National Vaccine Information Center
www.NVIC.org

Human Papilloma Virus Vaccine Safety

Analysis of Vaccine Adverse Events Reporting System Reports:
Adverse Reactions, Concerns and Implications

On June 8th 2006, the Food and Drug Administration (FDA) announced the approval of GARDASIL, and on June 29th the Advisory Committee on Immunizations Practices (ACIP) voted to recommend adding GARDASIL human papilloma virus vaccine to the Centers for Disease Control's national childhood recommended immunization schedule. On July 14th the first report of a serious reaction to the vaccine was filed with the federal Vaccine Adverse Event Reporting System (VAERS).
A 16-year-old Illinois girl was vaccinated July 7th and 13 days later developed symptoms eventually diagnosed as Guillian-Barre Syndrome. A 14-year-old girl in the District of Columbia was vaccinated on July 11th and complained of severe pain immediately following the injection, fell off the examining table and experienced a 10 to 15 second fainting spell ending up in the emergency room with a headache and speech problems. The report of this reaction, the first in the nation, was filed on July 14th, 15 days after the ACIP vote.

Six months later, 82 reports of GARDASIL reactions have been submitted to VAERS on behalf of at least 84 young girls and 2 boys.[1] Reaction reports have come in from 21 states and the District of Columbia.[2] Reactions were reported for children and young adults ranging in age from 11 to 27. Of the reports indicating what day the vaccine was given and the reaction occurred, 63 percent stated that the reaction occurred the same day the vaccine was given. All but three of the reports were for reactions that occurred within one week of vaccination.

This document is divided into three sections. The first section describes reaction reports for a number of reported adverse events: neurological symptoms including syncopal episodes and seizures, arthralgia and joint pain, Guillian-Barre Syndrome, and other immunological reactions. The second section addresses concerns related to vaccinating individuals already infected with HPV. The last section discusses issues that need to be addressed by government regulators and the manufacturer and considerations for clinicians and consumers.

Reported Adverse Events

Presumably, the reactions described below occurred after the first dose of GARDASIL. GARDASIL is given in a three-dose series. None of the reports stated that the children and adults experiencing problems had previously been vaccinated with GARDASIL.

Syncopal Episodes and Seizures. One-quarter of all reports filed after GARDASIL vaccination were for neurologic adverse events including loss of consciousness, syncope, syncopal events and seizures. An additional five reports included symptoms of dizziness and feeling faint.

Syncope is defined as a temporary suspension of consciousness due to generalized cerebral ischemia (inadequate blood flow and lack of oxygen). The reports of syncopal episodes and their descriptions are remarkable. A physician from Washington State reported that in one morning, three patients experienced syncopal episodes. On August 8th another physician's office reported that two patients experienced syncopal episodes on the same day.

Although these reports did not detail what happened to the individuals experiencing these syncopal episodes, other reports did. The 14-year-old DC girl mentioned earlier experienced a syncopal episode combined with amblyopia (poor vision in one eye), abnormal speech, vomiting, and headache. Also experiencing vision problems, a 17-year-old New York girl reported feeling dizzy and her vision went "black for a few seconds" and she turned pale and lips turned purple and she also had fever and chills. Similar to the DC girl, on July 18th immediately after being vaccinated, a 22-year-old Kentucky woman experienced slurred speech accompanied by pallor and shock. On August 29th, two hours after being vaccinated, a 15-year-old New York girl who had a history of asthma and was on four asthma medications experienced difficulty swallowing prompting a visit to the emergency room. On August 17th, 15 minutes after being vaccinated, a 14-year-old Pennsylvania girl passed out in the car on the way home.

Most of the reports do not describe what happened as a result of the syncopal episode but a few do. One 11-year-old Florida girl fell from the examining table and two Washington girls fell - a 16-year-old girl fell and hit her head on a carpeted concrete surface and a 14-year-old girl fell down and broke her nose.

Whether the 22 girls who experienced syncopal episodes actually experienced atonic seizures cannot be determined from these reports. Four girls, however, displayed observable seizure activity. The 11-year-old Florida girl who fell from the table also displayed "tonic posturing." Tonic posturing is a type of seizure where sustained contraction of muscles in the legs and arms occurs and consciousness is impaired. The 16-year-old Washington girl who fell and hit her head on the floor lost consciousness for one minute and displayed tonic posturing of her right hand. Additionally, a 15-year-old girl from Virginia was described as having "a mild seizure." In California, a 13-year-old girl was walking down the hall after her vaccination, fell and had a 15-second tonic/clonic seizure. Tonic/clonic seizures are also known as "grand mal" seizures.

Additionally, there were reports of dyskinesia (difficulty or distortion in performing voluntary movements) and hypokinesia (slow or diminished movement of the body musculature) both of which have neurological implications.

Arthralgia, Joint Pain and Fever. Arthralgia is defined as pain in the joints. Concerns about arthritis were raised during the GARDASIL clinical trials. Reports of arthralgia in one or more joints accompanied by fever were noted in five instances from four young girls and women in Wisconsin, Texas and New York, and one 18-year-old New York male.

