Infect Med 19(2):73-79, 2002.
Douglas R. Jeffery, MD, PhD
Abstract and Introduction
The administration of vaccines to patients suffering from multiple sclerosis (MS) has long been controversial because of the immune-mediated nature of myelin destruction in MS. Numerous case reports have suggested that both onset and worsening of MS may occur following vaccination against a variety of illnesses. Postulated mechanisms include molecular mimicry and a nonspecific adjuvant-like effect of vaccines on cellular immunity. Double-blind prospective studies, however, have shown that influenza vaccination is safe in MS patients. Hepatitis B vaccine has also become controversial but there are no well-controlled prospective studies demonstrating its safety or lack thereof.
Multiple sclerosis (MS) is a neurologic disorder in which CNS myelin is destroyed by immune-mediated mechanisms. There are approximately 350,000 patients with MS in the United States. Among young adults, this disease now constitutes a leading cause of disability. There are 2 main theories of pathogenesis. One holds that MS is truly autoimmune and normal myelin antigens are the target of a T-cell-mediated attack possibly initiated by molecular mimicry and perpetuated by an aberrant immune response. The other holds that MS represents a chronic viral infection of the CNS in which the immune system targets abnormal myelin antigens.
Whatever the cause, inflammation and demyelination in MS are immune-mediated events in which T cells are thought to play a primary role. It is hypothesized that antigen-presenting cells in the periphery interact with T cells, resulting in the activation of T cells and the subsequent initiation of a TH1 cytokine response. This results in the trafficking of T cells and macrophages across the blood-brain barrier, leading to the destruction of myelin and axons by activated macrophages, T cells, B cells, and toxic effects of cytokines on oligodendrocytes.
The pathologic hallmark of MS is perivascular lymphocytic infiltration in which both macrophages and T cells are found within active lesions.[2,3] In addition to demyelination, axonal transection may occur during the course of the inflammatory response, suggesting that irreversible damage may be an early event in the course of the disease.
Disease activity in patients with MS varies over time and is widely variable between individuals. One event capable of activating the inflammatory response in MS is a viral upper respiratory tract infection (URTI).[5,6] Exacerbations or attacks in MS are defined as the appearance of new neurologic symptoms or the significant worsening of existing neurologic symptoms accompanied by objective deficits and occurring in the absence of systemic illness. The physiologic underpinning of the appearance of new neurologic symptoms in MS is inflammation within regions of the nervous system that mediate important motor or sensory functions. In patients with relapsing-remitting MS, exacerbations vary in frequency, occurring at an average of about 1 or 2 per year. The most frequent event preceding a relapse is a viral infection.[6,7] In one study, 27% of viral infections were followed by MS relapses and fully 8% of all relapses were associated with viral infection. The most common forms of infection were viral URTI and gastroenteritis.
The mechanism responsible for immune activation following infection might involve a nonspecific effect of increased cell-mediated immunity, molecular mimicry, or the release of proinflammatory cytokines. Interferon-gamma (IFN-gamma) and tumor necrosis factor a are released following viral infections, and their levels are elevated before attacks and in clinical disease progression. In addition, the administration of IFN-gamma increases relapse rates in patients with MS. Since vaccines act by simulating viral or bacterial infection, they could stimulate a cytokine cascade, resulting in increased immune-mediated inflammatory demyelination. Alternatively, some vaccines could contain antigens sufficiently similar to myelin antigens to induce an immune response directed against myelin.
Despite numerous case reports of neurologic deterioration following vaccination in patients with MS, the majority of controlled trials have not shown an increase in disease activity following vaccination against a wide variety of infectious illnesses.[9-14] Nevertheless, it is clear that vaccination may appear to be temporally related to relapse onset and probably trigger relapse in rare instances. As a result, the most important consideration in deciding whether to administer vaccines to patients with MS is to weigh the consequences of the disease being vaccinated against versus the risk that vaccination may result in increased MS disease activity.
