NEW Vaccines in Autoimmunity - Discovery Medicine

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February 12, 2010

Article Published in the Author Account of

Hedi Orbach

Vaccines and Autoimmune Diseases of the AdultPublished on

February 4, 2010

Author: Hedi

Orbach

Specialty:

Immunology,

Rheumatology,

Microbiology,

Infectious Diseases

Institution: Department of Medicine B, Wolfson Medical Center

Address: Holon, Israel

Author:

Agmon-Levin

Specialty:

Immunology,

Rheumatology,

Microbiology,

Infectious Diseases

Institution: Center for Autoimmune Diseases & Department of Medicine

B, Sheba Medical Center

Address: Ramat Gan, Israel

Author:

Gisele Zandman-Goddard

Specialty:

Immunology,

Rheumatology,

Microbiology,

Infectious Diseases

Institution: Department of Medicine C, Wolfson Medical Center

Address: Holon, Israel

Institution: Sackler Faculty of Medicine, Tel-Aviv University

Address: Tel-Aviv, Israel

Abstract: Infectious agents contribute to the environmental

factors involved in the development of autoimmune diseases possibly

through molecular mimicry mechanisms. Hence, it is feasible that

vaccinations may also contribute to the mosaic of autoimmunity. Evidence

for the association of vaccinations and the development of these diseases

is presented in this review. Infrequently reported post-vaccination

autoimmune diseases include systemic lupus erythematosus, rheumatoid

arthritis, inflammatory myopathies, multiple sclerosis, Guillain-Barré

syndrome, and vasculitis. In addition, we will discuss macrophagic

myofasciitis, aluminum containing vaccines, and the recent evidence for

autoimmunity following human papilloma virus vaccine.

Introduction

Systemic and organ derived autoimmune diseases are known to develop

following infectious triggers. Recently we have suggested that certain

autoimmune diseases like

systemic lupus erythematosus

(SLE) may result

due to specific viral agents. Furthermore, the spectrum of disease may be

influenced by a certain microbial agent in the genetically predisposed

individual (Zandman-Goddard et al., 2009).

Vaccines are a prototypic source for natural immune stimulation, but may

be involved in pathogenic disease in the setting of aberrant immune

system function. Possibly, the burden on the immune system resulting from

simultaneous multiple vaccines and even the different types of vaccines

may also be an overwhelming challenge in the autoimmune prone individual

(Shoenfeld et al., 2008). In this review, we discuss the evidence for the

development of autoimmune diseases following infections.

While vaccinations are generally safe, warranted and have virtually

eradicated endemic diseases and probably lessened morbidity and

mortality, a question arises regarding the evaluation of possible

autoimmune phenomena in vaccinated individuals.

Reported

post-

vaccination autoimmune diseases in the adult include SLE,

rheumatoid arthritis (RA),

inflammatory myopathies,

multiple sclerosis (MS), Guillain-Barré syndrome (GBS), and

vasculitis. Evidence for the association of vaccinations and the

development of these diseases is presented in this review. In addition,

we will discuss

macrophagic myofasciitis, post aluminum containing vaccines and the

recent support for

autoimmunity following human papilloma virus vaccine.

The Role of Infections in the Induction of Autoimmune

Diseases

Infections, including viruses, bacteria, parasites and fungi, have

pivotal roles as environmental factors contributing to the mosaic of

autoimmune diseases (Shoenfeld et al., 2008).

