Keywords
viral diseases, vaccines, pertussis, measles, mumps, rubella, tetanus, smallpox, hepatitis B, adjuvants, encephalitis
Yet it was with those who had recovered from the disease that the sick and the dying found most compassion. These knew what it was from experience, and had now no fear for themselves; for the same man was never attacked twice—never at least fatally. Thucydides, The Peloponnesian War: Plague of Athens , 430 bc
Moreover, I have known certain persons who were regularly immune, though surrounded by the plague-stricken, and I shall have something to say about this in its place, and shall inquire whether it is impossible for us to immunize ourselves against pestilential fevers. Fracastoro, On Contagion , 1546
Infectious diseases have historically been the major cause of human morbidity and mortality, and vaccinations have added immeasurably to human health by preventing them. The benefits of vaccinations have not come without some costs, however, and rare adverse effects of vaccines occur. Many important adverse events are neurologic, and these are discussed in this chapter. The US Centers for Disease Control and Prevention (CDC) regularly update and publish useful summaries of vaccine recommendations. Figure 48-1 shows a current schedule for the routine immunization of healthy children and adolescents.
History of Vaccines
The idea of vaccination came from the observation that a survivor of “the plague” was unlikely to fall ill from that disease a second time. It had long been known that matter from smallpox lesions, when inoculated into the skin of a naive recipient, often caused a mild form of the disease, yet protected against the full disease. This method, called variolation, was introduced to Europe in 1721; however, variolation occasionally resulted in fully virulent smallpox. In 1798, cowpox inoculation was shown to protect against smallpox, with no possibility of transmitting fully virulent smallpox. This basic strategy of vaccination was employed to generate Louis Pasteur’s rabies vaccine, Max Theiler’s yellow fever vaccine, and Jonas Salk’s and Albert Sabin’s polio vaccines. Other important, currently used vaccines include those against influenza, whooping cough (pertussis), diphtheria, tetanus, hepatitis B, measles, mumps, and rubella, and infection with Haemophilus influenzae B, meningococcus, human papillomavirus, and varicella zoster. Vaccines are available in Asia to prevent Japanese encephalitis and in central Europe to prevent tick-borne encephalitis.
Types of Vaccines
Vaccines are made up of relevant antigens presented to the immune system in a way that generates protective immunity against the fully virulent pathogen without causing disease. Different vaccines have distinct mechanisms of action. These include inactivated, attenuated, subunit, recombinant, component, DNA, and vector vaccines.
Inactivated vaccines consist of pathogens that have been treated by chemical or physical methods so that they are nonviable. These treatments generally modify viral proteins essential to some critical function, such as attachment of the virus to the cell. In successful vaccines, these inactivated organisms still have sufficient antigenicity that protective immunity is achieved without the possibility of causing infection. Examples of inactivated vaccines include influenza vaccine, the Salk polio vaccine, rabies vaccine, and the whole-cell pertussis vaccine.
Attenuated vaccines use a virus (or other pathogen) that has been adapted to replicating in a different host system, such as in tissue culture or in chicken eggs. This is achieved by serially passaging the virulent (or wild-type) pathogen in an alternative host system. The pathogen is now “adapted” to the alternative host system and humans become an “unnatural host.” The agent is unable to express its full virulence and therefore causes a mild infection while still stimulating full immunity. An example of an attenuated vaccine is the combined measles, mumps, and rubella (MMR) vaccine.
Subunit vaccines are composed of subunits of a pathogen that are both nontoxic and immunogenic. The older hepatitis B vaccine is an example, as is the acellular pertussis vaccine. The older hepatitis B vaccine consisted of a hepatitis B surface antigen (HBsAg) that was originally purified from the plasma of hepatitis B carriers. Because of concerns about using human-derived material, the gene for the hepatitis B surface antigen was introduced into yeast that then synthesized pure hepatitis B surface antigen.
Viral envelope proteins can self-assemble and form virosomes or “virus-like” particles (VLPs). These virosomes stimulate both cell-mediated and humoral immunity and have been used in the human papillomavirus vaccine.
Component vaccines usually consist of the capsular material of common bacterial pathogens. Antibodies to the capsules allow opsonization of the organism. Examples of component vaccines are those for pneumococcus, meningococcus, and Haemophilus influenzae B. These vaccines are often not sufficiently immunogenic in very young infants and have to be specially formulated by conjugation to peptides, which enhances their antigenicity.
