Trial of Two Versus Three Doses of Human Papillomavirus (HPV) Vaccine in India

Randomised Trial of Two Versus Three Doses of Human Papillomavirus (HPV) Vaccine in India

The primary study hypothesis wasthat a two-dose human papillomavirus (HPV) vaccine regimen would offer similar immunogenicity and protection as that of a three-dose regimen to girls against persistent HPV infection and cervical neoplasia caused by HPV types included in the vaccine. The Government of India stopped vaccination in all the HPV vaccine trials in the country in April 2010 due to reasons not related to this study.

Study Overview

• Status: Active, not recruiting
• Conditions: Cervical Cancer; Cervical Precancerous Lesions
• Intervention / Treatment: Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®)

Detailed Description

The suspension of vaccination resulted in girls receiving 3 doses (days 1, 60 and ≥180), receiving 2 doses (days 1 and ≥180), receiving 2 doses at days 1 and 60 due to incomplete treatment ("by default"), and receiving one dose by default. A first age and site-matched cohort of unvaccinated married women was recruited, starting in May 2012 to serve as the unvaccinated control group of women for the analysis of HPV incidence and persistence outcomes. A second age and site-matched (age and site matched to the vaccinated women undergoing screening) cohort of unvaccinated married women is being recruited starting in June 2017 and is to be used in addition to the first unvaccinated cohort for the assessment of the cervical neoplasia outcome.

• Study Type: Interventional
• Enrollment (Actual): 22729
• Phase: Phase 4

Contacts and Locations

Study Locations

• India
  • New Delhi, India, 110029
    • All India Institute of Medical Sciences
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500004
      • MNJ Institute of Oncology & Regional Cancer Center
  • Bengal
    • Kolkata, Bengal, India, 700031
      • Cancer Foundation of India
  • Gujarat
    • Ahmedabad, Gujarat, India, 380 016
      • Gujarat Cancer & Research Institute (GCRI)
  • Maharashtra
    • Barshi, Maharashtra, India, 413 401
      • Tata Memorial Centre Rural Cancer Project, Nargis Dutt Memorial Cancer Hospital
    • Mumbai, Maharashtra, India, 400 012
      • Tata Memorial Center, Tata Memorial Hospital & Cancer Research Inst
    • Pune, Maharashtra, India, 411 001
      • Jehangir Clinical Development Centre (JCDC) Pvt. Ltd.
  • Tamil Nadu
    • Ambilikkai, Tamil Nadu, India, 624612
      • Christian Fellowship Community Health Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Apparently healthy, ambulant girls aged 10 - 18 years
• Unmarried girls
• Girls with intact uterus
• Resident in the villages chosen for the study

Exclusion Criteria:

• Girls with any severe and/or debilitating illness
• Past history of allergy to any medication

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 3-dose; The participants received three doses of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) at days 1, 60 and 180+.	Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®); The participants received either one, two or three doses of the avaccine. Each injection contains 20 microgram type 6, 40 microgram type 11, 40 microgram type 16, and 20 microgram type 18.; Other Names: Gardasil®
Experimental: 2-dose; The participants received two doses of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) at days 1 and 180+.	Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®); The participants received either one, two or three doses of the avaccine. Each injection contains 20 microgram type 6, 40 microgram type 11, 40 microgram type 16, and 20 microgram type 18.; Other Names: Gardasil®
Experimental: 2 doses by default; The participants received two doses of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) at days 1 and 60 by default (incomplete doses)	Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®); The participants received either one, two or three doses of the avaccine. Each injection contains 20 microgram type 6, 40 microgram type 11, 40 microgram type 16, and 20 microgram type 18.; Other Names: Gardasil®
Experimental: Single-dose; The participants received one dose of the Prophylactic quadrivalent HPV vaccine Merck (Gardasil®) by default (incomplete doses)	Biological: Prophylactic quadrivalent HPV vaccine Merck (Gardasil®); The participants received either one, two or three doses of the avaccine. Each injection contains 20 microgram type 6, 40 microgram type 11, 40 microgram type 16, and 20 microgram type 18.; Other Names: Gardasil®
No Intervention: Unvaccinated; A cohort of unvaccinated women

