Vaccines and Neurologic Disease

James J. Sejvar, M.D.


Semin Neurol. 2011;31(3):338-355. 

In This Article

Vaccines and Vaccine Immunology

The premise of vaccination is to produce an antigen-specific immune response against a virulent infectious agent without actually causing disease. The ability to achieve this was first scientifically demonstrated famously by Edward Jenner in the late 1700s, when he inoculated a young boy with cowpox virus material, a less-virulent relative to the deadly smallpox virus.[3] When the boy was subsequently inoculated with fully virulent material from a smallpox lesion, the child did not develop disease.

Vaccines effect their immune protection primarily by stimulation of B lymphocytes, and with rare exception, CD4 + T cells, to produce antibodies that are capable of binding specifically to a toxin or pathogen epitope.[4] With some live-attenuated vaccines, a CD8 + T cell response develops in parallel with the B-cell response, resulting in T cells capable of killing infected cells. Vaccination ultimately results in the formation of antigen-specific IgG antibodies, thus conferring protection.

There are several different types of vaccines, which can essentially be broken down into live and nonlive vaccines. Live vaccines involve the attenuation of disease-causing viruses by serial passage in cells or tissues from nonhuman species, rendering them less virulent to human cells. This attenuated virus is able to infect and replicate in human cells, but results in a mild or subclinical infection. Such live attenuated vaccines effectively trigger strong activation of the innate immune system, generally resulting in higher immunogenicity. Nonlive vaccines come in several different forms, and can include "killed" whole virus or bacteria, proteins, polysaccharides, glycoconjugates, or toxoids. These nonlive vaccines frequently require the use of adjuvants, or agents that increase immune system stimulation by enhancing antigen presentation; aluminum salts are frequently used as adjuvants. Killed vaccines involve inactivation of microorganisms through exposure to chemical or physical agents that render the organism noninfectious and unable to replicate. Protein or polysaccharide vaccines include epitopes associated with a microorganism or toxin that are readily recognized by B cells and T-helper cells, allowing for a specific IgG response to these proteins/polysaccharides. Glycoconjugated vaccines provide foreign peptide antigens within the vaccine that allows for recruitment of antigen-specific CD4 + T-helper cells producing a T-dependent, and thus more immunogenic, antibody response. Toxoid vaccines include bacterial toxins that have been chemically treated to be rendered immunogenic, but nonpathogenic. More recent vaccine technologies include nucleic acid-based vaccines, which entail the use of DNA that encodes a vaccine antigen, and is subsequently taken up by host cells and processed similar to a natural infection, or a nonpathogenic viral "vector" is used to introduce the nucleic acid.

Vaccines may be used in various different scenarios or situations. Many vaccines are administered as part of standard routine childhood vaccination schedules to prevent various childhood infections.[5] [6] Some vaccines are given in the setting of a suspected exposure to a particular infectious agent (e.g., rabies vaccine in the setting of an animal exposure).[7] Some vaccines are used in particular settings, such as in attempts to control an outbreak of disease; this is true, for instance, with typhoid, meningococcal, and cholera vaccines.[8,9] In the United States and Europe, some vaccines are reserved for travelers to an area endemic for a particular pathogen, for instance, yellow fever or Japanese encephalitis vaccines.[10] Finally, some vaccines are reserved for persons with particular risks for exposure and are not widely available, for instance, vaccines against Venezuelan equine encephalitis virus.[11]

Vaccines for Neurologic Infections

Vaccines for Infections Occasionally Resulting in Neurologic Disease In some cases, infections associated with other prominent clinical syndromes, such as rash, pneumonia, or other manifestations, may result in neurologic illness. These include such infections as measles, mumps, rubella, influenza, and smallpox. Effective vaccines have substantially decreased the overall burden of morbidity and mortality from these agents, including those due to neurologic disease manifestations. Details on the specific nature of these vaccines are provided in Table 1.

Vaccines for Infections Predominantly Associated with Neurologic Disease In some cases, neurologic disease is the primary or principal manifestation of an infectious agent, and although other clinical syndromes may be present, the development of neurologic disease is the principal syndrome. Additionally, toxoid vaccines against bacterial toxins resulting in neurologic illness have been developed, and are important and effective interventions for toxin-mediated neurologic diseases.[12] Some of the medically important vaccine-preventable neurologic illnesses are highlighted in this section and in Table 1.

