gather insights to inform vaccination practice and national policy. This study used a qualitative case study research design. We conducted semi-structured interviews on experiences, barriers, and challenges in HPV vaccination at the Greater-Accra Regional Hospital between October 1 and November 26, 2023. Participants (N = 16) included HPV vaccinators (n = 8) and program/policy leaders (n = 8). Our thematic analysis focused on HPV vaccination processes, practice challenges, and policy interests. Four main themes emerged from our analyses. Our findings revealed many challenges faced by the HPV vaccination program. These include a lack of guiding policy/framework for the HPV vaccination program, an emphasis on sexual history, cervical screening, and HPV DNA test in determining vaccination eligibility by vaccinators, and a lack of formal provider and recipient HPV education programs. Although many vaccinators advocated for a universal HPV program, some policy/program leaders were reluctant to prioritize HPV vaccination advocacy due to their focus on acute health concerns. A vaccination program without a policy can be limited in quality and efficiency, as there will be no accountability and sustainability measures. We recommend the need to develop standardized guidelines to support evidence-based HPV vaccination practice.

Head-to-head comparison of two human papillomavirus vaccines for efficacy against cervical intraepithelial neoplasia grade 3 and adenocarcinoma in situ-population-based follow-up of two cluster-randomized trials.

Introduction: We report head-to-head comparison of the bivalent and quadrivalent HPV vaccine efficacies against immediate precursors of cervical cancer from 15 years' country-wide cancer registry follow-up of phase III trial cohorts and an age-aligned cohort of unvaccinated women. Methods: These individually and/or clusterrandomized cohorts of HPV6/11/16/18- and HPV16/18-vaccinated and unvaccinated women were enrolled, respectively, in 2002, 2004, and 2003/2005. The trial cohorts comprised initially 16- to 17-year-old HPV6/11/16/18-vaccinated FUTURE II (NCT00092534) participants (866) and HPV16/18-vaccinated PATRICIA (NCT00122681) and 012 trial (NCT00169494) participants (2,465), and 16,526 initially 16- to 19-year-old unvaccinated controls. After active 4-year clinical follow-up, passive, country-wide Finnish Cancer Registry (FCR) follow-up for cervical intraepithelial neoplasia grade 3 (CIN3) and adenocarcinoma in situ (AIS) was based on consented use of unique personal identifiers and started 6 months after the end of the FUTURE II and PATRICIA trials in 2007 and 2009, and ended at the end of 2019. The follow-up with altogether 229,020 follow-up years was age-aligned to ensure that similarly aged cohorts were passively followed up for 15 years post=vaccination for the intention-to-treat analyses of vaccine efficacy. Results: Overall, we identified 5 and 16 CIN3 (no AIS) cases in the HPV6/11/16/18 and HPV16/18 cohorts, respectively, during the FCR-based follow-up. In the unvaccinated cohort, we identified 281 CIN3 cases, 20 AIS cases, and 13 cases with invasive cervical cancer. Vaccine efficacies against CIN3+ were 68.4% and 64.5% for the quadrivalent and the bivalent vaccines, respectively, with overlapping confidence intervals. Discussion: Long-term follow-up of randomized, initially adolescent HPV-vaccinated and unvaccinated cohorts shows, in this head-to-head setting, that the bivalent and quadrivalent HPV vaccines are equally effective against immediate precursors of cervical cancer.

Effectiveness of HPV vaccine as part of national immunization program for preventing HPV infection in Thai schoolgirls after seven years post-vaccination.

Thailand introduced a two-dose regimen of bivalent HPV vaccines for Grade 5 schoolgirls, approximately 11 years old, initially piloted in Ayutthaya province in 2014, and nationwide under the National Immunization Program (NIP) in 2017. This cross-sectional, case-control study evaluated the vaccine effectiveness in schoolgirls 7 years after a two-dose administration. Between May and June 2023, 211 grade 12 female students from Ayutthaya, who received the two-dose bivalent HPV vaccine CERVARIXⓇ (HPV types 16 and 18), and 376 grade 12 students from Nakhon Pathom who did not receive the HPV vaccine, were enrolled. HPV infection was detected by testing for HPV DNA in the first-void urine samples using real-time PCR (Cobas® 4800 and AnyplexTM HPV28). The study found that the HPV vaccine 100% effective against high-risk HPV (HR-HPV) types included in the vaccine (16, 18) and 32.8% effective against other HR-HPV types not included in the vaccine. Our findings indicated that the bivalent HPV vaccine does not provide cross-protection against non-vaccine HPV types. Prioritizing vaccines with the highest coverage of HR-HPV types, such as the nonavalent HPV vaccine, is crucial to effectively prevent a broader range of HR-HPV infections under the NIP.

