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A case-control study of serious autoimmune adverse events following
hepatitis B immunization
DAVID A. GEIER
1,†
& MARK R. GEIER
2,‡
1
MedCon, Inc., Silver Spring, MD 20905, USA, and
2
The Genetic Centers of America, Silver Spring, MD 20905, USA
(Received 14 February 2005; accepted 22 April 2005)
Abstract
Hepatitis B infection is one of the most important causes of acute and chronic liver disease. During the 1980s, genetically
engineered hepatitis B vaccines (HBVs) were introduced in the United States. A large-series of serious autoimmune
conditions have been reported following HBVs, despite the fact that HBVs have been reported to be “generally well-
tolerated.” A case-control epidemiological study was conducted to evaluate serious autoimmune adverse events prospectively
reported to the vaccine adverse events reporting system (VAERS) database following HBVs, in comparison to an age, sex, and
vaccine year matched unexposed tetanus-containing vaccine (TCV) group for conditions that have been previously identified
on an a priori basis from case-reports. Adults receiving HBV had significantly increased odds ratios (OR) for multiple
sclerosis (OR ¼5:2;p,0:0003;95% Confidence Interval ðCIÞ¼1:9220), optic neuritis (OR ¼14;p,0:0002;
95% CI ¼2:32560), vasculitis (OR ¼2:6;p,0:04;95% CI ¼1:03 28:7), arthritis (OR ¼2:01;p,0:0003;95%
CI ¼1:323:1), alopecia (OR ¼7:2;p,0:0001;95% CI ¼3:2220), lupus erythematosus (OR ¼9:1;p,0:0001, 95%
CI ¼2:3276), rheumatoid arthritis (OR ¼18;p,0:0001, 95% CI ¼3:12740), and thrombocytopenia (OR ¼2:3;
p,0:04;95% CI ¼1:02 26:2) in comparison to the TCV group. Minimal confounding or systematic error was observed.
Despite the negative findings of the present study regarding the rare serious adverse effects of HBVs, it is clear that HBV does,
indeed, offer significant benefits, but it is also clear that chances of exposure to hepatitis B virus in adults is largely life-style
dependent. Adults should make an informed consent decision, weighing the risks and benefits of HBV, as to whether or not to
be immunized.
Keywords: Aluminum, autoimmunity, HBsAg, thimerosal, yeast
Introduction
Hepatitis B is one of the most important infectious
causes of acute and chronic liver disease in the United
States and worldwide [1]. Each year prior to the
introduction of universal childhood vaccination in the
United States [2], approximately 3,00,000 people in
the United States acquired new hepatitis B virus
infection; 25,000 were reported with acute hepatitis;
and between 18,000 and 30,000 people became
hepatitis B virus carriers at risk of chronic liver disease,
including chronic active hepatitis, cirrhosis, and primary
hepatocellular carcinoma (PHC). In addition, between
4000 and 5000 people died annually due to hepatitis B
infection, and the centers for disease control
and prevention (CDC) estimated that the direct costs
of hepatitis B infection exceeded $500 million
annually [3,4].
Genetically engineered hepatitis B vaccines (HBVs)
were developed and licensed during the 1980s in the
United States. These vaccines are most commonly
produced by inserting the gene for the Hepatitis B
surface Antigen (HBsAg) into the yeast Saccharomyces
cerevisiae. Following growth of the yeast, vaccine is
ISSN 0891-6934 print/ISSN 1607-842X online q2005 Taylor & Francis Group Ltd
DOI: 10.1080/08916930500144484
†
David Geier has been a consultant in vaccine cases before the no-fault National Vaccine Injury Compensation Program (NIVCP) and in
civil litigation.
‡
Dr Mark Geier has been a consultant and expert witness in vaccine cases before the no-fault NVCIP and in civil litigation.
Correspondence: M. R. Geier, President, The Genetic Centers of America, 14 Redgate Ct., Silver Spring, MD 20905, USA.
Tel: 1 301 989 0548. Fax: 1 301 989 1543. E-mail: mgeier@comcast.net
Autoimmunity, June 2005; 38(4): 295–301
prepared by lysing the yeast to free HBsAg particles,
which are separated from yeast components by
biochemical and biophysical methods. Two recombi-
nant HBVs produced in yeast (Merck, Recombivax;
GlaxoSmithKline Biologicals, Energix) are available in
the United States and many countries worldwide [5,6].
