Vaccine 29 (2011) 886889

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

GuillainBarr syndrome after Gardasil vaccination: Data from Vaccine Adverse Event Reporting System 20062009
Nizar Souayah a, , P.A. Michas-Martin c , Abu Nasar d , Nataliya Krivitskaya a , Hussam A. Yacoub a , Haz Khan e , Adnan I. Qureshi b
a

Department of Neurology, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, United States Zeenat Qureshi Stroke Research Center, University of Minnesota, Minneapolis, MN 55454, United States New York Medical College, Valhalla, NY 10595, United States d Department of Surgery, Columbia University Medical Center, New York, NY 10032, United States e Department of Epidemiology & Biostatistics, Robert Stempel College of Public Health & Social Work, Florida International University, Miami, FL 33199, United States
b c

a r t i c l e

i n f o

a b s t r a c t
Using data from Vaccine Adverse Event Reporting System, we identied 69 reports of GuillainBarr Syndrome (GBS) after Gardasil vaccination that occurred in the United States between 2006 and 2009. The onset of symptoms was within 6 weeks after vaccination in 70% of the patients in whom the date of vaccination was known. The estimated weekly reporting rate of post-Gardasil GBS within the rst 6 weeks (6.6 per 10,000,000) was higher than that of the general population, and higher than post-Menactra and post-inuenza vaccinations. Further prospective active surveillance for accurate ascertainment and identication of high-risk groups of GBS after Gardasil vaccination is warranted. 2010 Elsevier Ltd. All rights reserved.

Article history: Received 11 June 2010 Accepted 9 September 2010 Available online 23 September 2010 Keywords: Gardasil Vaccination GuillainBarr syndrome Papillomavirus Adverse effect

1. Introduction On June 8, 2006, a quadrivalent vaccine (Gardasil) that provides protection against four human papilloma virus (HPV) variants associated with approximately 70% of cervical cancers and more than 90% of genital warts was licensed for use in the United States in women between 9 and 26 years of age [1]. The availability of cervical cancer vaccine has elicited enormous enthusiasm from the medical community, particularly after the publication of several reports showing the effectiveness of the vaccine in preventing precancerous cervical lesions caused by HPV-16 and HPV-18 [24]. However, several reports derived from analysis of data from the Vaccine Adverse Events Reporting System (VAERS) pointed to several cases of post-Gardasil vascular and neurological complications [5]. Since GuillainBarr syndrome (GBS) is considered one of the most common neurological sequelae of vaccination, we investigated the occurrence of GBS after vaccination with Gardasil to provide further information about the characteristics and temporal prole of these occurrences. We also compared the occurrence of GBS in patients vaccinated with Gardasil to that following

other vaccinations, and to the incidence of GBS in the general population.

2. Methods We used data derived from the Vaccine Adverse Event Reporting System (VAERS) supplemented by data from the Center for Biologics and Research under the freedom of information act. The VAERS is a national cooperative program instituted by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA). The VAERS collects information about adverse events that occur after the administration of licensed vaccines in the United States. The database records the demographics and clinical characteristics of the events, results of diagnostic tests, and outcome using a non-standardized format. We searched the database between June 2006 and September 2009 using the following keywords and subject terms: GuillainBarr syndrome, acute polyneuropathy, MillerFisher syndrome, paraparesis, paraplegia, paralysis, accid paralysis, weakness, and numbness. The clinical ndings and diagnostic test results were reviewed by a board-certied neuromuscular specialist to identify events that met the diagnostic criteria of GBS dened by progressive arm and leg weakness and areexia. The diagnosis was supported by the presence of elevated cerebrospinal

Corresponding author at: 90 Bergen Street, DOC 8100, Newark, NJ, 07103, United States. Tel.: +1 973 972 8577; fax: +1 973 072 8738. E-mail address: souayani@umdnj.edu (N. Souayah). 0264-410X/$ see front matter 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2010.09.020

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uid protein concentration with fewer than 10 cells/mm2 or by electrodiagnostic study ndings consistent with primary demyelination. Cases of MillerFisher syndrome, a variant of GBS, were also included in the study. The occurrence of GBS within 6 weeks of Gardasil vaccination was suggestive of a causal association [6,7]. The estimated reporting rate of GBS cases identied after vaccination with Gardasil was compared to that after vaccination with the meningococcal (Menactra) and the inuenza vaccines. We chose the Menactra vaccine, licensed by the FDA in January 2005, as a comparative control since it is used in a similar patient population, including children approximately 11 years of age or older. Since Menactra and Gardasil vaccines are indicated for the same patient population, they are frequently co-administrated. The reporting rates of GBS associated with Menactra and inuenza vaccines, both of which have been associated with GBS, were used to provide the relative values for comparative purposes [610]. The crude reporting rate of occurrence of GBS was estimated by dividing the number of events reported within 6 weeks by the total number of vaccinations administered each year. We used the rst 2 weeks after Gardasil vaccination to determine peak weekly incidence of GBS based on previous observations that the highest incidence of GBS occurred within the rst 2 weeks of seasonal inuenza vaccination [9,11]. The total number of vaccinations administered each year was derived from either estimates provided by the CDC or the National Health Interview Survey. The incidence of GBS in the general population was estimated based on a literature review. We searched the medical literature using MEDLINE, BIOSIS, and Cochrane databases for pertinent publications from 1966 to 2009 using the keywords mentioned above. The weekly incidence of GBS was derived from the annual incidence and based on events that were reported within 2 and 6 weeks of vaccination. We estimated the total number of reported events, lifethreatening events, emergency department visits, hospitalizations, and disability per 100,000 vaccinated subjects for Gardasil, Menactra, and inuenza vaccines using the VAERS database.