Viral Infections

Poliovirus Prior to the development of vaccine, poliovirus was the leading cause of permanent disability worldwide.[13] Polio is an acute infection caused by one of three serotypes of virus within the Picornavirus family, consisting of a single-stranded RNA genome, and similar in properties to other enteroviruses. The three antigenic serotypes (1, 2, and 3) generally result in asymptomatic infection or mild febrile illness associated with mild gastrointestinal symptoms, or less commonly aseptic meningitis. The most feared complication is infection of the anterior horn cells of the spinal cord, resulting in limb and/or cranial nerve paralysis; although paralytic poliomyelitis occurs in less than 1% of infections overall, it is devastating. Paralysis tends to be asymmetric, with proximal greater than distal weakness and intact sensation; paralysis tends to be permanent, although some functional recovery may be seen. Uncommonly, exacerbation of existing weakness or development of new-onset weakness may occur many years following acute poliovirus infection, a phenomenon referred to as "postpolio syndrome."[14,15] The cause of postpolio syndrome is not clear, but does not appear to be due to persistent infection.[15]

Development of poliovirus vaccine was viewed as a major public health triumph, given the severity and persistence of the disease. The findings that (1) poliomyelitis could be caused by three viral serotypes spread by fecal-oral contact, (2) viral replication occurs first in the gastrointestinal tract prior to spread to the nervous system, and (3) poliovirus viremia precedes paralysis led to the near-simultaneous development of both a live-attenuated oral vaccine (oral polio vaccine, OPV), and an inactivated intramuscular vaccine (inactivated polio vaccine, IPV). The latter vaccine was developed by Jonas Salk and was licensed in the United States in 1955,[16] and for several years was the predominant form of vaccine administered worldwide. In the early 1960s, the live-attenuated polio vaccine developed by Albert Sabin came into widespread use, and the use of these vaccines quickly controlled poliomyelitis in much of the world, eradicating the disease from the Western Hemisphere by 1994.[17] IPV is currently used in the United States and much of the industrialized world. OPV, generally in monovalent form, is used worldwide in polio eradication campaigns; the ability of OPV to infect contacts of vaccine recipients (i.e., "contact spread"), resulting in indirect vaccination of contacts, is thought to be an advantage over IPV in these settings. Attempts to eradicate poliovirus have been successful in much of the world, but sporadic outbreaks of poliomyelitis in Africa and parts of Asia continue to make global eradication a challenging task.[18]

A rare, but potentially severe complication following OPV is vaccine-derived poliovirus illness, presumably based upon attenuated vaccine poliovirus strains reverting to forms with increased virulence. Vaccine-derived poliovirus disease has been estimated to have an incidence of 0.14 per 1 million vaccinees; the risk appears to be highest following the first dose of OPV, particularly among immunocompromised individuals.[19,20]

Rabies Rabies is an acute, severe, progressive, and nearly invariably fatal central nervous system (CNS) infection caused by lyssaviruses, such as rabies virus, which are negative-stranded RNA viruses in the Rhabdovirus family. Rabies is transmitted to humans by exposure to animals infected with the virus through saliva or other infected fluids, most commonly through an animal bite or scratch; inhalation exposure is also possible.[21] During a prolonged incubation lasting up to weeks, the virus is transported to the CNS from the periphery by axonal transport, eventually making its way to the spinal cord, brainstem, and then caudally. Disease is characterized by dramatic and severe neurologic illness with rhombencephalitis, psychosis, and autonomic instability. Death inevitably occurs within days or weeks. Less commonly, a paralytic form of the illness may occur, resulting in severe peripheral neuropathy and limb weakness but maintained consciousness. Although uncommon in North America and the industrialized world, rabies remains a significant public health problem in much of the developing world.[22,23]

Early preparations of rabies vaccine were developed from live-attenuated or phenol-inactivated viruses, which were derived from neural tissues of rabbits, mice, goats, or sheep. However, the presence of myelinated neural tissue in these formulations resulted in the unacceptably frequent development of neurologic illness (so-called neuroparalytic accidents). Neonatal mouse brain-derived vaccine, free of myelin, was introduced in 1956, and shortly thereafter, vaccine derived from embryonated duck eggs and cell culture preparations free of neural tissue were introduced.[24,25] These vaccines have greatly decreased the number of postvaccinal neurologic complications, and have balanced good immunogenicity with less risk of neurologic complications.

