Neurologic Complications of Vaccination

Possible Mechanisms

Inappropriate immune responses are well-recognized consequences of vaccinations, especially with vaccines made from viruses grown in neural tissue. The classic example is that of the old neurally derived rabies virus, which often resulted in “neuroparalytic accidents” of acute demyelination in either the central or peripheral nervous system. Both acute disseminated encephalomyelitis (ADEM) and Guillain–Barré syndrome (GBS) were observed after the use of these older rabies vaccines and most recently with influenza vaccines.

Two major mechanisms proposed to explain development or activation of autoreactive immune cells after immunizations are molecular mimicry and bystander activation. Molecular mimicry is a process by which antigenic epitopes in the vaccine resemble those in myelin. This structural similarity can result in the development of self-reactive, naïve T and B lymphocytes. Once activated, these cells expand in number and mature into effector T cells leading to pathologic responses mediated by cytokine release and cell-mediated cytotoxicity. Although this mechanism of mimicry has not clearly been shown to act in central demyelination (except possibly for measles, as discussed later), neurally derived vaccines contain myelin antigens themselves (rather than mimics) and therefore can trigger such disease. Peripheral demyelination is known to occur by this mechanism.

Bystander activation is a process by which the activation and expansion of self-reactive lymphocytes is produced by cytokine release and antigenic response to tissue damage. It is conceivable that vaccine antigens could trigger bystander activation just as an infectious agent does.

Detection of Vaccine Adverse Events

Detection of vaccine adverse events can be difficult as they are uncommon and often manifest as illnesses that are known to occur in the unvaccinated. Many of these illnesses are not reportable to health departments. Health officials, however, will take note of an unusually high incidence of disease and launch an investigation. Surveillance for any unusual disease activity can be active or passive. Active surveillance is when cases are actively sought by sending questionnaires to physicians’ offices and hospitals or by systematically examining hospital records. Passive surveillance occurs when physicians or the public send unsolicited information about cases to health department officials. Passive surveillance provides very limited epidemiologic information, as it does not indicate the proportion of those with the complication who were actually reported (no numerator information) and how many were actually exposed to the vaccine (no denominator information); furthermore, the clinical details often are insufficient to make a secure diagnosis. The Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system in which complications are reported to the FDA. Table 48-2 summarizes selected neurologic syndromes reported to VAERS in association with various vaccines. Another passive surveillance system consists of the National Vaccine Injury Compensation Program, which compensates individuals who have had a serious and permanent adverse effect from a vaccine and who meet other criteria.

Case reports and case series of illnesses following a vaccination may be published, but it is difficult to establish causality on this basis and, in fact, such reports may be misleading. The older literature is replete with case reports of illness following vaccination but in which a causal connection was never made. Certain reports have generated considerable controversies that have led to a decrease in vaccine use and to outbreaks of disease, emphasizing the necessity of performing controlled studies that can address the issue of causality. Randomized, double-blind, placebo-controlled trials of vaccines are required as part of the FDA approval process and are very reliable, but only common adverse events are detected.

The establishment of extensive databases provides a new resource for vaccine safety studies. The CDC is operating a Vaccine Safety Datalink (VSD) project, which links to the databases of eight health maintenance organizations with 6 million members. This database has been used for a number of population-based studies, including vaccine safety studies. General information on vaccinations and reporting of adverse events is available from various internet sites ( Table 48-3 ).

Adjuvants and Preservatives

In order to attract the attention of the immune system and build an immune response, most vaccines require the addition of an adjuvant. Aluminum salts such as aluminum hydroxide, aluminum phosphate, and aluminum potassium sulfate have been used safely in vaccines for more than 70 years. A recently developed adjuvant suspension used with the Shingrix vaccine is ASO1B. AS01B is made of up of monophosphoryl lipid A (MPL), an immune-boosting substance isolated from the surface of bacteria, and QS-21, a natural compound extracted from the Chilean soapbark tree. Adjuvants have to be carefully used and manufactured since they can lead to severe inflammation. The US Food and Drug Administration (FDA) does not currently approve the use of pure adjuvants outside of a vaccine.

Controversies around the safety of adjuvants have emerged in the last decades. The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a term coined by Shoenfeld and co-workers. A careful review of over 300 cases of ASIA syndrome collected from an international registry revealed useful clinical information. The mean age at disease onset was 37 years and the mean latency between adjuvant administration and development of symptoms was 16 months, ranging from 3 days to 5 years. The most frequent symptoms included arthralgias, myalgias, and chronic fatigue syndromes, but most patients had a concomitant autoimmune disorder, most commonly undifferentiated connective tissue disease (UCTD) and a positive antinuclear antibody test (ANA).

