Human Papilloma Virus Vaccine Safety

Human Papilloma Virus Vaccine Safety

Analysis of Vaccine Adverse Events Reporting System Reports Part II

by Vicky Debold, PhD, RN and Barbara Loe Fisher

February 21, 2007

This document is a follow-up to the February 1, 2007 report detailing adverse events, concerns and clinical implications related to use of GARDASIL based on submissions made to the federal Vaccine Adverse Event Reporting System (VAERS). This report covers all reactions submitted in 2006 and supplements the first NVIC analysis of reported adverse events - NVIC Analysis of VAERS Reports on GARDASIL - which can be found here. Readers are encouraged to review the previous report. A number of clinical and patient safety concerns and potential problems arising from co-administration of GARDASIL with other vaccines not evaluated by the manufacturer were discussed in the previous report.

Also, readers are referred to the VAERS website for cautions related to use of VAERS data.[1] The information in this report does not prove a cause and effect relationship between any of the reactions and administration of GARDASIL. This document only summarizes the information in VAERS as it relates to use of GARDASIL, either alone or in combination with other vaccines.
 

[2]

As of mid-February 2007, there were 430 case reports associated with administration of the GARDASIL vaccine. After the duplicate case records were removed (about 10 percent of files), 385 unique case records remained. The data from the 385 case reports are used for this analysis unless stated otherwise.

Since GARDASIL was licensed on June 8, 2006 and added to the recommended American vaccination schedule on June 29, 2006, the number of reports per month filed with VAERS has steadily increased. Two reports were filed in July, 12 in August, 65 in September, 79 in October, 108 in November and 119 in December. Between June 8 and December 31st, an average of 1.87 [3] reports per day have been filed. In December, 3.97 reports per day were filed.

As previously reported, the earliest adverse event report date following vaccine licensure and recommendations was July 14, 2006 for a girl vaccinated July 7, 2006. The earliest reported adverse event overall was for a woman vaccinated on September 1, 2003 during a clinical trial. The most recent report included in this analysis was submitted December 28, 2006.

Reports were submitted to VAERS at various dates throughout each month but tended to be grouped around four dates. In particular, 247 reports (64 percent of all reports) were submitted on September 19th (44 reports), October 17th (45 reports), November 16th (108 reports) and December 18th (87 reports).
 

Patient Demographics

In 98 case reports (25.4 percent) age was not identified. Patient age, where reported, ranged from 1 to 57 years. Among the case reports where age was identified, 111 reports (38.7 percent) were submitted for children 16 and under. The distribution by age of these children is as follows: 1.0/1.5 years (2 cases)[4], 9 (1 case), 11 (9 cases), 12 (10 cases), 13 (14 cases), 14 (25 cases), 15 (27 cases) and 16 (23 cases).

In 14 reports, the gender of the patient was not identified. In all but four of the remaining cases, the patients were females. The males for whom case reports were submitted were 1.0, 1.5, 12 and 18-years-old.

As of the end of December, case reports have been submitted to VAERS from 43 states and the District of Columbia. Two months earlier, reports had been submitted from 20 states.
 

Description Of Reported Reactions

In the case reports submitted to VAERS, five of the reactions were described as "life-threatening," six were "disabling," and 210 (54.5 percent) had "not recovered" as of the date data were provided by VAERS. Hospitalization was reported in 12 cases and two-thirds sought additional care in an emergency room or doctor's office (see Use of Health Services section).

A number of symptoms were reported, with varying levels of severity.[5] The most frequently reported reactions were: pain of various types (89), syncope (55) and dizziness (41), fever/pyrexia (41), paresthesia and hypoaestesia (32), rash (33) and pruritis/itching (31), vasodilation (19), headache (19), and vomiting (16). The following sections focus on three reactions: syncope and dizziness, paresthesia, and Guillain-Barre Syndrome.

Descriptions of the symptoms presented in the following condition-specific sections includes verbatim passages taken from VAERS case reports. No attempt was made to correct spelling or modify what was reported. Symptom description passages are often truncated mid-sentence in the VAERS database.