Comparative Analysis of HPV16 Variants in the Untranslated Regulatory Region, L1, and E6 Genes among Vaccinated and Unvaccinated Young Women: Assessing Vaccine Efficacy and Viral Diversity.

HPV16 is occasionally detected in vaccinated women who received the bivalent HPV16/18 vaccine, usually at low viral loads. This study explored potential differences in HPV16 variants between vaccinated and unvaccinated women. HPV16-postive viral loads were detected in 1.9% (17/875) and 13% (162/760) of vaccinated and unvaccinated women, respectively, showcasing the vaccine's high efficacy. The L1, E6, and URR regions of HPV16 were sequenced from genital swabs from 16 vaccinated and 25 unvaccinated women in the HAVANA (HPV Among Vaccinated And Non-vaccinated Adolescents) study. The majority of HPV16 variants from vaccinated and unvaccinated women clustered similarly with sub-lineages A1 and A2. Additionally, a separate cluster within lineage A was found, with the variants sharing the L1-located SNP A753G (synonymous) and the URR-located SNP T340C, which did not occur in the other variants. Furthermore, four variants from vaccinated women had relatively long branches, but were not characterized by specific SNPs. The frequency of G712A in the URR was the only SNP observed to be marginally higher among vaccinated women than unvaccinated women. Non-synonymous SNPs T266A in the FG-loop of L1 and L83V in E6 were common among variants from vaccinated and unvaccinated women, but present in similar frequencies. In conclusion, the detection of HPV16 in vaccinated (and unvaccinated) women seemed to be the result of random circulation within this study population.

Unveiling the seroprevalence of human papillomavirus in Guangdong, China: Implications for vaccination strategies.

Seroepidemiological characteristics of human papillomavirus (HPV) in community residents reflect natural infection and can guide the reform of vaccination programs. A population-based serological survey was conducted in Guangdong Province. Serum anti-HPV IgG antibody levels were determined by an ELISA. Neutralizing antibodies against HPV6, 11, 16, and 18 were detected via a pseudovirus-based neutralization assay (PBNA). A total of 5122 serum samples were collected from community residents, including 1989 males and 3133 females, in three cities of Guangdong Province. The rate of HPV IgG antibody positivity in females was 5.39% (95% CI: 4.6-6.2), which was greater than that in males (2.36%; 95% CI: 1.7-3.1). HPV IgG antibodies were more frequently detected in females aged 51-60 years (11.30%; 95% CI: 7.6-16.0), whereas in males, the detection increased with age and reached 4.94% (95% CI: 2.8-6.9) in the group aged ≥71 years. The seropositivity of neutralizing antibodies against HPV6 and 11 was greater than that against HPV16 and 18. The serum neutralizing antibody titers in individuals who received three doses of a vaccine were 7- to 12-fold greater than those in individuals who did not receive the vaccine. The neutralizing antibody titers slightly decreased within 40 months and ranged from 0.038 to 0.057 log ED50 per month. A moderate consistency between the HPV ELISA and PBNA results was observed (Kappa score = 0.49, r = 0.249, 0.635, 0.382, and 0.466 for HPV6, 11, 16, and 18, respectively). The HPV seropositivity rate among healthy residents of Guangdong Province was found to be low among children and adolescents and to increase with age. The serum neutralizing antibody titers were significantly greater in the vaccine group than that in the control group, and this difference persisted over time, which indicated promising protection against HPV infection.

The polymorphism analysis and therapy vaccine target epitopes screening of HPV-35 E6 E7 among the threaten α-9 HPV in Sichuan area.

