Mapping the Global Research Landscape of HPV Vaccination and Oral Cancer

Mapping the Global Research Landscape of HPV Vaccination and Oral Cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Mapping the Global Research Landscape of HPV Vaccination and Oral Cancer Ye Han, Wenyu Ge, Lichen Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8314623/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Oral cancer remains a significant global health challenge, with research focusing on the role of HPV vaccination in its prevention. This study aimed to fill that gap by analyzing publications related to HPV vaccination and oral cancer from 2012 to 2025, retrieved from the Web of Science Core Collection. Using tools like VOSviewer, CiteSpace, and the R package "bibliometrix," the analysis included 397 articles, revealing a steady increase in research output over time, with the United States leading in publication volume. Key institutions such as NCI, along with prominent authors like Giuliano AR, contributed significantly to the field. Emerging topics included vaccine innovations and economic evaluations. Despite growth, the research landscape remains geographically skewed, highlighting the need for expanded studies in underrepresented regions. This bibliometric analysis offers valuable insights into the development, collaborations, and future directions of HPV vaccination research related to oral cancer, guiding future efforts to achieve equitable global prevention. oral cancer HPV vaccines Human Papillomavirus Vaccines bibliometrix VOSviewer CiteSpace Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Oral cancer (OC) is a leading cause of cancer-related morbidity and mortality worldwide [ 1 , 2 ] . Human papillomavirus (HPV) is a well-established oncogenic agent implicated in the pathogenesis of oral cancer (OC) [ 3 – 5 ] . Over the past decade, the incidence of HPV-positive OC has risen dramatically in many regions, including North America, Europe, and parts of Asia [ 6 – 8 ] . In contrast to HPV-negative OC, which is strongly associated with tobacco and alcohol use, HPV-positive cases tend to occur in younger, non-smoking individuals and are associated with better prognosis [ 9 – 11 ] . Despite this, the global burden of HPV-related oral cancers continues to increase, underscoring the urgent need for effective prevention strategies [ 12 – 14 ] . Prophylactic HPV vaccination, primarily targeting high-risk types such as HPV-16 and HPV-18, has been widely implemented in cervical cancer prevention programs worldwide [ 9 , 15 ] . However, its impact on the prevention of HPV-associated oral cancers remains underexplored, particularly in the context of global research trends, policy adoption, and public health integration [ 16 – 18 ] . While several studies have demonstrated the potential of HPV vaccination to reduce the incidence of oral HPV infection and subsequent malignancy [ 15 , 19 , 20 ] , disparities in vaccine uptake, policy implementation, and research focus persist across regions [ 21 , 22 ] . Recent bibliometric analyses have provided valuable insights into the evolving landscape of various research fields, identifying key contributors, research hotspots, and emerging trends, including HPV-related research [ 23 – 35 ] . For instance, studies have highlighted the increasing focus on HPV-associated head and neck cancers in high-income countries, while low- and middle-income countries (LMICs) continue to face challenges in vaccine access and surveillance [ 36 – 38 ] . Additionally, the integration of artificial intelligence and machine learning in HPV-related cancer research has opened new avenues for early detection and risk stratification [ 15 , 20 ] . Despite these advances, a comprehensive bibliometric analysis specifically examining the global research landscape of HPV vaccination and its relationship to oral cancer prevention has not been conducted. This study aims to fill this gap by systematically analyzing publication trends, citation networks, and research themes from 2012 to 2025. By leveraging bibliometric tools and methodologies, we seek to identify key research clusters, influential authors, and regional disparities in HPV vaccination and oral cancer research. This analysis will provide critical insights for policymakers, researchers, and public health practitioners to optimize HPV vaccination strategies and reduce the global burden of HPV-related oral cancers. Search Strategy We conducted a literature search in the Web of Science Core Collection (WoSCC) database ( https://www.webofscience.com/wos/woscc/basic-search ) on 12th July 2025. The search strategy, detailed in Fig. 1 , was limited to document types “Article” and “Review,” yielding 397 eligible publications for the subsequent bibliometric analysis. Data Analysis VOSviewer (v1.6.20) was employed to construct and visualize networks of countries, institutions, journals, authors, and keywords [ 39 , 40 ] . In these maps, node size reflects publication volume or citation frequency related to HPV vaccine,and oral cancer; node colour denotes thematic clusters, and edge thickness signifies the strength of collaboration or co-citation ties. CiteSpace (v6.3.1) was subsequently used to detect citation bursts, thereby spotlighting seminal papers that have shaped discourse on optimal dosing regimens, vaccines thresholds, and long-term oncological outcomes [ 41 , 42 ] . The R package “bibliometrix” (v4.3.0) enabled temporal analyses of research themes and the construction of a global knowledge-flow network, revealing how concepts such as HPV vaccines and oral cancer have evolved across time and geography [ 43 , 44 ] . Journal quality metrics—quartile rank and 2025 impact factor—were extracted from Journal Citation Reports to contextualize the influence of publishing venues. Finally, Microsoft Excel 2021 facilitated data cleaning, quantitative tabulation, and graphical refinement, ensuring transparent and reproducible reporting [ 33 ] . These tools provide an integrated, data-driven overview of dose–response investigations linking HPV immunization to the prevention of oral cancer, highlighting both established partnerships and emerging research frontiers. Result Quantitative Analysis of Publications Figure 2 presented a bar chart illustrating the annual publication trends of HPV vaccines in oral cancer from 2012 to 2025. In 2012, 22 articles were produced by the field. A slight dip to 21 articles was observed in 2013, followed by a rebound to 22 in 2014, and then a rise to 24 in 2015—marking the highest level of the first half-decade. After a brief retreat to 21 in 2016, the count fell to 17 in 2017, which was recorded as the period’s lowest point. A dramatic upswing was then registered: 42 publications were indexed in 2018, nearly 2.5 times the previous year’s total, and 40 were documented in 2019. A modest contraction was noted in 2020, when 27 papers were tallied, but a rapid recovery was seen in 2021 with 38 publications and in 2022 with 33. Relative stability was maintained in the most recent years, as 28 articles were counted in 2023, 39 in 2024, and 23 have