HBV has been reported to be “generally well-
tolerated.” Despite the fact that HBV has been
reported to be ‘generally well-tolerated,’ a large-series
of serious autoimmune adverse events (SAAEs) has
been reported in the scientific literature following
hepatitis B vaccination [7 –10]. Case-repor ts of SAAEs
following HBV have generally been reported in adult
vaccine recipients with an initial onset of symptoms
from several days to several weeks following immuniz-
ation and, in many instances, mirror the extrahepatic
manifestations experienced by patients with hepatitis B
virus infection [7 – 11].
The purpose of this case-control epidemiological
study was to evaluate the potential risk for SAAEs
reported to the Vaccine Adverse Events Reporting
System (VAERS) database, following HBVs in
comparison to a matched vaccine control group for
adverse events that had been previously identified, on
an a priori basis, from case-reports that were reported
following immunization.
Methods
The VAERS database
The VAERS is an epidemiological database that has
been maintained by the CDC since 1990 as a
surveillance tool to evaluate vaccine safety. Specific
adverse events following vaccination are required to be
reported to this database as mandated by law. The
VAERS Working Group of the CDC has previously
reported that less than 5% of the total adverse events
reported to VAERS are reported by parents [12]. The
VAERS Working Group of the CDC and the food and
drug administration (FDA) analyze and publish
epidemiologic studies based upon analyses of VAERS.
They note that VAERS is simple to use, flexible by
design, and the data are available in a timely fashion, but
warn that the potential limitations may include
systematic error due to underreporting, erroneous
reporting, frequent multiple exposures, multiple out-
comes and lack of precise denominators [12].
Analysis methods
The VAERS was analyzed using a case-control
epidemiological methodology whilst employing a
Bradford Hill criteria [13] framework to assess
observed associations. SAAEs reported following
HBVs to the VAERS database, including: Multiple
sclerosis (MS) (Costart Code ¼Sclerosis Mult), optic
neuritis (ON) (Costart Code ¼Neuritis Optic),
vasculitis (Costart Code ¼Vasculitis), alopecia (Cost-
art Code ¼Alopecia), arthritis (Costart Code ¼
Arthritis), rheumatoid arthritis (RA) (Costart Code ¼
Arthritis Rheumat), lupus erythematosus (LE) (Cost-
art Code ¼LE Synd), and thrombocytopenia (Costart
Code ¼Thrombocytopenia) were evaluated. Descrip-
tions of these adverse events were based upon those
reporting them and coded by VAERS technical staff
into defined symptom fields contained in each report.
The reports analyzed were prospectively reported from
the US following vaccines administered from January
1, 1990 through May 25, 2004, and had to specify the
sex of the vaccine recipient, the age of the vaccine
recipient (only reports among those 7 year s-old or older
were included), the year the vaccine was administered,
and to indicate that only one type of vaccine was
administered. As an unexposed group, adverse events
reported to VAERS following tetanus toxoid-contain-
ing vaccines (with the above mentioned conditions)
were evaluated.
In conducting the present study, the online public
access VAERS was analyzed for prospective reports, of
adverse events reported to VAERS, from July 7, 1990
through May 28, 2004. In this study of VAERS, adverse
event reports that specified a specific outcome of interest
(cases) in the exposed HBV group and in the unexposed
tetanus toxoid-containing vaccine group were ident-
ified. The cases were then matched to control adverse
event reports in VAERS based upon sex (male or
female), age(within 1 year), and vaccine administration
year (within 1 year). A control adverse event report, as
identified in VAERS, did not have the outcome of
interest under study. Additionally, at least one control
was required to be matched for every case, in order for
the case to be included in the present study.
Control outcomes
In order to determine if confounding or systematic
error were present in the VAERS data examined,
a series of control outcomes were examined in VAERS.
