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Clinical Trial and Post-Licensure Safety Profile of a Prophylactic Human Papillomavirus (Types 6, 11, 16, and 18) L1 Virus-Like Particle Vaccine

Block, Stan L. MD*; Brown, Darron R. MD; Chatterjee, Archana MD, PhD; Gold, Michael A. MD§; Sings, Heather L. PhD; Meibohm, Anne PhD; Dana, Adrian MD; Haupt, Richard M. MD, MPH; Barr, Eliav MD; Tamms, Gretchen M. BS; Zhou, Haiping MA; Reisinger, Keith S. MD, MPH

The Pediatric Infectious Disease Journal: February 2010 - Volume 29 - Issue 2 - p 95-101
doi: 10.1097/INF.0b013e3181b77906
Original Studies

Background: We describe the safety of the human papillomavirus (HPV)-6/11/16/18 vaccine using updated clinical trial data (median follow-up time of 3.6 years) and summarize up to 3 years of post-licensure surveillance.

Methods: In 5 clinical trials, 21,480 girls/women aged 9 to 26 years and boys aged 9 to 16 years received ≥1 dose of HPV-6/11/16/18 vaccine or placebo. All serious and nonserious adverse experiences (AEs) and new medical conditions were recorded for the entire study period(s). As of June 2009, >25 million doses of HPV-6/11/16/18 vaccine had been distributed in the United States with >50 million doses globally. Post-licensure safety as summarized by the Centers for Disease Control and Prevention using the United States Vaccine Adverse Event Reporting System database is also reported.

Results: Eight subjects experienced a treatment-related serious AE (0.05% vaccine; 0.02% placebo). Of 18 deaths (0.1% vaccine; 0.1% placebo), all were considered unrelated to study treatment. New medical conditions which were potentially consistent with autoimmune phenomena were reported in 2.4% of both vaccine and placebo recipients. Pain, the most common injection-site AE, occurred more frequently with vaccine (81% vaccine; 75% placeboaluminum; 45% placebo-saline). No differences were seen in the incidence of the most common nonserious AEs–headache and pyrexia. The Vaccine Adverse Event Reporting System has received 14,072 reports for the HPV-6/11/16/18 vaccine since licensure, with only 7% being serious AEs, about half the average reported for licensed vaccines in general.

Conclusions: HPV-6/11/16/18 vaccination was associated with more injection-site pain than placebo but similar incidences of systemic and serious AEs and new medical conditions potentially consistent with autoimmune phenomena. Based on review of post-licensure safety information, the benefits of vaccination to prevent the majority of genital tract precancers and cancers continue to far outweigh its risks.


From the *Kentucky Pediatric/Adult Research, Inc., Bardstown, KY; †Indiana University School of Medicine, Indianapolis, IN; ‡Creighton University School of Medicine, Omaha, NE; §The University of Oklahoma Health Sciences Center, Oklahoma City, OK; ¶Merck Research Laboratories, West Point, PA; and ∥Primary Physicians Research, Pittsburgh, PA.

Accepted for publication July 15, 2009.

Supported by Merck Research Laboratories. S.B. and K.R. have received research support from and are consultants for Merck and Co., Inc. S.B. and K.R. have also received research grants from GlaxoSmithKline. M.G. has received research support from Merck and Co. Inc., GenProbe, GlaxoSmithKline, MediSpectra, MGI Pharma, sanofi aventis, 3M, ARIAD, Precision Therapeutics, and Tigris Pharmaceuticals, and honoraria from Merck and Co. Inc., GlaxoSmithKline, MGI Pharma, and Monogen.

Michael A. Gold is currently at Vanderbilt University Medical Center, Nashville, TN.

Authors are responsible for the work described in this article. All authors were involved in at least one of the following: conception, design, acquisition, statistical analysis, interpretation of data, drafting the manuscript, and/or revising the manuscript for important intellectual content.

D.R.B. has received lecture fees, advisory board fees, and intellectual property fees from Merck and Co., Inc. A.C. has received lecture fees, grant support and consulting fees from Merck and Co., Inc and GlaxoSmithKline.

H.L.S., A.M., A.D., R.M.H., E.B., G.T., and H.Z. are employees of Merck & Co, Inc and hold stock/stock options.

Address for correspondence: Stan Block, MD, Kentucky Pediatric Research, Inc., 201 South 5th St, Bardstown, KY 40004. E-mail:

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© 2010 Lippincott Williams & Wilkins, Inc.