Evidence exists for the association of streptococcus pyogenes infection

with the development of rheumatic fever (Cunningham et al., 1988),

Trypanosoma cruzi parasitic infection and Chagas disease

cardiomyopathy (Cunha-Neto et al., 1995), the spirochete Borrelia

burgdorfeii and Lyme disease (Chen et al., 1999), Campylobacter

jejuni infection and Guillain-Barré syndrome (Vucic et al., 2009;

Khamaisi et al., 2004; Yuki, 2007), viral infections and

diabetes mellitus I (Goldberg et al., 2009), Chlamydia

pneumoniae and

Epstein-Barr virus

(EBV) and

multiple sclerosis (Ercolini et al., 2009; Bagert, 2009), and EBV

infection and SLE (Zandman-Goddard et al., 2009; Pender, 2003). Our group

recently screened more than 1,300 patients with different autoimmune

diseases and found a significant association of

hepatitis C virus with other diseases including autoimmune

thyroiditis, Crohn’s disease, pemphigus vulgaris, antiphospholipid

syndrome, and vasculitides. In addition, in this study, EBV was found to

be linked to SLE, RA, pemphigus vulgaris, giant cell arteritis,

Wegener’s granulomatosis, polyarteritis nodosa, MS, Sjogren’s

syndrome, and polymyositis (Kivity et al., 2009).

The Role of Vaccines in the Induction of Autoimmune Diseases

SLE

SLE patients show decreased immune responsiveness and are

vulnerable for

infectious diseases, due to the underlying disease and the frequent

use of immunosuppressive drugs (Zandman-Goddard et al., 2005).

In studies of more than 10 patients, the reported manifestations

following

hepatitis B vaccination were arthritis, thrombocytopenia,

demyelinating encephalitis, and demyelinating

neuropathy. A case-control study of 265 newly diagnosed lupus

patients did not show that

HBV vaccine was a

risk factor for developing SLE [odds ratio (OR)-1.4] (Schattner, 2005).

In a current study, 10 lupus patients were diagnosed within several days

and up to one year following hepatitis B vaccination (Agmon-Levin et al.,

2009). Previously, 11 cases were reported in the literature regarding the

onset or exacerbation of SLE post hepatitis B vaccination (Schattner,

2005).

In concordance, a latency period of less than one week and up to 2 years

between vaccination and SLE onset was reported. The classical period

between vaccination and autoimmunity was considered to be several weeks,

similarly to the time frame suggested in the past for post-infectious

autoimmunity phenomena. Interestingly, in this case series, 70% of

patients continued their

immunization protocol although adverse events were documented.

Similarly, in previously reported cases, the affected subjects continued

to be vaccinated and aggravation of their condition by additional doses

had been documented (Agmon-Levin et al., 2009). Overall, SLE patients

presented post hepatitis B vaccination with mild to moderate disease and

without life threatening organ involvement.

A summary of the serious autoimmune adverse events following vaccination

with hepatitis B vaccination reported to the vaccine adverse events

reporting system (VAERS) include in descending order by odds ratio: RA

(OR-18), optic neuritis (OR-14), SLE (OR-9.1), alopecia (OR-7.2), MS

(OR-5.2), and vasculitis (OR-2.6). Many of the adverse events associated

with hepatitis B vaccination were extra-hepatic and are manifestations of

infection with HBV. In addition to the potential epitopes in the

HBsAg (HBV

surface antigen) vaccine, adjuvants containing aluminum and mercury may

provide potential antigenic stimulation (Geier et al., 2005).

Routine

influenza vaccination of SLE patients seems indicated although the

activation of an autoimmune response is feasible. Of 10 studies on 265

SLE patients that received

influenza vaccine (with a follow-up period of 4-24 weeks) only 6 were

reported to develop a flare, of those two patients had renal involvement

(Conti et al., 2008; Del Porto et al., 2008; Holvast et al., 2007;

Abu-Shakra et al., 2007). It is not clear that the composition of the

modern vaccines is identical to those of over 30 years ago where most of

the studies were performed.

In SLE, the immune response to influenza vaccination led to a blunted

humoral response (Holvast et al., 2007). Generally, in the lupus patient

in remission, flares are infrequent and influenza vaccine can be

administered without harm. Why a few lupus patients had a flare following

influenza immunization as evaluated utilizing the systemic lupus

erythematosus disease activity index (SLEDAI) score is yet to be

established (Abu-Shakra et al., 2007).