Toxoid vaccines are bacterial toxins (e.g., diphtheria, tetanus) that have been rendered nontoxic through chemical treatment, but remain immunogenic.
DNA vaccines are DNA sequences of the gene for an immunogenic antigen that are injected into muscle, where they direct the synthesis of the antigenic peptide. This is then presented to the immune system by the “infected” muscle cell, mimicking a natural infection. DNA vaccines, however, have proved to be poorly immunogenic in humans and none are currently available for human use.
Vector vaccines consist of a nonpathogenic virus that has one of its genes replaced with a gene for an antigen of interest. Such vaccines are being investigated but are not yet available for human use.
Adjuvants
Many vaccines that consist of protein molecules, as opposed to attenuated organisms or multicomponent bacterial cells, may not be very immunogenic, since to attract the attention of the immune system, some damage or injury is required along with the relevant antigen. Often a simple molecule can be added to the vaccine antigen to yield a stronger immune response; such a molecule is known as an adjuvant and probably acts as an agonist to pattern recognition receptors (PRRs) in innate immune cells. Alum salts are an example of a commonly used adjuvant that was first used in the 1930s. Adjuvants have to be carefully formulated since they can lead to severe inflammation. Freund’s complete adjuvant is an example that is used in the laboratory, mixed with white matter or purified myelin antigens, to trigger experimental allergic encephalomyelitis (EAE), an inflammatory demyelination of the brain in an animal model of multiple sclerosis. The US Food and Drug Administration (FDA) does not currently approve the use of pure adjuvants outside of a vaccine, and alum salts and ASO4 (a lipid compound) are the only adjuvants approved for use in a vaccine formulation. Several other adjuvants have been approved in Europe.
Reverse Vaccinology
More recently, the methods of “reverse vaccinology” have been exploited to make effective vaccines. The process involves sequencing the genome of a target pathogen and scanning for genes that may be useful for vaccines, such as those encoding for virulence factors or surface proteins. These proteins can then be separately expressed and screened for use in animal models, after which human trials can be organized. The advantage of reverse genetic methods is that all of the proteins are available for testing, rather than only an unsuitable subset expressed by a cell line. An example is that of vaccines against meningococcal meningitis, which are protective to all but one serotype, the capsular polysaccharide of which mimics certain neural antigens and is therefore poorly immunogenic.
Complications of Vaccination
The benefits of vaccination are balanced against the adverse effects that vaccinations can cause. Most often, they induce a nonspecific inflammatory reaction with headache, malaise, mild fever, and pain at the injection site. This reaction is self-limited and needs no treatment beyond mild analgesics. More serious adverse effects include contamination of the vaccine with fully virulent virus, reversion of attenuated virus to a fully virulent form, contamination of the vaccine with previously unrecognized agents, the use of inappropriate antigens that cause an aberrant immune response with injurious effects, and induction of an immune response with autoimmune character. Some other adverse effects are of unknown mechanisms.
Some vaccines have inadvertently contained fully virulent virus. In the so-called Cutter incident, inadequate inactivation of the virulent virus during manufacturing occurred shortly after the introduction of the Salk inactivated poliovirus vaccine. Procedures for inactivation of the virus by treatment with formalin were not followed precisely, and as a result some of the virus that went into the vaccine was fully virulent, causing cases of paralytic poliomyelitis.
Reversion to a virulent form occurs rarely with the use of the Sabin vaccine, which is an attenuated poliovirus vaccine. During replication of the virus, mutations that restore pathogenicity may occur in rare instances and result in vaccine-associated paralytic poliomyelitis. In some cases, the virulent vaccine virus spreads to the vaccinated person’s contacts, and small outbreaks of polio can result.
Contamination with previously unrecognized agents is an ever-present danger, and there are numerous examples. In World War II, US military personnel serving in the tropics contracted hepatitis after being vaccinated for yellow fever. The yellow fever vaccine, an attenuated vaccine, had human serum added to it for stabilization of the attenuated virus; some of this serum had been obtained from carriers of hepatitis B. Another contaminant of yellow fever vaccine was avian sarcoma leukosis virus, present silently in chicken eggs, which were used for growing virus for vaccine manufacture. The Salk polio vaccine virus was grown in monkey kidney tissue culture, which contained the simian vacuolating virus 40 (SV40) in latent form, thus contaminating the vaccine with this agent. Recently a few rotavirus vaccine lots were found to be contaminated with porcine circovirus, which has never been associated with human infection or disease.
