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Human Vaccines & Immunotherapeutics 10:1, 232–237; January 2014; © 2014 Landes Bioscience

Guillain–Barre syndrome following quadrivalent

human papillomavirus vaccination among
vaccine-eligible individuals in the United States
Rohit P Ojha1,†,*, Bradford E Jackson2,†, Joseph E Tota3, Tabatha N Offutt-Powell4, Karan P Singh2, and Sejong Bae2
1
Department of Epidemiology and Cancer Control; St. Jude Children’s Research Hospital; Memphis, TN USA; 2Division of Preventive Medicine; Department of Medicine;
University of Alabama at Birmingham; Birmingham, AL USA; 3Division of Cancer Epidemiology; Department of Epidemiology; Biostatistics, and Occupational Health; McGill
University; Montreal, QC Canada; 4Office of Infectious Disease Epidemiology; Delaware Health and Social Services; Dover, DE USA

© 2014 Landes Bioscience. Do not distribute.

These authors contributed equally to this work.
†

Keywords: human papillomavirus, vaccine, post-marketing surveillance, Guillain–Barre syndrome, adverse event, safety
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

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-spe-
cific 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.

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 follow-
ing 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”) vac-
cine 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 per-
sists, 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 vac-
cine 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 fol-
lowing 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

*Correspondence to: Rohit P Ojha; Email: rohit.ojha@stjude.org

Submitted: 07/26/2013; Revised: 08/08/2013; Accepted: 08/28/2013
http://dx.doi.org/10.4161/hv.26292

232 Human Vaccines & Immunotherapeutics Volume 10 Issue 1


discrepant results in the recent study.25 Of greater current rel-
evance 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 infor-
mation 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, manu-
facturers, 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 qual-
ify 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 syn-
drome following vaccination.28 Nonetheless, we explored poten-
tial differences in reporting frequency by using an expanded
latency period that included all reports of Guillain–Barre syn-
drome between 0 and 42 d following vaccination, and a restricted
latency period that included all reports between 7 and 21 d fol-
lowing vaccination (consistent with the period during which
most cases are observed 28).
VAERS reports include all vaccine products that were admin-
istered on the vaccination date of interest. We defined receipt of
HPV4 as any report that listed “HPV4” as one of the adminis-
tered vaccines. We confirmed reports of HPV4 by cross-check-
ing 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 X 2 values for reports of Guillain–
Barre syndrome following HPV vaccination compared with
reports of Guillain–Barre syndrome following all other vaccina-
tions.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 mini-
mum criteria for a signal that should be further considered are
3 or more reports, PRR ≥2, and X 2 ≥ 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
www.landesbioscience.com Human Vaccines & Immunotherapeutics 233
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
Human Japanese encepha-
Influenza (H1N1)
papillomavirus litis virus
Measles Meningococcal Mumps
Pertussis Pneumococcal Poliovirus
Rabies Rotavirus Rubella
© 2014 Landes Bioscience. Do not distribute.
Smallpox Tetanus Typhoid
Varicella zoster Yellow fever
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 misclas-
sified 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 sensitiv-
ity 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 var-
ied 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 submit-
ted to VAERS, of which 4670 noted HPV4 as one of the admin-
istered 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 vaccina-
tion (0.19% of all reports listing HPV4) and 36 reports followed
all other vaccines (0.35% of all reports listing all other vaccines).
Table 2 summarizes the signal detection parameters (i.e.,
number of cases, PRR estimates, and X 2 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 regard-
less of latency definition. In addition, the overall, age-, and sex-
specific X 2 values were uniformly below 3 regardless of latency
definition.
 Table 2. Signal detection parameters for Guillain–Barre syndrome following quadrivalent
Table 3 summarizes the results of our sen- human papillomavirus (HPV4) vaccination among vaccine-eligible individuals
sitivity analysis. Briefly, if perfect specificity is in the United States
assumed, the sensitivity of reported Guillain–
Barre syndrome would need to be >60% lower Reports of Guillain–
Reports of Guillain–
Barre syndrome
among reports following HPV4 vaccination Barre syndrome PRRa
following all other Χ2
than among reports following all other vac- following HPV4; (95% CL)
vaccines;
cines for a signal to be missed in our analy- n (%)
n (%)
sis (i.e., PRR >2), For example, a PRR of 2.7 Standard latency b

results from an extreme scenario (Scenario 5)

0.54
in which specificity is perfect but sensitivity of Overallc 9 (0.19%) 36 (0.35%) 2.7
(0.26, 1.1)
reported Guillain–Barre syndrome is 20% fol-
lowing HPV4 vaccination and 100% following 0.55
Femalesd 5 (0.14%) 14 (0.25%) 1.3

© 2014 Landes Bioscience. Do not distribute.

