Abstract
Post-marketing surveillance studies provide conflicting evidence about whether Guillain–Barre syndrome occurs more frequently following quadrivalent human papillomavirus (HPV4) vaccination. We aimed to assess whether Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among females and males aged 9 to 26 y in the United States. We used adverse event reports received by the United States Vaccine Adverse Event Reporting System (VAERS) between January 1, 2010 and December 31, 2012 to estimate overall, age-, and sex-specific proportional reporting ratios (PRRs) and corresponding Χ2 values for reports of Guillain–Barre syndrome between 5 and 42 d following HPV vaccination. Minimum criteria for a signal using this approach are 3 or more cases, PRR ≥2, and Χ2 ≥ 4. Guillain–Barre syndrome was listed as an adverse event in 45 of 14 822 reports, of which 9 reports followed HPV4 vaccination and 36 reports followed all other vaccines. The overall, age-, and sex-specific PRR estimates were uniformly below 1. In addition, the overall, age-, and sex-specific Χ2 values were uniformly below 3. Our analysis of post-marketing surveillance data does not suggest that Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among vaccine-eligible females or males in the United States. Our findings may be useful when discussing the risks and benefits of HPV4 vaccination.
Keywords: human papillomavirus, vaccine, post-marketing surveillance, Guillain-Barre syndrome, adverse event, safety
Guillain–Barre syndrome comprises a group of peripheral-nerve disorders characterized by weakness or paralysis, which is believed to have an autoimmune etiology.1 Although generally considered an acute condition, prolonged and severe disability can occur in 20% of patients.1 The median estimated incidence of Guillain–Barre syndrome in Western countries is 1.1 per 100 000 person-years,2 and putative risk factors include age, sex, and viral or bacterial infections.1 This syndrome has also been documented in the literature as a potential adverse event following immunization (AEFI) as early as 1956.3 The concern about Guillain–Barre syndrome as an AEFI dramatically increased after reports that the 1976 influenza (A/New Jersey; “swine flu”) vaccine was associated with the syndrome.4 Continued assessments of influenza and other vaccines provide inconsistent evidence of an association with Guillain–Barre syndrome, particularly because of recent reports of a modest increased risk following the 2009 pandemic influenza vaccination.5-19 Consequently, interest in and anxiety about Guillain–Barre syndrome as an AEFI persists, particularly when new vaccines are publicly disseminated.
One of the newest vaccines to be publicly disseminated in the United States is designed to immunize against 4 types of human papillomavirus (HPV4)—2 of which are high-risk types found in 70% of cervical tumors (HPV-16 and -18) and 2 of which are associated with genital warts (HPV-6 and -11). The HPV4 vaccine was recommended for routine use in 2007 among females aged 9 to 26 y,20 and in 2010 for use among males aged 9 to 26 y.21 A recent post-marketing surveillance study using spontaneous reports of adverse events data in the United States suggested that Guillain–Barre syndrome is reported more frequently following HPV4 vaccination,22 which contradicts other studies on the topic.23,24 A flawed approach to the analysis of spontaneous reports of adverse events data was the major reason cited for the discrepant results in the recent study.25 Of greater current relevance is that prior studies analyzed data from a period before recommendation of routine HPV4 vaccination for males in the United States.21 A systematic assessment of whether Guillain–Barre syndrome is reported more frequently among females and males following HPV4 vaccination may provide useful information as part of ongoing surveillance of HPV4 vaccine safety. Therefore, we aimed to assess whether Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among females and males aged 9 to 26 y.
We used adverse event reports received by the United States Vaccine Adverse Event Reporting System (VAERS)26 to address our objective. VAERS is a nationwide passive surveillance system for adverse events that was established in 1990, and is operated by the United States Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC). Adverse event reports may be submitted by health care providers, manufacturers, and patients or their parents.27 We selected all reports submitted between January 1, 2010 and December 31, 2012 for analysis. The de-identified publicly-available VAERS data qualify as exempt from Institutional Review Board approval.
VAERS uses standardized Medical Dictionary for Regulatory Activities (MedDRA) terminology to document adverse event information. We defined Guillain–Barre syndrome as any report that listed the MedDRA term “Guillain–Barre syndrome” as an adverse event between 5 and 42 d following vaccination.28 This period between 5 and 42 d (i.e., standard latency) is considered the biologically plausible latency period for Guillain–Barre syndrome following vaccination.28 Nonetheless, we explored potential differences in reporting frequency by using an expanded latency period that included all reports of Guillain–Barre syndrome between 0 and 42 d following vaccination, and a restricted latency period that included all reports between 7 and 21 d following vaccination (consistent with the period during which most cases are observed28).