High-risk human papilloma virus (HR-HPV) persistent infection is closely associated with the development of cervical cancer and squamous intraepithelial lesion (SIL).The α-9 HPVs, which is predominantly composed of HR-HPV types, account for 75% of HR-HPV infection in Sichuan. The oncoproteins E6 and E7 of HPV play a crucial role in tumor initiation and progression. Notably, HPV-35 is the only HR-HPV type within the α-9 genus that is not included in the nine-valent HPV prophylactic vaccine. Cervical cell samples obtained from Sichuan were collected for HPV detection and genotyping. Among the 406 HPV-positive samples, 31 HPV-35 were detected, 24 HPV-35 E6 and 26 E7 were successfully amplified and sequenced, five nucleotide mutations in E6 and three in E7 were detected, T232C, T434G of E6 (W78R, I145R) and C67T, G84T of E7 (H23Y, L28F) were non-synonymy mutation. PAML 4.8 server was used to detect positive selection sites of HPV-35 E6, E7, and E6 is W78R. Phyre2 were used to predict and analyze protein structures, W78R made influences on protein structure. IEDB were used to screen epitopes vaccine target for HPV-35 affection therapy, and 5 HPV-35 E6 and 3 HPV-35 E7 most potential epitopes were obtained, the most potential peptides for therapy vaccine design were 79-91YRYSVYGETLEKQ, 45-60FACYDLCIVREGQPY, 124-135RFHNIGGRWTGR of E6; 3-19GEITTLQDYVLDLEPEA, 38-47TIDGPAGQAK, 70-88VQSTHIDIRKLEDLLMGTF of E7 and W78R mainly decreased the epitopes affinity.Conclusions Amino acid substitution in the positive selection sites of HPV-35 E6 and E7 genes have been found to influence protein structure and to decrease the overall affinity of antigen epitopes. This observation aligns with the evolutionary significance of positive selection site, which may confer advantages to the virus by making infected cells more challenging for the immune system to detect, thereby enhancing HPV's adaptability to the host environment. The polymorphism analysis of HPV-35 E6, E7 contributes to the enrichment of α-9 HPV data in Sichuan China, which is instrumental in improving the effectiveness of clinical detection. Furthermore, these findings provide a relevant theoretical foundation for the prevention and treatment of HPV-related diseases.

Unveiling the multifaceted realm of human papillomavirus: a comprehensive exploration of biology, interactions, and advances in cancer management.

Human Papillomavirus (HPV), an extensive family of DNA viruses, manifests as a persistent global health challenge. Persistent HPV infection is now firmly established as a significant aetiological factor for a spectrum of malignancies. In this review, we examine the latest insights into HPV biology and its intricate relationship with the host. We delve into the complex dynamics of co-infections involving HPV alongside other viruses, such as HIV, EBV, and HSV, as well as the burgeoning role of the microbiome in cancer development. We also explore recent advancements in understanding the specific contributions of HPV in the development of various cancers, encompassing cancers of the anogenital region, head and neck, as well as breast, lung, and prostate. Moreover, we focus on the current preventive strategies, including vaccination and screening methods, and therapeutic interventions that range from traditional approaches like surgery and chemotherapy to emerging modalities such as targeted therapies and immunotherapies. Additionally, we provide a forward-looking view on the future directions of HPV research, highlighting potential areas of exploration to further our understanding and management of HPV and its associated cancers. Collectively, this review is positioned to deepen readers' understanding of HPV biology and its complex interplay with cancer biology. It presents innovative strategies for the prevention, management, and therapeutic intervention of HPV-associated malignancies.

How has post-implementation surveillance of high-coverage vaccination with HPV16/18-AS04 vaccine in England added to evidence about its cross-protective effects?

BACKGROUND: Bivalent human papillomavirus HPV16/18-AS04 vaccine (Cervarix, GSK) offers direct protection against HPV16/18. Results from randomised controlled trials showed cross protective effects and suggested that declines in some closely related HPV types could be expected in a population with high vaccination coverage. AIM: To evaluate the evidence for cross-protection afforded by HPV16/18-AS04 from post-implementation surveillance in England, and how this complements clinical trial data and post-implementation observations in other countries. METHODS: Evidence of cross-protection in young women offered vaccination with HPV16/18-AS04 was gathered from HPV surveillance in England. Data from clinical trials and other post-implementation studies were reviewed. RESULTS: Surveillance using anonymised residual specimens in England found declines of 52.3%, 67.4% and 33.3% against grouped HPV-31/33/45 in 16-18, 19-21, and 22-24 year olds, respectively. Additionally, type-specific analysis found that the prevalence of HPV31 declined to below 1% across all age groups. Cross-protection has been monitored and maintained for over 10 years since the introduction of the vaccination programme. Cross-protection against HPV6/11 was not found in English surveillance outcomes. CONCLUSION: Surveillance of type-specific infections in vaccine-eligible populations in England has generated clear evidence of cross-protective effects from HPV16/18-AS04 vaccination against high-risk HPV 31/33/45 infections, consistent with other post-implementation observations and confirming and in some ways exceeding expectations from clinical trials.

