Pamela Stratton1,2, Minoo Battiwalla3,4, Xin Tian5, Suzanne Abdelazim6,7, Kristin Baird8, A John Barrett3,9, Caroline R Cantilena3,10, Richard W Childs11, Jessica DeJesus5, Courtney Fitzhugh11, Daniel Fowler12,13, Juan Gea-Banacloche12,14, Ronald E Gress12, Dennis Hickstein12, Matthew Hsieh11, Sawa Ito3,15, Troy J Kemp16, Izabella Khachikyan2,17, Melissa A Merideth18, Steven Z Pavletic12, Wim Quint19, Mark Schiffman20, Claire Scrivani3,21, Dana Shanis2,22, Aarthi G Shenoy3,23, Linda Struijk19, John F Tisdale11, Sarah Wagner24, Kirsten M Williams11,25, Quan Yu3, Lauren V Wood26,27, Ligia A Pinto16. 1. Office of the Clinical Director, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. 2. Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. 3. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. 4. Sarah Cannon Research Institute, Nashville, Tennessee. 5. Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. 6. Clinical Center, National Institutes of Health, Bethesda, Maryland. 7. Riverside Regional Medical Center, Newport News, Virginia. 8. Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 9. GW Cancer Center, The George Washington University Hospital, Washington, DC. 10. University of Kansas School of Medicine, Kansas City. 11. Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. 12. Experimental Transplant and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. 13. Rapa Therapeutics, Rockville, Maryland. 14. Infectious Diseases Division, Mayo Clinic Arizona, Phoenix, Arizona. 15. Hematopoietic Stem Cell Transplant and Cell Therapy, Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania. 16. HPV Immunology Laboratory, Frederick National Laboratory for Cancer Research, Frederick, Maryland. 17. Office of New Drugs, Center for Drug Evaluation and Research, Division of Anesthesia, Analgesia, and Addiction Products, US Food and Drug Administration, Silver Spring, Maryland. 18. Office of the Clinical Director, National Human Genome Research Institute, Bethesda, Maryland. 19. DDL Diagnostic Laboratory, Rijswijk, the Netherlands. 20. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland. 21. University of Virginia School of Medicine, Charlottesville. 22. Rittenhouse Women's Wellness Center, Philadelphia, Pennsylvania. 23. Department of Hematology/Oncology, MedStar Washington Hospital Center, Washington, DC. 24. Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, Frederick, Maryland. 25. Children's Research Institute, Children's National, Washington, DC. 26. Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. 27. PDS Biotechnology, Berkeley Heights, New Jersey.
Abstract
Importance: Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms. Objective: To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post-allogeneic transplant compared with female healthy volunteers. Interventions: Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later. Design, Setting, and Participants: This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019. Main Outcomes and Measures: Anti-HPV-6, -11, -16, and -18-specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay. Results: Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P < .001) but not significantly different across groups. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 correlated at month 7 (Spearman ρ = 0.92; P < .001 for both). Adverse events were mild and not different across groups. Conclusions and Relevance: Treatment with the HPV vaccination was followed by strong, functionally active antibody responses against vaccine-related HPV types and no serious adverse events. These findings suggest that HPV vaccination may be safely administered to women posttransplant to potentially reduce HPV infection and related neoplasia. Trial Registration: ClinicalTrials.gov Identifier: NCT01092195.
Importance: Human papillomavirus (HPV) infection is found in about 40% of women who survive allogeneic hematopoietic stem cell transplant and can induce subsequent neoplasms. Objective: To determine the safety and immunogenicity of the quadrivalent HPV vaccine (HPV-6, -11, -16, and -18) in clinically stable women post-allogeneic transplant compared with female healthy volunteers. Interventions: Participants received the quadrivalent HPV vaccine in intramuscular injections on days 1 and 2 and then 6 months later. Design, Setting, and Participants: This prospective, open-label phase-1 study was conducted in a government clinical research hospital and included clinically stable women posttransplant who were or were not receiving immunosuppressive therapy compared with healthy female volunteers age 18 to 50 years who were followed up or a year after first receiving quadrivalent HPV vaccination. The study was conducted from June 2, 2010, until July 19, 2016. After all of the results of the study assays were completed and available in early 2018, the analysis took place from February 2018 to May 2019. Main Outcomes and Measures: Anti-HPV-6, -11, -16, and -18-specific antibody responses using L1 virus-like particle enzyme-linked immunosorbent assay were measured in serum before (day 1) and at months 7 and 12 postvaccination. Anti-HPV-16 and -18 neutralization titers were determined using a pseudovirion-based neutralization assay. Results: Of 64 vaccinated women, 23 (35.9%) were receiving immunosuppressive therapy (median age, 34 years [range, 18-48 years]; median 1.2 years posttransplant), 21 (32.8%) were not receiving immunosuppression (median age, 32 years [range, 18-49 years]; median 2.5 years posttransplant), and 20 (31.3%) were healthy volunteers (median age, 32 years [range, 23-45 years]). After vaccine series completion, 18 of 23 patients receiving immunosuppression (78.3%), 20 of 21 not receiving immunosuppression (95.2%), and all 20 volunteers developed antibody responses to all quadrivalent HPV vaccine types (P = .04, comparing the 3 groups). Geometric mean antibody levels for each HPV type were higher at months 7 and 12 than at baseline in each group (all geometric mean ratios >1; P < .001) but not significantly different across groups. Antibody and neutralization titers for anti-HPV-16 and anti-HPV-18 correlated at month 7 (Spearman ρ = 0.92; P < .001 for both). Adverse events were mild and not different across groups. Conclusions and Relevance: Treatment with the HPV vaccination was followed by strong, functionally active antibody responses against vaccine-related HPV types and no serious adverse events. These findings suggest that HPV vaccination may be safely administered to women posttransplant to potentially reduce HPV infection and related neoplasia. Trial Registration: ClinicalTrials.gov Identifier: NCT01092195.
Authors: Wendy Landier; Smita Bhatia; F Lennie Wong; Jocelyn M York; Jessica S Flynn; Harrison M Henneberg; Purnima Singh; Kandice Adams; Karen Wasilewski-Masker; Brooke Cherven; Rama Jasty-Rao; Marcia Leonard; James A Connelly; Saro H Armenian; Leslie L Robison; Anna R Giuliano; Melissa M Hudson; James L Klosky Journal: Lancet Child Adolesc Health Date: 2021-11-10