VAERS reports include all vaccine products that were administered on the vaccination date of interest. We defined receipt of HPV4 as any report that listed “HPV4” as one of the administered vaccines. We confirmed reports of HPV4 by cross-checking with the vaccine name and vaccine manufacturer variables included in VAERS. Reports that did not include HPV4 as one of the administered vaccines were defined as reports of all other vaccines for the analysis.
We estimated overall, age- (9–17 y and 18–26 y), and sex-specific proportional reporting ratios (PRRs), 95% confidence limits (CL), and corresponding Χ2 values for reports of Guillain–Barre syndrome following HPV vaccination compared with reports of Guillain–Barre syndrome following all other vaccinations.29 When applied to spontaneous reports of adverse events data, the PRR is a standard measure used to generate a signal about a potential hazard of vaccinations or drugs.29 The minimum criteria for a signal that should be further considered are 3 or more reports, PRR ≥2, and Χ2 ≥ 4,29 which were applied to our analyses.
We defined Guillain–Barre syndrome as any report that listed the MedDRA term “Guillain–Barre syndrome” as an adverse event but recognized that misclassification of Guillain–Barre syndrome is possible using this or any other definition. We thus explored the sensitivity of our overall PRR estimate to misclassified reports of Guillain–Barre syndrome using quantitative bias analysis, which uses standard formulae to re-estimate the PRR after adjustment for classification errors (i.e., accounting for imperfect sensitivity and specificity of reported Guillain–Barre syndrome).30 Given the lack of systematically derived sensitivity and specificity values of reported Guillain–Barre syndrome in VAERS, we applied a wide range of values for sensitivity and specificity of Guillain–Barre syndrome reports to explore changes in our PRR estimate. Unfortunately, modifying specificity to any value less than 100% resulted in adjusted cells with negative case counts and meaningless adjusted PRRs. Consequently, we varied sensitivity over a wide range but assumed perfect specificity (i.e., no false-positive reports of Guillain–Barre syndrome) in our bias analysis. Of interest were the scenarios in which PRR would be greater than 2 for Guillain–Barre syndrome following HPV4 vaccination.
During the study period, 14 822 unique adverse event reports for vaccine-eligible individuals in the United States were submitted to VAERS, of which 4670 noted HPV4 as one of the administered vaccines. Table 1 lists all vaccine types that were noted in adverse event reports submitted to VAERS. The majority of reports pertained to females (63%) and individuals aged 9 to 17 y (62%). Guillain–Barre syndrome was listed as an adverse event in 45 reports, of which 9 reports followed HPV4 vaccination (0.19% of all reports listing HPV4) and 36 reports followed all other vaccines (0.35% of all reports listing all other vaccines).
Table 1. Types of vaccines noted in adverse event reports submitted to the United States Vaccine Adverse Event Reporting System (VAERS) between January 1, 2010 and December 31, 2012 for individuals aged 9 to 26 y.
| Adenovirus | Anthrax | Bacillus Calmette-Guerin |
|---|---|---|
| Cholera | Diphtheria | Haemophilus influenza B |
| Hepatitis A | Hepatitis B | Influenza |
| Influenza (H1N1) | Human papillomavirus | Japanese encephalitis virus |
| Measles | Meningococcal | Mumps |
| Pertussis | Pneumococcal | Poliovirus |
| Rabies | Rotavirus | Rubella |
| Smallpox | Tetanus | Typhoid |
| Varicella zoster | Yellow fever |
Table 2 summarizes the signal detection parameters (i.e., number of cases, PRR estimates, and Χ2 values) for Guillain–Barre syndrome following HPV4 vaccination. Briefly, Guillain–Barre syndrome exceeded 3 reports in all except the standard and restricted latency definitions following HPV4 vaccination for individuals aged 18 to 26 y. The overall, age-, and sex-specific PRR estimates were uniformly below 1 regardless of latency definition. In addition, the overall, age-, and sex-specific Χ2 values were uniformly below 3 regardless of latency definition.