In this study, control outcomes were selected on a
priority basis, so that they should not be associated with
the exposed or unexposed groups, and the control
outcomes were also selected so that they should provide
information regarding the health statuses of each of the
exposed and unexposed groups examined. The control
outcomes examined in VAERS, included: Urinary tract
infection (Costart Code ¼Infect Urin Tract), medi-
cation error (Costart Code ¼Med Error), cerebrovas-
cular disease (Costart Code ¼Cerebrovascular
Accid), death, and cardiovascular disease (Costart
Code ¼Cardiovasc Dis).
In this assessment of VAERS, the validity of the
Costart Codes for the SAAEs analyzed, following
HBVs were examined. This assessment was under-
taken by manually evaluating the consistency between
the VAERS symptom text (examined for direct
D. A. Geier & M. A. Geier296
mention of or for direct mention of symptoms that
were thought to be consistent with, the outcome under
study) and the Costart Code for each type of SAAE
analyzed, following HBVs. As a result of this manual
review of the VAERS reports, the percent validity of
the Costart Codes analyzed in the VAERS database,
with the clinical experience of the patient, was
assessed (percent validity ¼total number of VAERS
report symptom texts consistent with the Costart
Code examined for a specific outcome/total number of
VAERS Costart Codes for a specific outcome).
Statistical methods
The premise of equality between the groups examined
forms the basis of the null hypothesis employed in the
present study. Odds ratios (OR), 95% OR Confidence
Intervals (CI) for reported adverse events, and
p-values, were determined from 2 £2 contingency
tables employed in the present study. The statistical
package in StatsDirect
e
(Version 2.4.1) was utilized,
and the nominal Fisher’s exact test statistic was used to
determine statistical significance. In order for stat istical
significance testing to be performed for an outcome,
there had be at least a total of 10 outcomes identified in
VAERS. A two-sided p-value ,0.05 was considered
statistically significant.
Results
In Table I is a summary of SAAEs reported to
VAERS following HBVs. It was determined that MS
(female/male ratio ¼4.1),ON(female/male
ratio ¼4.3), vasculitis (female/male ratio ¼2.2),
arthritis (female/male ratio ¼3.0), RA (female/male
ratio ¼4.3), alopecia (female/male ratio ¼5.3), and
LE (female/male ratio ¼6.8) were predominantly
reported in females, to the VAERS database,
following HBVs, whereas thrombocytopenia
(female/male ratio ¼1.2) was reported more simi-
larly among males and females to VAERS following
HBVs. The SAAEs examined in VAERS were
reported primarily among adult HBV recipients
(median age range ¼24– 39 years 2old), and the
initial onset of symptoms occurred within fairly
close temporal association to HBV administration
(median onset range ¼3 – 19 days). It was also
observed that among those experiencing SAAEs
following HBVs, as were reported to VAERS,
resulted in a significant number of disabilities,
especially among those with MS (48% disabled),
ON (32% disabled), RA (46% disabled), LE (34%
disabled). As part of the present assessment of the
validity of the actual VAERS symptom text in
comparison to the Costart Code for each condition
examined, it was determined that there was a good
correspondence between the two fields within
VAERS ( ^60% validity for each type of SAAE
outcome examined in VAERS).
Table II presents the results of the case-control
epidemiological study for SAAEs reported in the
HBV exposed group in comparison to the tetanus-
containing vaccine (TCV) unexposed group. It was
observed that there were significant increased
odds ratios following HBVs, in comparison to
TCVs, for the following SAAE outcomes in
VAERS, including: MS (OR ¼5:2;p,0:0003;
95% CI ¼1:9220), ON (OR ¼14;p,0:0002;
95% CI ¼2:32560), vasculitis (OR ¼2:6;p,
0:04;95% CI ¼1:03 28:7), arthritis (OR ¼2:01;
p,0:0003;95% CI ¼1:323:1), alopecia
(OR ¼7:2;p,0:0001;95% CI ¼3:2216), LE
(OR ¼9:1;p,0:0001;95% CI ¼2:3276), RA
(OR ¼18;p,0:0001;95% CI ¼3:12740), and
thrombocytopenia (OR ¼2:3;p,0:04;95%
CI ¼1:04 25:2).
