Immunogenicity and safety of quadrivalent and 9-valent human papillomavirus vaccines in Indian clinical trial participants

Suzanne M Garland, Manjula Anagani, Neerja Bhatla, Sukanta Chatterjee, Sanjay Lalwani, Cecil Ross, Thomas Group, Jianxin Lin, Alain Luxembourg, Anuj Walia, Yingmei Tu, Suzanne M Garland, Manjula Anagani, Neerja Bhatla, Sukanta Chatterjee, Sanjay Lalwani, Cecil Ross, Thomas Group, Jianxin Lin, Alain Luxembourg, Anuj Walia, Yingmei Tu

Abstract

The quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) and 9-valent HPV (9vHPV; HPV6/11/16/18/31/33/45/52/58) vaccines have demonstrated efficacy, immunogenicity, and safety in international clinical trials. We report outcomes from three completed clinical trials in India: a single-arm study (V501-029 [NCT00380367]) in Indian girls (aged 9-15 years; N = 110) evaluating qHPV vaccine immunogenicity and safety; a subgroup analysis (n = 225) of Indian girls/boys (9-15 years) and women (16-26 years) from a global study (V503-002 [NCT00943722]) evaluating 9vHPV vaccine immunogenicity and safety; and a qHPV vaccine post-marketing safety surveillance study (V501-125) in Indian females (aged 9-45 years; N = 188) vaccinated during routine care. In V501-029 and V503-002, HPV vaccines were administered as 3 doses (Day 1, Month 2, Month 6). Serum HPV antibodies were evaluated by competitive Luminex immunoassays at Day 1 and Month 7 (both studies) and Months 12, 24, and 36 (V503-002 only). Adverse events (AEs) were collected by Vaccination Report Card. In V501-125, participants were actively surveilled for serious AEs (SAEs) within 30 days post-qHPV vaccination. In per-protocol analyses, qHPV and 9vHPV vaccines induced robust anti-HPV6/11/16/18 (V501-029) and HPV6/11/16/18/31/33/45/52/58 (V503-002) responses, respectively; ≥97% of participants seroconverted at Month 7 for each vaccine HPV type in both studies, and antibody responses persisted through 36 months in V503-002. The most common AEs were injection-site-associated. Most AEs were mild/moderate; no deaths, vaccine-related SAEs, or discontinuations due to AEs were reported. In V501-125, no SAE was reported. Overall, the qHPV and 9vHPV vaccines elicited robust antibody responses and were generally well tolerated in Indian participants.

Keywords: Clinical trial; India; human papillomavirus vaccine; immunogenicity; safety.

Conflict of interest statement

Suzanne M. Garland reports fees for board membership and travel support from Merck, consulting fees from Merck and Sanofi Pasteur, lecture fees from Merck, Sanofi Pasteur, and GlaxoSmithKline, and grant support from Merck, GlaxoSmithKline, and CSL Behring.

Manjula Anagani has no interests to declare.

Neerja Bhatla has received research funding through her Institute from MSD, GlaxoSmithKline, and Digene/Qiagen Inc.

Sukanta Chatterjee has no interests to declare.

Sanjay Lalwani has no interests to declare.

Cecil Ross has no interests to declare.

Thomas Group is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock/stock options in the Company.

Jianxin Lin is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock/stock options in the Company.

Alain Luxembourg is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock/stock options in the Company.

Anuj Walia is a former employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock/stock options in the Company.

Yingmei Tu is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and may own stock/stock options in the Company.

Figures

Figure 1.
Figure 1.
Participant disposition for Indian participants in the qHPV vaccine (Study V501–029) (a) and 9vHPV vaccine (Study V503–002) (b) clinical trials.