been expected or already indexed for 2025. Country Analysis Figure 3 was presented as a bibliometric dissection of the global landscape of HPV research in oral cancer. In Figure 3A, a country-level collaboration network was generated by bibliometrix and was depicted on a world map. Bilateral or multilateral co-authorships were encoded by connecting edges, whereas chromatic gradients from light to dark were used to mirror the intensity of research activity. Figure 3B was produced with VOSviewer, in which nodes were overlaid to cluster countries according to their joint publication profiles. The size of each node was scaled to reflect document counts, and the proximity between nodes was employed to indicate the strength of collaborative ties; warmer colors were assigned to denote higher centrality within the network. Table 1 was compiled to summarize the national publication output on HPV in oral cancer over the study period. The United States was found to dominate the field, with 199 documents recorded, far exceeding the contributions of any other country. England was ranked second, with 32 publications, and was followed closely by Italy with 31. China and Spain were listed as the fourth and fifth contributors, with 28 and 27 documents, respectively. This distribution underscored a pronounced concentration of research activity in North America and Europe, while the emerging—yet comparatively modest—engagement of China and Spain in the global discourse on oral HPV was also highlighted. Co-authorship Organization and Citation Organizations Analysis Figure 4 was depicted as a bibliometric evaluation of HPV research in oral cancer, and was constructed with VOSviewer through two complementary network analyses: co-authorship organisation in Figure 4 A and citation organisation in Figure 4 B . In Figure 4 A , institutions were represented as nodes whose diameters were scaled according to the number of co-authored publications on oral HPV; inter-node links were used to denote collaborative ties, with shorter distances and thicker lines being employed to indicate stronger co-authorship intensity. Prominent university medical centres, comprehensive cancer institutes, and specialised stomatology hospitals were identified as the principal hubs. The largest publication clusters were generated by these institutions, and central positions within the network were occupied by them, thereby underscoring their pivotal role in the coordination of multi-centre studies. Figure 4 B was presented as the citation organisation overlay, in which node size was scaled proportionally to the cumulative citations that had been received by each institution’s oral-HPV corpus, and colour gradients were applied to reflect the average citation per paper. A clear concentration of influence was observed, and the citation landscape was dominated by the same leading institutions. Journals Analysis In Figure 5 A , journals were rendered as nodes whose sizes were scaled to the total citation volume received by articles on oral HPV; colour gradients were applied to indicate the average citations per paper. Figure 5 B presented the co-citation-sources network, in which journals were positioned according to their co-citation frequency—that is, how often pairs of journals were cited together. Clusters of strongly co-cited journals were revealed, and their thematic coherence was interpreted as evidence of shared disciplinary focus. Author Analysis Figure 6 was constructed to delineate the author-level landscape of HPV research in oral cancer. In Figure 6A , the co-authorship network was generated with VOSviewer: authors were rendered as nodes whose sizes were scaled to publication counts, and inter-node distances together with edge thicknesses were employed to quantify collaborative intensity. Distinct clusters of investigators—each representing sustained multi-centre collaborations—were clearly delineated, thereby mapping the core research communities active in this domain. Figure 6B was produced with bibliometrix to identify the most relevant authors by document volume. Giuliano AR was positioned first, with 13 publications; Alemany L followed in second place with 8. Bencina G, Gillison ML, and Pinto LA were jointly ranked third, each having contributed 7 papers. Keyword Analysis In Figure 7A , VOSviewer was employed to construct a co-occurrence network of all keywords extracted from titles, abstracts, and author keywords. Terms were represented as nodes whose sizes were scaled to their occurrence frequency, and edges denoted co-occurrence strength. Figure 7B was generated with CiteSpace to identify citation bursts—sudden, transient surges in citation frequency that mark influential turning points. Four burst terms were detected: “HORMONAL CONTRACEPTIVES”, “indirect cost”, “HUMAN-PAPILLOMAVIRUS”, and “RG1-VLP vaccine”. These bursts were interpreted as indicators of pivotal conceptual shifts or methodological innovations that had rapidly attracted scholarly attention and had subsequently redirected research trajectories within the HPV–oral cancer domain. Discussion The present bibliometric analysis is the first to comprehensively map the global research landscape of HPV vaccination and its role in oral cancer prevention over a 13-year period (2012–2025). Our findings reveal a steadily growing body of literature, with a marked acceleration after 2018, coinciding with the WHO’s call for global elimination of cervical cancer and expanded HPV vaccination programs [ 5 , 8 ] . This temporal trend underscores the increasing recognition of HPV vaccination as a potential strategy to mitigate not only cervical but also oral cancers [ 45 – 50 ] . Basic Mechanisms of HPV in Oral Cancer Human papillomavirus (HPV) infects basal epithelial cells of the oral mucosa through microabrasions or compromised mucosal barriers (e.g., trauma, inflammation, or tobacco/alcohol exposure). High-risk subtypes HPV-16/18 play a pivotal role in oncogenesis via the following mechanisms: 1. E6/E7 Oncoprotein Synergy: E6 recruits the E6-AP ubiquitin ligase to degrade p53, disrupting DNA damage repair and apoptosis. E7 binds pRb (retinoblastoma protein), releasing E2F transcription factors to drive uncontrolled cell-cycle progression. Combined E6/E7 activity leads to genomic instability and accumulation of key mutations (e.g., TP53 loss, PIK3CA activation) [ 51 – 54 ] . 2. Epigenetic Reprogramming: Promoter methylation (e.g., CDKN2A, MGMT) silences tumor-suppressor genes. hTERT (telomerase) activation maintains cellular immortality and clonal expansion [ 55 – 57 ] . 