18 16 14 12 10 8 6 4 2 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6

Fig. 1. The incidence of GuillainBarr syndrome within 6 weeks after Gardasil vaccination.

3. Results There were 69 reported cases of GBS after vaccination with Gardasil in the United States between June 2006 and September 2009. The mean patients age (standard deviation) was 16.7 (6.2) years. GBS occurred after administration of Gardasil as a single vaccine in 47 (68%) subjects, in combination with Menactra in 18 (26%) subjects, and in combination with vaccines other than Menactra in 4 (6%) subjects. Among 48 patients with a known date of occurrence, 34 (70%) GBS cases occurred within 6 weeks of vaccination with Gardasil. The number of days between vaccine administration and symptoms onset was unknown in 21 cases. The distribution of time interval between Gardasil vaccination and occurrence of GBS showed a peak within the rst 2 weeks postvaccination (Fig. 1). Of the 34 patients who developed GBS within 6 weeks post-vaccination, 25 (74%) developed symptoms within the rst 2 weeks. The probability of observing an asymmetrical distribution over the 6 weeks by chance alone was low (p = 0.0002). Hospitalization after Gardasil vaccination occurred in 42 (61%) subjects. Disability, dened by a substantial disruption of subjects ability to conduct normal life function, occurred in 12 (17%) subjects. Death was not reported in any of the cases. Between June 2006 and September 2009, 52 cases of GBS were reported following Menactra vaccination. GBS occurred after the administration of Menactra as a single vaccine in 18 (34.6%) cases and in combination with other vaccines in 34 (65.4%) cases. GBS occurred within 6 weeks after Menactra vaccination in 42 (80.1%) subjects and after 6 weeks of vaccination in 10 (19.2%) subjects.

In two subjects, the date of vaccination was unknown. Of the 42 patients who developed GBS within 6 weeks post-vaccination, 26 (62%) developed GBS within the rst 2 weeks. Between June 2006 and September 2009, 166 cases of GBS were reported following the inuenza vaccine. GBS occurred after the administration of the inuenza vaccine as a single vaccine in 145 (87%) cases and in combination with other vaccines in 21 (13%) cases. The onset of GBS occurred within 6 weeks after vaccination in 132 (80%) subjects and after 6 weeks of vaccination in 14 (8%) subjects. In 20 (12%) subjects, the date of vaccination was unknown. According to the CDC, as of September 1, 2009, approximately 26 million Gardasil doses were distributed in the United States [12]. This corresponds to approximately 8.6 million subjects vaccinated with Gardasil since its approval in the United States. The estimated annual reporting rate of GBS after vaccination with Gardasil was approximately 80.23 per 10 million patients. The average weekly reporting rate of GBS within the rst 6 weeks after vaccination with Gardasil was 6.6 events per week per 10 million subjects. The average weekly reporting rate within the rst 2 weeks after Gardasil vaccination was higher and estimated to be 14.5 cases per week per 10 million subjects. According to the CDC, approximately 22.6 million doses of Menactra have been distributed in the United States between June 2006 and September 2009 [13,14]. Consequently, the annual reporting rate of GBS occurrence post-Menactra vaccination is approximately 23 cases per 10 million treated patients. The average weekly reporting rate within the rst 6 weeks after vaccination with Menactra was three events per week per 10 million treated patients. The average weekly reporting rate within the rst 2 weeks after Menactra vaccination was 5.7 cases per week per 10 million patients treated. From June 2006 to September 2009, it is estimated using the National Health Interview Survey that approximately 173 million inuenza vaccines were administered in the United States [15]. The annual reporting rate of GBS following the inuenza vaccination is estimated to be 9.6 cases per 10 million patients treated. The average weekly reporting rate within the rst 6 weeks after vaccination with inuenza was 1.3 events per week per 10 million patients treated. In the general population, the annual incidence of GBS is reported to be 34134 cases per 10 million [16]. This corresponds to an average weekly incidence of 0.652.57 cases per week per 10 million. The average weekly reporting rate of post-Gardasil GBS within the rst 6 weeks of vaccine administration was higher than the estimated incidence of GBS in the general population: 29 cases per 10 million within the rst 2 weeks of Gardasil vaccination compared to 1.35 per 10 million cases in the general population. According to the VAERS, there were more life-threatening events, emergency department visits, hospitalizations, and disability

