{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T06:53:02Z","timestamp":1781765582519,"version":"3.54.5"},"reference-count":24,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: Human papillomavirus (HPV) infection is the leading cause of cervical cancer and is associated with several anogenital and oropharyngeal malignancies. Although licensed HPV vaccines are highly effective, access remains limited in many low- and middle-income countries due to cost, supply shortages, and implementation barriers. In this study, we evaluated the immunogenicity and safety of Gardisun, a newly developed quadrivalent prophylactic HPV vaccine, compared with Gardasil\u00ae. Methods: This Phase III randomized, double-blind, active-controlled, parallel-group non-inferiority trial enrolled 450 healthy participants stratified by sex and randomized (1:1) to receive three 0.5 mL intramuscular doses of Gardisun or Gardasil\u00ae on Days 0, 60, and 180. Participants were followed through to Day 210. The primary endpoint was the geometric mean titer (GMT) of antibodies against HPV types 6, 11, 16, and 18 one month after the administration of the third dose. Non-inferiority was defined as the lower bound of the 95% confidence interval (CI) for the GMT ratio exceeding 0.67. Safety was assessed through adverse event monitoring. Results: Of the 450 randomized participants, 422 completed the Month 7 visit and 429 received all three doses. Both vaccines induced antibody responses and seroconversion rates for all HPV types. The primary analysis met the non-inferiority criterion for HPV-6, while prespecified sensitivity analyses supported the existence of non-inferiority across all evaluated HPV types. Most adverse events were mild and transient, with no vaccine-related serious adverse events reported. Conclusions: Gardisun demonstrated robust immunogenicity and a safety profile comparable to that of Gardasil\u00ae, supporting its potential as an accessible alternative quadrivalent HPV vaccine for broader vaccination programs in resource-limited settings.<\/jats:p>","DOI":"10.3390\/vaccines14060540","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T05:52:37Z","timestamp":1781761957000},"page":"540","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Phase III, Randomized, Double-Blind, Active-Controlled Non-Inferiority Trial Evaluating the Immunogenicity and Safety of Gardisun, a Quadrivalent Human Papillomavirus Vaccine, Compared with Gardasil\u00ae in Healthy Volunteers Aged 15\u201335 Years"],"prefix":"10.3390","volume":"14","author":[{"given":"Erfan","family":"Pakatchian","sequence":"first","affiliation":[{"name":"Biosunpharmed Company, Tehran 14369335359, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoo","family":"Mohraz","sequence":"additional","affiliation":[{"name":"Department of Infectious and Tropical Diseases, Iranian Research Center for HIV\/AIDS (IRCHA), School of Medicine, Tehran University of Medical Sciences, Tehran 1416753955, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad","family":"Taghavian","sequence":"additional","affiliation":[{"name":"Biosunpharmed Company, Tehran 14369335359, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babak","family":"Javadimehr","sequence":"additional","affiliation":[{"name":"Biosunpharmed Company, Tehran 14369335359, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajar","family":"Mohammadi Barzelighi","sequence":"additional","affiliation":[{"name":"Biosunpharmed Company, Tehran 14369335359, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majid","family":"Teymoori-Rad","sequence":"additional","affiliation":[{"name":"Biosunpharmed Company, Tehran 14369335359, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehrdad","family":"Ghodsi","sequence":"additional","affiliation":[{"name":"Biosunpharmed Company, Tehran 14369335359, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahra Naderi","family":"Saffar","sequence":"additional","affiliation":[{"name":"Biosunpharmed Company, Tehran 14369335359, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1093\/cid\/ciz887","article-title":"Immunogenicity of 2 and 3 doses of the quadrivalent human papillomavirus vaccine up to 120 months postvaccination: Follow-up of a randomized clinical trial","volume":"71","author":"Donken","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e069616","DOI":"10.1136\/bmjopen-2022-069616","article-title":"Efficacy and safety of therapeutic HPV vaccines to treat CIN 2\/CIN 3 lesions: A systematic review and meta-analysis of phase II\/III clinical trials","volume":"13","author":"Zhang","year":"2023","journal-title":"BMJ Open"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2478702","DOI":"10.1080\/21645515.2025.2478702","article-title":"Human papillomavirus (HPV) vaccine clinical trials: A cross-sectional analysis of clinical trials registries","volume":"21","author":"Mavundza","year":"2025","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1042\/BST20253041","article-title":"Advances in understanding the mechanisms of the human papillomavirus oncoproteins","volume":"53","author":"Obanya","year":"2025","journal-title":"Biochem. Soc. Trans."