3. Immune Evasion and Microenvironment Modulation: Downregulation of HLA-I molecules and interferon pathways impairs antigen presentation [ 58 ] . PD-L1 overexpression fosters an immunosuppressive microenvironment (Treg infiltration, TGF-β upregulation), accelerating tumor progression [ 59 – 61 ] . Geographic Disparities and Research Gaps While the United States dominated publication output (50.1%), followed by England and Italy, research contributions from LMICs remain disproportionately low. This disparity is concerning, given that over 70% of HPV-related oral cancer cases occur in regions such as South and Southeast Asia, where vaccine uptake and surveillance infrastructure are limited [ 62 ] . Our findings align with prior reports highlighting inequities in HPV vaccine access and research funding [38]. Future efforts must prioritize capacity-building and collaborative networks to ensure equitable global prevention. Institutional and Author Leadership The National Cancer Institute (NCI) and leading academic centers in North America and Europe emerged as central hubs for research, as evidenced by co-authorship and citation networks. Notably, Giuliano AR and Alemany L, both highly cited authors, have significantly shaped the discourse through seminal studies on HPV vaccine efficacy and cross-continental epidemiology. However, the dominance of Western institutions raises questions about the generalizability of findings to diverse populations, particularly regarding vaccine effectiveness in regions with high HPV genotype diversity. Emerging Research Themes Keyword clustering revealed a shift from foundational studies on HPV16/p16INK4a to emerging themes such as vaccine innovations, economic evaluations, and the role of adjunctive therapies like metformin in modulating HPV-driven carcinogenesis. The detection of citation bursts for terms like “RG1-VLP vaccine” and “indirect cost” signals a pivot toward implementation science and cost-effectiveness, critical for policy adoption in resource-limited settings. Future Directions Future research should pivot toward three interlinked priorities: (1) validate single-dose HPV vaccine regimens through adaptive platform trials in LMICs, integrating local epidemiology and health-system constraints to generate cost-effectiveness evidence for policy uptake; (2) elucidate metformin’s mechanistic synergy with standard prophylaxis—using multi-omics and organoid models—to determine optimal dosing schedules for high-risk cohorts with persistent oral HPV-16/18; and (3) build implementation-science toolkits that translate “indirect cost” metrics into real-time decision dashboards for ministries of health, leveraging AI-driven simulation to forecast vaccine impact under varying resource scenarios and social determinants. Limitations Our analysis is constrained by the WoSCC database’s potential underrepresentation of non-English publications and grey literature from LMICs. Additionally, the focus on vaccination and oral cancer may have overlooked broader HNSCC research. Conclusion This study provides a road-map for optimizing HPV vaccination strategies in oral cancer prevention. By highlighting geographic inequities and emerging research foci, we advocate for targeted investments in LMICs, cross-disciplinary collaborations, and policy frameworks that integrate oral HPV surveillance into broader cancer control programs. The ultimate goal is to translate vaccination science into equitable cancer prevention globally. Abbreviations Human Papillomavirus (HPV) Web of Science Core Collection (WoSCC) oral cancer (OC) retinoblastoma protein (pRb) National Cancer Institute (NCI) Declarations Acknowledgments Not applicable. Funds This study was supported by the scientific research of the Heilongjiang Provincial Health Commission (grant number 20240909010037), Heilongjiang Postdoctoral Fund (LBH-Z24304) and Heilongjiang provincial scientific research project of traditional Chinese Medicine(ZHY2024-041). Authors’ contributions Y. H. drafted the manuscript. W. G. and L. L. reviewed and revised the manuscript. All the authors have read and approved the final version of the manuscript. All the authors contributed to the manuscript and approved the submitted version. Consent for publication Not applicable. Availability of data and materials Not applicable. Competing interests There is no competing interests. Institutional Review Board Statement: Not applicable for studies not involving humans or animals. Informed Consent Statement: Not applicable. Data Availability Statement: The original contributions of this study are included in the article and supplementary material at http://www.webofscience.com/wos/woscc/basic-search. Further inquiries can be directed to the corresponding authors. Acknowledgments: We acknowledge any support given which is not covered by the author contribution or funding sections. References Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10–45. Wu Y, He S, Cao M, Teng Y, Li Q, Tan N, Wang J, Zuo T, Li T, Zheng Y, Xia C, Chen W. Comparative analysis of cancer statistics in China and the United States in 2024. Chin Med J (Engl). 2024;137(24):3093–100. Zhang J, Ke Y, Chen C, Jiang Z, Liu H, Liu Y, Cao H. HPV cancer burden by anatomical site, country, and region in 2022. Sci Rep. 2025;15(1):21048. 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Szewczyk M, Ostapowicz J, Piotrowski I, Ostrowska K, Suchorska W, Golusiński W. Prognostic value of human papilloma virus (HPV) status and programmed cell death ligand 1 (PD-L1) status in oral tongue cancer. Contemp Oncol (Pozn). 2024;28(4):291–6. Kashif M, Minhas S, Jahan S, Shahzad F, Tahir R, Abbas A, Idrees M, Afzal N. Exploring HPV-linked head and neck cancer in Southern Punjab, Pakistan: Insights from HPV-16 phylogenetic analysis. J Taibah Univ Med Sci. 2025;20(2):242–50. Tables Table 1 The article counts across different countries Country documents USA 199 England 32 Italy 31 China 28 Spain 27 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8314623","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":588466016,"identity":"68c19b24-2cf0-40dc-ba68-0bd85816be68","order_by":0,"name":"Ye Han","email":"","orcid":"","institution":"Heilongjiang Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ye","middleName":"","lastName":"Han","suffix":""},{"id":588466020,"identity":"28ec2292-868e-445b-9fd1-35737b4968fe","order_by":1,"name":"Wenyu Ge","email":"","orcid":"","institution":"Heilongjiang Provincial Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wenyu","middleName":"","lastName":"Ge","suffix":""},{"id":588466023,"identity":"aae5766c-244f-4b90-8c64-c798f1589456","order_by":2,"name":"Lichen Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYBACAwglUd8m//jAgQ8/iNPC2MDAYMHYx5CWeHBmD/FaKhjnMeQYH+ZgI0YL+xnzBx93SDCzMZz5cJiBh0GeX+wAAS08OYaNM89IsLEx9m44XGDBYDhzdgIhh+UYNvO2SfCwMfNuODyDhyHB4DYhLfxvwFqA1vA8OMzDRowWCYgtBmw8PAzEanlWOHNmm0QCmwSbATCQJQj7xb4/ecOHj211CfIzmB9/+PDDRp5fmoAWBgYOA2SeBCHlIMD+gBhVo2AUjIJRMJIBABA6QLBuNABnAAAAAElFTkSuQmCC","orcid":"","institution":"Heilongjiang Provincial Hospital","correspondingAuthor":true,"prefix":"","firstName":"Lichen","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-12-09 07:53:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8314623/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8314623/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102321522,"identity":"22aa8ea7-4421-4588-941d-cf8572c61192","added_by":"auto","created_at":"2026-02-10 13:47:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2870957,"visible":true,"origin":"","legend":"\u003cp\u003eTitle: Flowchart of the Search Strategy\u003c/p\u003e\n\u003cp\u003eLegend: The flowchart depicts the stepwise selection and screening of articles.