The results of the case-control epidemiological study
for control adverse events, reported to VAERS,
following HBVs, in comparison to those following
TCVs, are summarized in Table III. It was observed
that following HBVs, in comparison to immunization
with TCVs, the following control adverse events were
reported similarly to VAERS, including: Urinary tract
infection (OR ¼1:04;p¼1:0;95% CI ¼0:4322:9),
Table I. A summary of the serious autoimmune adverse events reported following hepatitis B vaccination to the VAERS database.
Type of adverse event [% Validity]*
Number of
female reports
Number of
male reports
Female/male
ratio
Median age
(years)
Median onset of
symptoms (days)
Percent
disabled
Multiple sclerosis [64%] 49 12 4.1 35 19 48
Optic neuritis [85%] 35 11 3.2 35 15 32
Vasculitis [67%] 27 12 2.2 27 7 5.1
Arthritis
†
[80%] 152 50 3.0 39 3 15
Rheumatoid Arthritis [68%] 43 10 4.3 36 11 46
Alopecia
†
[90%] 91 17 5.3 29 14 9.2
Lupus Erythematosus [60%] 41 6 6.8 31 11 34
Thrombocytopenia [73%] 26 22 1.2 24 9 14
*Percent validity ¼total number of VAERS report symptom texts consistent with the Costart Code examined for a specific outcome / total
number of VAERS Costart Code for a specific outcome.
†
A sample of 50 VAERS reports with the outcome under study were analyzed to
determine the percent validity.
Hepatitis B 297
medication error (OR ¼1:2;p¼0:78;95%
CI ¼0:35 24:40), death (OR ¼1:4;p¼0:45;95%
CI ¼0:62 24:0), cerebrovascular disease
(OR ¼1:2;p¼1:0;95% CI ¼0:30 26:8), and car-
diovascular disease (OR ¼1:1;p¼1:0;95%
CI ¼0:44 23:5).
Discussion
This case-control epidemiological study showed that
HBV administration to adults was associated with an
increased risk of SAAEs. The initial onset of symptoms
occurred within several weeks following immunization,
and many patients experiencing SAAEs sustained
disabilities.
This study used a novel technique to evaluate SAAEs
following HBVs in VAERS similar to that used by the
CDC in a recent study [14]. The technique allows
the identification of a significant population that had
experienced SAAEs, with an initial onset of symptoms
that occurred in reasonably close temporal association
with immunization. The technique also minimizes
Table II. An assessment of the odds ratio for serious autoimmune adverse events reported to the VAERS database following hepatitis B
vaccines in comparison to TCVs.
Type of Adverse Event Number of Cases Number of Controls Odds Ratio p-value 95% Confidence Interval
Multiple Sclerosis
Hepatitis B Vaccines 61 1,188 5.2 ,0.0003 1.9–20
Tetanus-containing vaccines 4 403
Optic Neuritis
Hepatitis B Vaccines 46 887 14 ,0.0002 2.3–560
Tetanus-containing vaccines 1 265
Vasculitis
Hepatitis B Vaccines 39 781 2.6 ,0.04 1.03– 8.7
Tetanus-containing vaccines 5 266
Arthritis
Hepatitis B Vaccines 202 3,410 2.01 ,0.0003 1.3–3.1
Tetanus-containing vaccines 30 1,016
Alopecia
Hepatitis B Vaccines 108 1,473 7.2 ,0.0001 3.2– 20
Tetanus-containing vaccines 6 591
Lupus Erythematosus
Hepatitis B Vaccines 47 782 9.1 ,0.0001 2.3– 76
Tetanus-containing vaccines 2 302
Rheumatoid Arthritis
Hepatitis B Vaccines 53 963 18 ,0.0001 3.1–740
Tetanus-containing vaccines 1 334
Thrombocytopenia
Hepatitis B Vaccines 48 712 2.3 ,0.04 1.02– 6.2
Tetanus-containing vaccines 7 241
The Fisher’s exact test statistic was employed to determine statistical significance.
Table III. An assessment of the odds ratio for control adverse events reported to the VAERS database following hepatitis B vaccines in
comparison to TCVs.