Rabies vaccine may be used both for preexposure immunization, and for postexposure prophylaxis, in combination with rabies immune globulin (RIG), in exposed persons. Standard regimens for both preexposure and postexposure immunization have been developed by the World Health Organization (WHO), and involve multiple doses at specific intervals and generally utilize an intramuscular administration.[7] Alternative schedules involving fewer vaccinations and cost-effective use of intradermal administration, however, have been designed for use in developing countries, where biologics are less available, complicated regimens are less feasible, compliance is difficult, and where a high burden of rabies exists.[26] The effectiveness of cell culture-based vaccines are thought to be good, both preexposure and postexposure, although no placebo-controlled studies of efficacy have been performed.

Japanese Encephalitis Arboviruses (arthropod-borne viruses) refer to a group of viruses transmitted to humans by arthropod vectors, and include members from a variety of viral families. Arboviral diseases may manifest clinically as uncomplicated febrile illness; however, many human arboviral infections result in more severe manifestations, including hemorrhagic fever, arthritic illness, and neurologic complications. There are several arboviral diseases of medical importance that result in predominantly neurologic disease, and for which effective vaccines exist; however, for most North American encephalitic arboviruses (e.g., West Nile virus, St. Louis encephalitis virus, and Lacrosse virus), no vaccines are currently available.[27]

Japanese encephalitis virus (JEV) is a mosquito-borne flavivirus, and is the leading cause of childhood encephalitis throughout South and Southeast Asia. It is maintained in an enzootic cycle involving mosquitoes as the transmitting vectors, and birds and swine as amplifying hosts; human infection with JEV occurs when a susceptible human is bitten by a mosquito harboring the virus. Following an incubation period of ~4 to14 days, the vast majority of infected humans develop clinically silent infection or self-limited febrile illness. Approximately 1 in 250 infected persons will develop severe neurologic illness, including aseptic meningitis, encephalitis, and anterior myelitis. Overall case fatality is ~10%, but is likely an underestimation in areas where JEV outbreaks commonly occur;[28,29] persistent neurologic sequelae including seizures, encephalopathy, and movement disorders may frequently be observed in survivors.[30–33] In endemic areas, children under age 15 years and the elderly are at highest risk of neurologic illness.

Vaccination has been tremendously successful in the control of JEV. The first JEV vaccines were developed shortly after the recognition of the virus in the 1930's,[34] and were inactivated mouse brain-derived formulations. In the late 1960s, an inactivated vaccine derived from primary hamster kidney cells was prepared and used in China, serving as that country's principal JEV vaccine. More recently, a live-attenuated JEV vaccine utilizing the 14-14-2 strain of the virus has been developed, and has been shown to be safe and immunogenic.[35] This vaccine has the benefit of being able to be given in a single dose, rather than the three-dose regimen required of other JEV vaccine formulations, to achieve immunogenicity. In many endemic countries, JEV vaccine programs have been initiated and have decreased the incidence of JEV dramatically.[35] Japanese encephalitis virus vaccine is also sometimes given to special groups outside of endemic areas, including travelers and military personnel spending significant time in JEV-endemic areas, and laboratory workers handling the virus.[36]

Varicella Zoster Virus Varicella zoster virus (VZV) is a double-stranded DNA herpesvirus. Primary infection with VZV generally occurs in childhood in temperate climates, and is spread through airborne exposure to virions, resulting in a febrile illness associated with a vesicular exanthema (e.g., chickenpox). Most childhood primary infections resolve uneventfully within a week or so; however, more severe extracutaneous manifestations may occur, including pneumonia, arthritis, and hepatitis. Neurologic manifestations of VZV infection may include cerebellitis with resultant cerebellar ataxia, which has been estimated to occur in 1 in 4,000 infections in children <15 years.[37–39] Primary VZV infection can also result in varicella encephalitis, a far less common but severe neurologic manifestation.[37]