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-8314623/v1/eb23e4c427f45b161dd96c8e.png"},{"id":102321519,"identity":"f7e1fb0b-5dfc-4700-ba1e-3f2f5dee1221","added_by":"auto","created_at":"2026-02-10 13:47:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":938003,"visible":true,"origin":"","legend":"\u003cp\u003eTitle:\u003cstrong\u003e \u003c/strong\u003eAnnual Output of Research on HPV in Oral Cancer\u003c/p\u003e\n\u003cp\u003eLegend: The figure illustrates the annual number of published research articles on HPV in oral cancer.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-8314623/v1/a565d6d0c220c8fdff9a7930.png"},{"id":102321524,"identity":"46807130-aaed-4bca-bf0c-91e5b68286af","added_by":"auto","created_at":"2026-02-10 13:47:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3766179,"visible":true,"origin":"","legend":"\u003cp\u003eTitle: Country Collaboration Map\u003c/p\u003e\n\u003cp\u003eLegend: The map visualizes international collaborations and highlights the countries of corresponding authors, providing insights into the geographical distribution and collaborative patterns in this field.\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-8314623/v1/1680408fee546b4f08c916d9.png"},{"id":102321523,"identity":"2ecd69bb-3ca4-4d34-b1ca-e75e3582a596","added_by":"auto","created_at":"2026-02-10 13:47:42","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":6354255,"visible":true,"origin":"","legend":"\u003cp\u003eTitle: Top Relevant Affiliations and Their Output in HPV–Oral Cancer Research\u003c/p\u003e\n\u003cp\u003eLegend: (A) Co-authorship organizations. (B) Citing organizations.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-8314623/v1/0da2629eddcef63107c709f6.png"},{"id":102321526,"identity":"f6f299dc-568b-4cc3-b438-3c35dc438d94","added_by":"auto","created_at":"2026-02-10 13:47:42","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":6797517,"visible":true,"origin":"","legend":"\u003cp\u003eTitle: Journal-Level Citation Patterns in Oral HPV Research\u003c/p\u003e\n\u003cp\u003eLegend: (A) Citation-volume map of publishing journals. (B) Co-citation network of journals.\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-8314623/v1/8ee32fcb3478a2e144f06635.png"},{"id":102321525,"identity":"d5e068cc-c5e6-4d92-abe5-9a7b68f896cc","added_by":"auto","created_at":"2026-02-10 13:47:42","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":1526252,"visible":true,"origin":"","legend":"\u003cp\u003eTitle: Author-Level Landscape of HPV–Oral Cancer Research\u003c/p\u003e\n\u003cp\u003eLegend: (A) Co-authorship network generated with VOSviewer. (B) Top five most-prolific authors identified with bibliometrix.\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-8314623/v1/08bdf038123db1d489239385.png"},{"id":102321521,"identity":"0ef1cb4c-9bd6-462d-805a-06d100df8eaf","added_by":"auto","created_at":"2026-02-10 13:47:42","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":8924574,"visible":true,"origin":"","legend":"\u003cp\u003eTitle: Keyword-Level Evolution and Impact in HPV–Oral Cancer Research\u003c/p\u003e\n\u003cp\u003eLegend: (A) Co-occurrence network generated with VOSviewer. (B) Citation-burst timeline generated with CiteSpace.\u003c/p\u003e","description":"","filename":"image7.png","url":"https://assets-eu.researchsquare.com/files/rs-8314623/v1/d40383376d022b9b51a4c7ca.png"},{"id":106960607,"identity":"b5d4e6a0-526e-4972-8b19-df1130064275","added_by":"auto","created_at":"2026-04-15 09:22:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":28946236,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8314623/v1/0877c9c3-821d-4c30-850d-2f177923a263.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mapping the Global Research Landscape of HPV Vaccination and Oral Cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOral cancer (OC) is a leading cause of cancer-related morbidity and mortality worldwide\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Human papillomavirus (HPV) is a well-established oncogenic agent implicated in the pathogenesis of oral cancer (OC)\u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. Over the past decade, the incidence of HPV-positive OC has risen dramatically in many regions, including North America, Europe, and parts of Asia \u003csup\u003e[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. In contrast to HPV-negative OC, which is strongly associated with tobacco and alcohol use, HPV-positive cases tend to occur in younger, non-smoking individuals and are associated with better prognosis \u003csup\u003e[\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Despite this, the global burden of HPV-related oral cancers continues to increase, underscoring the urgent need for effective prevention strategies \u003csup\u003e[\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eProphylactic HPV vaccination, primarily targeting high-risk types such as HPV-16 and HPV-18, has been widely implemented in cervical cancer prevention programs worldwide \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. However, its impact on the prevention of HPV-associated oral cancers remains underexplored, particularly in the context of global research trends, policy adoption, and public health integration \u003csup\u003e[\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. While several studies have demonstrated the potential of HPV vaccination to reduce the incidence of oral HPV infection and subsequent malignancy \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e, disparities in vaccine uptake, policy implementation, and research focus persist across regions \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRecent bibliometric analyses have provided valuable insights into the evolving landscape of various research fields, identifying key contributors, research hotspots, and emerging trends, including HPV-related research\u003csup\u003e[\u003cspan additionalcitationids=\"CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e. For instance, studies have highlighted the increasing focus on HPV-associated head and neck cancers in high-income countries, while low- and middle-income countries (LMICs) continue to face challenges in vaccine access and surveillance \u003csup\u003e[\u003cspan additionalcitationids=\"CR37\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e. Additionally, the integration of artificial intelligence and machine learning in HPV-related cancer research has opened new avenues for early detection and risk stratification \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite these advances, a comprehensive bibliometric analysis specifically examining the global research landscape of HPV vaccination and its relationship to oral cancer prevention has not been conducted. This study aims to fill this gap by systematically analyzing publication trends, citation networks, and research themes from 2012 to 2025. By leveraging bibliometric tools and methodologies, we seek to identify key research clusters, influential authors, and regional disparities in HPV vaccination and oral cancer research. This analysis will provide critical insights for policymakers, researchers, and public health practitioners to optimize HPV vaccination strategies and reduce the global burden of HPV-related oral cancers.