Strengthening HPV Immunization Through EPI Leveraged Delivery

A Randomized, Observer-Blind, Placebo-Controlled, Proof-of-Concept Study to Assess the Safety, Tolerability and Immunogenicity of a Bivalent Human Papillomavirus (HPV) Vaccine in 9 and 15 Month Old Infants and Toddlers, 2-5 Year Old Children and an Open Label Single Dose Study in Young Unmarried Females Aged 15-20 Years in Ghana

This is a randomized observer-blind placebo-controlled proof-of-concept study with the aim to assess the safety and tolerability, and the immunogenicity of a bivalent HPV vaccine administered in healthy infants and toddlers (9- and 15-month-olds) comparing them to an immune-bridging population of 15-20-year-old unmarried females in an open label study in Ghana at the Dodowa Health Research Center.

Cervical cancer is a significant public health problem in Africa and a leading cause of cancer deaths in women. According to the WHO, Africa has the highest cervical cancer disease incidence and associated mortality in the world accounting for 19% of all global cases of cervical cancer and 23% of all cervical cancer related deaths. The high-risk Human Papillomavirus (HPV) Types16 and 18 are responsible for 70% of all global cervical cancers with a high prevalence of 22% in sub-Saharan Africa compared to a prevalence of 12%globally. The bivalent Cecolin HPV vaccine, manufactured by Innovax of China, has demonstrated >95% efficacy against HPV16/18 infections in women aged 18 to 26 years and some protection against HPV 31, 33 and 45. The hypothesis of this trial is that infants/toddlers vaccinated with the bivalent Cecolin will show similar safety, tolerability, and immunogenicity as compared to that observed in older age groups, 15 to 20year old, where efficacy has been established.

This trial is a proof-of-concept study to descriptively compare the safety, tolerability, and immunogenicity of HPV vaccination in a pediatric population. The aim is to demonstrate safety and tolerability, and that short-term immune responses in infants and toddlers are comparable to the responses in older girls and women between 15-20 years, an age group in whom efficacy has been shown. If the vaccines are shown to be safe, well tolerated, and sufficiently immunogenic in this pilot study, this would provide evidence to support larger statistically robust studies to test the safety, immunogenicity, longevity of immune response, and acceptability of including HPV vaccines in the routine EPI.

A total of one hundred and fifteen (N=115) eligible participants will be enrolled in the study with an age de-escalation approach for the pediatric cohort. First, the safety cohort of 15 children between the age of 2-5 years will be randomized in a 3:2 ratio to receive HPV (n=9) and placebo (n=6). To progress enrolment of toddlers aged 15 months, the DSMB will review safety data of the preceding safety cohort (2-5 years old) collected in the first week (until D7 visit) of follow-up according to pre-specified halting criteria. If halting criteria are not met, a further 15 toddlers (15 months) will be recruited similarly in a 3:2 ratio to receive HPV (n=9) and placebo (n=6). After the recruitment of the first 15 of 35 toddlers, there will be a second safety review by the DSMB. If halting criteria are not met, the remaining 20 participants of the 15-month-old cohort will continue recruitment. Following confirmation by the DSMB, 15 infants (9 months old) will be recruited similarly in a 3:2 ratio to receive HPV (n=9) and placebo (n=6). After the recruitment of the first 15 of 35 infants, there will be another safety review by the DSMB. If halting criteria are not met, the remaining 20 participants of the 9-month-old cohort will continue recruitment. The safety cohort and the toddlers will receive either a single dose of the HPV vaccine or placebo while the 9-month-old will either receive two doses of the HPV vaccine 6 months apart or the placebo. Adolescent girls and young women aged between 15 and 20 year olds will be recruited in open label study in parallel.

Inclusion Criteria:

• Healthy male and female individuals aged 9 months, 15 months, 2-5 years and unmarried females aged 15-20 years at the time of vaccination
• Participants aged 9 months, 15 months and 2-5 years who are up to date with their EPI vaccinations.
• Residing within the area of the study and planning to stay for the study duration.
• Participants that are HIV negative at screening (for the 9-15-month-olds a documented negative maternal ANC HIV screening).
• Unmarried females with a negative pregnancy test at screening practicing/willing to practice continuous effective contraception as recommended by the Ghana Health Services guidance in Ghana
• Able and willing to comply with all study requirements.
• Willingness to provide written informed consent before any trial procedure. Assent will be required for young female participants aged 15-17 years at vaccination in addition to their parent's/LAR's consent.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

• Pregnancy, lactation, or intention to become pregnant during the vaccination phase through three months after the study vaccine dose
• Previous vaccination against HPV (Only for the 15-20-year-old efficacy cohort)
• Presence of malnutrition (weight-for-length z-score ≤-2SD median, per WHO published child growth standards)
• Planning to migrate out of the study areas before the end of the study follow-up
• Any underlying known condition or criteria, including acute or chronic clinically significant abnormality or infection that in the opinion of the investigator might compromise the wellbeing of the participant or interfere with the outcome of the study.
• Administration of immunoglobulins and/ or any blood products within the three months preceding the administration of the study vaccine.
• Known history of allergy or anaphylaxis to study vaccine components and/or excipients or other medications, or any other allergies deemed by the investigator to increase the risk of an adverse reaction.
• Any confirmed or suspected immunosuppressive or immunodeficient state, asplenia, recurrent severe infections and chronic use (more than 14 days) of immunosuppressant medication within 3 months prior to recruitment (topical steroids may be allowed).
• Any other finding that in the opinion of the investigators would increase the risk of an adverse outcome from participation in the trial or result in incomplete or poor-quality data.