References

    1. Lacey CJN, Lowndes CM, Shah KV.. Chapter 4: burden and management of non-cancerous HPV-related conditions: HPV-6/11 disease. Vaccine. 2006;24(Supplement 3):1–9. doi:10.1016/j.vaccine.2006.06.015.
    1. de Martel C, Georges D, Bray F, Ferlay J, Clifford GM. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob Health. 2020;8(2):e180–190. doi:10.1016/S2214-109X(19)30488-7.
    1. Bruni L, Albero G, Serrano B. ICO/IARC information centre on HPV and cancer (HPV information centre). Human papillomavirus and related diseases in India. Summary Report; 2021. Oct 14 [accessed 2022 Jan 14]. .
    1. Arbyn A, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, and Bray F. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob Health. 2020;8(2):e191–e203. doi:10.1016/S2214-109X(19)30482-6.
    1. Luxembourg A, Moeller E. 9-Valent human papillomavirus vaccine: a review of the clinical development program. Expert Rev Vaccines. 2017;16(11):1119–1139. doi:10.1080/14760584.2017.1383158.
    1. de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 2017;141(4):664–670. doi:10.1002/ijc.30716.
    1. Garland SM, Steben M, Sings HL, James M, Lu S, Railkar R, Barr E, Haupt RM, and Joura EA. Natural history of genital warts: Analysis of the placebo arm of 2 randomized phase III trials of a quadrivalent human papillomavirus (types 6, 11, 16, and 18) vaccine. J Infect Dis. 2009;199(6):805–814. doi:10.1086/597071.
    1. Barr E, Gause CK, Bautista OM, Railkar RA, Lupinacci LC, Insinga RP, Sings HL, and Haupt RM. Impact of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine in a sexually active population of North American women. Am J Obstet Gynecol. 2008;198(3):261.e1–261.e11. doi:10.1016/j.ajog.2007.09.001.
    1. Majewski S, Bosch FX, Dillner J, Iversen O-E, Kjaer SK, Muñoz N, Olsson S-E, Paavonen J, Sigurdsson K, Bryan J. et al. The impact of a quadrivalent human papillomavirus (types 6, 11, 16, 18) virus-like particle vaccine in European women aged 16 to 24. J Eur Acad Dermatol Venereol. 2009;23(10):1147–1155. doi:10.1111/j.1468-3083.2009.03266.x.
    1. Perez G, Lazcano-Ponce E, Hernandez-Avila M, García PJ, Muñoz N, Villa LL, Bryan J, Taddeo FJ, Lu S, Esser MT. et al. Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like-particle vaccine in Latin American women. Int J Cancer. 2008;122(6):1311–1318. doi:10.1002/ijc.23260.
    1. Tay EH, Garland S, Tang G, Nolan T, Huang L-M, Orloski L, Lu S, Barr E. Clinical trial experience with prophylactic HPV 6/11/16/18 VLP vaccine in young women from the Asia-Pacific region. Int J Gynaecol Obstet. 2008;102(3):275–283. doi:10.1016/j.ijgo.2008.03.021.
    1. Giuliano AR, Lazcano-Ponce E, Villa L, Nolan T, Marchant C, Radley D, Golm G, McCarroll K, Yu J, Esser MT. et al. Impact of baseline covariates on the immunogenicity of a quadrivalent (types 6, 11, 16, and 18) human papillomavirus virus-like-particle vaccine. J Infect Dis. 2007;196(8):1153–1162. doi:10.1086/521679.
    1. Huh WK, Joura EA, Giuliano AR, Iversen O-E, de Andrade RP, Ault KA, Bartholomew D, Cestero RM, Fedrizzi EN, Hirschberg AL. et al. Final efficacy, immunogenicity, and safety analyses of a nine-valent human papillomavirus vaccine in women aged 16–26 years: a randomised, double-blind trial. Lancet. 2017;390(10108):2143–2159. doi:10.1016/S0140-6736(17)31821-4.
    1. Petersen LK, Restrepo J, Moreira ED, Jr., Iversen O-E, Pitisuttithum P, Van Damme P, Joura EA, Olsson S-E, Ferris D, Block S. et al. Impact of baseline covariates on the immunogenicity of the 9-valent HPV vaccine – a combined analysis of five phase III clinical trials. Papillomavirus Res. 2017;3:105–115. doi:10.1016/j.pvr.2017.03.002.