Characterization of a triple-type chimeric vaccine against human papillomavirus types 18, 45, and 59.

Persistent infection with high-risk human papillomavirus (HPV) types can lead to the development of cancer in HPV-infected tissues, including the cervix, oropharynx, anus, penis, vagina, and vulva. While current HPV vaccines cover approximately 90 % of cervical cancers, nearly 10 % of cases associated with HPV types not included in the vaccines remain unaddressed, notably HPV59. This study describes the development of a chimeric virus-like particle (VLP) targeting HPV18/45/59, proposed as a vaccine candidate for high-risk HPV type (HPV59) currently lacking commercial vaccines. Given that the majority of neutralizing antibody epitopes are located on the surface loops, we engineered a strategic swap of these loops between the closely related HPV18 and HPV45. This methodology was then extended to incorporate surface loops of HPV59, resulting in the lead candidate construct of the H18-45BCEF-59HI chimeric VLP with two surface loops swapping from HPV45 to HPV18. Characterization confirmed that H18-45BCEF-59HI closely resembled the wild-type (WT) backbone types in particle size and morphology, as verified by Transmission Electron Microscopy (TEM), High-Performance Size-Exclusion Chromatography (HPSEC), and Analytical Ultracentrifugation (AUC), and demonstrated similar thermal stability as evidenced by Differential Scanning Calorimetry (DSC). Immunization studies in mice with the chimeric VLPs assessed their immunogenicity, revealing that the H18-45EF-59HI chimeric VLP exhibited optimal cross-neutralization. Additionally, when produced in a Good Manufacturing Practice (GMP)-like facility, the H18-45BCEF-59HI VLP was selected as a promising vaccine candidate for the prevention of HPV18/45/59 infection. This study not only offers a potential solution to the current vaccination gap but also provides a foundational approach for the design of vaccines targeting viruses with multiple subtypes or variants.

Update on Effects of the Prophylactic HPV Vaccines on HPV Type Prevalence and Cervical Pathology.

Most national prophylactic HPV vaccination programs started in approximately 2008, with either the bivalent Cervarix HPV16/18 or quadrivalent Gardasil (HPV6/11/16/18) vaccines, which were then followed by introduction of the nonavalent Gardasil 9 (HPV6/11/16/18/ 31/33/45/52/58) vaccine from 2015. Since that time, these products have demonstrated their ability to prevent infection with vaccine-covered HPV types and subsequent development of HPV-related cervical and genital pathologies. The data indicate that vaccination of young girls prior to sexual debut is more effective than vaccination of older HPV+ve women. Although some studies have shown a decline in the prevalence of vaccine-covered HPV types, there are national and regional differences in overall vaccine efficacy. Furthermore, several recently published studies show an increase in the prevalence of non-vaccine-covered HPV types in vaccinated populations, which is indicative of HPV type-replacement. It is also notable that vaccine-related changes in HPV type prevalence spread between vaccinated and unvaccinated women at the same geographical location-presumably via sexual transmission. In conclusion, it is not yet clear what effect dissemination of vaccine-associated changes in HPV type prevalence will have on vaccine efficacy and cervical pathology, particularly in mixed populations of vaccinated and unvaccinated women. However, it is very clear these observations do underscore the need for long-term continuation of cervical screening combined with regular reassessment of testing practices.

Assessing real world vaccine effectiveness: A review of Scotland's approach to monitoring human papillomavirus (HPV) vaccine impact on HPV infection and cervical disease.

High-risk human papillomavirus (HPV) infections can progress to cervical cancer which is the fourth most common cancer in women globally. In Scotland, the incidence of cervical cancer has a strong socioeconomic deprivation gradient disproportionately affecting women from more deprived areas. An HPV vaccination programme was initiated in Scotland in 2008 targeting girls aged 12-13 years with a catch-up campaign running for the first three years for girls aged up to 18 years. The programme has evolved over the last 16 years with changes in the type of vaccine, dosing schedules and the extension of the programme to boys and gay, bisexual and other men who have sex with men. Vaccine uptake in Scotland has historically been high but has gradually decreased over time and disparities exist in women from more deprived areas of Scotland. The ability to link national immunisation and screening databases in Scotland has allowed direct monitoring of the impact of the HPV vaccine on virological and histological outcomes. Analyses of this linked data have demonstrated real-world evidence of high vaccine effectiveness against HPV infection, cervical disease, and cervical cancer with evidence of herd immunity in unvaccinated women. Continued monitoring is crucial to assess the duration of protection, the impact of vaccine and dosing schedules changes and the emergence of potential type replacement. With the World Health Organisation's aim to eliminate cervical cancer as a public health problem by the next century addressing the inequalities in cervical cancer incidence will be crucial. This will require targeted interventions for women most at risk of cervical cancer to ensure elimination is achieved timely for all women in Scotland.