The time of reaction onset was noted in 192 reports (72 percent). Among the reports that noted when the reaction occurred, 60 percent (115 reports) indicated a reaction on the day the vaccine was given. An additional 21 percent (41 reports) stated that the reaction occurred the day after the vaccine was given. Reports indicated that 94 percent (181 reports) occurred within one week of vaccination.
 

Syncope

Syncope is defined as a temporary suspension of consciousness due to generalized cerebral ischemia (inadequate blood flow and lack of oxygen).

At the end of December 2006, there were 62 case reports stating that a patient had experienced a syncopal episode suggesting that 14.4 percent of case records involve syncope and/or fainting (62/430).[6] Among children 9 to 16 years of age, 12.2 percent of case reports (14/115) documented a syncopal episode. In comparison, only 5.8 percent of children 9 to 16 years of age who received the Tdap (tetanus-diptheria-pertussis) vaccine experienced a syncopal episode.[7]

When syncope is considered along with reports of dizziness (41 cases), approximately 25 percent of all VAERS case reports are involved. Although most syncope reports indicate that it occurred immediately after vaccine administration, some do not. Despite the impression that syncopal episodes are commonplace and harmless, some of the episodes appear to be atypical and worthy of attention. Specifically of concern are the reactions that occur well after the vaccine was given and, in some cases, are combined with seizures and injuries because the patients were either in a sitting or standing position when the syncopal event occurred, fell, and suffered injuries including fractures as a result. For example:

• Case record - 269192 - (14 y/o) - Information has been received from a physician concerning a 14 year old female who on an unspecified date was vaccinated with Gardasil (yeast). It was reported that the patient was sitting on a bench and when the personnel left the room, the patient apparently fainted and ended up falling off bench. It was reported that it was unsure if the patient had broken her nose but there was blood. At the time of this report, the outcome of the events were unknown. The physician feels that the patient "might be anore [report truncated]
   
• Case record - 260144 - (13 y/o) - Patient received Hep A in right arm. Then received HPV in left arm. C/O pains, numbness. Started walking down hall fainted and had tonic/clonic movement for 15 sec. Symptoms: Dyskinesia, hypertonia, hypotonia, pain, paresthesia, syncope
   
• Case record - 265305 - (21 y/o) - According to my daughter, the following happened: 1. Shot was given between 1100-1115 am 2. Proceed to wait a few minutes with doctor in room and then went to check out 3. Between 1120-1125 am...she passed out in doctors office. 4. Day 2-4: tightness in muscles especially around lower legs. Also tigtness in arms, but not as bad as legs. 5. Hard time walking after first waking up in morning and gradually loosens up after she starts moving around. 6. I suggested to her to take a Tylenol to help with m [report truncated]. Symptoms: Gait abnorm, hypertonia, syncope.
   
• Case record - 262242 - (14 y/o) - Vasovagal syncope shortly after receiving hep A and Gardasil vaccine, fell, hit nose on a drawer, loss of consciousness, sent to ER in transport broke nose. Symptoms: Bone fract spontan, injury accid, syncope.
   
• Case record - 264959 - (14 y/o) - Administr4ed Vaqta, then Gardasil, immediately after Gardasil child became unresponsive, stiff, pale about 30 sex. Child lost bladder control, pulse 46-55 after event, child alert and aware after events. Symptoms: Arrhythmia, bradycardia, hypertonia, incontin urin, pallor, stupor, syncope.

NVIC again raises questions about the advisability of allowing children who are believed to be susceptible to syncopal episodes to be vaccinated in a sitting position, left unattended, and not required to lie down for at least 5 to 15 minutes following vaccination.
 

Paresthesia [8]

Paresthesia (paraesthesia) is an abnormal sensation of the skin, such as numbness, tingling, pricking, burning, or creeping on the skin that has no objective cause. Hypesthesia (hypoaesthesia) is the name of the condition that occurs when the skin loses some of its sensitivity to pain or touch. Both have a number of causes and are symptoms of a number of both minor and serious diseases and conditions.

