A Dose Reduction Immunobridging and Safety Study of Two HPV Vaccines in Tanzanian Girls

Human papillomavirus (HPV) infection is the primary cause of cervical cancer, a major public health problem in Africa. Currently there are three vaccines (Cervarix, Gardasil® and Gardasil-9®) that offer excellent protection against HPV infection with vaccine-related HPV genotypes. The objective of this trial is to demonstrate non-inferiority of immune responses with 1 dose of HPV vaccine compared with the recommended 2 or 3 doses of the same vaccine by evaluating HPV 16/18-specific seropositivity, antibody avidity and memory B cell responses at M36. Specifically, the investigators will determine whether a single dose of the 2-valent HPV vaccine (Cervarix, that protects against HPV 16/18 genotypes) or of a new 9-valent HPV vaccine (Gardasil-9,that protects against HPV 6/11/16/18/31/33/45/52/58) produces immune responses that are non-inferior to those observed with 3 doses of vaccine when given to HIV-negative 9-14 years old girls in a malaria-endemic region of Tanzania.

The trial will also determine whether the World Health Organization's (WHO) recently recommended 2 dose strategy for girls aged under 15 years produces similar immune responses in Sub-Saharan Africa (SSA) compared to the previously recommended 3 dose schedule. In addition, the cost-effectiveness of alternative dosing schedules and of the two vaccines will be explored.

The trial will enrol 900 girls who are resident in Mwanza into an un-blinded, individually-randomised trial with 6 arms. Arm A will comprise participants randomised to receive 3 doses of the 2-valent vaccine, Arm B those randomised to receive 2 doses of the 2-valent vaccine and Arm C those randomised to receive 1 dose of the 2-valent vaccine. Arms D, E and F will be those participants randomised to receive 3, 2 or 1 dose of the 9-valent vaccine, respectively.

The effect of different dose schedules and type of HPV vaccine on a range of immune responses will be measured up to 36 months after the first dose. In a trial extension that will extend follow-up, we will also determine whether the one dose schedule of these vaccines produces non-inferior immune responses to the recommended two dose schedule for up to 108 months, and examine the long-term stability of the immune responses to 9 years after the first dose.

The protocol will be harmonised, and laboratory procedures and immunological endpoints will be cross-validated, with those of a large HPV vaccine dose-reduction efficacy trial being planned by the NIH in Costa Rica to examine the protective effect of the same vaccines given as 1 or 2 doses. This trial will allow the examination of quality and durability of antibody responses, and safety and cost-effectiveness of reduced dose schedules compared to the originally recommended 3 dose schedule in a population with high burden of malaria and other infections that may affect vaccine immune responses.

Inclusion criteria

• Born female;
• Aged between 9 and 14 years inclusive;
• Enrolled in a government primary or secondary day school in Mwanza city (or neighbouring district if included);
• Living in Mwanza city (or neighbouring district if included) without plans to move away in the next 36 months;
• Willing to participate in the study and sign the informed assent form;
• Supported in this study participation by at least one of their parents (or LAR), who has signed the informed consent document;
• In good health as determined by a medical history (a physical examination will be conducted if necessary according to the clinician's judgement); and
• Able to pass a Test of Understanding (TOU) if aged 12 years or above, or if younger than 12 years old, a parent or LAR is able to pass a TOU

Exclusion criteria

• They are diagnosed with chronic conditions, such as autoimmune conditions, degenerative diseases, neurologic or genetic diseases among others;

• They are HIV positive, or immunocompromised;
• They are pregnant, less than three months post-partum or currently breastfeeding;
• They are allergic to one of the vaccine components or to latex;
• They are sexually active and are not willing to use an effective birth control method from 28 days before the first dose until 60 days after the last vaccine dose;
• The nurse or clinician determining the eligibility, in agreement with principal investigator, considers that there is a reason that precludes participation;
• They have been previously vaccinated against HPV