A more ominous example is that of the contamination of louping-ill vaccine, used in animals, with the scrapie agent. The vaccine virus was initially grown in the brains of sheep and processed to vaccine virus. At least one of these sheep had scrapie, and the vaccine was contaminated with infectious prions, causing an outbreak of scrapie in the vaccinated animals. As a consequence of this incident, the FDA requires that any animal protein products used in the manufacture of vaccines are from countries certified to be free of bovine spongiform encephalopathy, which is known to be transmissible to humans.
Inactivation of some viruses may render certain important antigens nonantigenic. For example, the formalin-inactivated measles vaccine used in the 1960s provided short-term protection but in some cases resulted in “atypical measles,” an unusually severe form of measles often complicated by pneumonia. These patients were found not to have antibodies to the F (fusion) protein of the measles virus, so that the virus was able to spread by cell-to-cell fusion. It is thought that formalin rendered the F protein nonimmunogenic, so that the spread of wild virulent virus infection was unchecked.
Inappropriate immune responses are well recognized to occur after 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. Other vaccines have also been thought to have a causal connection to demyelination. Restricted forms of central demyelination, such as optic neuritis and transverse myelitis, have been described but are rare enough that a causal connection is in doubt. Restricted peripheral forms of demyelination, such as brachial plexopathy, have also been reported.
One potential mechanism of demyelination by vaccines is that of molecular mimicry, in which antigenic epitopes in the vaccine resemble those in myelin. 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.
An instructive example of demyelination triggered by a neurally based vaccine is that of rabies vaccine. The idea of using modified infectious material to protect from viral disease was adopted by Pasteur, who used attenuated rabies virus from infected rabbit spinal cord to protect dogs from rabies. His strategy was to take infected rabbit spinal cord and allow it to dry, which attenuated the virus present in the cord. The longer the desiccation, the more attenuated the virus became. Eventually, the virus was sufficiently attenuated that it was innocuous but sufficiently immunogenic that it could prevent infection by fully virulent virus. The vaccine was originally administered as a series of injections of ever less attenuated virus, the idea being to stimulate the immune system with more virulent and therefore antigenic virus. The original Pasteur vaccine was thus rather cumbersome to administer, with multiple painful injections, and frequently gave rise to “neuroparalytic accidents.” This phenomenon inspired experiments by Thomas Rivers, who showed that a similar central demyelination could be induced in monkeys by serial injections of sterile white matter; this was the origin of experimental allergic encephalomyelitis, a model now used to study multiple sclerosis.
In order to minimize this complication of neurally based vaccines, vaccines have been made from virus that was grown in myelin-free environments. Fuenzalida first produced a myelin-free vaccine in 1956 by propagating virus in neonatal mouse brains, which still contained neural antigens. The first non-neural tissue-based vaccine was the duck embryo vaccine, in which vaccine virus was propagated in duck eggs. Human cells were used to develop rabies vaccines that were free of animal proteins, and the human diploid cell vaccine, the contemporary standard, was first developed in the early 1960s. Very few “neuroparalytic accidents” have occurred with the current neural antigen–free vaccines. Thus, the more free vaccines are of neural tissue, the lower the risk. In some parts of the world, however, the cheaper neurally based vaccines are still in use.
Some adverse events are of unknown mechanism. For example, rare episodes of intussusception were reported several years ago after the administration of rotavirus vaccine, with 15 cases occurring with administration of 1.5 million doses, leading to withdrawal of that vaccine.
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.
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 Vaccine Adverse Event Reporting System (VAERS) is a passive surveillance system in which complications are reported to the FDA. Another passive surveillance system consists of the National Vaccine Injury Compensation Program (NVICP), which compensates individuals who have had a serious and permanent adverse effect from a vaccine and who meet other criteria.
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 48-1 ).
| www.vaccine.org | General site of Allied Vaccine Group |
| www.cispimmunize.org | General information site |
| Vaers.hhs.gov | Vaccine Adverse Event Reporting System |
| www.cdc.gov/vaccines/ACIP/index.html | Advisory Committee on Immunization Practices |
| www.hrsa.gov/vaccinecompensation | National Vaccine Injury Compensation Program |
A particularly valuable resource regarding the evaluation of these adverse event reports is a series of reviews published by the Institute of Medicine. A committee of experts is convened to review all published and available unpublished reports of adverse events attributed to vaccines. The evidence for and against a vaccine is divided into mechanistic and epidemiologic categories. The former establishes a direct causal relation; thus a case of aseptic meningitis following varicella zoster virus vaccination will be considered to be due to the vaccine only if the vaccine strain virus is present in the cerebrospinal fluid (CSF). This mechanistic evidence must be complemented by epidemiologic data to determine the precise risk of an adverse event.