As of the end of December 2006, there were 34 case reports stating that patients had experienced either paresthesia, paraesthesia or hypoaesthesia episodes. Thus, 7.9 percent of case records involve reports of paresthesia-type symptoms (34/430).[9] Among children 9 to 16 years of age, 7.0 percent of case reports (8/115) documented a paresthesia episode. In comparison, only 1.6 percent of children 9 to 16 years of age who received the Tdap vaccine (tetanus-diptheria-pertussis) experienced paresthesia symptoms.

• Case record - 264761 - (18 y/o) - Information has been received from a physician concerning his "around 18" year old daughter who was vaccinated IM with a 0.5 ml dose of HPV rL1 6 11 16 18 VLP vaccine (yeast). Concomitant therapy included a dose of diphtheria toxoid (+) pertussis acellular 3-component vaccine (+) tetanus toxoid (BOOSTRIX). Subsequently, the patient experienced numbness in her arms and lower extremities. Unspecified medical attention was sought. On an unspecified date, the patient recovered. No product quality complaint was [report truncated]. Symptoms: Hypesthesia.
   
• Case record - 264950 - (57 y/o) - 09/19/2006 MMR and HBV adm 1, 10/03/2006 swollen glands, numbness and tingling of arm and legs bilat. Pt called hotline and states she was told this was from the MMR. 10/15/06 chest pain. Pt wonders if this is related to immunizations. Symptoms: Lymphadenopathy, chest pain, paresthesia.
   
• Case record - 267171 - (13 y/o) - INfluenza vaccine and Human Papilloma VIrus vaccines given November 10 about 11:45 AM. Patient woke up with numbness on right side of face on November 11. Presented to Emergency Room on November 12 with Bells Palsy of right side of face. Unable to move right side of face. Unable to close right eye. Previously healthy, no symptoms on day of vaccine administration. Symptoms: Paralysis, facial paralysis, paresthesia.
   
• Case record - 268459 - (14 y/o) - With in five minutes of administration complaint of headache, then felt faint. I had my daughter sit down in the waiting room with her head down before we walked out. Not thinking this had anything to do with the vaccine. We walked out the door and she began have difficlty walking, weaving, I asked her if she was okay and she could only respond yes. I took her arm and tried to turn her back to the Doctor's office and she collapsed on the ground. Though, she remainded conscious her eyes were glazed and [record truncated]. Symptoms: Cold sweat, difficulty in walking, disorientation, dizziness, dyskinesia, headache, hyperventilation, pallor, paraesthesia, tinnitus, tremor

Guillain-Barre Syndrome

According to the National Institute for Neurological Disorders and Stroke:

As of the end of December 2006, there were five case reports that identified Guillain-Barre Syndrome in GARDASIL recipients. The first two of the case reports were described in NVIC's first report. As previously stated, both girls had also received a meningococcal vaccine at the same time that they received GARDASIL.[10]

The three new case reports involve two 13-year-old girls, from Arkansas and Washington, and a 16-year-old from Ohio. All three of these girls received only GARDASIL.

• Case report - 265839 - (16 y/o) - Information has been received from a physician concerning a 16 year old female who on an unspecified date was vaccinated with the first dose of HPV vaccine. subsequently the pt developed lower extremity weakness and was hospitalized for two days with Guillain Barre. The pt received treatment with gamma globulin during her hospitalization. At the time of this report, the pt was back to school and was 99% recovered having only some area of numbness to her lower extremities. The physician did not believe that [report truncated]. Symptoms were: asthenia, Guillain-Barre Syndrome, and paresthesia.
   
• Case report - 268143 - (13 y/o) - Pt admitted to hospital on 12/1/06 with chief complaint of ascending weakness bilaterally, upper and lower extremities. Neuro consult diagnosed Guillain-Barre syndrome. Pt received the Gardasil vaccine on 11/22/06. Resident MD asked pharmacist to write up possible ADR of Guillain-Barre from this vaccine. Symptoms: CSF test abnormal, Guillain-Barre Syndrome, muscular weakness
   
•  Case report - 269328 - (13 y/o) - Information has been received from a physician concerning a 13 year old female who on 22-Nov-2006 was vaccinated with HPV rL1 6 11 16 18 VLP vaccine (yeast). A few days later she had cold symptoms and was prescribed azithromycin (ZITHROMAX). A few days after that the patient developed hives and was prescribed amoxicillin. A few days later the patient was hospitalized and diagnosed on 01-Dec-2006 with Guillian-Barre Syndrome. The patient sought unspecified medical attention. At the time of the report, it was [reported truncated] Symptoms: Guillain-Barre Syndrome, urticaria (hives).