\u003c/p\u003e\n\u003ch3\u003eSearch Strategy\u003c/h3\u003e\n\u003cp\u003eWe conducted a literature search in the Web of Science Core Collection (WoSCC) database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.webofscience.com/wos/woscc/basic-search\u003c/span\u003e\u003cspan address=\"https://www.webofscience.com/wos/woscc/basic-search\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) on 12th July 2025. The search strategy, detailed in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, was limited to document types \u0026ldquo;Article\u0026rdquo; and \u0026ldquo;Review,\u0026rdquo; yielding 397 eligible publications for the subsequent bibliometric analysis.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData Analysis\u003c/h2\u003e \u003cp\u003eVOSviewer (v1.6.20) was employed to construct and visualize networks of countries, institutions, journals, authors, and keywords\u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e, \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]\u003c/sup\u003e. In these maps, node size reflects publication volume or citation frequency related to HPV vaccine,and oral cancer; node colour denotes thematic clusters, and edge thickness signifies the strength of collaboration or co-citation ties.\u003c/p\u003e \u003cp\u003eCiteSpace (v6.3.1) was subsequently used to detect citation bursts, thereby spotlighting seminal papers that have shaped discourse on optimal dosing regimens, vaccines thresholds, and long-term oncological outcomes\u003csup\u003e[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe R package \u0026ldquo;bibliometrix\u0026rdquo; (v4.3.0) enabled temporal analyses of research themes and the construction of a global knowledge-flow network, revealing how concepts such as HPV vaccines and oral cancer have evolved across time and geography\u003csup\u003e[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eJournal quality metrics\u0026mdash;quartile rank and 2025 impact factor\u0026mdash;were extracted from Journal Citation Reports to contextualize the influence of publishing venues.\u003c/p\u003e \u003cp\u003eFinally, Microsoft Excel 2021 facilitated data cleaning, quantitative tabulation, and graphical refinement, ensuring transparent and reproducible reporting\u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThese tools provide an integrated, data-driven overview of dose\u0026ndash;response investigations linking HPV immunization to the prevention of oral cancer, highlighting both established partnerships and emerging research frontiers.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cp\u003eQuantitative Analysis of Publications\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 2\u003c/strong\u003e presented a bar chart illustrating the annual publication trends of HPV vaccines in oral cancer from 2012 to 2025. In 2012, 22 articles were produced by the field. A slight dip to 21 articles was observed in 2013, followed by a rebound to 22 in 2014, and then a rise to 24 in 2015\u0026mdash;marking the highest level of the first half-decade. After a brief retreat to 21 in 2016, the count fell to 17 in 2017, which was recorded as the period\u0026rsquo;s lowest point. A dramatic upswing was then registered: 42 publications were indexed in 2018, nearly 2.5 times the previous year\u0026rsquo;s total, and 40 were documented in 2019. A modest contraction was noted in 2020, when 27 papers were tallied, but a rapid recovery was seen in 2021 with 38 publications and in 2022 with 33. Relative stability was maintained in the most recent years, as 28 articles were counted in 2023, 39 in 2024, and 23 have been expected or already indexed for 2025.\u003c/p\u003e\n\u003cp\u003eCountry Analysis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3\u003c/strong\u003e was presented as a bibliometric dissection of the global landscape of HPV research in oral cancer. In Figure 3A, a country-level collaboration network was generated by bibliometrix and was depicted on a world map. Bilateral or multilateral co-authorships were encoded by connecting edges, whereas chromatic gradients from light to dark were used to mirror the intensity of research activity.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 3B\u003c/strong\u003e was produced with VOSviewer, in which nodes were overlaid to cluster countries according to their joint publication profiles. The size of each node was scaled to reflect document counts, and the proximity between nodes was employed to indicate the strength of collaborative ties; warmer colors were assigned to denote higher centrality within the network.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e was compiled to summarize the national publication output on HPV in oral cancer over the study period. The United States was found to dominate the field, with 199 documents recorded, far exceeding the contributions of any other country. England was ranked second, with 32 publications, and was followed closely by Italy with 31. China and Spain were listed as the fourth and fifth contributors, with 28 and 27 documents, respectively. This distribution underscored a pronounced concentration of research activity in North America and Europe, while the emerging\u0026mdash;yet comparatively modest\u0026mdash;engagement of China and Spain in the global discourse on oral HPV was also highlighted.\u003c/p\u003e\n\u003cp\u003eCo-authorship Organization and Citation Organizations Analysis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 4\u003c/strong\u003e was depicted as a bibliometric evaluation of HPV research in oral cancer, and was constructed with VOSviewer through two complementary network analyses: co-authorship organisation in\u0026nbsp;\u003cstrong\u003eFigure 4\u003c/strong\u003e\u003cstrong\u003eA\u003c/strong\u003e and citation organisation\u0026nbsp;\u003cstrong\u003ein Figure 4\u003c/strong\u003e\u003cstrong\u003eB\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eIn \u003cstrong\u003eFigure 4\u003c/strong\u003e\u003cstrong\u003eA\u003c/strong\u003e, institutions were represented as nodes whose diameters were scaled according to the number of co-authored publications on oral HPV; inter-node links were used to denote collaborative ties, with shorter distances and thicker lines being employed to indicate stronger co-authorship intensity. Prominent university medical centres, comprehensive cancer institutes, and specialised stomatology hospitals were identified as the principal hubs. The largest publication clusters were generated by these institutions, and central positions within the network were occupied by them, thereby underscoring their pivotal role in the coordination of multi-centre studies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 4\u003c/strong\u003e\u003cstrong\u003eB\u003c/strong\u003e was presented as the citation organisation overlay, in which node size was scaled proportionally to the cumulative citations that had been received by each institution\u0026rsquo;s oral-HPV corpus, and colour gradients were applied to reflect the average citation per paper. A clear concentration of influence was observed, and the citation landscape was dominated by the same leading institutions.