(0.20, 1.5)
all other vaccines. This scenario would require
36 reports of actual Guillain–Barre syndrome 0.80
Malese 4 (0.39%) 22 (0.49%) 0.18
(0.27, 2.3)
following HPV4 vaccination to be incorrectly
classified as not being Guillain–Barre syndrome 0.64
Age 9 – 17 yf 7 (0.21%) 19 (0.32%) 1.0
(i.e., false-negative). (0.27, 1.5)
We aimed to assess whether Guillain–Barre Age 18 – 26 yg 2 (0.15%) 17 (0.40%)
0.39
1.6
syndrome is reported more frequently follow- (0.09, 1.7)
ing HPV4 vaccination than other vaccinations Expanded latencyh
among females and males aged 9 to 26 y. Our 0.56
analysis of post-marketing adverse event reports Overallc 11 (0.24%) 43 (0.42%) 3.0
(0.29, 1.1)
submitted to VAERS between January 1, 2010 0.57
and December 31, 2012 does not suggest that Femalesd 7 (0.19%) 19 (0.34%) 1.6
(0.24, 1.3)
Guillain–Barre syndrome is reported more fre-
0.73
quently following HPV4 vaccination (i.e., no Malese 4 (0.39%) 24 (0.54%) 0.34
(0.25, 2.1)
analysis yielded ≥3 reports of Guillain–Barre
0.58
syndrome, PRR ≥ 2, and X 2 ≥ 4) regardless of Age 9 – 17 yf 8 (0.24%) 24 (0.41%)
(0.26, 1.3)
1.8
latency definition. In our analysis, Guillain–
0.52
Barre syndrome is reported less frequently fol- Age 18 – 26 yg 3 (0.23%) 19 (0.45%) 1.1
(0.15, 1.8)
lowing HPV4 than all other vaccines. This
finding extends to age- and sex-specific sub- Restricted latencyi
groups regardless of latency definition. Overallc 7 (0.15%) 21 (0.21%)
0.72
0.54
Several limitations should be considered (0.31, 1.7)
when interpreting our findings. Despite being 0.86
Femalesd 5 (0.14%) 9 (0.16%) 0.08
a national database, VAERS is a passive surveil- (0.29, 2.6)
lance system with variable data quality, and is 0.73
Malese 2 (0.20%) 12 (0.27%) 0.17
sensitive to reporting biases sometimes driven (0.16, 3.3)
by social or media attention to vaccines.27 In 0.95
Age 9 – 17 yf 6 (0.18%) 11 (0.19%) 0.01
addition, VAERS data are intended for detect- (0.35, 2.6)
ing signals about adverse events that may require 0.33
further assessment.27 These data should not be Age 18 – 26 yg 1 (0.08%) 10 (0.23%) 1.1
(0.04, 2.6)
used to infer causality between particular vac- aPRR, proportional reporting ratio; CL, confidence limits. bDefined as Guillain–Barre syndrome
cines and adverse events.27 reported between 5 and 42 d post-vaccination. cOverall reports of HPV4, n = 4670; overall
An additional limitation of any study about reports of all other vaccines, n = 10 152. dOverall reports of HPV4, n = 3631; overall reports of
Guillain–Barre syndrome is potential disease all other vaccines, n = 5593. eOverall reports of HPV4, n = 1021; overall reports of all other vac-
misclassification, which prompted the recent cines, n = 4468. fOverall reports of HPV4, n = 3372; overall reports of all other vaccines, n = 5884.
g
Overall reports of HPV4, n = 1298; overall reports of all other vaccines, n = 4267. hDefined as
development of the Brighton Collaboration Guillain-Barre syndrome reported between 0 and 42 d post-vaccination. iDefined as Guillain–
criteria.31 The Brighton Collaboration criteria Barre syndrome reported between 7 and 21 d post-vaccination.
were difficult to apply in our study given the
often incomplete case information in VAERS.31
Consequently, we quantitatively explored the sensitivity of our the HPV4 vaccine would have to be dramatically lower than the
overall PRR estimate to potential misclassification of reported sensitivity of reported Guillain–Barre syndrome following all
Guillain–Barre syndrome. The results of our sensitivity analysis other vaccines (i.e., differential misclassification) for a missed
suggest that if specificity is perfect (i.e., no false-positive reports), signal in our analysis. Given the increased media attention to
the sensitivity of reported Guillain–Barre syndrome following vaccines and increased public concerns about vaccine safety

234 Human Vaccines & Immunotherapeutics Volume 10 Issue 1

Table 3. Sensitivity of the proportional reporting ratio (PRR) to potential
misclassification of reported Guillain–Barre syndrome case definitions,32 would better inform parameters for
future sensitivity analyses of misclassification.
Scenario HPV4 All other vaccines PRR Although the impact of the Brighton Collaboration
criteria on our data is unknown, the impact of these
Sensitivity Specificity Sensitivity Specificity
criteria may be evident in recent studies of the 2009
1a 1.0 1.0 1.0 1.0 0.54 H1N1 influenza vaccine. Studies that reviewed medical
2 0.80 1.0 1.0 1.0 0.68 records and defined Guillain–Barre syndrome accord-
ing to the Brighton Collaboration criteria observed
3 0.60 1.0 1.0 1.0 0.91
fewer overall cases but generally consistent evidence of
4 0.40 1.0 1.0 1.0 1.4 modest increase in risk of the syndrome.11,13 In contrast,
5 0.20 1.0 1.0 1.0 2.7 studies conducted prior to formulation of the Brighton
Collaboration criteria that also reviewed medical

© 2014 Landes Bioscience. Do not distribute.