Human Papilloma Virus Infections

There were several case reports of infection with human papilloma virus and cervical dysplasia and genital warts. For example, case reports 260907, 267457, and 269228 describe infections with genital warts, and 267410, 267480, 269248 reported infection with HPV; and 263204, 267415, 268483, 269192, 269202, 269213 report abnormal pap smears and in some cases, cervical dysplasia. A few of the case reports note that procedures to address dysplasia were planned including colposcopy and loop electrosurgical excision procedures.

In most cases, it was not documented whether patients were infected prior to vaccination and whether an exacerbation of disease was experienced following vaccination. Two exceptions include:

• Case report - 267457 - (age not reported) - Information has been received from a midwife registered nurse concerning a female with genital warts who "within the last few weeks" was vaccinated with HPV rL1 6 11 16 18 VLP vaccine (yeast). Concomitant therapy included imiquimod (Aldara). Subsequently "within the last few weeks" the patient experienced "swelling in genital warts". At the time of the report the patient was recovering. Unspecified medical attention was sought. Other information has been requested. Symptoms: Edema
   
• Case report - 267418 - (22 y/o) - Information has been received spontaneously from a gynecologist concerning a 22 year old female patient who had participated in an HPV study. On 29-SEP-2006 the patient tested positive for high risk HPV. The patient's outcome was unknown. Upon internal request, the patient was unblinded on 25-OCT-2006, she received her first dose of HPV on 06-FEB-2003, her second dose in March 2003, and her third dose in September 2003. She showed strong conversion to all 4 vaccine types. At baseline the patient had been se…[report truncated]. Diagnostic lab data - 07-DEC-2004: "ASC-H". 04-APR-2005 colposcopy biopsy negative for lesion, discrepancy noted - biopsy was of less severity than the Papanicolaou (PAP) test result and repeat colposcopy, PAP, and endocervical curettage (ECC) (among other choic…[report truncated]. Symptoms: No drug effect
   

Co-administration of Vaccines

The manufacturer's insert only evaluated co-administration of GARDASIL with Hepatitis B vaccine. The case reports submitted to VAERS indicate that GARDASIL has been administered simultaneously with 18 additional vaccines. As categorized by VAERS, the following vaccines were given along with GARDASIL: DPP, DTAP, DTOX, FLU, FLUN, HEPA, HEPAB, HEP, IPV, MEN, MMR, MNQ, TDAP, TTOX, VARCEL, HIB, MMRV, PNC, and TD. The case reports show that 42 patients (13.9 percent) received at least one other vaccine along with GARDASIL. Additionally, 13 patients received three vaccines, three received four vaccines, and one, the 1-year-old infant, received five vaccines. In only two case reports was Hepatitis B the additional vaccine simultaneously administered. Among those who received two or more vaccines, 68.3 percent were 16 or younger. Of those 16 or younger for whom an adverse event report was submitted, 25.2 percent had received two or more vaccines.
 

Use Of Health Services Among Patients Reporting A Reaction

The case reports indicate that in 253 instances (66 percent), additional ambulatory services were used. It is not possible to determine how many total additional visits were made or to distinguish how many of the additional visits were made to an emergency room rather than a physician's office. Of those requiring additional visits, 57 (22.5 percent) were made by children 15 and under. Among all children 15 and under, 64.8 percent required an additional emergency room or doctor's office visit.

Case reports indicate that 12 patients ranging in age from 13 to 23 were admitted to the hospital and stayed up to five days. Table 1 reports the age and state of residence of the patient. It also shows the number of days following vaccination, use of vaccines other than GARDASIL, symptoms, narrative description and use of tests as noted in the VAERS database.
 