In a small observational study on 24 lupus patients, the 23 serotype

pneumococcal vaccine did not confer disease activity (Elkayam et al.,

2005).

Multiple sclerosis

Neurological manifestations are common following vaccinations

(Huynh et al., 2008). In a case-control epidemiological study for

serious adverse events reported in the hepatitis B vaccination exposed

group compared to those that received tetanus vaccine, MS was prominent

with an odds ratio of 5.2 (P<0.0003). Optic neuritis was also very

commonly encountered (OR-14, p< 0.0002) (Geier et al., 2005).

Guillain-Barré syndrome

In GBS, activated macrophages invade intact myelin sheaths

resulting in myelin damage and demyelination (Vucic et al.,

2009).

Vaccines reported as associated with GBS are diverse (Schonberger et al.,

1979; Hemachudha et al., 1988; Khamaisi et al., 2004; CDC, 2006; Slade et

al., 2009; Haber et al., 2009). The evidence of casual relationship with

GBS is strongest with the swine

flu

(

H1N1) vaccine that was used in 1976-7. An increased relative risk

[relative risk (RR)-4-8] to develop GBS 6-8 weeks after the injection was

encountered in the vaccinated group compared to the non vaccinated group.

The risk for GBS was slightly less than 1 excess case of GBS per 100,000

vaccinated individuals, and hence the vaccine program was suspended

(Schonberger et al., 1979). Further studies substantiated the association

between the H1N1 vaccine and an increased relative risk (RR-7/1) for GBS

6 weeks after the vaccine (Safranek et al., 1991). The pathophysiology is

unclear but may be related to vaccine induced anti-ganglioside antibodies

(GM1) (Nachamkin et al., 2008).

Studies of influenza vaccines in the following years were not associated

with a substantial increase in the rate of GBS (Lasky et al., 1998).

Immunizing patients with a history of GBS requires caution.

An increased risk for GBS was found in Semple and SMB rabies vaccines.

The vaccine most probably included brain protein that could cause cross

reactive antibodies to the neural tissue and were discontinued. The

current rabies vaccines are derived from chick embryo cells and are not

associated with an increased rate of GBS (Hemachudha et al.,

1988).

The vaccine against Neisseria meningitides is for use among

individuals aged 11-55 years old. The VAERS published a warning of a

possible association between the Meningococcal Polisaccharide Diphteria

Toxoid Conjugated Vaccine (MCV4) and GBS, because of 5 cases of GBS

following the MCV4 vaccine, and later 12 additional cases were reported

(CDC, 2005). Based on reports, statistical analysis did not show any

significant increase in the rate of GBS occurring 6 weeks after the MCV4

vaccine compared to non-vaccinated population. However, it is recommended

that individuals with a history of GBS should not be vaccinated with MCV4

unless they are in a high risk for meningococcal infection. In a mass

meningococcal C conjugate vaccine (CMCV not MCV4) campaign in Quebec,

Canada in 2001, 2 cases of GBS 8 weeks after the vaccine were identified

among 1.5 million administered vaccinations, a rate expected in the

healthy normal population (De Wals et al., 2008).

The FDA licensed the quadrivalent human papilloamavirus recombinant

vaccine (qHPV) in the United States in June 2006 for use in females 9-26

years old. In a review of the adverse effects reported over two years to

the VAERS (Slade et al., 2009), 12 of 42 cases reported as GBS were

confirmed, 11 of them in the age 13-30 years old. Only eight of the

confirmed cases were in the range of 4-42 days post vaccination. The

relative risk in 9-26 year old females vaccinated with qHPV vaccine for

GBS was low (Callreus et al., 2009).

Vaccine induced myopathies

The reports on vaccine induced inflammatory myopathies are

sporadic and include cases of following immunization with HBV, bacillus

Calmette-Guérin, tetanus, influenza,

smallpox, polio, diphtheria, or combinations with diphtheria (Orbach

et al., 2009). There is no statistically significant increase in the

incidence of polymyositis or dermatomyositis after any mass vaccination.

