Lea E Widdice1, Elizabeth R Unger2, Gitika Panicker3, Rebecca Hoagland4, S Todd Callahan5, Lisa A Jackson6, Andrea A Berry7, Karen Kotloff8, Sharon E Frey9, Christopher J Harrison10, Barbara A Pahud11, Kathryn M Edwards12, Mark J Mulligan13, Jon Sudman14, David I Bernstein15. 1. Division of Adolescent and Transition Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 4000, Cincinnati, OH 45229, United States. Electronic address: lea.widdice@cchmc.org. 2. Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, United States. Electronic address: eru0@cdc.gov. 3. Division of High-Consequence Pathogens and Pathology, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30329, United States. Electronic address: dhv1@cdc.gov. 4. Cota Enterprises, Inc., 16570 46th Street, McLouth, KS 66054, United States. Electronic address: rhoagland@cotaenterprises.com. 5. Division of Adolescent and Young Adult Health, Vanderbilt University, 719 Thompson Lane, Suite 36300, Nashville, TN 37204, United States. Electronic address: todd.callahan@vanderbilt.edu. 6. Group Health Research Institute, 1730 Minor Avenue, Suite 1600, Seattle, WA 98101, United States. Electronic address: jackson.l@ghc.org. 7. Division of Infectious Disease and Tropical Pediatrics, Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF 480, Baltimore, MD 21201, United States. Electronic address: aberry@medicine.umaryland.edu. 8. Division of Infectious Disease and Tropical Pediatrics, Center for Vaccine Development, Institute for Global Health, University of Maryland School of Medicine, 685 W. Baltimore Street, HSF 480, Baltimore, MD 21201, United States. Electronic address: kkotloff@medicine.umaryland.edu. 9. Division of Infectious Diseases, Allergy and Immunology, Saint Louis University, 1100 S. Grand Boulevard, St. Louis, MO 63104, United States. Electronic address: freyse@slu.edu. 10. Division of Pediatric Infectious Diseases, Children's Mercy - Kansas City, 2401 Gillham Road, MO 64108, United States. Electronic address: cjharrison@cmh.edu. 11. Division of Pediatric Infectious Diseases, Children's Mercy - Kansas City, 2401 Gillham Road, MO 64108, United States. Electronic address: bapahud@cmh.edu. 12. Division of Pediatric Infectious Diseases, Vanderbilt Vaccine Research Program, D7227 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232, United States. Electronic address: kathryn.edwards@vanderbilt.edu. 13. The Hope Clinic of the Emory Vaccine Center, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, 500 Irvin Court, Suite 200, Decatur, GA 30030, United States. Electronic address: mark.mulligan@emory.edu. 14. Kaiser Permanente Georgia, 200 Crescent Centre Parkway, Lower Level, Tucker, GA 30084, United States. Electronic address: jon.sudman@kp.org. 15. Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, MLC 6014, Cincinnati, OH 45229, United States. Electronic address: david.bernstein@cchmc.org.
Abstract
BACKGROUND: The originally recommended dosing schedule, 0, 2, 6 months, for the 3-dose quadrivalent human papillomavirus vaccine (4vHPV) was often not followed, resulting in longer than recommended intervals between doses and interest in the effect of prolonged intervals. Recent two-dose recommendations require investigations into the effect of delaying dose 2. METHODS: This multi-site, prospective study enrolled healthy 9-17 year old girls (n = 1321) on the day of or within 28 days following a third dose of 4vHPV vaccination. Antibody titers to 4vHPV types were measured at one and six months post-dose 3 from all participants and post-dose 2 from participants who were on time for dose 3. To compare antibody responses, participants were categorized into groups: second and third doses on time (control group); on-time dose 2, substantially late dose 3 (group 2); substantially late dose 2, on-time dose 3 (group 3); both doses substantially late (group 4). Analyses compared age-adjusted geometric mean titers (GMTs) at one-month and six-months post-dose 3, effect of delaying the second dose, and two versus three doses as well as post-dose 2 GMTs, stratified by age. RESULTS: Compared to on-time dosing, one-month post-dose 3 GMTs were non-inferior in groups 2, 3, and 4 and were superior in group 2. Six month post-dose 3 GMTs were superior in groups 2, 3, and 4 for each genotype, except HPV 18 in group 3. Age-adjusted post does 2 titers were significantly lower than post-dose 3 titers when dose 2 was on time but were significantly higher when dose 2 was substantially late. Participants ≥15 years old had no difference in post-dose 2 titers compared to <15 year olds when dose 2 was substantially delayed. CONCLUSIONS: Prolonged intervals between doses do not appear to diminish and may enhance antibody response to 4vHPV. ClinicalTrials.gov (NCT00524745).
BACKGROUND: The originally recommended dosing schedule, 0, 2, 6 months, for the 3-dose quadrivalent human papillomavirus vaccine (4vHPV) was often not followed, resulting in longer than recommended intervals between doses and interest in the effect of prolonged intervals. Recent two-dose recommendations require investigations into the effect of delaying dose 2. METHODS: This multi-site, prospective study enrolled healthy 9-17 year old girls (n = 1321) on the day of or within 28 days following a third dose of 4vHPV vaccination. Antibody titers to 4vHPV types were measured at one and six months post-dose 3 from all participants and post-dose 2 from participants who were on time for dose 3. To compare antibody responses, participants were categorized into groups: second and third doses on time (control group); on-time dose 2, substantially late dose 3 (group 2); substantially late dose 2, on-time dose 3 (group 3); both doses substantially late (group 4). Analyses compared age-adjusted geometric mean titers (GMTs) at one-month and six-months post-dose 3, effect of delaying the second dose, and two versus three doses as well as post-dose 2 GMTs, stratified by age. RESULTS: Compared to on-time dosing, one-month post-dose 3 GMTs were non-inferior in groups 2, 3, and 4 and were superior in group 2. Six month post-dose 3 GMTs were superior in groups 2, 3, and 4 for each genotype, except HPV 18 in group 3. Age-adjusted post does 2 titers were significantly lower than post-dose 3 titers when dose 2 was on time but were significantly higher when dose 2 was substantially late. Participants ≥15 years old had no difference in post-dose 2 titers compared to <15 year olds when dose 2 was substantially delayed. CONCLUSIONS: Prolonged intervals between doses do not appear to diminish and may enhance antibody response to 4vHPV. ClinicalTrials.gov (NCT00524745).
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