6 0.80 1.0 0.90 1.0 0.61
records yielded consistently null findings for seasonal
7 0.60 1.0 0.90 1.0 0.82
influenza vaccination.5 Nonetheless, these discrepant
8 0.40 1.0 0.90 1.0 1.2 results may be attributable to more than just changes in
9 0.20 1.0 0.90 1.0 2.5 case definition. Discrepancies may also be attributable
10 0.80 1.0 0.80 1.0 0.54 to heterogeneity by vaccine type, study design, analytic
approach, vaccine coverage, and changes in population
11 0.60 1.0 0.80 1.0 0.72
characteristics over time.33
12 0.40 1.0 0.80 1.0 1.1 Case definitions of Guillain–Barre syndrome and
13 0.20 1.0 0.80 1.0 2.2 analytic approaches in post-marketing surveillance
14 0.80 1.0 0.70 1.0 0.48
studies of HPV4 safety vary, but our results are con-
sistent with prior studies. Slade et al.23 also estimated
15 0.60 1.0 0.70 1.0 0.63
PRRs and did not detect a signal (PRR = 0.40) for
16 0.40 1.0 0.70 1.0 0.95 Guillain–Barre Syndrome following HPV4 vaccina-
17 0.20 1.0 0.70 1.0 1.9 tion among females aged 6 to 29 y using VAERS data
18 1.0 1.0 0.80 1.0 0.43
between June 1, 2006 and December 31, 2008. Gee
et al.24 used data from the Vaccine Safety Datalink
19 1.0 1.0 0.60 1.0 0.33
between August 2006 and October 2009 to compare
20 1.0 1.0 0.40 1.0 0.22 rates of Guillain–Barre syndrome for females aged 9 to
21 1.0 1.0 0.20 1.0 0.11 26 y with rates from a historical population, and did not
22 0.90 1.0 0.80 1.0 0.48
observe an increased risk. In contrast, Souayah et al.22
reported that Guillain–Barre syndrome occurred more
23 0.90 1.0 0.60 1.0 0.36
frequently following HPV4 vaccination compared with
24 0.90 1.0 0.40 1.0 0.24 the general population in their analysis of VAERS data
25 0.90 1.0 0.20 1.0 0.12 between 2006 and 2009. In addition to published criti-
26 0.80 1.0 0.80 1.0 0.54
cism of the analytic approach by Souayah et al. (e.g.,
flawed comparisons with the general population25), the
27 0.80 1.0 0.60 1.0 0.41
use of standard measures of comparison for spontaneous
28 0.80 1.0 0.40 1.0 0.27 reports of adverse events data, such as the PRR 29 or the
29 0.80 1.0 0.20 1.0 0.14 reporting odds ratio (ROR),34 could have avoided mis-
a
Assumes no misclassification, same as overall PRR for standard latency reported
leading results. For example, Souayah et al.22 selected
in Table 1. seasonal influenza vaccination for comparison with
HPV4 vaccination. The data 22 comprised 69 reported
cases of Guillain–Barre syndrome within 6 weeks fol-
during the past 20 y, dramatically lower accuracy in reports of lowing HPV4 vaccination (13 115 total reports) and 166 reported
Guillain–Barre syndrome following the HPV4 vaccine com- cases within 6 weeks following seasonal influenza vaccination
pared with all other vaccines seems unlikely. Nonetheless, the (13 801 total reports). The PRR estimate for this comparison is
accuracy of reported Guillain–Barre syndrome in VAERS has 0.44, which precludes the interpretation of a signal for Guillain–
not been systematically assessed, and our sensitivity analysis was Barre syndrome.
limited to assumptions of perfect specificity because of math- In summary, we used a well-established method of analyz-
ematical impossibilities (i.e., negative case counts after adjust- ing spontaneous reports of adverse events data,29 which addresses
ment) if we used lower specificity values. A systematic assessment key limitations of a prior study.22 More importantly, our findings
of the accuracy of reported Guillain–Barre syndrome in VAERS, provide new evidence of HPV4 vaccine safety for females and
similar to a previous assessment of the accuracy of other AEFI males. In contrast to findings from the most recently published

www.landesbioscience.com Human Vaccines & Immunotherapeutics 235

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 con-
cerns about Guillain–Barre syndrome following HPV4 vaccina-
tion. Misinformation about HPV vaccine safety is cited as one
reason for parental refusal to vaccinate their children35 and ulti-
mately 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
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 sup-
ported by National Cancer Institute awards to the University of
Alabama at Birmingham Comprehensive Cancer Center (P30
CA013148, Cervical SPORE grant P50CA098252, and part-
nership grant 2U54-CA118948). The funding sources were not
involved in the study design, data collection, analysis, interpreta-

© 2014 Landes Bioscience. Do not distribute.

part of the cumulative evidence about the risks and benefits of
HPV vaccination, may be useful information for healthcare pro-
viders to share with parents and patients.
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