Among 289 patients with inflammatory myopathies followed in the Mayo

Clinic, no recent immunization was recorded (Winkelman, 1968; Winkelmann,

1982).

Macrophagic myofasciitis

Macrophagic myofasciitis is a reaction to intramuscular

injections of vaccines containing aluminum hydroxide as an adjuvant and

affects mainly adults. The symptoms are usually myalgia, arthralgia,

asthenia and, less frequently, muscle weakness and fever, in the presence

of elevated creatine kinase and erythrocyte sedimentation rates. The

electromyogram has a unique pathologic pattern characterized mainly by

focal infiltration of the epimysium, perimysium, and perifascicular

endomysium by sheets of large, non-epithelioid macrophages, which show

fine granular staining for periodic acid-Schiff (PAS) stain that appear

as small, osmiophilic, spiky structures on

electron microscopy, representing the aluminum hydroxide crystals

(Gherardi et al., 2001). Immunizations containing aluminum may trigger

Macrophagic myofasciitis in the context of an

HLA-DRB1*01

genetic background (Guis et al., 2002). Frequently, patients improve with

steroid therapy.

Vasculitis

Numerous case reports reported a possible association between

polyarteritis nodosa (PAN) and hepatitis B vaccination. Overall, 25 cases

of PAN were submitted to VAERS over an 11 year period until 2001. Among

them, only 10 individuals were diagnosed as definite or possible PAN and

are discussed here. The median age of patients was 45 years old and 5

patients were hospitalized. A modal peak of 2 weeks and median of 2.8

weeks post-vaccination was noted. All cases received at least 2 doses of

vaccine prior to symptom onset. Hepatitis B surface antigenemia

frequently follows hepatitis B vaccination and is detected many days

after the 20 microgram vaccine. This could explain related immune-complex

disease. Recently, there were less than 20 reports on the development of

vasculitis following influenza vaccination. Small, medium, and large

vessels were involved (Begier et al., 2004). All in all, this would be

considered a rare event.

Rheumatoid arthritis

A total of 48 out of 898 (5.3%) of patients with early

inflammatory polyarthritis reported an immunization in the 5 weeks prior

to symptom onset. There were no important clinical or demographic

differences between the 48 immunized patients and 185 consecutive

patients who did not report prior immunization. The frequencies of HLA

DRB1 *01 and *04 and the shared epitope in 33 of the immunized patients

were no different in the non- immunized patients compared to healthy

controls. Possibly, in a small number of susceptible individuals,

immunization may act as a trigger for RA (on et al.,

1997).

Seropositive

HLA-DR4

-positive RA is reported in a few case reports after hepatitis B

vaccination. In a series of 11 patients who developed RA after hepatitis

B vaccination, all individuals were healthy prior to vaccination and they

developed persistent polyarthritis fulfilling the present American

College of

Rheumatology criteria for RA (Pope et al., 1998). Five subjects

expressed HLA-DR4, and HLA class II genes with the RA shared motif were

identified in nine of 11 patients. In a case-control epidemiological

study, adults receiving hepatitis B vaccination had an odds ratio of 18

to develop RA (P<0.0001) (Geier et al., 2005), However, the available

data suggests a benefit of the vaccine that outweighs the risk (Sibilia

et al., 2002).

RA patients have almost a doubled risk level of developing an infection

in comparison with age- and sex-matched subjects. In two randomized

studies on RA patients, a good safety profile for the influenza vaccine

without an increased rate of exacerbation was shown (Conti et al., 2008).

Ninety nine

adalimumab

treated patients had a less significant immune response than 99 placebo

treated RA, but the difference was not statistically relevant (Kaine et

al., 2007). Infliximab and etanercept did not influence the

immunogenicity of influenza vaccine (Kubota et al., 2007). The effect of

rituximab on the efficacy and immunogenicity of influenza vaccine was

studied in 14 RA patients. During the 4-week follow-up after vaccination,

there was no difference in disease activity in both groups of patients.