Disease Course In MS
Before a discussion of the use of vaccines in patients with MS, it useful to briefly review the basic clinical forms of the illness and their underlying pathophysiology. Disease course in MS has 1 of 4 characteristic patterns (Table). The first is relapsing-remitting (RR) MS. Eighty-five percent of patients have disease that is initially RR in character. In this form of MS, illness begins with attacks of acute neurologic dysfunction separated by periods of apparent neurologic stability. Despite the appearance of neurologic stability, MRI studies show frequent new inflammatory lesions. New inflammatory lesions can be visualized on T1-weighted MRI scans with gadolinium contrast (Figure). Focal gadolinium-enhanced lesions correspond to breakdown of the blood-brain barrier and acute inflammatory changes with macrophage and lymphocyte infiltration, edema, and demyelination. For every clinical relapse, there are 5 to 10 new gadolinium-enhanced lesions. New gadolinium-enhanced lesions are the most frequently observed event in MS and probably represent the most sensitive measure of disease activity.
After 26 years of disease, secondary progressive (SP) disease, in which there is a gradual and uninterrupted clinical deterioration with or without superimposed relapses, will have developed in approximately 90% of patients who began with an RR course. Patients with SP MS tend to have more advanced disability, and they may be more susceptible to influenza and to its associated complications.
About 15% of the entire cohort of MS patients will exhibit a form of disease that is progressive from its onset. There are 2 subtypes of this disease pattern. The first is referred to as primary progressive (PP), and it is characterized by a slow deterioration from the onset in the absence of true attacks or remissions. It should be noted that remission does not refer to a normalization on neurologic examination; it only suggests that there is neurologic stability between attacks.
The second is referred to as progressive relapsing (PR), and it accounts for only 4% of the total MS population. In this form of disease, patients start out with a slow progressive deterioration and subsequently superimposed relapses develop. There is some evidence to suggest that there is no important clinical difference between PR and PP MS. The disease course in MS patients may be an important consideration in the administration of vaccines because of the possibility that vaccinations that are otherwise safe could stimulate disease activity in patients who show active inflammatory demyelination at the time of vaccine administration. The remainder of this article discusses the evidence for ill effects of vaccines for influenza, hepatitis B, measles-mumps-rubella, and other diseases in patients with MS.
Several early case reports have suggested that relapse or onset of MS
may follow vaccination against influenza.[20-22] While a theoretical mechanism
of increased disease activity might postulate a broad or uncontrolled spread
of immune activation in patients with MS, carefully controlled studies
have not demonstrated an increase in relapse rate or progression of disability
following influenza vaccination. De Keyser et al conducted a retrospective
study of 180 patients with RR MS and found that only 5% suffered relapse
within 6 weeks of influenza vaccination. Of greater significance was the
finding that 33% of patients in whom an influenza-like illness developed
suffered relapse within 6 weeks. Clearly, the risk of relapse is far greater
following a flu-like illness than following vaccination. Further, the relapse
rate following vaccination was probably no greater than that seen in a
Similar results were reported even in early studies. Sibley et al reviewed the cases of 93 patients who had received 209 inoculations against influenza and reported only 1 relapse in the entire group following vaccination. This was less than expected for the clinic population being studied.
More definitive evidence demonstrating a lack of effect of the influenza vaccine on disease activity in MS has been provided in a recent double-blind prospective study comparing influenza vaccine with placebo. This study involved 104 patients at 5 centers in the United States. Three vaccine-treated patients and 2 patients who received placebo experienced relapse within 28 days of inoculation. The difference was not statistically significant and suggested that influenza vaccination did not result in an increase in the risk of relapse. Further, the placebo and treated groups showed no difference in progression of disability over a 6-month period, suggesting that the vaccine had no effect on disease activity.
The results of clinical trials with influenza vaccine have been confirmed in smaller studies using gadolinium-enhanced MRI. Visualizing gadolinium-enhanced lesions on T1-weighted MRI represents one of the most sensitive measures of disease activity in MS. Patients with RR MS who are not receiving immunomodulating therapy average 20 new gadolinium-enhanced lesions per year. Only 2 small studies have been carried out using the frequency of new gadolinium-enhanced lesions on MRI as the primary outcome measure.[24,25] In the first study, 11 patients with RR MS underwent MRI 3 weeks before vaccination, at the time of vaccination, and 3 weeks following vaccination. Three new gadolinium-enhanced lesions were detected in the 11 patients before vaccination and only 1 in the postvaccination period. While the number of patients examined in this study was small, the results strongly suggest that there is no increase in subclinical disease activity following influenza vaccination. In a similar study of 6 patients, 5 had no increase in disease activity following vaccination. One patient with active disease before vaccination showed continuing disease activity on gadolinium-enhanced MRI and substantial deterioration over the course of the following year. While this probably represents a continuation of previously severe and active disease, it may raise a point of caution in patients with active disease.