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eJournals Analysis\u003c/p\u003e\n\u003cp\u003eIn \u003cstrong\u003eFigure 5\u003c/strong\u003e\u003cstrong\u003eA\u003c/strong\u003e, journals were rendered as nodes whose sizes were scaled to the total citation volume received by articles on oral HPV; colour gradients were applied to indicate the average citations per paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 5\u003c/strong\u003e\u003cstrong\u003eB\u003c/strong\u003e presented the co-citation-sources network, in which journals were positioned according to their co-citation frequency\u0026mdash;that is, how often pairs of journals were cited together. Clusters of strongly co-cited journals were revealed, and their thematic coherence was interpreted as evidence of shared disciplinary focus.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthor Analysis\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 6\u003c/strong\u003e was constructed to delineate the author-level landscape of HPV research in oral cancer. In\u0026nbsp;\u003cstrong\u003eFigure 6A\u003c/strong\u003e, the co-authorship network was generated with VOSviewer: authors were rendered as nodes whose sizes were scaled to publication counts, and inter-node distances together with edge thicknesses were employed to quantify collaborative intensity. Distinct clusters of investigators\u0026mdash;each representing sustained multi-centre collaborations\u0026mdash;were clearly delineated, thereby mapping the core research communities active in this domain.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 6B\u003c/strong\u003e was produced with bibliometrix to identify the most relevant authors by document volume. Giuliano AR was positioned first, with 13 publications; Alemany L followed in second place with 8. Bencina G, Gillison ML, and Pinto LA were jointly ranked third, each having contributed 7 papers.\u003c/p\u003e\n\u003cp\u003eKeyword Analysis\u003c/p\u003e\n\u003cp\u003eIn \u003cstrong\u003eFigure 7A\u003c/strong\u003e, VOSviewer was employed to construct a co-occurrence network of all keywords extracted from titles, abstracts, and author keywords. Terms were represented as nodes whose sizes were scaled to their occurrence frequency, and edges denoted co-occurrence strength.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFigure 7B\u003c/strong\u003e was generated with CiteSpace to identify citation bursts\u0026mdash;sudden, transient surges in citation frequency that mark influential turning points. Four burst terms were detected: \u0026ldquo;HORMONAL CONTRACEPTIVES\u0026rdquo;, \u0026ldquo;indirect cost\u0026rdquo;, \u0026ldquo;HUMAN-PAPILLOMAVIRUS\u0026rdquo;, and \u0026ldquo;RG1-VLP vaccine\u0026rdquo;. These bursts were interpreted as indicators of pivotal conceptual shifts or methodological innovations that had rapidly attracted scholarly attention and had subsequently redirected research trajectories within the HPV\u0026ndash;oral cancer domain.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present bibliometric analysis is the first to comprehensively map the global research landscape of HPV vaccination and its role in oral cancer prevention over a 13-year period (2012\u0026ndash;2025). Our findings reveal a steadily growing body of literature, with a marked acceleration after 2018, coinciding with the WHO\u0026rsquo;s call for global elimination of cervical cancer and expanded HPV vaccination programs \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. This temporal trend underscores the increasing recognition of HPV vaccination as a potential strategy to mitigate not only cervical but also oral cancers \u003csup\u003e[\u003cspan additionalcitationids=\"CR46 CR47 CR48 CR49\" citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eBasic Mechanisms of HPV in Oral Cancer\u003c/h2\u003e \u003cp\u003eHuman papillomavirus (HPV) infects basal epithelial cells of the oral mucosa through microabrasions or compromised mucosal barriers (e.g., trauma, inflammation, or tobacco/alcohol exposure). High-risk subtypes HPV-16/18 play a pivotal role in oncogenesis via the following mechanisms:\u003c/p\u003e \u003cp\u003e1. E6/E7 Oncoprotein Synergy:\u003c/p\u003e \u003cp\u003eE6 recruits the E6-AP ubiquitin ligase to degrade p53, disrupting DNA damage repair and apoptosis. E7 binds pRb (retinoblastoma protein), releasing E2F transcription factors to drive uncontrolled cell-cycle progression. Combined E6/E7 activity leads to genomic instability and accumulation of key mutations (e.g., TP53 loss, PIK3CA activation)\u003csup\u003e[\u003cspan additionalcitationids=\"CR52 CR53\" citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e2. Epigenetic Reprogramming:\u003c/p\u003e \u003cp\u003ePromoter methylation (e.g., CDKN2A, MGMT) silences tumor-suppressor genes. hTERT (telomerase) activation maintains cellular immortality and clonal expansion\u003csup\u003e[\u003cspan additionalcitationids=\"CR56\" citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e3. Immune Evasion and Microenvironment Modulation:\u003c/p\u003e \u003cp\u003eDownregulation of HLA-I molecules and interferon pathways impairs antigen presentation\u003csup\u003e[\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]\u003c/sup\u003e. PD-L1 overexpression fosters an immunosuppressive microenvironment (Treg infiltration, TGF-β upregulation), accelerating tumor progression\u003csup\u003e[\u003cspan additionalcitationids=\"CR60\" citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eGeographic Disparities and Research Gaps\u003c/h2\u003e \u003cp\u003eWhile the United States dominated publication output (50.1%), followed by England and Italy, research contributions from LMICs remain disproportionately low. This disparity is concerning, given that over 70% of HPV-related oral cancer cases occur in regions such as South and Southeast Asia, where vaccine uptake and surveillance infrastructure are limited \u003csup\u003e[\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]\u003c/sup\u003e. Our findings align with prior reports highlighting inequities in HPV vaccine access and research funding [38]. Future efforts must prioritize capacity-building and collaborative networks to ensure equitable global prevention.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eInstitutional and Author Leadership\u003c/h2\u003e \u003cp\u003eThe National Cancer Institute (NCI) and leading academic centers in North America and Europe emerged as central hubs for research, as evidenced by co-authorship and citation networks. Notably, Giuliano AR and Alemany L, both highly cited authors, have significantly shaped the discourse through seminal studies on HPV vaccine efficacy and cross-continental epidemiology. However, the dominance of Western institutions raises questions about the generalizability of findings to diverse populations, particularly regarding vaccine effectiveness in regions with high HPV genotype diversity.