Enhancement of HPV therapeutic peptide-based vaccine efficacy through combination therapies and improved delivery strategies: A review.

Human papillomavirus (HPV) has been linked to the development of various cancers, including head and neck, cervical, vaginal, penile, and anal cancers. The development of therapeutic vaccines against HPV-positive tumors is crucial for protecting individuals already infected with HPV, preventing tumor progression, and effectively treating the disease. The HPV therapeutic peptide-based vaccines demonstrate specificity and safety advantages by targeting specific epitopes while minimizing the risk of allergic or autoimmune reactions. However, HPV therapeutic peptide-based vaccines typically lack immunogenicity and frequently fail to induce effective immune responses. Therefore, there is a need for more effective approaches to improve the immunogenicity of HPV peptide-based vaccines. Here, we review relevant research and possible uses for increasing the immunogenicity and therapeutic efficacy of HPV peptide-based vaccines through combined therapy and improved delivery strategies. Additional research is necessary to validate the application of combination therapy and delivery strategy modifications as standard treatment approaches for HPV therapeutic peptide-based vaccines.

Viral vector-based therapeutic HPV vaccines.

Replication-defective viral vector vaccines have several advantages over conventional subunit vaccines, including potent antibody responses, cellular responses critical for eliminating pathogen-infected cells, and the induction of highly immunogenic and durable immune responses without adjuvants. The Human papillomavirus (HPV), a microorganism with over 200 genotypes, plays a crucial role in inducing human tumors, with the majority of HPV-related malignancies expressing HPV proteins. Tumors associated with HPV infection, most of which result from HPV16 infection, include those affecting the cervix, anus, vagina, penis, vulva, and oropharynx. In recent years, the development of therapeutic HPV vaccines utilizing viral vectors for the treatment of premalignant lesions or tumors caused by HPV infection has experienced rapid growth, with numerous research pipelines currently underway. Simultaneously, screening for optimal antigens requires more basic research and more optimized methods. In terms of preclinical research, we present the various models used to assess vaccine efficacy, highlighting their respective advantages and disadvantages. Further, we present current research status of therapeutic vaccines using HPV viral vectors, especially the indications, initial efficacy, combination drugs, etc. In general, this paper summarizes current viral vector therapeutic HPV vaccines in terms of HPV infection, antigen selection, vectors, efficacy evaluation, and progress in clinical trials.

Validation of a triple-color pseudovirion-based neutralization assay for immunogenicity assessment of a 14-valent recombinant human papillomavirus vaccine.

Validation of bioanalytical methods is crucial, especially in the pharmaceutical industry, to determine their suitability for specific purposes and the accuracy of analytical results. The pseudovirion-based neutralization assay (PBNA) is considered the gold standard for detecting and quantifying neutralizing antibodies against human papillomavirus in vaccine development for disease prevention. This paper introduces an improved triple-color PBNA method, capable of simultaneous detection of two or three human papillomavirus (HPV types for use in the development of a 14-valent HPV vaccine candidate. The primary objective was to comprehensively validate the triple-color PBNA method for general vaccine immunogenicity assays. Results show that the method has good specificity, accuracy, precision, linearity, robustness, and applicability. This innovative triple-color PBNA offers an improved approach for large-scale immunogenicity assessment in vaccine development. This study lays a solid foundation that can serve as a guiding paradigm for assessing vaccine responses in preclinical and clinical phases, providing valuable insights to the field.

Exploring the complexity of the implementation determinants of human papillomavirus vaccination in Africa through a systems thinking lens: A rapid review.

A rapid review was conducted to explore the implementation determinants of human papillomavirus (HPV) vaccination in the World Health Organization African Region and describe their dynamic relationship. PubMed and Google Scholar were searched in October 2023 to find relevant literature. A total of 64 published studies that reported factors affecting HPV vaccination were identified. Analysis of identified factors yielded 74 implementation determinants of HPV vaccination across the five domains of the Consolidated Framework for Implementation Research (CFIR): two (2.70%) were in the innovation domain, seven (9.46%) were in the outer setting domain, 14 (18.92%) were in the inner setting domain, 37 (50%) were in the individual domain and 14 (18.92%) were in the implementation process domain. A causal loop diagram of these implementation determinants revealed four balancing and seven reinforcing loops. Applying systems lens promoted a more holistic understanding of the implementation determinants of HPV vaccination, exposing leverage points for interventions.