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.
Vaccinia is quite reactogenic and has a spectrum of systemic complications including nonspecific malaise and fever, as well as a number of skin reactions including urticaria, erythema multiforme, bacterial infection at the injection site, and progressive vaccinia infection, which occurs in the immunosuppressed and can be fatal. A few cases of mild myopericarditis have been reported in civilian and military vaccinees, with resolution and return to active duty in 7 to 10 days.
Neurologic complications are uncommon, but well reported. In a report from south Wales in which a large population was vaccinated against smallpox as a result of an epidemic in 1962, the risk of any neurologic complications was 5 per 100,000 subjects vaccinated, and the risk of encephalitis-encephalopathy was roughly 2 per 100,000 vaccinations.
More recent series suggest that postvaccinal encephalitis is uncommon, occurring 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.
Measles, Mumps, and Rubella
Measles, mumps, and rubella were once common childhood illnesses in the developed world, but they became rare after the introduction of vaccines that prevent them. These vaccines are commonly given together in combination as the MMR vaccine. More recently, polyvalent vaccines have been introduced to minimize the number of injections to which small children are subjected. Formulations containing only some of these have been used in the past: measles (M) vaccine and measles plus rubella (MR).
Measles
Measles is a viral exanthem caused by an enveloped single-stranded RNA virus that is transmitted through the air and initially infects the respiratory epithelium, where it replicates. This replication gives rise to a primary viremia that implants virus in lymphoid tissues. A secondary viremia follows, and the virus is disseminated throughout the body. During measles a significant distortion of the immune system occurs, with paradoxic features. There is a nonspecific systemic immune activation, along with immunosuppression, causing susceptibility to bacterial and viral superinfections that are the main causes of morbidity and mortality and are enhanced by malnutrition, making measles a major cause of death in developing countries. The main complication of measles is pneumonia, due to bacterial superinfection in children and due to direct measles virus infection of the lungs in adults. Pneumonia occurs in roughly 10 percent of patients and causes more than 60 percent of the mortality resulting from the disease. Other complications include otitis media and laryngotracheobronchitis.
The main neurologic complication of measles, occurring in roughly 1 per 1,000 cases, is ADEM, in which multifocal inflammatory demyelination occurs within the central nervous system. ADEM may be due to molecular mimicry, since T cells from measles-associated ADEM patients proliferate upon exposure to myelin basic protein; cells from patients with uncomplicated measles do not. The mortality rate of ADEM is between 10 and 30 percent, and long-term sequelae are common and severe.
Measles virus was first isolated and propagated in tissue culture by Enders and Peebles in 1954, and efforts at making measles vaccine followed shortly thereafter. The first vaccines were made from the Edmonston B strain, which was obtained from the original Edmonston isolate (named after the individual from whom it was first obtained) by serial passage in primary kidney cells (24 passages), primary human amnion cells (28 passages), chicken embryos (6 passages), and then into chicken embryo cells. This vaccine was first introduced in 1963, but the high rate of fever and rash prompted its discontinuation. Other vaccine strains that were less reactogenic were then developed. One of these, the Moraten strain introduced in 1968, was derived from the Edmonston B strain by a further 40 passages in chicken embryo cells. Another strain, the Schwarz strain, was obtained from the Edmonston B strain by a further 85 passages in chicken embryo cells and was used from 1965 to 1976. The Moraten vaccine is the only one used in the United States today, although other vaccine strains are used elsewhere in the world. Before vaccination, 4 million cases of measles occurred annually in the United States, whereas there were only 309 cases in 1995 due to widespread vaccination.
Neurologic complications of measles vaccination have been reported but are uncommon. Case reports of encephalopathies do not, by themselves, provide evidence of causation. In order to better understand the risk of adverse events with measles vaccine, Weibel and co-workers analyzed data from claims of measles vaccine–induced encephalopathy submitted to the National Vaccine Injury Compensation Program. In the years 1970 to 1993, 403 claims of postvaccination encephalopathy were reviewed; inclusion criteria included an acute encephalopathy 2 to 15 days after vaccination (M, MR, MMR) with permanent brain damage or death, with no other known cause that would explain the illness. Of these 403 purported cases, 48 met the criteria. The mean age of the cases was 17.5 months (range, 10 to 49 months).