The events reported following the widespread administration of the swine flu vaccine deserve special mention. There was considerable controversy regarding an increased incidence of acute inflammatory demyelinating polyneuropathy and an increase in MS-like syndromes following swine flu vaccination.[22,26] In 1976, more so than any other year, there were numerous reports of neurologic syndromes following the administration of the swine flu vaccine. It had been suggested that disease activity in MS patients was increased and that new cases were more likely in patients who had received the vaccine. However, systematic, controlled studies of relapse frequency and incidence of MS failed to show any increase in disease activity in persons vaccinated against swine flu.[12-14]
When the benefits versus the risk of influenza vaccination are considered, it is clear that in the vast majority of cases there is considerable benefit to vaccination. In patients with advanced disability, influenza may constitute a life-threatening illness. Even in those with minimal disability, severe flu may be followed by secondary bacterial infection. Further, the risk of relapse following influenza may be as high as 33%, whereas the risk of relapse following vaccination appears to be negligible. The only exception to this general rule would be in those patients with rapidly evolving neurologic deficits due to active disease. In that instance, vaccination should probably be withheld pending treatment with high-dose corticosteroids to suppress inflammatory disease activity or stabilization through the use of immunomodulatory treatment, such as interferon-b (IFN-b) or glatiramer (GLAT). Further, there is no contraindication to vaccination in MS patients receiving IFN-b or GLAT. Care should be taken in those patients being treated with methotrexate, azathioprine, or other chemotherapeutic agents, since these drugs are more potent and less specific in their immunosuppressant effect. In the absence of active disease, influenza vaccination is strongly recommended for patients with MS.
Hepatitis B Vaccination
Vaccination against hepatitis B in patients with coexistent MS has been
more controversial than vaccination against influenza.[27,28] Numerous
case reports have suggested a relationship between hepatitis B vaccine
and adverse neurologic events involving demyelination.[29-36] Transverse
myelitis is an inflammatory injury to the spinal cord that is thought to
be mediated by an autoimmune mechanism involving molecular mimicry. Optic
neuritis may theoretically be brought about by an identical mechanism involving
the optic nerve. Both syndromes are common manifestations of relapse and
presentation in patients with MS and both have been reported in close temporal
relationship following the administration of hepatitis B vaccine.[29-36]
The temporal relationship between vaccination and the development of neurologic
syndromes is an important consideration in the establishment of a possible
causal relationship. In postinfectious myelitis, the average interval between
infection and myelitis was 10 days. In studies of the relationship
between infection and relapse in MS, the interval of time used to establish
a temporal relationship has been placed at 4 weeks. Therefore, the development
of neurologic syndromes more than 4 weeks after vaccination should probably
not be considered temporally related.
A point should be made regarding other neurologic syndromes reported following hepatitis B vaccination. Bell palsy, Guillain-Barré syndrome, brachial plexus neuropathy, and lumbar radiculopathy have been reported in association with hepatitis B vaccination. All of these syndromes involve immune-medi-ated demyelinating processes affecting the peripheral nervous system. Their pathophysiologic underpinning may have significant similarities to immune-mediated disorders involving the CNS. Even in the absence of molecular mimicry, some vaccines may have the ability to enhance immune activation in a fashion similar to adjuvants. Mechanisms of this nature might be important in considering relationships between vaccination and disease activity in MS. Whatever the mechanism, occasional examples of MS relapse can be found in response to antigenic stimulation. In one well-documented case report, an MS patient who had recovered from acute infection with hepatitis A virus experienced exacerbations of MS after skin testing with hepatitis A antigens.