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eEmerging Research Themes\u003c/h2\u003e \u003cp\u003eKeyword clustering revealed a shift from foundational studies on HPV16/p16INK4a to emerging themes such as vaccine innovations, economic evaluations, and the role of adjunctive therapies like metformin in modulating HPV-driven carcinogenesis. The detection of citation bursts for terms like \u0026ldquo;RG1-VLP vaccine\u0026rdquo; and \u0026ldquo;indirect cost\u0026rdquo; signals a pivot toward implementation science and cost-effectiveness, critical for policy adoption in resource-limited settings.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eFuture Directions\u003c/h2\u003e \u003cp\u003eFuture research should pivot toward three interlinked priorities: (1) validate single-dose HPV vaccine regimens through adaptive platform trials in LMICs, integrating local epidemiology and health-system constraints to generate cost-effectiveness evidence for policy uptake; (2) elucidate metformin\u0026rsquo;s mechanistic synergy with standard prophylaxis\u0026mdash;using multi-omics and organoid models\u0026mdash;to determine optimal dosing schedules for high-risk cohorts with persistent oral HPV-16/18; and (3) build implementation-science toolkits that translate \u0026ldquo;indirect cost\u0026rdquo; metrics into real-time decision dashboards for ministries of health, leveraging AI-driven simulation to forecast vaccine impact under varying resource scenarios and social determinants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eOur analysis is constrained by the WoSCC database\u0026rsquo;s potential underrepresentation of non-English publications and grey literature from LMICs. Additionally, the focus on vaccination and oral cancer may have overlooked broader HNSCC research.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study provides a road-map for optimizing HPV vaccination strategies in oral cancer prevention. By highlighting geographic inequities and emerging research foci, we advocate for targeted investments in LMICs, cross-disciplinary collaborations, and policy frameworks that integrate oral HPV surveillance into broader cancer control programs. The ultimate goal is to translate vaccination science into equitable cancer prevention globally.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eHuman Papillomavirus (HPV)\u003c/p\u003e\u003cp\u003eWeb of Science Core Collection (WoSCC)\u003c/p\u003e\u003cp\u003eoral cancer (OC)\u003c/p\u003e\u003cp\u003eretinoblastoma protein (pRb)\u003c/p\u003e\u003cp\u003eNational Cancer Institute (NCI)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunds\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the scientific research of the Heilongjiang Provincial Health Commission (grant number 20240909010037), Heilongjiang Postdoctoral Fund (LBH-Z24304) and Heilongjiang provincial scientific research project of traditional Chinese Medicine(ZHY2024-041).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAuthors\u0026rsquo; contributions\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eY. H.\u0026nbsp;drafted the manuscript. W. G. and\u0026nbsp;L. L. reviewed and revised the manuscript. All the authors have read and approved the final version of the manuscript. All the authors contributed to the manuscript and approved the submitted version.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eConsent for publication\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cbr\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCompeting interests\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eThere is no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstitutional Review Board Statement:\u0026nbsp;\u003c/strong\u003eNot applicable for studies not involving humans or animals.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent Statement:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability Statement:\u0026nbsp;\u003c/strong\u003eThe original contributions of this study are included in the article and supplementary material at http://www.webofscience.com/wos/woscc/basic-search. Further inquiries can be directed to the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eWe acknowledge any support given which is not covered by the author contribution or funding sections.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10\u0026ndash;45.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu Y, He S, Cao M, Teng Y, Li Q, Tan N, Wang J, Zuo T, Li T, Zheng Y, Xia C, Chen W. Comparative analysis of cancer statistics in China and the United States in 2024. Chin Med J (Engl). 2024;137(24):3093\u0026ndash;100.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang J, Ke Y, Chen C, Jiang Z, Liu H, Liu Y, Cao H. HPV cancer burden by anatomical site, country, and region in 2022. 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Front Med (Lausanne). 2025;12:1565778.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Y, Soh KL, Jing X, Wei L, Rajen Durai R, Soh KG. Bibliometric analysis of resilience in stroke from 2000 to 2024 using CiteSpace and VOSviewer. Front Psychol. 2025;16:1452249.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie H, Kang B. Mental Health of Nursing Students: A Bibliometric Review Based on CiteSpace Visual Analysis. J Nurs Manag. 2025;2025:2169094.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGao S, Li L, Wei Y, Wen L, Shao S, Wu J, Zong X. Research Progress of ARTP Mutagenesis Technology Based on Citespace Visualization Analysis. Mol Biotechnol. 2025;67(7):2587\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTian J, Dong YX, Wang L, Wu YM, Zhao ZY, Che GW. Mapping the evolution of 3D printing in cardio-thoracic diseases: a global bibliometric analysis. Int J Surg. 2025;111(1):1629\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFu Q, Sandeep B, Li H, Wang BS, Huang X. Impact of perioperative dexmedetomidine on postoperative delirium in adult undergoing cardiac surgery: A comprehensive bibliometrix and meta-analysis. Asian J Psychiatr. 2025;108:104522.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology of Human Papillomavirus-Positive Head and Neck Squamous Cell Carcinoma. J Clin Oncol. 2015;33(29):3235\u0026ndash;42.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArag\u0026oacute;n-Ni\u0026ntilde;o \u0026Iacute;, Cuesta-Urqu\u0026iacute;a C, Gonz\u0026aacute;lez-Mart\u0026iacute;n-Moro J, Mor\u0026aacute;n-Soto MJ, Pozo-Kreilinger JJ, Pamp\u0026iacute;n-Martinez MM, Del Castillo-Pardo-de Vera JL, Cebri\u0026aacute;n-Carretero JL. HPV infection in oral cancer, our experience: prevalence, clinical implications, and current vaccination program in Spain. J Clin Exp Dent. 2023;15(7):e584-e589.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTimbang MR, Sim MW, Bewley AF, Farwell DG, Mantravadi A, Moore MG. HPV-related oropharyngeal cancer: a review on burden of the disease and opportunities for prevention and early detection. Hum Vaccin Immunother. 