Meeting report: Considerations for trial design and endpoints in licensing therapeutic HPV16/18 vaccines to prevent cervical cancer.

Cervical cancer is a major cause of morbidity and mortality globally with a disproportionate impact on women in low- and middle-income countries. In 2021, the World Health Organization (WHO) called for increased vaccination, screening, and treatment to eliminate cervical cancer. However, even with widespread rollout of human papillomavirus (HPV) prophylactic vaccines, millions of women who previously acquired HPV infections will remain at risk for progression to cancer for decades to come. The development and licensing of an affordable, accessible therapeutic HPV vaccine, designed to clear or control carcinogenic HPV and/or to induce regression precancer could significantly contribute to the elimination efforts, particularly benefiting those who missed out on the prophylactic vaccine. One barrier to development of such vaccines is clarity around the regulatory pathway for licensure. In Washington, D.C. on September 12-13, 2023, a meeting was convened to provide input and guidance on trial design with associated ethical and regulatory considerations. This report summarizes the discussion and conclusions from the meeting. Expert presentation topics included the current state of research, potential regulatory challenges, WHO preferred product characteristics, modeling results of impact of vaccine implementation, epidemiology and natural history of HPV infection, immune responses related to viral clearance and/or precancer regression including potential biomarkers, and ethical considerations. Panel discussions were held to explore specific trial design recommendations to support the licensure process for two vaccine indications: (1) treatment of prevalent HPV infection or (2) treatment of cervical precancers. Discussion covered inclusion/exclusion criteria, study endpoints, sample size and power, safety, study length, and additional data needed, which are reported here. Further research of HPV natural history is needed to address identified gaps in regulatory guidance, especially for therapeutic vaccines intended to treat existing HPV infections.

Parental hesitancy about COVID-19, influenza, HPV, and other childhood vaccines.

BACKGROUND: Some public health professionals have expressed concern that the COVID-19 pandemic has increased vaccine hesitancy about routine childhood vaccines; however, the differential prevalence of vaccine hesitancy about specific vaccines has not been measured. METHODS: Data from the National Immunization Survey-Child COVID-19 Module (NIS-CCM) were analyzed to assess the proportion of children ages 6 months-17 years who have a parent with hesitancy about: COVID-19, influenza, human papillomavirus (HPV) (for children ≥ 9 years) vaccines, and "all other childhood shots." Interviews from October 2022 through April 2023 were analyzed. RESULTS: The percentage of children with a vaccine-hesitant parent varied by vaccine. 55.9% of children had a parent hesitant about COVID-19 vaccine, 30.9% hesitant about influenza vaccine, 30.1% hesitant about HPV vaccine, and 12.2% had a parent hesitant about other vaccines such as measles, polio, and tetanus. CONCLUSION: The study findings suggest that differential interventions and communications to parents be used to educate about COVID-19, influenza, HPV, and routine childhood vaccinations because the hesitancy levels differ widely.

Current status and future directions for the development of human papillomavirus vaccines.

The development of human papillomavirus (HPV) vaccines has made substantive progress, as represented by the approval of five prophylactic vaccines since 2006. Generally, the deployment of prophylactic HPV vaccines is effective in preventing newly acquired infections and incidences of HPV-related malignancies. However, there is still a long way to go regarding the prevention of all HPV infections and the eradication of established HPV infections, as well as the subsequent progression to cancer. Optimizing prophylactic HPV vaccines by incorporating L1 proteins from more HPV subtypes, exploring adjuvants that reinforce cellular immune responses to eradicate HPV-infected cells, and developing therapeutic HPV vaccines used either alone or in combination with other cancer therapeutic modalities might bring about a new era getting closer to the vision to get rid of HPV infection and related diseases. Herein, we summarize strategies for the development of HPV vaccines, both prophylactic and therapeutic, with an emphasis on the selection of antigens and adjuvants, as well as implications for vaccine efficacy based on preclinical studies and clinical trials. Additionally, we outline current cutting-edge insights on formulation strategies, dosing schedules, and age expansion among HPV vaccine recipients, which might play important roles in addressing barriers to vaccine uptake, such as vaccine hesitancy and vaccine availability.