In the

rituximab

treated patients, the percentage of responders was low for all three

antigens tested, achieving statistical significance for the California

antigen (Oren et al., 2008).

The safety profile of pneumococcal vaccine was good without exacerbations

of RA (Elkayam et al., 2002). In 5 studies on the immunogenicity of the

pneumococcal vaccine in RA patients, elevated titers of antibodies

occurred but the response was partial. In 11 RA patients treated with

TNF-α blockers,

the titer of the antibodies increased to a lower level compared to other

disease modifying anti-rheumatic drugs

(DMARDs)

treated RA patients. In another study,

methotrexate treated patients had an inferior increase in antibodies

to the 23F and B6 serotypes when compared to patients treated by TNF-α

blockers and healthy controls. In the Aspire trial, 70 RA patients with

early disease were immunized by pneumococcal vaccine 34 weeks after

initiating therapy. The percentage of patients with antibody response was

similar in the three groups (infliximab at 2 different doses with

methotrexate or methotrexate alone) (20-25% response). All treatment

groups had a lower response to vaccine than would be expected in the

normal population. Interestingly, the addition of infliximab to

methotrexate therapy did not impair the immune response (Visvanathan et

al., 2007).

Hepatitis B vaccination was safe in 22 RA patients compared to controls

without any evidence of exacerbation of the disease and was effective in

68% of patients (Elkayam et al., 2002).

HPV

vaccine and autoimmune manifestations

The recently released vaccine for

human papillomavirus

(HPV) offers an

opportunity to assess the development of autoimmune phenomena in a high

risk population of young women. Hence, we chose to investigate and report

separately on this vaccine.

Recently developed vaccines against human papillomavirus (HPV) and

hepatitis B virus (HBV) contain a novel Adjuvant System, AS04, which

is composed of 3-O-desacyl-4’ monophosphoryl liipid A and aluminum salts.

All randomized, controlled trials of

HPV-16/18,

herpes simplex virus

(HSV), and HBV

vaccines were analyzed in an integrated analysis of individual data (N =

68,512). A separate analysis of the HPV-16/18 vaccine trials alone was

also undertaken (N = 39,160). The reported rates of overall autoimmune

events were around 0.5% and did not differ between the AS04 and control

groups. The relative risk (AS04/control) of experiencing any autoimmune

event was 0.98 (95% confidence intervals 0.80, 1.21) in the integrated

analysis and 0.92 (0.70, 1.22) in the HPV-16/18 vaccine analysis. This

integrated analysis of over 68,000 participants who received AS04

adjuvant vaccines or controls demonstrated a low rate of autoimmune

disorders, without evidence of an increase in relative risk associated

with AS04 adjuvanted vaccines (Verstraeten et al., 2008).

In the Danish Civil Registration system, among approximately half a

million adolescent girls, 414 autoimmune disorders were listed. The 5

most common autoimmune diseases occurring within 6 weeks of

vaccination among 100,000 girls were: type I diabetes, juvenile

arthritis, Crohn’s disease, Henoch-Schonlein disease, and

ulcerative colitis (Sutton et al., 2009). However, over a 10 year

period, the common autoimmune diseases, from the most to the least

common, were: type I diabetes, juvenile arthritis, Crohn’s disease,

ulcerative colitis, Basedow’s disease, Henoch-Schonlein purpura,

psoriasis, and SLE (Verstraeten et al., 2008).