2019;15(7\u0026ndash;8):1920\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWolf J, Kist LF, Pereira SB, Quessada MA, Petek H, Pille A, Maccari JG, Mutlaq MP, Nasi LA. Human papillomavirus infection: Epidemiology, biology, host interactions, cancer development, prevention, and therapeutics. Rev Med Virol. 2024;34(3):e2537.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKamolratanakul S, Pitisuttithum P. Human Papillomavirus Vaccine Efficacy and Effectiveness against Cancer. Vaccines (Basel). 2021;9(12).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGheit T, Muwonge R, Lucas E, Galati L, Anantharaman D, McKay-Chopin S, Malvi SG, Jayant K, Joshi S, Esmy PO, Pillai MR, Basu P, Sankaranarayanan R, Tommasino M. Impact of HPV vaccination on HPV-related oral infections. Oral Oncol. 2023;136:106244.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaur G, Yap T, Ramani R, McCullough M, Singh A. Assessing bias in the causal role of HPV in oral cancer: A systematic review and meta-analysis. Oral Dis. 2024;30(8):5379\u0026ndash;87.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng Q, Wang L, Zuo L, Gao S, Jiang X, Han Y, Lin J, Peng M, Wu N, Tang Y, Tian H, Zhou Y, Liao Q. HPV E6/E7: insights into their regulatory role and mechanism in signaling pathways in HPV-associated tumor. Cancer Gene Ther. 2024;31(1):9\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaberna M, Mena M, Pav\u0026oacute;n MA, Alemany L, Gillison ML, Mes\u0026iacute;a R. Human papillomavirus-related oropharyngeal cancer. Ann Oncol. 2017;28(10):2386\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWong GR, Ha KO, Himratul-Aznita WH, Yang YH, Wan Mustafa WM, Yuen KM, Abraham MT, Tay KK, Karen-Ng LP, Cheong SC, Zain RB. Seropositivity of HPV 16 E6 and E7 and the risk of oral cancer. Oral Dis. 2014;20(8):762\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePrawdzic Seńkowska A, Kiczmer P, Strzelczyk JK, Kowalski D, Krakowczyk Ł, Ostrowska Z. Impact of HPV infection on gene expression and methylation in oral cancer patients. J Med Microbiol. 2019;68(3):440\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiuliano AR, Nedjai B, Lorincz AT, Schell MJ, Rahman S, Banwait R, Boulware D, Sirak B, Martin-Gomez L, Abrahamsen M, Isaacs-Soriano KA, Wenig B, Chung CH, Caudell J. Methylation of HPV 16 and EPB41L3 in oral gargles: Associations with oropharyngeal cancer detection and tumor characteristics. Int J Cancer. 2020;146(4):1018\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnić P, Golubić Talić J, Božinović K, Dediol E, Mravak-Stipetić M, Grce M. Milutin Gašperov N. Methylation of Immune Gene Promoters in Oral and Oropharyngeal Cancer. Int J Mol Sci. 2023;24(9).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWickenhauser C, Bethmann D, Kappler M, Eckert AW, Steven A, Bukur J, Fox BA, Beer J, Seliger B. Tumor Microenvironment, HLA Class I and APM Expression in HPV-Negative Oral Squamous Cell Carcinoma. Cancers (Basel). 2021;13(4).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWu J, Pang X, Yang X, Zhang M, Chen B, Fan H, Wang H, Yu X, Tang Y, Liang X. M1 macrophages induce PD-L1(hi) cell-led collective invasion in HPV-positive head and neck squamous cell carcinoma via TNF-α/CDK4/UPS14. J Immunother Cancer. 2023;11(12).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMishra A. PD-1/PD-L1 biology and immunotherapy in HPV-positive oral cancers. Future Oncol. 2017;13(22):1907\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSzewczyk M, Ostapowicz J, Piotrowski I, Ostrowska K, Suchorska W, Golusiński W. Prognostic value of human papilloma virus (HPV) status and programmed cell death ligand 1 (PD-L1) status in oral tongue cancer. Contemp Oncol (Pozn). 2024;28(4):291\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKashif M, Minhas S, Jahan S, Shahzad F, Tahir R, Abbas A, Idrees M, Afzal N. Exploring HPV-linked head and neck cancer in Southern Punjab, Pakistan: Insights from HPV-16 phylogenetic analysis. J Taibah Univ Med Sci. 2025;20(2):242\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e The article counts across different countries\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"590\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 266px;\"\u003e\n \u003cp\u003eCountry\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 324px;\"\u003e\n \u003cp\u003edocuments\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 266px;\"\u003e\n \u003cp\u003eUSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 324px;\"\u003e\n \u003cp\u003e199\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 266px;\"\u003e\n \u003cp\u003eEngland\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 324px;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 266px;\"\u003e\n \u003cp\u003eItaly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 324px;\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 266px;\"\u003e\n \u003cp\u003eChina\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 324px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 266px;\"\u003e\n \u003cp\u003eSpain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 324px;\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"oral cancer, HPV vaccines, Human Papillomavirus Vaccines, bibliometrix, VOSviewer, CiteSpace","lastPublishedDoi":"10.21203/rs.3.rs-8314623/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8314623/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOral cancer remains a significant global health challenge, with research focusing on the role of HPV vaccination in its prevention. This study aimed to fill that gap by analyzing publications related to HPV vaccination and oral cancer from 2012 to 2025, retrieved from the Web of Science Core Collection. Using tools like VOSviewer, CiteSpace, and the R package \"bibliometrix,\" the analysis included 397 articles, revealing a steady increase in research output over time, with the United States leading in publication volume. Key institutions such as NCI, along with prominent authors like Giuliano AR, contributed significantly to the field. Emerging topics included vaccine innovations and economic evaluations. Despite growth, the research landscape remains geographically skewed, highlighting the need for expanded studies in underrepresented regions. This bibliometric analysis offers valuable insights into the development, collaborations, and future directions of HPV vaccination research related to oral cancer, guiding future efforts to achieve equitable global prevention.\u003c/p\u003e","manuscriptTitle":"Mapping the Global Research Landscape of HPV Vaccination and Oral Cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-10 13:47:18","doi":"10.21203/rs.3.rs-8314623/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2289826f-f99d-4ac0-a6b6-d36e18891c4b","owner":[],"postedDate":"February 10th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T06:09:24+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-10 13:47:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8314623","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8314623","identity":"rs-8314623","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}