Both activation of previously existing MS and the appearance of new CNS demyelination consistent with MS have been reported following hepatitis B vaccination.[29,34] While activation of inflammatory demyelination in a patient with preexisting MS is plausible, the development of new MS as a result of vaccination appears much less likely. Herroelen et al reported the development of new neurologic symptoms consistent with MS in a 28-year-old nurse 6 weeks after vaccination against hepatitis B. One month after treatment with corticosteroids, recurrent neurologic deficits consistent with a relapse developed. The patient reported was HLA-DR2-positive. This major histocompatibility profile is associated with a greater risk of MS. Since this patient's first symptoms occurred more than 6 weeks following vaccination and she was HLA-DR2-positive, it is unlikely that vaccination was causally related to the development of MS.
Tourbah et al also have reported the development of recurrent CNS demyelination in 8 patients following hepatitis B vaccination. Two of their patients had a history of at least 1 neurologic symptom consistent with MS before vaccination, and 2 had a family history of MS. All of the patients had persistent inflammatory disease activity or new lesions seen on T2-weighted MRI at periods of follow-up ranging from 9 to 30 months. Neurologic symptoms developed in only 4 of the patients within 30 days of vaccination. While the development of new MS as a result of vaccination is probably unlikely, the reactivation of MS following vaccination could occur. The question remains whether the rate of relapse exceeds that which would normally be expected in a population of patients with MS. In the small series and case reports describing MS relapse following hepatitis B vaccination, it is difficult to determine whether the cases reported could have occurred by chance in the absence of vaccination. Large, well-controlled studies will be required to address this question.
Recurrent demyelinating syndromes have been reported in patients with high titers of hepatitis B surface antigen (HBsAg). Matsui et al described a patient with recurrent demyelinating transverse myelitis in whom elevated titers of HBsAg were associated with transverse myelitis. Levels of myelin basic protein were markedly elevated in the absence of oligoclonal bands and in the absence of any evidence of vasculitis. Since hepatitis B polymerase shares a 6 amino acid sequence with the encephalitogenic portion of rabbit myelin basic protein, it was thought that this could have represented molecular mimicry. In this case, there was thought to be cross-reactivity between HBsAg and myelin antigens within the spinal cord. It should be noted, however, that recombinant hepatitis B vaccine (the commonly used hepatitis B vaccine) does not contain the gene for hepatitis B polymerase.
Other antigens within the hepatitis B vaccine are probably capable of cross-reactivity with myelin or neural antigens and might serve as a stimulus for a misdirected immune response. Evidence supporting this comes from a recent study demonstrating cross-reactivity of HBsAg with a myelin peptide derived from a proteolipid protein (PLP). In that study, T cells isolated from the peripheral blood of a patient in whom MS developed following vaccination against hepatitis B showed cross-reactivity between PLP and HBsAg. While these findings are preliminary, they suggest that molecular mimicry could serve as a mechanism by which hepatitis B vaccination could increase disease activity in susceptible MS patients.
Despite this demonstration of molecular mimicry, at least 1 retrospective study has not shown an increase in relapse rate following hepatitis B vaccination. In that study, a group of 20 patients had a first CNS demyelinating event less than 2 months after vaccination against hepatitis B. Two other patients did experience relapse following a second dose of the vaccine. These patients differed from a control MS population that did not receive vaccine only in that they were younger. In another population-based case-control study, hepatitis B vaccination was associated with a 1.5-fold increase in the risk of a demyelinating event within the CNS and a 1.2-fold increase in the risk of MS. While these data have only been presented in abstract form and not published in a peer-reviewed journal, the results suggest that hepatitis B vaccination is probably safe for the majority of MS patients. Clearly, further research in the form of well-controlled prospective studies will be required to better define any risk associated with hepatitis B vaccination in MS patients.
A more recent study, using a case-crossover design, also failed to document an increase in the risk of relapse following vaccination against hepatitis B, influenza, and tetanus.