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/s41392-024-02083-w","article-title":"Roles of human papillomavirus in cancers: Oncogenic mechanisms and clinical use","volume":"10","author":"Zhang","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"187","DOI":"10.4103\/2278-330X.119877","article-title":"Efficacy and safety of human papillomavirus vaccine for primary prevention of cervical cancer: A review of evidence from phase III trials and national programs","volume":"2","author":"Basu","year":"2013","journal-title":"S. Asian J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Pal, A., and Kundu, R. (2020). Human papillomavirus E6 and E7: The cervical cancer hallmarks and targets for therapy. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.03116"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/nrc.2018.13","article-title":"Opportunities and challenges for human papillomavirus vaccination in cancer","volume":"18","author":"Roden","year":"2018","journal-title":"Nat. Rev. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Akg\u00f6r, U., Temiz, B.E., Cengiz, M., Ege, H.V., Joura, E., and G\u00fcltekin, M. (2026). New HPV Vaccines on the Market and Future Trends: A State-of-the-Art Review. Vaccines, 14.","DOI":"10.3390\/vaccines14020140"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/S1470-2045(05)70101-7","article-title":"Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: A randomised double-blind placebo-controlled multicentre phase II efficacy trial","volume":"6","author":"Villa","year":"2005","journal-title":"Lancet Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S1473-3099(21)00327-3","article-title":"Efficacy, immunogenicity, and safety of a quadrivalent HPV vaccine in men: Results of an open-label, long-term extension of a randomised, placebo-controlled, phase 3 trial","volume":"22","author":"Goldstone","year":"2022","journal-title":"Lancet Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1016\/S0140-6736(17)31821-4","article-title":"Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16\u201326 years: A randomised, double-blind trial","volume":"390","author":"Huh","year":"2017","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4453","DOI":"10.1038\/s41598-025-34501-6","article-title":"Age distribution of high-risk HPV infection and cervical lesions in an unvaccinated adult Brazilian population within an organized screening program","volume":"16","author":"Rego","year":"2026","journal-title":"Sci. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"197","DOI":"10.30699\/IJP.2019.90356.1861","article-title":"The prevalence of HPV genotypes in Iranian population: An update","volume":"14","author":"Kesheh","year":"2019","journal-title":"Iran. J. Pathol."},{"key":"ref_15","unstructured":"ICO\/IARC Information Centre on HPV and Cancer (2023). Human Papillomavirus and Related Cancers, Fact Sheet 2023 (Iran), ICO\/IARC Information Centre on HPV and Cancer."},{"key":"ref_16","unstructured":"Bruni, L., Albero, G., Serrano, B., Mena, M., Collado, J.J., Gomez, D., Munoz, J., Bosch, F.X., and de Sanjose, S. (2023). Human Papillomavirus and Related Diseases in Iran (Islamic Republic of Iran), ICO\/IARC Information Centre on HPV and Cancer (HPV Information Centre). Summary Report 10 March 2023."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S1473-3099(14)71073-4","article-title":"Population-level impact and herd effects following human papillomavirus vaccination programmes: A systematic review and meta-analysis","volume":"15","author":"Drolet","year":"2015","journal-title":"Lancet Infect. Dis."},{"key":"ref_18","unstructured":"International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (2025). ICH Harmonised Guideline: Guideline for Good Clinical Practice E6(R3), ICH."},{"key":"ref_19","unstructured":"World Health Organization (2017). Guidelines on Clinical Evaluation of Vaccines: Regulatory Expectations, World Health Organization. WHO Technical Report Series No. 1004, Annex 9."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1928","DOI":"10.1056\/NEJMoa061760","article-title":"Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases","volume":"356","author":"Garland","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5571","DOI":"10.1016\/j.vaccine.2006.04.068","article-title":"Immunologic responses following administration of a vaccine targeting human papillomavirus Types 6, 11, 16, and 18","volume":"24","author":"Villa","year":"2006","journal-title":"Vaccine"},{"key":"ref_22","unstructured":"(WHO) World Health Organization (2017). Recommendations to Assure the Quality, Safety and Efficacy of Recombinant Human Papillomavirus Virus-Like Particle Vaccines, World Health Organization. Annex 4, TRS No 999."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/S0140-6736(07)61416-0","article-title":"Human papillomavirus and cervical cancer","volume":"370","author":"Schiffman","year":"2007","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Zhou, X., Sun, L., Yao, X., Li, G., Wang, Y., and Lin, Y. (2020). Progress in vaccination of prophylactic human papillomavirus vaccine. 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