Concerns

NVIC previously raised concerns about the seriousness of some of the reported reactions. Syncopal episodes combined with seizures and injury, as well as certain types of paresthesia, weakness, paralysis and Guillain-Barre Syndrome are serious health events. In the interest of protecting the public's health, action is needed on the part of all stakeholders.

Doctors, nurses and parents should promptly report all reactions following vaccination to VAERS. Failure to submit reports of all reactions to VAERS weakens efforts to monitor and improve the safety and effectiveness of the national vaccination program.

Doctors, nurses and parents should note that a substantial number of children are experiencing dizziness and syncopal episodes after vaccination and some are sustaining injuries when they lose consciousness and fall. This is a clear patient safety issue and children should be protected from potential and unnecessary injury whenever possible. They should be vaccinated laying down and required to lie down for at least 5 to 15 minutes after vaccination. They should not be left unattended.

The manufacturer's product insert should be updated to include explicit precautions related to use of GARDASIL in combination with vaccines not evaluated during clinical trials. Nearly 25 percent of children were vaccinated with one or more of 18 vaccines not evaluated by the manufacturer. There are no evidence-based guidelines that support use of such a protocol. NVIC is also concerned that the numbers of children vaccinated with Hepatitis B along with GARDASIL during the clinical trials were insufficient to establish safety. Until the adverse reactions reported to VAERS can be evaluated fully, doctors and nurses should not administer other vaccines at the same time GARDASIL is given.

The manufacturer's product insert should also be updated to include the serious reactions that have been reported to VAERS.

Click Here to see TABLE 1.

[1] Information about the VAERS reporting system can be found here http://vaers.hhs.gov.  The government has issued the following warning to people using VAERS data: When evaluating data from VAERS, it is important to note that for any reported event, no cause and effect relationship has been established. VAERS is interested in all potential associations between vaccines and adverse events. Therefore, VAERS collects data on any adverse event following vaccination, be it coincidental or truly caused by a vaccine. The report of an adverse event to VAERS is not documentation that a vaccine caused the event.

[2] Unless otherwise noted, our report uses the data for adverse events reported July 1, 2006 to November 30, 2006 and retrieved on two dates in January and February 2007.  For the adverse events reported December 1 through December 31, 2006, our report uses data retrieved mid-February 2007.  As of February 18, 2007 some of the data in the VAERS database – reported symptoms, in particular -- have been modified.  See footnote related to paresthesia. 

[3] Between recommendation date (6/29/07) and December 31, 2007, 2.07 reports per day have been filed with VAERS. Per day reports by month: July .06, August .39, September 2.63, October 2.55, November 3.60, and December 3.97.

[4] In two cases, GARDASIL was unintentionally given to two male infants. 

