Immunogenicity and Reactogenicity of Alternative Schedules of Gardasil

OBJECTIVES:

Primary objective:

To test the hypothesis that Gardasil® vaccine, when administered to girls 11-13 years of age according to 1 of 3 alternative 3-dose schedules (0,3,9 months; 0,6,12 months; or 0,12,24 months), results in anti-HPV 16 and anti-HPV 18 responses 28 days post-dose 3 that are similar to those obtained when the vaccine is administered on the standard 3-dose schedule of 0,2,6 months.

Secondary objectives:

1. To test the hypothesis that Gardasil® vaccine, when administered to girls 11-13 years of age according to 1 of 3 alternative 3-dose schedules (0,3,9 months; 0,6,12 months; or 0,12,24 months), results in anti-HPV 6 and anti-HPV 11 responses 28 days post-dose 3 that are similar to those obtained when the vaccine is administered on the standard 3-dose schedule of 0,2,6 months.
2. To describe the safety profile of the administration of Gardasil® according to each of the four schedules by assessing:

(i) immediate reactogenicity (reactions within 30 minutes after each injection); (ii) solicited (local reactogenicity and fever) and unsolicited events occurring during the first 7 days following each vaccination; (iii) serious adverse events occurring up to one month following the last dose of vaccine; (iv) deaths or adverse events occurring at any time determined to be vaccination-related.

• Biological: quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (Biological): Three doses of quadrivalent HPV recombinant vaccine administered at different dosing intervals in each of four study arms.

Primary outcomes

• Comparison of Antibody Response to HPV Type 16 1 Month Post-dose 3 for Each Alternative Schedule Compared to the Standard Schedule. [25 months]
• Comparison of Antibody Response to HPV Type 18 1 Month Post-dose 3 for Each Alternative Schedule Compared to the Standard Schedule. [25 months]

Secondary outcomes

• Comparison of Antibody Response to HPV Type 6 1 Month Post-dose 3 for Each Alternative Schedule Compared to the Standard Schedule. [25 months]
• Comparison of Antibody Response to HPV Type 11 1 Month Post-dose 3 for Each Alternative Schedule Compared to the Standard Schedule. [25 months]

Sex: Female, ages: 11 Years to 13 Years, accepts healthy volunteers

Inclusion Criteria:

1. 11-13 years of age.
2. Signed informed consent form (both parent's \& daughter's signature).
3. Good health status.
4. Able to comply with trial protocol.
5. Plans to stay at current school for duration of study.

Exclusion Criteria:

1. Prior HPV vaccination
2. Pregnant or lactating or intends to become pregnant during study period.
3. Apparent moderate or severe acute illness.
4. Clinical history of bleeding disorder such as hemophilia, thrombocytopenia, or anticoagulant therapy.
5. Clinical history of impaired immune responsiveness, whether due to use of immunosuppressive therapy, a genetic defect, HIV infection, or other causes.
6. Hypersensitivity to the active substances or to any of the excipients of the HPV vaccine, or such reactions to other vaccines received in the past.
7. Investigational drug or investigational vaccine administered during the period from 30 days before to 30 days after any dose of HPV vaccine.

Participant flow

Outcome results

• Comparison of Antibody Response to HPV Type 16 1 Month Post-dose 3 for Each Alternative Schedule Compared to the Standard Schedule. (Primary), Number, GMT ratio: 0,3,9 Month Schedule 0.93 (0.71 to 1.21); 0,6,12 Month Schedule 0.99 (0.75 to 1.30); 0,12,24 Month Schedule 0.63 (0.48 to 0.83); Standard (0,2,6 Month) Schedule 1.0 (NA to NA)
• Comparison of Antibody Response to HPV Type 18 1 Month Post-dose 3 for Each Alternative Schedule Compared to the Standard Schedule. (Primary), Number, GMT ratio: 0,3,9 Month Schedule 0.88 (0.69 to 1.12); 0,6,12 Month Schedule 0.92 (0.71 to 1.18); 0,12,24 Month Schedule 0.77 (0.62 to 0.96); Standard (0,2,6 Month) Schedule 1.0 (NA to NA)
• Comparison of Antibody Response to HPV Type 6 1 Month Post-dose 3 for Each Alternative Schedule Compared to the Standard Schedule. (Secondary), Number, GMT ratio: 0,3,9 Month Schedule 1.07 (0.80 to 1.44); 0,6,12 Month Schedule 1.14 (0.85 to 1.52); 0,12,24 Month Schedule 0.64 (0.46 to 0.90); Standard (0,2,6 Month) Schedule 1.0 (NA to NA)
• Comparison of Antibody Response to HPV Type 11 1 Month Post-dose 3 for Each Alternative Schedule Compared to the Standard Schedule. (Secondary), Number, GMT ratio: 0,3,9 Month Schedule 0.86 (0.70 to 1.06); 0,6,12 Month Schedule 0.86 (0.69 to 1.06); 0,12,24 Month Schedule 0.96 (0.80 to 1.15); Standard (0,2,6 Month) Schedule 1.0 (NA to NA)

Adverse events

Time frame: Solicited local reactions within 7 days post-vacciantion

Other adverse events by term

• Results publication: Neuzil KM, Canh DG, Thiem VD, Janmohamed A, Huong VM, Tang Y, Diep NT, Tsu V, LaMontagne DS. Immunogenicity and reactogenicity of alternative schedules of HPV vaccine in Vietnam: a cluster randomized noninferiority trial. JAMA. 2011 Apr 13;305(14):1424-31. doi: 10.1001/jama.2011.407. PMID 21486975
• Results publication: Widdice LE, Unger ER, Panicker G, Hoagland R, Callahan ST, Jackson LA, Berry AA, Kotloff K, Frey SE, Harrison CJ, Pahud BA, Edwards KM, Mulligan MJ, Sudman J, Bernstein DI. Antibody responses among adolescent females receiving two or three quadrivalent human papillomavirus vaccine doses at standard and prolonged intervals. Vaccine. 2018 Feb 1;36(6):881-889. doi: 10.1016/j.vaccine.2017.12.042. Epub 2018 Jan 3. PMID 29306506
• Results publication: Lamontagne DS, Thiem VD, Huong VM, Tang Y, Neuzil KM. Immunogenicity of quadrivalent HPV vaccine among girls 11 to 13 Years of age vaccinated using alternative dosing schedules: results 29 to 32 months after third dose. J Infect Dis. 2013 Oct 15;208(8):1325-34. doi: 10.1093/infdis/jit363. Epub 2013 Jul 30. PMID 23901077

• Kathy Neuzil, MD, MPH, Principal investigator, PATH