Severe adverse events associated with HPV vaccine are rare

Post-licensure study data suggest few reports of severe adverse events are related to vaccination with Gardasil.

Issue: August 2007

ATLANTA — The Vaccine Adverse Event Reporting System received 1,763 event reports following administration of the quadrivalent human papillomavirus vaccine.

Severe adverse events were rarely reported, according to John Iskander, MD, MPH, Immunization Safety Office, Office of the Chief Science Officer, CDC.

Dizziness, syncope, injection site pain and nausea were the most commonly reported adverse events after receiving the vaccine (Gardasil, Merck), according to Iskander.

“Many commonly reported adverse events, most notably syncope, occur in the general population and do not have a specific relation to this vaccine or to vaccination in general,” Iskander said at the Meeting of the Advisory Committee on Immunization Practices, held here.

Pre- and post-licensure data

Prelicensure study data showed few severe adverse events, according to Iskander. Ten deaths occurred during pre-licensure studies, and none were believed to be associated with the vaccine. Merck reported 1,291 of the adverse events to the Vaccine Adverse Event Reporting System (VAERS), and providers reported another 272 events.

Most of the post-licensure adverse events occurred within a day or so of vaccination, according to Iskander. Eighty-seven percent occurred in participants who received the HPV vaccine alone, and 3% occurred in participants who also received meningococcal conjugate vaccine (MCV4, Menactra; Sanofi Pasteur). According to VAERS data, 49% of the reports occurred after the first dose, 13% after the second dose and 1% after the third dose; however, the researchers reported that it was unknown after which dose the adverse event occurred among 37%.

Dizziness was the most commonly reported adverse event (13%), followed by syncope (10%) and injection site pain (10%). VAERS also received reports of nausea (9%), pain (7%), rash (7%), pyrexia (6%), urticaria (6%), headache (6%) and loss of consciousness (5%).

The ACIP recommends a 15-minute waiting period following all vaccinations to reduce episodes of syncope, according to Iskander. In addition, syncope is common and associated with a variety of triggers. About 50% of young adults experience at least one syncope episode at some point in their lives, he said.

Severe adverse events rare

“Only 5% of the reports were classified as serious,” Iskander said.

VAERS received 94 reports of serious adverse events; 77 of the reports occurred in vaccine recipients who received the HPV vaccine alone. The most common symptoms among severe adverse events were vomiting (14%), syncope (12%), pyrexia (11%), nausea (11%) and headache (10%).

“The safety profile of all serious reports does not differ from the overall safety profile,” Iskander said.

Four deaths occurred among HPV vaccine recipients following vaccination. One was reported erroneously and was initially associated with influenza A virus, but was later amended to viral myocarditis, according to Iskander. Another death was associated with pulmonary embolism in a 19-year-old woman who was taking oral contraceptives. A third death occurred, but the researchers had little information about the patient. The fourth death occurred in a 14-year-old girl who had laboratory-confirmed influenza B virus and methicillin-resistant Staphylococcus aureus, according to Iskander.

“Although some reported [severe adverse events] lacked sufficient clinical data, the reported deaths do not appear to be causally related to vaccination,” Iskander said.

In addition, thromboembolism is associated with multiple risk factors, including oral contraceptives, according to Iskander.

“Thromboembolism among [oral contraceptive] users has been detected as a [severe adverse event], and was noted during prelicensure studies,” Iskander said.

VAERS received 13 reports of Guillain-Barré syndrome, but six occurred in vaccine recipients who also received the MCV4 vaccine. Only 11 of the 13 occurred within 42 days of vaccination and two were unknown, according to Iskander.

Iskander found that VAERS received several reports of adverse events associated with off-label use, which is not necessarily in violation of standards of care. Some off-label use was intentional and some was unintentional, he said.

Thirteen reports occurred in children aged younger than 9 years, 10 of which occurred in children aged younger than 2 years. VAERS received no serious reports among these vaccine recipients, according to Iskander. Forty-four reports occurred in people aged younger than 40 years but older than 26 years. Fifteen of the reports in those older than 26 (n=63) were associated with administration errors, and three reports were serious, he said. Eleven boys received vaccine, but VAERS received no reports of serious adverse events among these recipients.

As of Feb. 1, 2007, Gardasil is covered under the National Vaccine Injury Compensation Program, according to Iskander. The CDC prepared a website with commonly asked questions about the vaccine and interviews with experts, which can be found at www.cdc.gov/nip/vaccine/hpv/default.htm.

Post-licensure reporting has been extensive, Iskander said, which was expected for a new vaccine that attracted media and medical attention. The company and providers rarely reported severe adverse events, and the CDC will continue to collaborate with the FDA and WHO for post-licensure safety data. – by Lauren Riley

For more information:

Iskander J. Quadrivalent human papillomavirus vaccine (HPV4): United States post-licensure safety update. Presented at: the Meeting of the Advisory Committee on Immunization Practices; June 27-28, 2007; Atlanta.