[5] Symptoms reported are as follows (in alphabetical order): acne (3), abasia (2), abdominal pain (3), abnormal behaviour (1), abortion (1), agitation (3), albuminuria (1), allerg react (3), amblyopia (3), amenorrhea (1), angioedema (1), anorexia (1), anxiety (2), applicat site react (2), arrhythmia (3), arthralgia (7), asthenia (14), asthma (1), bacterial infection (1), blood glucose increased (1), blood potassium decreased (2), blood pressure decreased (1), blood pressure increased (1), blood urine present (1), body temperature decreased (1), bone fract spontan (1), bradycardia (2), breast pain (1), cellulitis (2), chest pain (3), chills (7), cold sweat (1), colitis (1), condition aggravated (2), confusion (2), conjunctivitis (1), contusion (2), convulsion (5), convulsion grand mal (1), cough inc (1), csf test abnormal (1), culture urine positive (1), cyanosis (1), decreased appetite (2), dehydration (3), depersonal (1), depression (1), diarrhea (2), difficulty in walking (1), diplopia (1), discomfort (1), disorientation (1), dizziness (41), dry eye (1), dyskinesia (2), dysphagia (1), dyspnea/ dyspnoea (7), dysuria (1), ecchymosis (1), edema/oedema (9), edema face (8), edema inject site (4), edema/oedema periph (8), edema tongue (1), emotion labil (1), epistaxis (1), erythema (2), esr inc (1), euphoric mood (1), eyes gaze upward (1), fall (1), fatigue (1), feeling abnormal (1), fever (36), flu synd (4), flushing (1), fracture (1), gait abnorm/disturbance (3), guillain barre synd (5), haemorrhage (1), headache (19), hem (1), hepatitis (2), herpes simplex (2), high-pitched crying (1), hostility (1), hyperhidrosis (5), hyperkinesia (3), hypersensitivity (1), hypertonia (9), hyperventil (2), hypesthesia (5), hypoaesthesia (4), hypokinesia (4), hypotens (1), hypotonia (1), hypoxia (1), hysn inject site (5), incontin urin (1), incorrect route of drug administration (1), infect (2), infect fung (2), infect viral (2), inflam inject site (1), influenza like illness (5), inject site react (13), injection site anaesthesia (1), injection site erythema (4), injection site induration (1), injection site mass (9), injection site oedema (2), injection site pain (5), injection site rash (2), injection site swelling (1), injury accid (5), insomnia (2), joint stiffness (1), lab test abnorm (7), lactation fem (1), laryngismus (3), loss of consciousness (6), lymphadenopathy (10), malaise (12), med error (9), menorrhagia (1), menstrual disorder (1), menstruation irregular (1), migraine (2), movement dis (1), mucous mem dis (1), muscular weakness (2), myalgia (13), mydriasis (1), myositis (1), nausea (30), neopl skin (1), nervousness (1), no drug effect (1), nodule skin (1), pain (38), pain abdo (5), pain back (1), pain chest (2), pain inject site (37), pain pelvic (1), pallor (9), paralysis (1), paralysis facial (3), paresthesia/paraesthesia (28), pelvic pain (1), pharyngitis (2), photosensitivity (1), platelet count decreased (1), post vac synd (2), pregn unintend (1), pregnancy test false positive (1), pregnancy test negative (1), pruritus (31), pruritus genital (1), pyrexia (5), rash (26). rash erythematous (1), rash mac pap (5), rash macular (1), rash vesic bull (5), react aggrav (2) react uneval (4), rhinitis (1), rhinorrhoea (1), scan brain (1), screaming synd (1), sensation of heaviness (3), shock (1), similar reaction on previous exposure to drug (1), skin discolor (2), skin disorder (1), skin papilloma (1), smear cervix abnormal (2), spasm general (2), speech dis (2), stomatitis ulcer (1), stupor (2), suicide attempt (1), sweat (5), swelling (2), syncope (55), taste pervers (1), thinking abnorm (1), tinnitus (2), tremor (3), twitch (2), ulcer skin (2), unintended pregnancy (1), urticaria (23), vaccination complication (1), vaginitis (2), vasc dis periph (1), vasodilat (19), vertigo (1), viral infection (2), vision abnorm (1), vision blurred (2), visual disturbance (1), vomit (16), wheezing (1), white blood cell count increased (1), white blood cells urine positive (1).

[6] Computations in this section used VAERS data that contained duplicate entries.  NVIC found duplicate records in the VAERS database, including among case reports of syncope.  After correcting for duplicate records, 14.3 percent of patients (55/385) experienced a syncopal episode. 

[7] At the same office visit, three children also received Hepatitis A vaccine and one received chickenpox vaccine. 

[8] When the VAERS database was checked on two different dates in February 2007, in a number of cases the person reporting the adverse event to VAERS (e.g., a doctor, nurse, or parent) included the symptom paresthesia.  However, in the current version of the VAERS database, a number of these earlier reports have been modified without explanation.  Either the symptom was removed entirely or re-spelled as “paraesthesia” or more frequently, reclassified as hypoaesthesia.  For the this analysis, the three terms were grouped. 

[9] Computations in this section used uncorrected VAERS data that contained duplicate entries.  Using data corrected for duplicate entries, the rate for paresthesia-type symptoms was 8.3 percent (32/385). 

[10] 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.

[11] Data in Table 1 are taken verbatim from the VAERS database.  The narratives within case reports are frequently truncated mid-sentence.  Additionally, data for age, date of vaccination and interval between vaccination and onset of symptoms is sometimes missing. 

---