Guillain-Barre Syndrome. Reports state that two recently vaccinated 16-year-old girls - one from Illinois and the other from Mississippi - were diagnosed with Guillian-Barre Syndrome (GBS) following vaccination with GARDASIL. In both cases, the onset of symptoms occurred 13 days after vaccination. According to the National Institute for Neurological Disorders and Stroke:

GBS is a serious disorder in which the body's immune system attacks part of the peripheral nervous system. The first symptoms of this disorder include varying degrees of weakness or tingling sensations in the legs. In many instances, the weakness and abnormal sensations spread to the arms and upper body. These symptoms can increase in intensity until certain muscles cannot be used at all and, when severe, the patient is almost totally paralyzed. … Vaccinations can trigger onset of GBS.[3]

The Illinois girl described earlier was vaccinated on July 7th and symptoms were evident by July 20th. The girl also experienced gait abnormalities (trouble walking properly), asthenia (weakness without loss of strength), paresthesia (burning, prickling, tingling or numbness sensation usually felt in the hands, arms, feet and legs), and hyperkinesia (abnormal increase in muscle movement). The Mississippi girl was vaccinated on July 31st and by August 13th she had increasing numbness and tingling in her feet and hands and was subsequently evaluated by a neurologist and diagnosed with GBS. The current health status of these girls is not known.

In both of these cases, the girls were also vaccinated with Aventis Pasteur's Menactra, a vaccine for meningococcal infections. Menactra has previously been associated with Guillain-Barre Syndrome, and the FDA and others have issued alerts.

Other Adverse Reactions. Additionally, a number of other reactions to GARDASIL are noted in VAERS reports and they include: urticaria (hives); pruritus (itching); macular and papular rashes; blisters and vesicles near the injection site; swollen arms; lymphadenopathy (swollen lymph nodes); red, hot swollen knots at injection site; burning, stabbing, severe and radiating pain at the injection site and in the affected limb during and after injection; nausea and vomiting; infections and skin ulcers, and other allergic reactions.

Other Considerations

GARDASIL is marketed as a "cervical cancer vaccine" and intended to prevent infection with specific HPVs - common viruses among sexually active women. It isn't clear what benefits or potential harms could arise from vaccinating sexually active women who have already contracted HPV. Of the 86 reaction reports filed with VAERS so far, 12 reports were generated by young women 18 and older who were taking hormonal contraceptives and presumably sexually active.

With respect to concerns related to vaccinating women with known HPV infections, adverse reaction reports were filed on behalf of a 17-year-old Texas girl who was already diagnosed with HPV and genital warts. Similarly, the 22 year-old Kentucky woman who experienced slurred speech following vaccination already had an abnormal pap smear with evidence of cervical dysplasia.

Implications

The early reports of potential safety problems with GARDASIL raise concerns and questions that need to be addressed by government regulators, manufacturers and prescribing physicians. Specifically, the following concerns need to be addressed:

1.  Syncope, seizures and Guillian-Barre Syndrome have now been reported with hours to a week after GARDASIL vaccination. GARDASIL manufacturer, Merck, should add these serious adverse events to the product manufacturer insert.
   
2. Considering that over 20 girls have experienced syncopal episodes sometimes combined with seizures and serious injuries, physicians should consider only giving GARDASIL when the patient is safely laying down on the examining table. Because there seems to be syncopal reactions up until 15 minutes after vaccination, patients should be asked to lie down for 15 minutes after receipt of GARDASIL.
   
3. The information provided by Merck indicates that it is safe to administer GARDASIL with Hepatitis B vaccine. The prescribing information states, "Results for clinical studies indicate that GARDASIL may be administered concomitantly (at a separate injection site) with hepatitis B vaccine (recombinant). Co-administration of GARDASIL with other vaccines has not been studied." [4] Due to the small number of girls aged 9 to 15 who appear to have been evaluated for GARDASIL safety in Merck clinical trials (fewer than 2,000) and lack of publicly available information about how many of these girls were given GARDASIL and hepatitis B vaccine simultaneously, the safety of administering GARDASIL and hepatitis B vaccine to all pre-adolescent girls is uncertain.[5]
   
4. Aside from Hepatitis B, Merck does not state that it is safe to simultaneously administer GARDASIL with any other vaccine. Considering that there are ongoing evaluations of a reported association between Menactra (meningococcal vaccine) and Guillain-Barre Syndrome, and Merck does not explicitly indicate that it is safe to administer to administer GARDASIL and Menactra simultaneously, consumers and clinicians should question whether administering both GARDASIL and Menactra at the same time is safe.
   
5.  Similarly, adverse reactions were reported when GARDASIL was administered with eight other vaccines: Hepatitis A, MNQ (?), MEN (Menactra), TD (Tetanus and Diptheria Toxoids), DPP (Diptheria/Pertussis/Polio), PNC Prevnar (Heptavalent pneumococcal conjugate), DTaP (Diphtheria And Tetanus Toxoids and Acellular Pertussis Vaccine), and TDAP (Tetanus, Diptheria and Pertussis). Because Merck does not state that it is safe to administer simultaneously GARDASIL with any vaccine other than Hepatitis B, consumers and clinicians should question whether co-administration of GARDASIL and other vaccines is safe.
   