In the absence of carefully collected data from larger, well-controlled studies, the benefits versus the risk of hepatitis B vaccination in MS patients must be weighed carefully. In the general population, there is overwhelming evidence for significant benefit from hepatitis B vaccination. There are more than 350 million chronic hepatitis B virus carriers at high risk for cirrhosis and hepatocellular carcinoma. Vaccination is 95% effective in preventing the hepatitis B carrier state and has decreased rates of hepatocellular carcinoma.
The dilemma in hepatitis B vaccination occurs in those patients suffering from known MS. While the evidence suggesting that hepatitis B vaccine may aggravate disease activity in MS has arisen from case reports and small, uncontrolled series, only those MS patients at high risk for hepatitis B should be vaccinated until results of larger, well-controlled studies are available. If a patient with diagnosed MS has risk factors for hepatitis B, the vaccine should be administered; patients should be told that the question of relapse following hepatitis B vaccination is controversial, but that there is no strong evidence showing an increased risk of relapse or disease progression following vaccination. Relapses are treatable with intravenous cortico-steroids. Without appropriate treatment, relapses can result in permanent neurologic deficits, and even with appropriate treatment, such deficits may result. If the patient has active disease, as shown by evolving neurologic deficits or MRI evidence of new gadolinium-enhanced lesions, vaccination should be withheld until the MS disease activity can be adequately treated with available therapies.
There is little evidence even in the form of case reports of possible adverse events in patients with MS following measles-mumps-rubella (MMR) vaccination. Of interest in regard to this vaccine is the association between measles and postinfectious encephalomyelitis. Natural infection is associated with post-infectious encephalomyelitis in approximately 1 of every 1000 cases. Its pathologic hallmark is the presence of perivenular inflammatory infiltrates similar to those seen in MS. Since this inflammatory illness of the CNS is observed following natural infection, the risk of similar illness following vaccination might make logical sense. Despite this, the occurrence of neurologic sequelae following measles vaccination has been uncommon.
While both encephalitis and optic neuritis have been reported following vaccination,[44-48] only 1 study has suggested an association between measles vaccination and encephalitis. This study reported 48 cases of encephalitis occurring within 15 days of measles vaccination. The onset of illness occurred at day 8 or 9 in 17 children; this was found to be a statistically significant nonrandom distribution, suggesting that an 8- or 9-day latency between vaccination and onset of illness may be of biologic importance. Rare cases of transverse myelitis have also been reported in adults following vaccination, but such reports have been so infrequent as to suggest that the temporal relationship may have been fortuitous.
In the mid-1970s, one theory regarding the pathogenesis of MS held that MS might be a response to chronic measles virus infection of the CNS. If this were true, then measles vaccination should prevent or decrease the rate of MS. Unfortunately, however, measles vaccination has not been found to affect the eventual development of MS.[50,51]
In the case of rubella vaccination, a rubella virus titer should be checked before vaccine administration. If the titer is inadequate, the vaccine should be administered. Since there is no firm evidence suggesting an increased risk of relapse follow-ing MMR vaccination, the vaccine should be given if there is an indication for any of its components.
Relapse in patients with MS has also been reported following the administration of a variety of other vaccines, including rabies, smallpox, yellow fever, typhoid fever, and polio.[51,52] Most reports have been in the form of small case series, and the intervals between vaccination and relapse have been highly variable. As pointed out earlier, any vaccine could theoretically trigger relapse in a patient with MS. There is no available evidence from controlled retrospective studies or prospective studies regarding the safety of the vaccines listed above in patients with MS. The general procedure for the administration of these vaccines to MS patients is to weigh the risk of possible relapse or progression of MS against the consequences of the disease being vaccinated against.
In most cases, the consequences of a vaccine-preventable illness are far greater than the risk of MS relapse. Nevertheless, patients should be informed that vaccination can, on rare occasion, trigger an MS relapse but that the risk of an infectious illness poses a far greater threat. In patients with MS who exhibit evidence of active disease as manifested by rapidly evolving neurologic deficits or in those who show active disease by MRI criteria, vaccination should be withheld until the disease activity can be brought under control with appropriate immunomodulating therapy.
Douglas R. Jeffery, MD, PhD, Assistant Professor of Neurology, Wake Forest University School of Medicine, Winston-Salem, NC
© 2002 Cliggott Publishing