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Florescent Intensities (MFI) of the Total Antibodies to Vaccine-included HPV Types (16/18/6/11) at Different Time Points	Samples were treated with EDTA and analysed with Luminex (Austin, TX, USA) based multiplex serology to assess the concentration of binding antibodies against the major capsid protein L1 as mean median fluorescence intensity (MFI). MFI values as a measure of antibody concentration quantified by use of HPV multiplex serology are directly comparable with optical densities measured with ELISA.	Month 7 (for 3-dose and 2-dose groups), 12 (for 2 doses by default and single-dose groups), 18, 36, 48
Frequency of Persistent HPV 16/18/6/11 Infection.	The first cervical cell samples were collected from women 18 months after married or 6 months after the first delivery. After that, 3 extra annual collections were obtained. The HPV genotyping method involved HPV-type-specific E7 PCR bead-based multiplex genotyping. The multiplex HPV-type-specific E7 PCR uses HPV type-specific primers targeting the E7 region for the detection of 19 high-risk or probable high-risk HPV types (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68a, 68b, 70, 73, and 82), and two low-risk HPV types (6 and 11), with detection limits ranging from ten to 1000 copies of the viral genome.	From date of marriage through to 7 years of follow-up
Frequency of HPV 16/18-associated Precancerous Lesions and Cancer.	Pathology Panel diagnosis of: CIN 2, CIN 3 (including squamous carcinoma in situ), adenocarcinoma in situ, invasive squamous cervical carcinoma, or invasive adenocarcinoma of the cervix and detection of HPV 16 and/or HPV 18 by PCR in the same biopsy tissue sample.	Cervical samples for HPV testing collected from married participants at the age of 25 and at 5 years after the first screen

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Infection by Other Non-targeted High-risk HPV Types.	The HPV genotyping method involved HPV-type-specific E7 PCR bead-based multiplex genotyping. The multiplex HPV-type-specific E7 PCR uses HPV type-specific primers targeting the E7 region for the detection of 19 high-risk or probable high-risk HPV types (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68a, 68b, 70, 73, and 82), and two low-risk HPV types (6 and 11), with detection limits ranging from ten to 1000 copies of the viral genome.	Cervical samples for HPV testing collected from married participants at the age of 25 and at 5 years after the first screen
Frequency of Cervical Neoplasia Associated With Non-included HPV Types.	Pathology Panel diagnosis of: CIN 2, CIN 3 (including squamous carcinoma in situ), adenocarcinoma in situ, invasive squamous cervical carcinoma, or invasive adenocarcinoma of the cervix and detection of other non vaccine included HPV types by PCR in the same biopsy tissue sample.	15 years from the base-line date

Collaborators and Investigators

• Sponsor: Partha Basu
• Collaborators: All India Institute of Medical Sciences, New Delhi; Tata Memorial Centre; Deutsches Krebsforschungszentrum (DKFZ); MNJ Institute of Oncology & Regional cancer Center; Cancer Foundation of India; Christian Fellowship Community Health Centre; Gujarat Cancer & Research Institute; Jehangir Clinical Development Centre; Rajiv Gandhi Centre for Biotechnology; Tata Memorial Centre Rural Cancer Project, Nargis Dutt Memorial Cancer Hospital
• Investigators: Principal Investigator: Partha Basu, MD, International Agency for Research on Cancer