The neurologic ramifications of VZV infection are somewhat more notable for the ability of the virus to cause latent infection in sensory ganglia, resulting in herpes zoster, a dermatomal-vesicular infection.[40] Following primary VZV infection, the virus results in a latent infection within cranial and/or dorsal root sensory ganglia, and VZV DNA may be demonstrated in ganglia by polymerase chain reaction (PCR). This latent VZV may periodically reactivate in infected individuals; symptomatic herpes zoster occurs when reactivation takes place in the absence of some critical level of cell-mediated immunity, and results in a ganglionitis in which neurons and supporting cells are damaged.[40] Such reactivation results in a prototypical prodromal neuropathic pain syndrome in the dermatome associated with the affected dorsal root sensory ganglia, which may last between 3 and 7 days and is frequently of a shooting, aching, or throbbing nature. During this period, VZV descends in involved nerves to the dermal-epidermal junction, leading to replication in the skin and producing a characteristic dermatomal rash. The rash is generally associated with worsening pain. In addition to pain, various other complications of herpes zoster can occur, including bacterial superinfection, motor nerve damage with resultant paralysis (including the facial nerve), and transverse myelitis. Less commonly, herpes zoster may cause encephalitis or cerebral vasculopathy and strokes. The most common complication of herpes zoster is persistent pain following resolution of the rash, so-called postherpetic neuralgia (PHN). The incidence of herpes zoster increases with age, and is more frequent in persons with immune compromise.

Only one vaccine strain (Oka) of VZV is used worldwide to produce a live-attenuated vaccine. It is given as a single antigen vaccine, or is available in combination with measles/mumps/rubella (MMR) vaccine.[41,42] Vaccination against primary VZV infection is indicated for various circumstances, and increasingly in many countries is becoming part of routine pediatric immunization schedules for children 9 or 12 months of age. It has been recognized that the vaccine virus may lay latent in ganglia and reactivate causing herpes zoster. The overall risk of this vaccine complication is not clear, but the incidence of herpes zoster does not appear to be increased in healthy immunized children.[43–45]

The observation that the frequency of herpes zoster increases with age, presumably on the basis of waning cell-mediated immunity, as well as the fact that second attacks of herpes zoster are uncommon, led to the hypothesis that the use of a VZV vaccine to prevent herpes zoster in older people may have utility. Studies assessing the utility of booster vaccination with live attenuated VZV vaccine in older persons have demonstrated that vaccinated individuals demonstrate increased levels of VZV-specific CD4 memory T-cells, and that the cumulative incidence of herpes zoster among vaccinated individuals was significantly lower than among nonvaccinated persons, with an overall vaccine efficacy against herpes zoster of 51%, and against PHN of 67%.[46,47] On this basis, herpes zoster vaccine was licensed for use in the United States in December 2005 for individuals at least 60 years of age, who had not had prior herpes zoster, for the prevention of herpes zoster and related morbidity.[45] The Advisory Committee on Immunization Practices (ACIP) subsequently suggested that the vaccine be indicated for persons over 60 years of age, regardless of a prior episode of herpes zoster.[48] Although still being assessed, current data suggest that the societal value of herpes zoster vaccine render it cost-effective in terms of its overall impact on quality-adjusted life-years (QALYs) among the elderly, in terms of decreasing burden of morbidity associated with herpes zoster and PHN.[49–51]

Bacterial Infections

Meningococcal Disease Meningococcus (Neisseria meningitidis) is a gram-negative, endotoxin-producing bacterium, and is a cause of severe disease worldwide.[52] It is one of the leading causes of bacterial meningitis in children and young adults, and may result in large bacterial meningitis outbreaks, particularly in the "meningitis belt" of sub-Saharan Africa.[53,54] Each year there are ~1,000 to 1,500 cases of meningococcal disease in the United States, and ~8,000 cases in Western Europe, approximately half of which are meningitis.[55,56] Other meningococcal syndromes include pneumonia, arthritis, and sepsis. Despite effective antibiotic therapy, case-fatality from meningococcal disease remains at 10 to 15%.[52] Meningococcal meningitis most commonly presents with the acute and abrupt onset of fever, headache, photophobia, and altered mental status; early seizures are frequent. A petechial or maculopapular rash is present in many cases. Cerebrospinal fluid is characterized by a significant polymorphonuclear pleocytosis and elevated protein concentration. Meningococcal meningitis may be extremely fulminant, with rapid progression to obtundation and coma. Meningococcus colonizes the human nasopharynx, and is carried by ~10% of the population;[52] spread is through aerosol droplets. Risk factors for severe meningitis include concomitant viral respiratory infection, exposure to cigarette or other smoke, and crowded living conditions (e.g., college dormitories, military barracks).[57]