Table 2. Signal detection parameters for Guillain–Barre syndrome following quadrivalent human papillomavirus (HPV4) vaccination among vaccine-eligible individuals in the United States.
| Reports of Guillain–Barre syndrome following HPV4; n (%) |
Reports of Guillain–Barre syndrome following all other vaccines; n (%) |
PRRa (95% CL) |
Χ2 | |
|---|---|---|---|---|
| Standard latencyb | ||||
| Overallc | 9 (0.19%) | 36 (0.35%) | 0.54 (0.26, 1.1) |
2.7 |
| Femalesd | 5 (0.14%) | 14 (0.25%) | 0.55 (0.20, 1.5) |
1.3 |
| Malese | 4 (0.39%) | 22 (0.49%) | 0.80 (0.27, 2.3) |
0.18 |
| Age 9 – 17 yf | 7 (0.21%) | 19 (0.32%) | 0.64 (0.27, 1.5) |
1.0 |
| Age 18 – 26 yg | 2 (0.15%) | 17 (0.40%) | 0.39 (0.09, 1.7) |
1.6 |
| Expanded latencyh | ||||
| Overallc | 11 (0.24%) | 43 (0.42%) | 0.56 (0.29, 1.1) |
3.0 |
| Femalesd | 7 (0.19%) | 19 (0.34%) | 0.57 (0.24, 1.3) |
1.6 |
| Malese | 4 (0.39%) | 24 (0.54%) | 0.73 (0.25, 2.1) |
0.34 |
| Age 9 – 17 yf | 8 (0.24%) | 24 (0.41%) | 0.58 (0.26, 1.3) |
1.8 |
| Age 18 – 26 yg | 3 (0.23%) | 19 (0.45%) | 0.52 (0.15, 1.8) |
1.1 |
| Restricted latencyi | ||||
| Overallc | 7 (0.15%) | 21 (0.21%) | 0.72 (0.31, 1.7) |
0.54 |
| Femalesd | 5 (0.14%) | 9 (0.16%) | 0.86 (0.29, 2.6) |
0.08 |
| Malese | 2 (0.20%) | 12 (0.27%) | 0.73 (0.16, 3.3) |
0.17 |
| Age 9 – 17 yf | 6 (0.18%) | 11 (0.19%) | 0.95 (0.35, 2.6) |
0.01 |
| Age 18 – 26 yg | 1 (0.08%) | 10 (0.23%) | 0.33 (0.04, 2.6) |
1.1 |
a PRR, proportional reporting ratio; CL, confidence limits. bDefined as Guillain–Barre syndrome reported between 5 and 42 d post-vaccination. cOverall reports of HPV4, n = 4670; overall reports of all other vaccines, n = 10 152. dOverall reports of HPV4, n = 3631; overall reports of all other vaccines, n = 5593. eOverall reports of HPV4, n = 1021; overall reports of all other vaccines, n = 4468. fOverall reports of HPV4, n = 3372; overall reports of all other vaccines, n = 5884. gOverall reports of HPV4, n = 1298; overall reports of all other vaccines, n = 4267. hDefined as Guillain–Barre syndrome reported between 0 and 42 d post-vaccination. iDefined as Guillain–Barre syndrome reported between 7 and 21 d post-vaccination.
Table 3 summarizes the results of our sensitivity analysis. Briefly, if perfect specificity is assumed, the sensitivity of reported Guillain–Barre syndrome would need to be >60% lower among reports following HPV4 vaccination than among reports following all other vaccines for a signal to be missed in our analysis (i.e., PRR >2), For example, a PRR of 2.7 results from an extreme scenario (Scenario 5) in which specificity is perfect but sensitivity of reported Guillain–Barre syndrome is 20% following HPV4 vaccination and 100% following all other vaccines. This scenario would require 36 reports of actual Guillain–Barre syndrome following HPV4 vaccination to be incorrectly classified as not being Guillain–Barre syndrome (i.e., false-negative).
Table 3. Sensitivity of the proportional reporting ratio (PRR) to potential misclassification of reported Guillain–Barre syndrome.