Type of adverse event Number of cases Number of controls Odds ratio p-value 95% Confidence interval
Urinary Tract Infection
Hepatitis B Vaccines 26 734 1.04 1.0 0.43– 2.9
Tetanus-containing vaccines 7 206
Medication Error
Hepatitis B Vaccines 8 39 1.2 0.78 0.35–4.4
Tetanus-containing vaccines 7 42
Death
Hepatitis B Vaccines 36 460 1.4 0.45 0.62–4.0
Tetanus-containing vaccines 7 131
Cerebrovascular Disease
Hepatitis B Vaccines 11 185 1.2 1.0 0.30– 6.8
Tetanus-containing vaccines 3 60
Cardiovascular Disease
Hepatitis B Vaccines 22 438 1.1 1.0 0.44– 3.5
Tetanus-containing vaccines 6 136
The Fisher’s exact test statistic was employed to determine statistical significance.
D. A. Geier & M. A. Geier298
potential systematic error/confounding associated with
vaccine administration. There are social and medical
attributes associated with both avoidance or delay of
vaccination and an increased risk of adverse events, and
studies that fail to control adequately for such
systematic error/confounding factors are likely to
underestimate the risks of adverse events attributable
to vaccination [15].
In a case-control study it is necessary to ensure that
there are similar demographics among both the
exposed and unexposed populations (i.e. differences
in the populations may account for systematic
error/confounding that tend to skew results, and result
in false-positive or negative findings). To ensure that
the exposed and unexposed populations examined in
VAERS were similar, only individuals receiving either a
HBV or TCV who reported an adverse event report to
VAERS were analyzed (i.e. this was the entrance
criteria for the present study). Inherently, submission
of an adverse event report to VAERS, in either the HBV
exposed or the tetanus toxoid-containing unexposed
groups, should occur at a similar frequency, and not
introduce systematic error/confounders towards one
vaccine or another. Further controls were employed in
evaluating the HBV exposed and the TCV unexposed
groups, by matching every case identified with controls
for age, sex, and date of vaccine administration. Finally,
control adverse events were employed to evaluate the
specificity of adverse event reporting and the general
health status of the exposed and unexposed groups
examined in VAERS.
In this study, chance significant associations
between HBV administration and SAAEs were
minimized. First, SAAEs were chosen to be epide-
miologically evaluated in VAERS on an a priori basis
because they had been previously reported as case-
reports, in the scientific literature, which were
associated with HBVs. Second, since only a limited
number of specific SAAEs were evaluated in the
present study (i.e. only a total of eight SAAEs were
examined, and only a total 13 adverse events
examined), and since a p-value ,0:05 was considered
significant (one in 20 outcomes would be expected to
found significant by chance), therefore, one would
expect that less than one of the types of SAAEs
examined in the present assessment of VAERS, would
by chance, be found to be significantly associated with
HBVs. Third, a series of different types of SAAEs were
examined, in VAERS, involving different systems in
the body. All eight types of SAAEs examined in
VAERS were significantly associated with HBV. This
consistency of observation across multiple types of
SAAEs argues against the present observations
resulting from a mere chance statistical association,
or even a simple reporting bias stemming from a
presumed association between HBVs and a given
outcome that resulted in an over reporting of a single
type of adverse event.
The present case-control assessment of VAERS
shows that very specific adverse affects were attribu-
table to HBVs. HBV was associated with an increased
risk of SAAEs, and potential systematic error or
confounding were found to be minimal in VAERS.
The results of the present study appear to be
biologically plausible. Many of the SAAEs reported
following HBVs are consistent with the extrahepatic
manifestations, generally believed to be immune-
mediated [11], that have been associated with
hepatitis B virus infection. These include: Thrombo-
cytopenia, arthralgias, arthritis, weakness, nephritis,
pulmonary disease, and generalized vasculitis. Cesur
et al. evaluated the prevalence of extrahepatic
manifestations in patients with chronic hepatitis B
virus infection. Among the outcomes evaluated in the
present study, they observed that 1% had systematic
lupus, 1% had RA and 22% had anemia [16].