Adverse events of potential autoimmune etiology for HPV 16/18, HBV, and

genital HSV vaccine trials (n = 42) were evaluated in an integrated

analysis of 68,512 individuals. Common to these 3 vaccines is their

adjuvant, ASO4. A separate analysis of HPV 16/18 vaccine trials was

performed in an integrated analysis of 39,160 individuals. The analysis

included all completed or ongoing controlled randomized studies of the 3

vaccines conducted by GlaxoKline Biologicals or collaborators. No

independent sources on this subject were retrieved in a literature

search. The control group received vaccines that were ASO4 free,

non-adjuvanted, or adjuvanted with aluminum or aluminum hydroxide. To be

included in the analysis, each individual received at least one dose of

vaccine. The mean follow-up period was 1.8 years. These studies were not

specifically set up to evaluate the development of autoimmune phenomena.

A total of 362 participants reported at least one autoimmune event with

an event rate of 0.52% in the vaccinated group which did not differ from

the control group (0.54%). Hypothyroidism was the most common individual

event, followed by unclassified musculoskeletal and neuroinflammatory

disorders.

The overall relative risk for developing an

autoimmune disease was 0.98, hence no direct statistically

significant difference between the groups was encountered. However, when

looking at each disease individually, the highest relative risk for an

individual event was idiopathic thrombocytopenic purpura (RR-3.74),

followed by SLE (RR-3.00). For organ specific disease, thyroid

involvement was most commonly detected. For analysis of the entire

database which included data for HBV and HSV vaccine as well, the highest

relative risk for an individual event was for SLE (RR-2.39) (Verstraeten

et al., 2008).

Discussion

Autoimmune diseases that are known to be infection induced and can be

prevented by proper therapy in most cases include rheumatic fever and

Lyme disease. A most probable causality occurred between exposure to

swine flu

vaccine and the development of GBS. In addition, MMF occurred

following exposure to aluminum containing adjuvant. Vaccines, like

infections, activate immune mediated mechanisms to induce a protective

effect. Hence, a complex vaccine may theoretically be more immunogenic

than a simple vaccine. Vaccines harbor added complex agents, for example,

adjuvants including aluminum, which may induce autoimmune disease.

Preservatives are more often found in viral vaccines compared to

bacterial vaccines suggesting that the preservatives may be the inciting

culprits (Israeli et al., 2009).

Given the background incidence of autoimmune disorders in some of the

groups targeted for immunization with these vaccines, it is likely that

autoimmune events will be reported in temporal association with

vaccination, even in the absence of a causal relationship (Table

1).

Table 1. Association of Vaccines with Autoimmune Disease

Type of vaccine

Autoimmune disease

Reference

Influenza

GBS

Schonberger et al., 1979

Meningococcal (MCV4)

GBS

CDC, 2006

HBV

MS, SLE, RA

Geier et al., 2005

HPV

IDDM, IBD,

vasculitis, SLE

Verstraeten et al., 2008; Sutton et al., 2009

MMR

ITP-like

Wraith et al., 2003

HAV, HBV, TT

Macrophagic myofasciitis

Gherardi et al., 2001

GBS, Guillain-Barré syndrome; SLE, systemic lupus erythematosus; MS,

multiple sclerosis; ITP, idiopathic thrombocytopenic purpura; IDDM,

insulin dependent diabetes mellitus; IBD,

inflammatory bowel disease; HAV, hepatitis A virus; TT, tetanus

toxoid.

A comprehensive strategy is required to develop a new vaccine that will

not induce autoimmune manifestations as previously proposed. Looking in

the future, experimental investigation may discover autoimmune phenomena

in spontaneous and naïve disease models.

Perhaps, the assessment of

autoantibody and HLA status prior to immunization will serve as a

marker for individuals at risk. More research is required to identify

those individuals who may develop autoimmune diseases following

immunizations. It is not clear if genomics or

proteomics will reveal the individuals with an increased risk to

develop autoimmune phenomena.

(Corresponding author: Dr. Gisele Zandman-Goddard, Department of

Medicine C, Wolfson Medical Center, Holon, Israel 58100.)

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[Discovery Medicine, Volume 9, Number 45, February 2010.

Pre-published.]

Sheri Nakken, R.N., MA, Hahnemannian

Homeopath

Vaccination Information & Choice Network, Washington State, USA

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