Number of Cases

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Table 1 Events reported after Gardasil, Menactra, and inuenza vaccine administration between June 2006 and September 2009 (VAERS). Events Total reports Total reports per 105 subjects Life-threatening Life-threatening per 105 subjects Emergency department visits Emergency department visits per 105 subjects Hospitalizations Hospitalizations per 105 subjects Disability Disability per 105 subjects GBS per 105 subjects Gardasil vaccination treated persons (n) 13,115 152.5 269 3.1 5851 68 1444 16.8 456 5.3 69 Menactra vaccination treated persons (n) 4903 21.7 71 0.31 1813 8 305 1.3 46 0.2 52 Inuenza vaccination treated persons (n) 13,801 8 352 0.2 5021 3 1326 0.76 284 0.16 166

reports associated with the Gardasil vaccine compared with Menactra and inuenza vaccines between June 2006 and September 2009 (p < 0.0001) (Table 1). 4. Discussion An increased risk of GBS associated with Gardasil vaccination may cause public concern, inuence public policy on vaccination, and reduce utilization of vaccination [17]. There was nearly a 2.5to 10-times greater risk of acquiring GBS within 6 weeks after Gardasil vaccination when compared with the general population. Compared to Menactra, the VAERS database reported more postGardasil GBS within the rst 2 weeks post-vaccination (29 cases versus 11.4 cases per 10 million vaccinated subjects). Gardasil vaccination was associated with approximately 8.5-times more emergency department visits, 12.5-times more hospitalizations, 10-times more life-threatening events, and 26.5-times more disability than the Menactra vaccination (Table 1). The distribution of time interval between Gardasil vaccination and onset of GBS suggested a peak occurrence within the rst 2 weeks post-vaccination followed by a decline in occurrence in the third week and a value close to the risk observed in the general population in the fourth to sixth weeks (Fig. 1). A similar pattern of association between GBS and inuenza vaccine was observed by Lasky et al. [9] and Haber et al. [11] with more GBS cases reported in the second week after vaccination. The highest relative risk of GBS onset after respiratory infection, a potential triggering factor, was also reported in the rst 2 weeks after infection [18]. Molecular mimicry and other immune system stimulation mechanisms may play a role in mediating GBS after Gardasil vaccination. Some vaccines, such as the Gardasil vaccine, may be more likely to trigger GBS because of the high antigenicity of the vaccinces recombinant proteins, antigenicity of components of the vaccine other than the recombinant proteins (especially aluminum), and the genetic predisposition of vaccinated subjects to develop vaccine-induced autoimmunity [1921]. The Gardasil vaccine leads to a 40-fold increase in HPV antibodies compared with the physiological antibody level triggered by a natural HPV infection [22]. The antibody titer against the HPV genotypes 16 and 18 may remain 11-times higher than those induced by a natural infection 5.5 years after vaccination [23]. Polyclonal sera from Gardasil recipients cross neutralize HPV 45 pseudovirions inducing a cross protection against persistent infection with HPV 45 [21,23]. Immediate and long-term elevation in non-physiological immunogenicity with cross reactivity with other antigens may explain the higher occurrence of GBS in genetically predisposed subjects. Amorphous aluminum hydroxyphosphate sulfate is used as an adjuvant to Gardasil vaccine. Although aluminum has been associated with post-vaccination macrophagic myofasciitis and heavy metal ingestion has been associated with a single case of GBS, the role of aluminum in the genesis of GBS is not clear [2427].

Our study has some limitations that need to be addressed prior to interpreting the data. Case ascertainment was based on VAERS reports, a passive surveillance system that is subject to underreporting, differential reporting, ascertainment bias, and variability in report quality and completeness [11]. The actual reporting rate of GBS following vaccination is probably higher because the reporting system is voluntary, and it is therefore likely that an undened proportion of GBS events were not reported to the VAERS. On the other hand, over-diagnosis of GBS following vaccination should be taken into consideration due to lack of a standard denition and diagnostic criteria. Therefore, besides the true increase of risk of GBS with vaccination, an increase in reports to the VAERS may be due to an increase in efciency of reporting, vaccine coverage, and background rate of GBS. Despite the limitations of our study, there is evidence that GBS was reported more frequently within 6 weeks of Gardasil vaccination compared with other vaccines and the general population. Because of possible underestimation incurred during ascertainment using passive surveillance, a prospective active surveillance for accurate ascertainment and identication of high-risk groups is warranted.

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