Elsevier

Vaccine

Volume 29, Issue 46, 26 October 2011, Pages 8279-8284
Vaccine

Monitoring the safety of quadrivalent human papillomavirus vaccine: Findings from the Vaccine Safety Datalink

https://doi.org/10.1016/j.vaccine.2011.08.106Get rights and content

Abstract

Background

In 7 large managed care organizations (MCOs), we performed a post-licensure safety assessment of quadrivalent human papillomavirus vaccine (HPV4) among 9–26 year-old female vaccine recipients between August 2006 and October 2009.

Methods

Sequential analyses were conducted weekly to detect associations between HPV4 exposure and pre-specified outcomes. The pre-specified outcomes identified by ICD-9 codes using computerized data at the participating MCOs included: Guillan–Barré Syndrome (GBS), stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reactions, and anaphylaxis. For rare outcomes, historical background rates were used as the comparison group. For more common outcomes, a concurrent unexposed comparison group was utilized. A standardized review of medical records was conducted for all cases of GBS, VTE, and anaphylaxis.

Results

A total of 600,558 HPV4 doses were administered during the study period. We found no statistically significant increased risk for the outcomes studied. However, a non-statistically significant relative risk (RR) for VTE ICD-9 codes following HPV4 vaccination of 1.98 was detected among females age 9–17 years. Medical record review of all 8 vaccinated potential VTE cases in this age group revealed that 5 met the standard case definition for VTE. All 5 confirmed cases had known risk factors for VTE (oral contraceptive use, coagulation disorders, smoking, obesity or prolonged hospitalization).

Conclusions

In a study of over 600,000 HPV4 vaccine doses administered, no statistically significant increased risk for any of the pre-specified adverse events after vaccination was detected. Further study of a possible association with VTE following HPV4 vaccination is warranted.

Highlights

► We performed a post-licensure safety assessment of HPV4 among 9–26 year old female vaccine recipients between 2006 and 2009. ► Weekly sequential analyses conducted to detect associations between HPV4 exposure and pre-specified outcomes. ► No statistically significant increased risk detected for the outcomes studied. ► A non-significant RR of 1.98 for venous thromboembolism detected, further study needed.

Introduction

In June 2006, the Food and Drug Administration (FDA) licensed the quadrivalent human papillomavirus (HPV) vaccine (Gardasil®; Merck & Co. Inc., Whitehouse Station, New Jersey) for females aged 9–26 years. Gardasil®, or HPV4, is a virus-like particle vaccine composed of the major L1 capsid protein for HPV types 6, 11, 16, and 18 and an aluminum-containing adjuvant. The vaccine, administered in a series of three doses, is recommended by the Advisory Committee on Immunization Practices (ACIP) for routine use among females ages 11–12 years, permitted for girls as young as nine years of age, and recommended for females 13–26 years of age not previously vaccinated [1]. Prelicensure clinical trials have shown no evidence for any major safety problems [2], [3]. However, prelicensure studies were not adequately powered to detect rare adverse events. Because of this limitation, post-licensure monitoring of HPV4 safety using large population-based cohorts is needed.

The Vaccine Safety Datalink (VSD) is a collaboration of managed care organizations (MCOs) in the United States which collects medical information on more than 9 million people each year [4]. The VSD has developed a near real-time surveillance system, called Rapid Cycle Analysis (RCA), to monitor potential adverse events following licensure of new vaccines [5]. The purpose of this study was to determine whether HPV4 is associated with an increased risk of pre-specified clinically well-defined and severe adverse events in a large, nationally representative population.

Section snippets

Design and study population

Seven VSD sites, including Group Health Cooperative (Seattle, WA), Harvard Pilgrim Health Care and Harvard Vanguard Medical Associates (Boston, MA), HealthPartners Research Foundation (Minneapolis, MN), Kaiser Permanente of Colorado (Denver, CO), Kaiser Permanente of Northern California (Oakland, CA), Marshfield Clinic (Marshfield, WI) and Kaiser Permanente Northwest (Portland, OR) participated in this prospective cohort study. Females aged 9–26 years, identified at the participating sites from

Results

Monitoring of HPV4 occurred for 164 weeks during which a total of 600,558 doses were administered in the VSD population. 416,942 doses were administered to youth and 183,616 doses to adults.

Discussion

With over 600,000 doses administered, this is the largest population-based, post-licensure study of HPV4 safety in the United States. We confirmed no statistically significant increased risk between HPV4 and Guillain–Barré Syndrome (GBS), stroke, venous thromboembolism (VTE), appendicitis, anaphylaxis, seizure, syncope, or allergic reaction. While we did not confirm any statistically significant signals, an elevated RR of 1.98 for VTE among the youth was observed when the upper limit was

Acknowledgements

This study was supported through the Vaccine Safety Surveillance and Assessment Projects contract (200-2002-00732) with America's Health Insurance Plans, funded by the Centers for Disease Control and Prevention. We thank Lauri Markowitz MD, Barbara Slade MD, Jerry Tokars MD, MPH and Claudia Vellozzi MD, MPH for their technical guidance and editorial assistance. We acknowledge the excellent work of the Vaccine Safety Datalink team who provided data management, programming, medical record review

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    Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention nor that of America's Health Insurance Plans.

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