Publications and helpful links

General Publications

• Basu P, Malvi SG, Joshi S, Bhatla N, Muwonge R, Lucas E, Verma Y, Esmy PO, Poli URR, Shah A, Zomawia E, Pimple S, Jayant K, Hingmire S, Chiwate A, Divate U, Vashist S, Mishra G, Jadhav R, Siddiqi M, Sankaran S, Prabhu PR, Kannan TPRA, Varghese R, Shastri SS, Anantharaman D, Gheit T, Tommasino M, Sauvaget C, Pillai MR, Sankaranarayanan R. Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study. Lancet Oncol. 2021 Nov;22(11):1518-1529. doi: 10.1016/S1470-2045(21)00453-8. Epub 2021 Oct 8. Erratum In: Lancet Oncol. 2022 Jan;23(1):e16.
• Sankaranarayanan R, Prabhu PR, Pawlita M, Gheit T, Bhatla N, Muwonge R, Nene BM, Esmy PO, Joshi S, Poli UR, Jivarajani P, Verma Y, Zomawia E, Siddiqi M, Shastri SS, Jayant K, Malvi SG, Lucas E, Michel A, Butt J, Vijayamma JM, Sankaran S, Kannan TP, Varghese R, Divate U, Thomas S, Joshi G, Willhauck-Fleckenstein M, Waterboer T, Muller M, Sehr P, Hingmire S, Kriplani A, Mishra G, Pimple S, Jadhav R, Sauvaget C, Tommasino M, Pillai MR; Indian HPV Vaccine Study Group. Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study. Lancet Oncol. 2016 Jan;17(1):67-77. doi: 10.1016/S1470-2045(15)00414-3. Epub 2015 Dec 2.
• Sankaranarayanan R, Joshi S, Muwonge R, Esmy PO, Basu P, Prabhu P, Bhatla N, Nene BM, Shaw J, Poli URR, Verma Y, Zomawia E, Pimple S, Tommasino M, Pawlita M, Gheit T, Waterboer T, Sehr P, Pillai MR; Indian HPV vaccine study group. Can a single dose of human papillomavirus (HPV) vaccine prevent cervical cancer? Early findings from an Indian study. Vaccine. 2018 Aug 6;36(32 Pt A):4783-4791. doi: 10.1016/j.vaccine.2018.02.087. Epub 2018 Mar 15.
• Bhatla N, Nene BM, Joshi S, Esmy PO, Poli URR, Joshi G, Verma Y, Zomawia E, Pimple S, Prabhu PR, Basu P, Muwonge R, Hingmire S, Sauvaget C, Lucas E, Pawlita M, Gheit T, Jayant K, Malvi SG, Siddiqi M, Michel A, Butt J, Sankaran S, Kannan TPRA, Varghese R, Divate U, Willhauck-Fleckenstein M, Waterboer T, Muller M, Sehr P, Kriplani A, Mishra G, Jadhav R, Thorat R, Tommasino M, Pillai MR, Sankaranarayanan R; Indian HPV vaccine study group. Are two doses of human papillomavirus vaccine sufficient for girls aged 15-18 years? Results from a cohort study in India. Papillomavirus Res. 2018 Jun;5:163-171. doi: 10.1016/j.pvr.2018.03.008. Epub 2018 Mar 22.
• Basu P, Muwonge R, Bhatla N, Nene BM, Joshi S, Esmy PO, Poli URR, Joshi G, Verma Y, Zomawia E, Shastri SS, Pimple S, Anantharaman D, Prabhu PR, Hingmire S, Sauvaget C, Lucas E, Pawlita M, Gheit T, Jayant K, Malvi SG, Siddiqi M, Michel A, Butt J, Sankaran S, Rameshwari Ammal Kannan TP, Varghese R, Divate U, Willhauck-Fleckenstein M, Waterboer T, Muller M, Sehr P, Vashist S, Mishra G, Jadhav R, Thorat R, Tommasino M, Pillai MR, Sankaranarayanan R; Indian HPV vaccine study group. Two-dose recommendation for Human Papillomavirus vaccine can be extended up to 18 years - updated evidence from Indian follow-up cohort study. Papillomavirus Res. 2019 Jun;7:75-81. doi: 10.1016/j.pvr.2019.01.004. Epub 2019 Jan 31.
• Muwonge R, Basu P, Gheit T, Anantharaman D, Verma Y, Bhatla N, Joshi S, Esmy PO, Poli URR, Shah A, Zomawia E, Shastri SS, Pimple S, Prabhu PR, Hingmire S, Chiwate A, Sauvaget C, Lucas E, Malvi SG, Siddiqi M, Sankaran S, Kannan TPRA, Varghese R, Divate U, Vashist S, Mishra G, Jadhav R, Tommasino M, Pillai MR, Sankaranarayanan R, Jayant K; Indian HPV vaccine study group. Acquisition, prevalence and clearance of type-specific human papillomavirus infections in young sexually active Indian women: A community-based multicentric cohort study. PLoS One. 2020 Dec 29;15(12):e0244242. doi: 10.1371/journal.pone.0244242. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2009
• Primary Completion (Actual): January 1, 2017
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: June 17, 2009
• First Submitted That Met QC Criteria: June 17, 2009
• First Posted (Estimated): June 18, 2009

Study Record Updates

• Last Update Posted (Actual): September 28, 2023
• Last Update Submitted That Met QC Criteria: September 27, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Cervical Diseases; Uterine Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Uterine Cervical Neoplasms
• Other Study ID Numbers: BMGF48979; ISRCTN98283094 (Other Identifier: BioMedCentral); REFCTRI-2009 000137 (Registry Identifier: Indian Clinical Trial Registry)