6. Most, if not all, of the reactions reported to VAERS were in response to the first of the three doses of GARDASIL. The Centers for Disease Control (CDC) Vaccine Information Sheet (VIS) developed for HPV vaccine states that severe reactions include "any unusual condition, such as a high fever or behavior changes. Signs of a serious allergic reaction can include difficulty breathing, hoarseness or wheezing, hives, paleness, weakness, a fast heart beat or dizziness." [6] The CDC also states that "anyone who has ever had a life-threatening allergic reaction to yeast, to any other component of HPV vaccine, or to a previous dose of HPV vaccine should not get the vaccine." Which of the reactions reported to VAERS constitute a "life-threatening allergic reaction" and which, if any, of the children and young adults who experienced reactions should receive additional doses of vaccine? At the October 2006 ACIP meeting, CDC staff stated that only "three serious reports were reported to VAERS after HPV vaccination in females 14 and 16 years of age. One of these patients had vasovagal syncope and was hospitalized overnight for observation." [7]CDC's summary of the first 76 VAERS reports suggests that CDC doesn't regard the remaining reports as "serious." CDC needs to clarify which of the reactions reported to VAERS constitute contraindications to further vaccination with GARDASIL and make this information available to the public and to prescribing physicians.
   
7.  What were the short and longer-term outcomes for the individuals who experienced the reactions reported to VAERS? Is there information available that would help to predict the characteristics that predispose one to be at greatest risk of experiencing a serious reaction?
   
8. The CDC's Vaccine Information Sheet indicates that allergy to yeast is a reason to avoid taking GARDASIL. Merck notes that contraindications to the vaccine include "hypersensitivity to the active substances or to any of the excipients of the vaccine. Individuals who develop symptoms indicative of hypersensitivity after receiving a dose of GARDASIL should not receive further doses of GARDASIL." The prescribing information provided by Merck does not specifically note that yeast allergy is a contraindication to taking GARDASIL. Government regulators and the manufacturer need to address the discrepancy between these documents and clarify the issues related to yeast allergy and make this information readily available to the public and prescribing physicians.
   
9. Additionally, Merck notes that vaccine ingredients include 225 mcg of aluminum (as amorphous aluminum hydroxyphosphate sulfate adjuvant), 0.78 mg of L-histidine, 50 mcg of polysorbate 80, and 35 mcg of sodium borate. These ingredients are not listed on the CDC's VIS sheet. The public needs this information so that they can identify whether they have "hypersensitivities" to any of the ingredients and whether they are at risk of experiencing a serious allergic reaction. Hypersensitivities and known allergic reactions are critical pieces of information that need to be communicated to prescribing physicians in order to make the safest possible vaccination decisions.

Government regulators including the CDC and FDA, in combination with Merck, should address the above safety concerns as soon as possible. Medical groups advocating use of GARDASIL should effectively communicate to physicians and patients the potential risks of using GARDASIL along with precautions to improve the safety of patient care.

For more information about HPV infection, GARDASIL vaccine and VAERS adverse event reports pertaining to GARDASIL, go to www.NVIC.org

[1] National Vaccine Information Center. VAERS reports related to HPV4 vaccine http://www.medalerts.org/vaersdb/findfield.php?PAGENO=2&PERPAGE=10&VAX=HPV4 (Accessed January 10, 2007).

[2] States reporting adverse reactions include: Arkansas (1), Arizona (3), California (14), Colorado (1), District of Columbia (1), Florida (4), Georgia (1), Illinois (2), Kansas (1), Kentucky (3), Massachusetts (4), Maine (1), Missouri (1), North Carolina (4), New Jersey (2), New York (7), Pennsylvania (4), Rhode Island (3), Tennessee (1), Texas (9), Virginia (1) and Washington (4). State of residence was not identified in at least 14 cases.

[3] National Institute of Neurological Disorders and Stroke. Guillain-Barre Fact Sheet http://www.ninds.nih.gov/disorders/gbs/detail_gbs.htm.  Accessed January 31, 2007.

[4 ] Merck and Co., Inc.  GARDASIL. www.merck.com/product/usa/pi_circulars/g/GARDASIL/GARDASIL_pi.pdf  (Accessed January 31, 2007).

[5] Food and Drug Administration. Product Approval Information – Licensing Action: GARDASIL Questions and Answers. http://www.fda.gov/cber/products/hpvmer060806qa.htm. Study 016: Studies in Younger Age Groups, page 19; Study 018: Safety and immune response younger children, page 20. 

[6]Centers for Disease Control, National Immunization Program, HPV Vaccine Information Sheet www.cdc.gov/nip/publications/VIS/vis-hpv.pdf (Accessed January 31, 2007.)

[7]Centers for Disease Contol, National Immunization Program, ACIP Meetings October 2006 http://www.cdc.gov/nip/ACIP/minutes.htm (Accessed January 31, 2007.)