Pathogenic forms of meningococcus are divided into several serogroups, based upon differences in immunochemistry of the bacterial capsular polysaccharide.[58] Group A is notable for the ability to cause large outbreaks, with rapid geographic spread in large areas. Groups B, C, and Y are more commonly associated with sporadic illness and smaller geographically limited outbreaks. More recently, group W135 has been associated with emerging epidemics of disease in sub-Saharan Africa, but is relatively infrequent in the United States and Europe.[59] Meningococcal vaccines are manufactured as polysaccharide vaccines, or as conjugate vaccines.[58,60] Polysaccharide vaccines are licensed in bivalent (groups A and C), trivalent (groups A, C, W135), or quadrivalent (groups A, C, Y, and W135) formulations. Polysaccharide vaccines elicit antibody response through a T cell-independent mechanism, and as such, tend to be immunogenic in older children and adults, but poorly immunogenic in infants; they benefit, however, from considerable stability in storage. More recently, meningococcal conjugate vaccines have been developed for groups A and C, and a quadrivalent A/C/Y/W135 conjugate vaccine has been formulated.[58] These vaccines conjugate bacterial polysaccharide to nontoxic forms of diphtheria toxin or tetanus toxoid or to Crm197, resulting in a T cell-mediated immunologic response, which are immunogenic in infants, result in a more rapid and persistent immunogenic response, and have the benefit of reducing nasopharyngeal carriage among vaccinees. Vaccine effectiveness from conjugate vaccines approaches 90% during the first year after vaccination, but subsequently decreases. Conjugate vaccines require additional logistical requirements for administration.

Recommendations for meningococcal vaccine vary by country. In the United States, meningococcal vaccine is recommended at age 11 to 12 years, with a booster dose at age 16 years, and for groups at increased risk of meningococcal meningitis, including college freshmen in dormitories, travelers, microbiologists, and military recruits.[61] In countries where the conjugated meningococcal quadrivalent vaccine is available, this is preferred over polysaccharide vaccines. Mass vaccination is also used in outbreak situations of meningococcal disease.[62]

Toxoid Vaccines

Tetanus is an illness caused by a toxin elaborated by the bacterium Clostridium tetani, a gram-positive, spore-forming anaerobic bacillus.[63]Clostridium tetani is widespread in the environment; when C. tetani spores are inoculated into anaerobic conditions, such as injured tissues or puncture wounds, the spores germinate to produce vegetative bacilli, which produce two exotoxins. Tetanospasmin (tetanus toxin) is the neurotoxin that produces the clinical manifestations of tetanus. Through a complex process, tetanospasmin is transported from the site of injury in the skin through uptake at the neuromuscular junction, transported through motor axons in retrograde fashion, and proceeds to the anterior horn cells of the spinal cord or to cranial nerve nuclei. Eventually tetanospasmin undergoes transsynaptic transport to inhibitory interneurons in the spinal cord, where it blocks synaptic release of inhibitory neurotransmitters, glycine and GABA, producing the characteristic spasms and contractions.[63]

There are three clinical syndromes of tetanus, depending upon the site of action.[63] Localized tetanus is associated with muscle spasms in a confined area close to the inoculation site. The majority of cases of tetanus, however, are generalized, where manifestations include widespread spasms, including muscles of mastication, facial muscles producing the characteristic trismus, and sustained generalized muscle spasms and diffuse hyperreflexia. Spasms are often triggered by external stimuli, such as sudden noises or tactile stimulation. Autonomic instability may occur resulting in cardiovascular instability and diaphoresis. Cephalic tetanus is an uncommon manifestation, and is generally associated with head or neck lesions. As opposed to generalized tetanus, cephalic tetanus is associated with multiple atonic cranial nerve palsies. Neonatal tetanus is the most common form of disease in the developing world, and occurs in newborn infants due to infection of the umbilical cord stump. The prognosis of tetanus may be variable; severe spasms and autonomic instability generally last for 1 to 4 weeks, following which symptoms gradually subside. Case-fatality rates in the United States have been reduced to ~10% with good intensive care, but remain much higher in developing countries.[64,65]