    1. Mugo N, Ansah NA, Marino D, Saah A, and Garner EIO. Evaluation of safety and immunogenicity of a quadrivalent human papillomavirus vaccine in healthy females between 9 and 26 years of age in Sub-Saharan Africa. Hum Vaccin Immunother. 2015;11(6):1323–1330. doi:10.1080/21645515.2015.1008877.
    1. Van Damme P, Olsson SE, Block S, Castellsague X, Gray GE, Herrera T, Huang L-M, Kim DS, Pitisuttithum P, Chen J. et al. Immunogenicity and safety of a 9-valent HPV vaccine. Pediatrics. 2015;136(1):e28–39. doi:10.1542/peds.2014-3745.
    1. Luxembourg A, Moreira ED, Jr., Samakoses R, Kim K-H, Sun X, Maansson R, Moeller E, Christiano S, and Chen J. Phase III, randomized controlled trial in girls 9-15 years old to evaluate lot consistency of a novel nine-valent human papillomavirus L1 virus-like particle vaccine. Hum Vaccin Immunother. 2015;11(6):1306–1312. doi:10.1080/21645515.2015.1009819.
    1. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) . ICH: E 6 (R2): guideline for good clinical practice - step 5. [accessed 2022. July 1]. .
    1. Dias D, Van Doren J, Schlottmann S, Kelly S, Puchalski D, Ruiz W, Boerckel P, Kessler J, Antonello JM, Green T. et al. Optimization and validation of a multiplexed luminex assay to quantify antibodies to neutralizing epitopes on human papillomaviruses 6, 11, 16, and 18. Clin Diagn Lab Immunol. 2005;12(8):959–969. doi:10.1128/CDLI.12.8.959-969.2005.
    1. Opalka D, Lachman CE, MacMullen SA, Jansen KU, Smith JF, Chirmule N, Esser MT. Simultaneous quantitation of antibodies to neutralizing epitopes on virus-like particles for human papillomavirus types 6, 11, 16, and 18 by a multiplexed luminex assay. Clin Diagn Lab Immunol. 2003;10(1):108–115. doi:10.1128/cdli.10.1.108-115.2003.
    1. Smith JF, Kowalski R, Esser MT, Brown MJ, Bryan JT. Evolution of type-specific immunoassays to evaluate the functional immune response to Gardasil: a vaccine for human papillomavirus types 16, 18, 6 and 11. Hum Vaccin. 2008;4(2):134–142. doi:10.4161/hv.4.2.5261.
    1. Roberts C, Green T, Hess E, Matys K, Brown MJ, Haupt RM, Luxembourg A, Vuocolo S, Saah A, Antonello J. Development of a human papillomavirus competitive luminex immunoassay for 9 HPV types. Hum Vaccin Immunother. 2014;10(8):2168–2174. doi:10.4161/hv.29205.
    1. The FUTURE II Study Group . Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007;356(19):1915–1927. doi:10.1056/NEJMoa061741.
    1. Olsson SE, Restrepo JA, Reina JC, Pitisuttithum P, Ulied A, Varman M, Van Damme P, Moreira ED, Jr., Ferris D, Block S. et al. Long-term immunogenicity, effectiveness, and safety of nine-valent human papillomavirus vaccine in girls and boys 9 to 15 years of age: Interim analysis after 8 years of follow-up. Papillomavirus Res. 2020;10:100203. doi:10.1016/j.pvr.2020.100203.
    1. Ferris DG, Samakoses R, Block SL. et al. 4-Valent human papillomavirus (4vhpv) vaccine in preadolescents and adolescents after 10 years. Pediatrics. 2017;140(6):e20163947. doi:10.1542/peds.2016-3947.
    1. Kjaer SK, Nygård M, Sundström K, Dillner J, Tryggvadottir L, Munk C, Berger S, Enerly E, Hortlund M, Ágústsson ÁI. et al. Final analysis of a 14-year long-term follow-up study of the effectiveness and immunogenicity of the quadrivalent human papillomavirus vaccine in women from four Nordic countries. EClinicalMedicine. 2020;23:100401. doi:10.1016/j.eclinm.2020.100401.
    1. Kjaer S, Nygard M, Sundström K, Munk C, Berger S, Dzabic M, Fridrich KE, Waldstrøm M, Sørbye SW, Bautista O. et al. Long-term effectiveness of the 9-valent human papillomavirus vaccine in Scandinavian women: interim analysis after 8 years of follow-up. Hum Vaccin Immunother. 2021;17(4):943–949. doi:10.1080/21645515.2020.1839292.