| Scenario | HPV4 | All other vaccines | PRR | ||
|---|---|---|---|---|---|
| Sensitivity | Specificity | Sensitivity | Specificity | ||
| 1a | 1.0 | 1.0 | 1.0 | 1.0 | 0.54 |
| 2 | 0.80 | 1.0 | 1.0 | 1.0 | 0.68 |
| 3 | 0.60 | 1.0 | 1.0 | 1.0 | 0.91 |
| 4 | 0.40 | 1.0 | 1.0 | 1.0 | 1.4 |
| 5 | 0.20 | 1.0 | 1.0 | 1.0 | 2.7 |
| 6 | 0.80 | 1.0 | 0.90 | 1.0 | 0.61 |
| 7 | 0.60 | 1.0 | 0.90 | 1.0 | 0.82 |
| 8 | 0.40 | 1.0 | 0.90 | 1.0 | 1.2 |
| 9 | 0.20 | 1.0 | 0.90 | 1.0 | 2.5 |
| 10 | 0.80 | 1.0 | 0.80 | 1.0 | 0.54 |
| 11 | 0.60 | 1.0 | 0.80 | 1.0 | 0.72 |
| 12 | 0.40 | 1.0 | 0.80 | 1.0 | 1.1 |
| 13 | 0.20 | 1.0 | 0.80 | 1.0 | 2.2 |
| 14 | 0.80 | 1.0 | 0.70 | 1.0 | 0.48 |
| 15 | 0.60 | 1.0 | 0.70 | 1.0 | 0.63 |
| 16 | 0.40 | 1.0 | 0.70 | 1.0 | 0.95 |
| 17 | 0.20 | 1.0 | 0.70 | 1.0 | 1.9 |
| 18 | 1.0 | 1.0 | 0.80 | 1.0 | 0.43 |
| 19 | 1.0 | 1.0 | 0.60 | 1.0 | 0.33 |
| 20 | 1.0 | 1.0 | 0.40 | 1.0 | 0.22 |
| 21 | 1.0 | 1.0 | 0.20 | 1.0 | 0.11 |
| 22 | 0.90 | 1.0 | 0.80 | 1.0 | 0.48 |
| 23 | 0.90 | 1.0 | 0.60 | 1.0 | 0.36 |
| 24 | 0.90 | 1.0 | 0.40 | 1.0 | 0.24 |
| 25 | 0.90 | 1.0 | 0.20 | 1.0 | 0.12 |
| 26 | 0.80 | 1.0 | 0.80 | 1.0 | 0.54 |
| 27 | 0.80 | 1.0 | 0.60 | 1.0 | 0.41 |
| 28 | 0.80 | 1.0 | 0.40 | 1.0 | 0.27 |
| 29 | 0.80 | 1.0 | 0.20 | 1.0 | 0.14 |
a Assumes no misclassification, same as overall PRR for standard latency reported in Table 1.
We aimed to assess whether Guillain–Barre syndrome is reported more frequently following HPV4 vaccination than other vaccinations among females and males aged 9 to 26 y. Our analysis of post-marketing adverse event reports submitted to VAERS between January 1, 2010 and December 31, 2012 does not suggest that Guillain–Barre syndrome is reported more frequently following HPV4 vaccination (i.e., no analysis yielded ≥3 reports of Guillain–Barre syndrome, PRR ≥ 2, and Χ2 ≥ 4) regardless of latency definition. In our analysis, Guillain–Barre syndrome is reported less frequently following HPV4 than all other vaccines. This finding extends to age- and sex-specific subgroups regardless of latency definition.
Several limitations should be considered when interpreting our findings. Despite being a national database, VAERS is a passive surveillance system with variable data quality, and is sensitive to reporting biases sometimes driven by social or media attention to vaccines.27 In addition, VAERS data are intended for detecting signals about adverse events that may require further assessment.27 These data should not be used to infer causality between particular vaccines and adverse events.27
An additional limitation of any study about Guillain–Barre syndrome is potential disease misclassification, which prompted the recent development of the Brighton Collaboration criteria.31 The Brighton Collaboration criteria were difficult to apply in our study given the often incomplete case information in VAERS.31 Consequently, we quantitatively explored the sensitivity of our overall PRR estimate to potential misclassification of reported Guillain–Barre syndrome. The results of our sensitivity analysis suggest that if specificity is perfect (i.e., no false-positive reports), the sensitivity of reported Guillain–Barre syndrome following the HPV4 vaccine would have to be dramatically lower than the sensitivity of reported Guillain–Barre syndrome following all other vaccines (i.e., differential misclassification) for a missed signal in our analysis. Given the increased media attention to vaccines and increased public concerns about vaccine safety during the past 20 y, dramatically lower accuracy in reports of Guillain–Barre syndrome following the HPV4 vaccine compared with all other vaccines seems unlikely. Nonetheless, the accuracy of reported Guillain–Barre syndrome in VAERS has not been systematically assessed, and our sensitivity analysis was limited to assumptions of perfect specificity because of mathematical impossibilities (i.e., negative case counts after adjustment) if we used lower specificity values. A systematic assessment of the accuracy of reported Guillain–Barre syndrome in VAERS, similar to a previous assessment of the accuracy of other AEFI case definitions,32 would better inform parameters for future sensitivity analyses of misclassification.