The current tetanus vaccine involves detoxification of toxin with formaldehyde, which retains immunogenicity without toxicity. Tetanus toxoid is generally combined with diphtheria toxoid (Table 1) (Td, DT) and either whole-cell (DTP) or acellular (DTaP) pertussis vaccines. Multiple doses of vaccine are necessary initially to confer persisting immunity. Although the need for booster doses of tetanus toxoid every 10 years has been questioned by some experts, such boosters are routinely recommended to afford continuing protection.[66–68] The use of tetanus toxoid in wound management is dependent on the type of wound, and the number and interval of previously administered booster doses. Despite a significant reduction in cases of tetanus worldwide, neonatal tetanus remains a significant public health problem in much of the developing world.[69]

Vaccines for Other Neurologic Diseases Although not yet available for the commercial market, vaccines for several other neurologic disorders are in various stages of development. A vaccine for multiple sclerosis (MS) is currently under phase II clinical trials.[70] Several vaccines directed against brain and CNS tumors and involving autologous tumor cells or transformed B-lymphoblastoid tumor fusion cells are undergoing phase I clinical trials.[71] Finally, new and improved vaccines against several neurologic infections, including meningococcus, West Nile virus, and botulism, are in various stages of clinical assessment.[72–74]

Neurologic Adverse Events Following Immunizations

Vaccines have undoubtedly decreased global morbidity and mortality from several infectious diseases by immeasurable amounts. The contributions of vaccines to global improvements in public health cannot be questioned. However, the nature of the mechanism by which vaccines afford protection through stimulation of the immune system, results in the fact that, in rare circumstances, adverse events may follow vaccination.

Concern about vaccine safety is based upon several issues. Unlike medications, which are given to persons with illness in an attempt to make them well, vaccines are given to otherwise healthy individuals, and the threshold for tolerance of adverse events is much lower. Illnesses or other adverse health events may be temporally associated with receipt of a vaccine, leading an individual or caregiver to infer a causal association even if one is not evident. Since adverse events following immunization affecting the nervous system tend to be more severe clinical events, they may garner a great deal of attention and greater recollection.

An important concept in the discussion of potential adverse events following immunization is that of causality. It is possible to find case reports or small case series of nearly any neurologic illness following nearly any vaccine. Case reports of "X illness associated with Y vaccine" are found throughout the literature. However, substantiation of such associations with data from clinical trials or large epidemiologic studies is essentially lacking for most vaccines, and drawing firm conclusions about causality from these case reports is not possible. Second, "temporal association" does not necessarily equate to "causality." There are many clinical events that may be related to an antecedent vaccination by virtue of temporal proximity; however, this is substantially different than providing a basis for a causal relationship. In many cases, several vaccines are administered simultaneously, making it impossible to determine which, if any, vaccine resulted in a particular adverse event.

There are presumably several hypothetical biologic mechanisms by which a particular vaccine may lead to neurologic illness in humans; most involve the concept of autoimmunity and the possibility that the vaccine's immunostimulatory effect resulted in an aberrant immunologic response.

Neurotoxic effect: A vaccine virus or vaccine proteins could directly damage the membranes of myelin or axons.[75,76]

Molecular mimicry: The concept of "molecular mimicry" involves a situation in which epitopes of a virus or vaccine, or other antigenic stimulus, could initiate the development of immune antibodies and/or T cells that could cross-react with epitopes on myelin or axonal glycoproteins of nerves,[77,78] leading to neuronal damage.

Immune complex formation: The vaccine elicits an antibody response with production of immune complexes. The latter provoke a vasculitis with resultant CNS damage.[79,80]

Loss of self-tolerance: A vaccine could result in perturbation of immunoregulatory mechanisms, interfering with self-tolerance of host myelin proteins, and leading to immune-mediated damage.[81]

In addition, various host factors and genetic polymorphisms are likely to lead to a predisposition to neurologic illness following vaccine in some individuals.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.