    1. Goldstone SE, Giuliano AR, Palefsky JM, Lazcano-Ponce E, Penny ME, Cabello RE, Moreira ED, Jr., Baraldi E, Jessen H, Ferenczy A. et al. 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. Lancet Infect Dis. 2022;22(3):413–425. doi:10.1016/S1473-3099(21)00327-3.
    1. Brown D, Müller M, Sehr P, Pawlita M, Seitz H, Rubio I, Antonello J, Radley D, Roberts C, Saah A. Concordance assessment between a multiplexed competitive Luminex immunoassay, a multiplexed IgG Luminex immunoassay, and a pseudovirion-based neutralization assay for detection of human papillomavirus types 16 and 18. Vaccine. 2014;32(44):5880–5887. doi:10.1016/j.vaccine.2014.08.004.
    1. Moreira ED, Jr., Block SL, Ferris D, Giuliano AR, Iversen O-E, Joura EA, Kosalaraksa P, Schilling A, Van Damme P, Bornstein J. et al. Safety profile of the 9-valent HPV vaccine: A combined analysis of 7 Phase III clinical trials. Pediatrics. 2016;138(2):e20154387. doi:10.1542/peds.2015-4387.
    1. Phillips A, Patel C, Pillsbury A, Brotherton J, Macartney K. Safety of human papillomavirus vaccines: an updated review. Drug Saf. 2018;41(4):329–346. doi:10.1007/s40264-017-0625-z.
    1. Block SL, Brown DR, Chatterjee A, Gold MA, Sings HL, Meibohm A, Dana A, Haupt RM, Barr E, Tamms GM. et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) 1 virus-like particle vaccine. Pediatr Infect Dis J. 2010;29(2):95–101. doi:10.1097/INF.0b013e3181b77906.
    1. World Health Organization (WHO) . Human papillomavirus vaccines: WHO position paper. Wkly Epidemiol Rec. 2017;92(19):241–268.
    1. Meites E, Kempe A, and Markowitz LE. Use of a 2-dose schedule for human papillomavirus vaccination - updated recommendations of the advisory committee on immunization practices. MMWR Morb Mortal Wkly Rep. 2016;65(49):1405–1408. doi:10.15585/mmwr.mm6549a5.
    1. Kasi SG, Shivananda S, Marathe S, Chatterjee K, Agarwalla S, Dhir SK, Verma S, Shah AK, Srirampur S, Kalyani S. et al. Indian Academy of Pediatrics (IAP) Advisory Committee on Vaccines and Immunization Practices (ACVIP): recommended immunization schedule (2020–21) and update on immunization for children aged 0 through 18 years. Indian Pediatr. 2021;58(1):44–54. doi:10.1007/s13312-021-2096-7.
    1. Dobson SRM, McNeil S, Dionne M, Dawar M, Ogilvie G, Krajden M, Sauvageau C, Scheifele DW, Kollmann TR, Halperin SA. et al. Immunogenicity of 2 doses of HPV vaccine in younger adolescents vs 3 doses in young women: a randomized clinical trial. JAMA. 2013;309(17):1793–1802. doi:10.1001/jama.2013.1625.
    1. Donken R, Dobson SRM, Marty KD, Cook D, Sauvageau C, Gilca V, Dionne M, McNeil S, Krajden M, Money D. et al. Immunogenicity of 2 and 3 doses of the quadrivalent human papillomavirus vaccine up to 120 months postvaccination: follow-up of a randomized clinical trial. Clin Infect Dis. 2020;71(4):1022–1029. doi:10.1093/cid/ciz887.
    1. Iversen OE, Miranda MJ, Ulied A, Soerdal T, Lazarus E, Chokephaibulkit K, Block SL, Skrivanek A, Nur Azurah AG, Fong SM. et al. Immunogenicity of the 9-valent HPV vaccine using 2-dose regimens in girls and boys vs a 3-dose regimen in women. JAMA. 2016;316(22):2411–2421. doi:10.1001/jama.2016.17615.
    1. Bornstein J, Roux S, Petersen LK, Huang L-M, Dobson SR, Pitisuttithum P, Diez-Domingo J, Schilling A, Ariffin H, Tytus R. et al. Three-year follow-up of 2-dose versus 3-dose HPV vaccine. Pediatrics. 2021;147(1):e20194035. doi:10.1542/peds.2019-4035.

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