Although the impact of the Brighton Collaboration criteria on our data is unknown, the impact of these criteria may be evident in recent studies of the 2009 H1N1 influenza vaccine. Studies that reviewed medical records and defined Guillain–Barre syndrome according to the Brighton Collaboration criteria observed fewer overall cases but generally consistent evidence of modest increase in risk of the syndrome.11,13 In contrast, studies conducted prior to formulation of the Brighton Collaboration criteria that also reviewed medical records yielded consistently null findings for seasonal influenza vaccination.5 Nonetheless, these discrepant results may be attributable to more than just changes in case definition. Discrepancies may also be attributable to heterogeneity by vaccine type, study design, analytic approach, vaccine coverage, and changes in population characteristics over time.33
Case definitions of Guillain–Barre syndrome and analytic approaches in post-marketing surveillance studies of HPV4 safety vary, but our results are consistent with prior studies. Slade et al.23 also estimated PRRs and did not detect a signal (PRR = 0.40) for Guillain–Barre Syndrome following HPV4 vaccination among females aged 6 to 29 y using VAERS data between June 1, 2006 and December 31, 2008. Gee et al.24 used data from the Vaccine Safety Datalink between August 2006 and October 2009 to compare rates of Guillain–Barre syndrome for females aged 9 to 26 y with rates from a historical population, and did not observe an increased risk. In contrast, Souayah et al.22 reported that Guillain–Barre syndrome occurred more frequently following HPV4 vaccination compared with the general population in their analysis of VAERS data between 2006 and 2009. In addition to published criticism of the analytic approach by Souayah et al. (e.g., flawed comparisons with the general population25), the use of standard measures of comparison for spontaneous reports of adverse events data, such as the PRR29 or the reporting odds ratio (ROR),34 could have avoided misleading results. For example, Souayah et al.22 selected seasonal influenza vaccination for comparison with HPV4 vaccination. The data22 comprised 69 reported cases of Guillain–Barre syndrome within 6 weeks following HPV4 vaccination (13 115 total reports) and 166 reported cases within 6 weeks following seasonal influenza vaccination (13 801 total reports). The PRR estimate for this comparison is 0.44, which precludes the interpretation of a signal for Guillain–Barre syndrome.
In summary, we used a well-established method of analyzing spontaneous reports of adverse events data,29 which addresses key limitations of a prior study.22 More importantly, our findings provide new evidence of HPV4 vaccine safety for females and males. In contrast to findings from the most recently published study, our results do not suggest that Guillain–Barre syndrome is reported more frequently following HPV4 compared with other vaccines among vaccine-eligible females or males in the United States. The continued post-marketing surveillance of adverse events is invariably necessary for guarding public health, but the cumulative evidence thus far does not suggest overt safety concerns about Guillain–Barre syndrome following HPV4 vaccination. Misinformation about HPV vaccine safety is cited as one reason for parental refusal to vaccinate their children35 and ultimately contributes to the current suboptimal HPV vaccination coverage in the United States.36 Given that healthcare providers have a key role in addressing misinformation,37 our findings, as part of the cumulative evidence about the risks and benefits of HPV vaccination, may be useful information for healthcare providers to share with parents and patients.
Disclosure of Potential Conflicts of Interest
The authors declare no financial or non-financial competing interests.
Acknowledgments
RPO was supported by the American Lebanese Syrian Associated Charities (ALSAC). KPS and SB were partially supported by National Cancer Institute awards to the University of Alabama at Birmingham Comprehensive Cancer Center (P30 CA013148, Cervical SPORE grant P50CA098252, and partnership grant 2U54-CA118948). The funding sources were not involved in the study design, data collection, analysis, interpretation, writing, or decision to submit this report. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding sources.
Glossary
Abbreviations:
- HPV4
quadrivalent human papillomavirus
- PRR
proportional reporting ratio
- CL
confidence limits
- AEFI
adverse event following immunization
- VAERS
Vaccine Adverse Event Reporting System
- FDA
Food and Drug Administration
- CDC
Centers for Disease Control and Prevention
- MedDRA
Medical Dictionary for Regulatory Activities
- ROR
reporting odds ratio
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