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  RANDOMIZED TRIAL OF 2 VERSUS 3 DOSES OF HPV VACCINE IN INDIA

Goals and objectives:

The overall goal of this project is to prevent cervical cancer in India and other developing countries by accelerating access to HPV vaccine by guiding public health policies for planning and implementing large-scale, sustained HPV vaccination programs and by catalyzing the augmentation of capacity to prevent cervical cancer by introducing and expanding HPV vaccination programs.

The project has three key objectives:
  1. Generate scientific evidence on the efficacy of two-dose HPV vaccination regimen as compared to the current standard three-dose regimen;
  2. Generate information on the feasibility, safety and acceptability of the two-dose HPV vaccination regimens;
  3. Provide decision makers in India and other developing countries with operational, efficacy and safety data to empower them to make an appropriate, evidence-based HPV vaccination policy and to invest in its wide-scale implementation and disseminate the information on the lessons learned to inform India and other developing countries about the feasibility, effectiveness, safety and acceptability of the vaccination approaches.


Project design and implementation:

Project activities are implemented in selected districts in Maharashtra, Tamil Nadu, Gujarat, Andhra Pradesh, Haryana, Sikkim and Mizoram States, India, during a five-year period, in partnership with national institutions, government health services and local health, educational and administrative authorities. The study design is a cluster-randomized clinical trial, the randomization unit being villages or clusters of households. The eligible participants are 20,000 healthy, ambulant, unmarried girls aged 10-18 years with intact uterus, residing in the selected clusters. The clusters are randomly allocated to one of two groups to receive a quadrivalent HPV vaccine targeting HPV 16, 18, 6, 11 types (Gardasil donated by Merck) as follows:

  • Group 1: 10,000 eligible girls receive 2 doses on days 1 and 180;
  • Group 2: 10,000 girls receive 3 doses on days 1, 60, and 180.
Clinics are organized in villages/clusters to vaccinate girls and to collect blood from them for HPV serology as per the protocol. Subjects are observed for 30 minutes after receiving the injection and are asked to document and report any adverse events occurring within 15 days after each injection on a vaccination report card. The frequency and next date of vaccination depends upon the randomization category.


Flowchart of the study design
All vaccinated girls will be followed up during the 5 years of the project to document outcomes and/or adverse events. Follow-up visits will be scheduled at 1 month after the last injection and at months 12, 24, 36 and 48 from the beginning of the study. Blood will be collected at 7 months from all girls and from a cohort of 15% of the girls on baseline and at the 12-, 24-, 36- and 48-month follow-up visits to evaluate sero-conversion and serum HPV 16 and 18 antibody titers. Clusters will be randomly selected in each study site to provide the cohort of 15% of girls. The blood samples will be analyzed at the Rajiv Gandhi Centre for Biotechnology (RGCB) in Trivandrum, Kerala. Cervical cells will be collected for HPV testing and typing from participants 6-months after their first delivery or 18 months after marriage, whichever is earlier, and once a year thereafter. HPV testing and typing of the collected cervical cells will be carried out in RGCB using standard methodology. Women positive on HPV testing will be advised colposcopy and directed biopsies, depending on colposcopic findings. Women diagnosed with high-grade cervical intraepithelial neoplasia (CIN 2-3) lesions and invasive cancers will be promptly treated. Those diagnosed with CIN 1 will be offered treatment only if the lesion persists or progresses at two years. A special follow-up system will be set up using health cards including a photo ID, house visits, as well as linkage with a family registry, to ensure adequate participation of girls for repeat vaccination and for follow-up.

Long term follow-up for up to 20 years has been planned for long-term endpoints such as the incidence of CIN 2-3 lesions and cervix cancer, after the completion of the initial 5 years of the study.


Monitoring, Evaluation and Dissemination:

A customized information system is designed and implemented in each project site with centralized data capture in IARC, to evaluate the process and outcome measures. We use a set of comprehensive input measures, milestones and outcome measures captured in the dedicated information system to evaluate the project. The input measures such as proportion of girls completing the vaccine injection protocols, dropouts, and proportion adhering with follow-up visits will be used to assess participation of eligible girls. Milestones will reflect the accomplishment of various activities in a timely fashion. Participant interviews and other survey mechanisms will provide qualitative assessments of vaccination approaches, community mobilization strategies and messages, user satisfaction and qualitative information about reasons for eventual non-acceptance of vaccination; socio-demographic predictors HPV vaccine acceptability by parents will provide related quantitative information.