Three main groups of complications were identified: ataxia, behavioral changes, and seizures. Fever preceded the encephalopathy in most, and one-quarter of the cases had a measles-like rash 1 to 2 weeks after vaccination. CSF was analyzed in most and was abnormal in 40 percent: pleocytosis was present in 70 percent, and protein concentration was elevated in more than one-third. No other viruses were found to be present. When the number of patients with encephalopathy was plotted against the day of onset, a typical epidemic curve was obtained with a peak at 8 to 9 days, suggesting a causal (rather than merely temporal) connection between the vaccination and the neurologic illness. Clinical and pathologic data do not point to any single neurologic disease entity. The risk of neurologic illness can be estimated from the fact that from 1970 to 1993, approximately 75 million children had measles vaccine by age 4 years, based on a 90 percent immunization rate and 83 million births. The limits of risk are, based on 48 claimants meeting criteria and on all 403 claimants, 0.64 to 5.37 cases per million vaccinees.
In a study of 1.8 million Finnish MMR vaccinees, actively surveyed from 1982 to 1996, adverse events included 77 that were neurologic and consisted mostly of febrile seizures with good recovery. One patient later developed Lennox–Gastaut syndrome. Four cases of encephalitis were reported, one of which was found to be due to herpes simplex virus; the others were uncharacterized. Some other neurologic complications were found to be due to other known causes (such as bacterial meningitis). Miscellaneous other neurologic disorders included cases of GBS (two patients, with eventual recovery), transient confusion, and transient ataxia. Interestingly, no cases of autism were found.
In 1998, MMR vaccine was proposed as a cause of autism, a complex and heterogeneous neurobehavioral syndrome. Much discussion has been stimulated by a report of 12 children who developed cognitive problems as well as inflammatory bowel disease a few days to a few months after receiving the MMR vaccine. Questions were raised about the conduct of the study, with improper consent procedures, inconsistent use of data, irreproducibility of some laboratory findings, and failure to declare conflicts of interest. In 2004, the interpretation of the paper as establishing a causal connection between MMR and autism was retracted by 10 of 12 authors who could be contacted. As further irregularities came to light, the paper was retracted in its entirety by the journal.
The ages at which MMR vaccine is given are also the ages when autism manifests clinically; however, the beginnings of this behavioral disease occur much earlier in life. A report from the Institute of Medicine reviewed published and unpublished reports concerning the issue of MMR vaccine and concluded that there is no causal connection between the vaccine and autism. Another hypothesis was that autism was caused in especially susceptible subjects by thimerosal, a mercury-containing preservative that was used in inactivated vaccines (but not attenuated vaccines such as MMR). A review of the literature also has shown no clear causal connection between thimerosal and autism, and, in any case, thimerosal is no longer used in childhood vaccines.
Mumps
Mumps is an acute febrile illness caused by rubulavirus, a member of the paramyxovirus group. The clinical illness in children usually is self-limited, with fever, malaise, headache, and often an acute painful parotitis. The disease is complicated occasionally by meningitis and rarely by meningoencephalitis, which may lead to residual deficits. Sensorineural deafness is an uncommon sequela but can be a major cause of deafness in children during epidemics. In adults, mumps has a higher rate of systemic complications such as orchitis in men and oophoritis and mastitis in women, as well as pancreatitis and myocarditis. The main original vaccine virus strains were named the Jeryl Lynn and Urabe strains, after the hosts from which the original unattenuated viruses were isolated. Mumps vaccine was first licensed for use in 1967. The number of cases of mumps in the United States was over 150,000 in 1968 and decreased to less than 3,000 two decades later. The number of cases increased briefly after vaccination rates declined, but decreased again after mumps vaccination was required for school entry.
Aseptic viral meningitis is the main neurologic complication of mumps vaccination and is probably related to natural mumps frequently causing meningitis. The Urabe strain vaccine was discontinued in the United States after it was linked to aseptic meningitis in 1 case in 900 vaccinees in one Japanese series and 1 case in 200,000 vaccinees in another. For the Jeryl Lynn vaccine, the incidence is 1 case in 1.8 million vaccinees; by comparison, aseptic meningitis occurs in approximately 1 in 400 cases of natural mumps. This aseptic meningitis is self-limited and requires no specific therapy.