Pennesi et al. described a case-report of positive
re-challenge for glomerulonephritis following HBV,
in which a renal biopsy demonstrated mesangial
proliferative glomerulonephritis with IgA deposits,
similar to what has been described in natural hepatitis
B virus-related glomerulonephritis [17]. Additionally,
Poirriez has reported that there maybe antigenic
community between HBV components and some
auto-antibodies produced in rare patients with an
autoimmune disease discovered in temporal associ-
ation with HBVs. Poirriez described a case of a 12-
year-old girl who developed transverse myelitis 2
months after a HBV. Later, high titers of antinuclear
antibodies (ANAs) were found, and a diagnosis of
neurolupus was established. The serum was then
mixed with various concentrations of HBV. The
ANAs were totally absorbed by the highest concen-
tration of vaccine, but not by the lowest. Anti-HBsAg
specific antibodies were absorbed by all concen-
trations of vaccine [18].
Furthermore, in addition to the potentially
immune-active epitopes in the HBsAg, recombinant
HBVs contain other extraneous antigenically active
components such as aluminum (vaccine adjuvant),
mercury (thimerosal - approximately 50% mercury by
weight, added as a vaccine preservative), and yeast
(,5% residual from vaccine production) that may
work synergistically to induce autoimmune phenom-
ena in genetically-susceptible vaccine recipients. The
role of immunization in the mosaic of autoimmunity
has been reviewed [19,20].
Ravel et al. have reported that even though the
mechanisms of autoimmunity are ill-elucidated, the
role of pre-existing risk factors including genetic
predisposition and environmental factors is largely
accepted [21]. Female lupus-prone mice adminis-
tered HBV plus mercuric chloride developed
marked increase in serum IgG levels, and a slight
increase in ANA levels. The authors concluded that
vaccination could enhance the risk of autoimmunity
Hepatitis B 299
in genetically-susceptible individuals when exposed
to certain environmental chemicals.
Several epidemiological studies have investigated the
potential link between HBVand an increased risk of MS
or demyelinating diseases [22– 28]. Most found no
consistent association between HBV and MS, but some
had methodological limitations [29]. The present
study is consistent with the observations made by
Hernan et al. on the risk of MS following recombinant
HBV [29]. The authors observed an increased risk of
MS (OR ¼3:1;95% CI ¼1:526:3) following HBVs
compared to no vaccination, consistent with our
observation (OR ¼5:2;95% CI ¼1:9220) for MS
following HBV. The authors concluded HBV is
associated with an increased risk of MS. Additionally,
other studies have also observed significant increased
risks for autoimmune disorders such as lupus, Graves’
disease, and sudden onset Chronic Fatigue Syndrome
(CFS) following HBVs [30,31], compatible with the
results for SAAEs observed in the present study.
We have reported in previous assessments of
VAERS that incidence rates of reported adverse
events following HBV in comparison to other adult
vaccine groups were significantly increased for
arthritic, gastrointestinal, immunological, and neuro-
logical adverse events [8]. In addition, we have
previously reported on case-reports of positive re-
challenge or significant exacerbation of symptoms for
SAAEs following HBVs, and even similar adverse
outcomes in identical twins following HBVs [9].
In conclusion, the present study, in conjunction
with emerging biological plausibility, case-reports,
case-series, positive re-challenge or significant exacer-
bation of symptom reports, and population epide-
miological studies, suggests that adult HBV is
associated with a significant increased risk for serious
autoimmune disorders. It is apparent that HBV can
induce adverse outcomes similar to the extrahepatic
manifestations of hepatitis B virus infection, albeit at a
much reduced frequency. The mechanism for HBV to
break self-tolerance, and induce SAAEs, appears to
involve the synergistic interaction between the
immunological stimulatory components of the immu-
nization (including: The HBsAg, aluminum adjuvant,
mercury preservative, and residual yeast proteins) in a
genetically-susceptible vaccine recipient, within fairly
close temporal association with vaccine adminis-
tration. Clearly, HBV offers significant benefits,
however, the chances of exposure to hepatitis B virus
in adults, is largely, life-style dependent. Therefore,
adult vaccine recipients need to make an informed
consent decision with their physicians, weighing the
risks and benefits of HBV, and reaching an informed
consent decision as to whether or not to be
immunized. In the United States, those rare vaccine
recipients that are adversely affected by HBV should
report their conditions to VAERS, so that more
information made be gleaned about the safety profile
of HBV, and should be advised that they may be
eligible for compensation from the no-fault National
vaccine injury compensation program (NVICP).
Acknowledgement
We wish to thank Lisa Sykes for her help in revising
and editing our manuscript.
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