Perhaps the strongest evidence of the safety of aluminum in childhood vaccines came from a recent study that carefully assessed blood and hair aluminum levels, vaccination history, and cognitive, language, and motor development scores in children aged between 9 and 13 months. The authors found no correlation between infant blood or hair aluminum concentrations and vaccine history or between blood aluminum and overall developmental status.

The mercury-containing preservative thimerosal has also been linked with neurologic complications, particularly with the risk of autism. Mercury is a naturally occurring element found in the Earth’s crust, air, soil, and water. At high levels, it can be neurotoxic. Using standards for methylmercury, the FDA conducted an assessment of mercury content in vaccines and found that infants up to 6 months of age could receive quantities of mercury from vaccines that exceeded the recommended safety guidelines for methylmercury of the Environmental Protection Agency. Thimerosal, however, contains ethylmercury, not methylmercury. Ethylmercury is broken down and excreted much more rapidly than methylmercury and is therefore much less likely to accumulate in the body and cause harm.

Several efforts have been made to address concerns about the risk of autism and other developmental disabilities in children exposed to thimerosal. Reviews of the evidence by the Institute of Medicine concluded that evidence favored rejection of a causal association between thimerosal in vaccines and autism. This conclusion was based on several factors. Large epidemiologic studies suggest that the incidence of autism in children who received thimerosal-containing vaccines is not different to those children that received thimerosal-free vaccines. Similarly, prenatal and early-life exposure to thimerosal from vaccines or immunoglobulins was not related to increased risk of autism. In a US cohort study, standardized tests were administered to children between 7 and 10 years of age to assess the association between neuropsychologic performance and exposure to thimerosal from vaccines or immune globulins during the prenatal period, the neonatal period (0 to 28 days), and the first 7 months of life. The results did not support an association between early life exposure to mercury and deficits in neuropsychologic functioning at the age of 7 to 10 years. As a precautionary measure, the United States has transitioned to a childhood vaccine schedule free of thimerosal. Currently, in the United States only multidose vial influenza vaccines contain preservative quantities (i.e., 25 μg per dose) of thimerosal, and thimerosal-free influenza vaccine preparations are widely available. Despite these changes, the incidence of autism continues to increase.

In conclusion, scientific evidence suggests that the presence of thimerosal in vaccines does not increase the risk of autism or other neurodevelopmental disorders.

Smallpox

Smallpox (or variola) is a highly contagious disease caused by a double-stranded DNA virus that is airborne. Smallpox is mostly of historic significance at this time, but its potential as a weapon of biowarfare has drawn public health interest in smallpox vaccination issues. The illness begins abruptly with headache, fever, and back pain followed by a characteristic rash that begins on the face, followed by the arms and legs, and finally spreads to the torso. The rash begins with scattered macules and evolves into papules, vesicles, and finally pustules that then dry and crust over. The patient ceases to be contagious after the crusts fall off. There are two broad forms of the disease: the severe form, variola major, which had a mortality rate of about 30 percent, and a milder form, variola minor (alastrim), with a mortality rate of approximately 1 to 5 percent. There are several types of variola major, with the hemorrhagic smallpox form of the disease having a mortality of nearly 100 percent.

The original smallpox vaccination (variolation) involved the transfer of material from smallpox pustules or crusts into a scratch in the skin of the subject to be vaccinated. This method often resulted in a milder form of the disease, presumably because the preparation of the material from the smallpox lesions attenuated the smallpox virus contained therein. Variolation was the first example of an attenuated vaccine. However, the attenuation was often inadequate and some recipients developed full-blown smallpox as well as other diseases such as syphilis. Jennerian vaccination uses an animal poxvirus to induce cross-protective immunity against smallpox. The modern vaccine virus is not cowpox but vaccinia, a related virus; at what point cowpox was replaced by vaccinia or whether the original “cowpox” was some mixture of cowpox and vaccinia viruses is unknown.

Neurologic complications are uncommon. Recent series suggest that postvaccinal encephalitis can occur in 2 to 6 per million primary vaccinees, depending on age. The risk in Europe is much higher, perhaps as high as 1 in 4,000, presumably because a different strain of vaccinia virus is used. There have been rare reports of isolation of vaccinia virus in the CSF in cases of encephalitis following vaccination. The overall death rate from all causes following smallpox vaccination is 0.5 to 5 per million vaccinees.