The following end points will be assessed in a blinded fashion to evaluate the clinical efficacy:
  • The frequency of vaccinated girls showing presence of serum neutralizing antibodies to vaccine included HPV types;
  • Geometric mean titres of Serum anti-HPV 16, 18, 6, 11 L1 antibody (sL1Ab) (GMTs) at baseline and months 7, 12, 24, 36 and 48 using blood samples collected from 15% of girls in the study groups;
  • Frequency of incident and persistent HPV 16 and 18 infections (12-month definition) and associated CIN 2/3 lesions and invasive cervical cancers;
  • Frequency of HPV infections other than HPV 16 and 18 and associated CIN 2/3 lesions;
The end-point used to evaluate feasibility of the two different dose regimens study will be frequency of protocol violations and drop-outs in the two study groups. The end-points used to evaluate acceptability will be based on the frequency of mild/moderate adverse events following vaccination. The frequency of serious adverse events (SAEs) following vaccination will form the basis of assessing safety of the two different dose regimens. A SAE will be defined as any medical condition threatening life, or requiring hospitalization for management or parenteral administration of drugs, or other important medical events that may not result in death, not be life threatening nor require hospitalization, but may be considered a serious adverse experience based upon appropriate medical judgment. The frequency of outcomes following pregnancy will be compared as part of the safety profile of the vaccination regimens.

Project impact will be measured using indicators such as new or updated national policies and/or guidelines, implementation of new HPV vaccination programs with national budget commitments in India and other developing countries.

Optimizing Public Health Outcomes:

Within the 5-year period of this project, only results on short-term endpoints such as limited term immunogenicity and frequency of HPV infections, CIN and adverse events may be available. The information on high-grade CIN will be based on very few numbers and may be insufficient to convince regulatory authorities to recommend the two-dose regimen over the three-dose regimen. For this reason, we will obtain additional support within the IARC, from participating institutions in India and local health services to keep these populations on long-term follow-up over 20 years to generate long-term efficacy and safety data. The long-term results from this project will catalyze state supported HPV vaccination reaching the right target groups as part of the public health immunization programs in India and in several developing countries leading to notable reduction in disease burden, suffering and to considerable cost savings in view of prevented disease and improved health of women in their most productive years.

The Collaborating institutions are:

India:
  • Tata Memorial Centre (TMC), Mumbai;
  • Nargis Dutt Memorial Cancer Hospital (NDMCH), Barshi;
  • Jehangir Clinical Development Centre (JCDC), Pune;
  • Christian Fellowship Community Health Centre (CFCHC), Ambillikai;
  • Gujarat Cancer Research Institute (GCRI), Ahmedabad;
  • All India Institute of Medical Sciences (AIIMS), New Delhi;
  • MNJ Cancer Institute (MNJCI), Hyderabad;
  • Cancer Foundation of India (CFI), Kolkata;
  • Civil hospital, Aizawl, Mizoram;
  • STNM hospital, Gangtok, Sikkim;
  • Rajiv Gandhi Centre for Biotechnology (RGCB), Trivandrum;

Germany:
  • Deutsches Krebsforschungszentrum (DKFZ), Heidelberg

Our collaborative partners are major national institutions with strong commitment and expertise in cancer prevention and control and they have vast experience in clinical and epidemiological research, cancer control, community outreach activities and have an effective national and international collaborative network.

The proposed HPV vaccine trial will be coordinated by the Screening Group in IARC in collaboration with the collaborating institutions in India participating in the study, through a project advisory group. A data safety monitoring board (DSMB) is constituted to monitor the trial. All SAEs are immediately reported to IARC through e-mail and fax within 24 hours and to the local Institutional Ethics Committee within one week. The study will be reviewed regularly by way of internal and external reviews by review boards of the Indian participating institutions and by the IARC Scientific Council.

Acknowledgements:
  • Bill & Melinda Gates Foundation for their financial support
  • Merck for their donation of Gardasil vaccines


More information about HPV:

Pictures gallery:

India - Ahmedabad (0:55)
HPV vaccination project in Ahmedabad, India
To see the diaporama click on the following link:
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India - Ambillikai (3:01)
HPV vaccination project in Ambillikai, India
To see the diaporama click on the following link:
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India - Barshi (2:55)
HPV vaccination project in Barshi, India
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India - Hyderabad (0:55)
HPV vaccination project in Hyderabad, India
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India - Mumbai (1:46)
HPV vaccination project in Mumbai, India
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India - New Delhi (2:10)
HPV vaccination project in New Delhi, India
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India - Pune (2:20)
HPV vaccination project in Pune, India
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India - Sikkim (1:16)
HPV vaccination project in Sikkim, India
To see the diaporama click on the following link:
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