Rubella
Rubella is a self-limited viral infection in children, characterized by a fever and rash, caused by a single- stranded RNA virus. The virus causes most of its damage through prenatal infection. This congenital rubella syndrome is well described, and the triad of neurologic, eye, and cardiac defects is characteristic. The disease also includes a spectrum of uncommon disorders in all age groups including thrombocytopenic purpura, hepatitis, bone lesions, interstitial pneumonitis, diabetes mellitus, and thyroid problems.
The vaccine has very few complications in children, with rare mild rash and fever. In adults, the most common side effect of the vaccine is polyarthralgias. A few scattered reports of peripheral mononeuropathies and radiculopathy following rubella vaccination have been published, but a review of these could not establish a causal relationship.
Diphtheria, Pertussis, and Tetanus
Diphtheria
Diphtheria is a disease caused by strains of Corynebacterium diphtheriae , which produce diphtheria toxin, a binary toxin consisting of two molecular components termed fragments A and B. Fragment B binds to the target cell and allows access of fragment A to the cytoplasm. Fragment A then inactivates elongation factor-2 (EF-2), inhibiting protein synthesis in the cell and leading to necrosis. Usually diphtheria infects the pharyngeal epithelium, where the superficial layers of the mucosa become necrotic and provide an excellent culture medium for the bacteria. These areas of tissue necrosis with exudation form the so-called diphtheritic “membranes.” Systemic absorption of diphtheria toxin from the pharynx causes cardiac and neurologic effects. Patients with diphtheritic myocarditis may develop congestive heart failure; pathologic examination shows interstitial inflammation and hyaline degeneration of fibers. Diphtheritic “neuritis” includes several entities, including an isolated paralysis of the soft palate, ocular motor palsies, paralysis of the diaphragm, and a disorder resembling GBS. The pathogenesis of these various disorders is not understood.
In the 1920s, before diphtheria toxoid was introduced, there were approximately 100,000 cases in the United States annually. In the past few decades, no more than a handful of cases have occurred each year. When vaccine coverage decreases, large epidemics of the disease follow, as happened in Russia in the 1990s, when the public health infrastructure could no longer cover the population adequately. The mortality rate of the untreated disease is 30 to 50 percent. After the introduction of antitoxin therapy, the mortality rate declined to 10 to 20 percent; modern intensive care has reduced this rate further to 5 to 10 percent.
Vaccination against diphtheria was originally undertaken by injecting mixtures of toxin and antitoxin. In the early 1920s, it was found that treatment of diphtheria toxin with formalin resulted in a nontoxic immunogenic toxoid. This toxoid was incorporated with tetanus toxoid and inactivated whole-pertussis cells to make the diphtheria-pertussis-tetanus (DPT) vaccine that first became widely available in the mid-1940s.
There have been remarkably few neurologic complications from diphtheria toxoid, although they may be difficult to discern, as the toxoid is usually given in combination with pertussis and tetanus vaccines. Local injection-site reactions can be painful as they are intramuscular; infants may react with prolonged crying, irritability, drowsiness, loss of appetite, and vomiting. Limitation of abduction of the injected arm may occur regardless of age.
Pertussis
Pertussis, or whooping cough, is caused by Bordetella pertussis , a commonly circulating bacterium that has multiple antigenic components. The disease begins with a seemingly minor upper respiratory infection, with minimal fever and an intermittent cough, that then becomes severe and progresses to paroxysms in which coughing becomes very vigorous, interfering with breathing and increasing intracranial pressure by continual coughing. This paroxysmal stage lasts between 2 and 6 weeks before resolving.
The disease was commonly lethal in the past. At the beginning of the 1900s, approximately 5 of every 1,000 liveborn infants died of pertussis before 5 years of age. Today, there are fewer than 10 deaths per year in the United States. When vaccine coverage declines, the disease reemerges because pertussis vaccine protects only against bacterial toxins but does not necessarily eliminate the pathogen from the population (unlike smallpox, for example). The pathogenesis of the disease is not completely known, but is probably due to a toxic effect on respiratory epithelium with denudation of respiratory passages.
An important complication of pertussis is pertussis encephalopathy, a vaguely described syndrome of encephalopathy and seizures. In the years 1997 to 2000, pertussis encephalopathy and seizures occurred in 0.1 and 0.8 percent of cases, respectively. There appear to be two clinical forms, one with an abrupt onset of seizures and coma and the other with the gradual onset of somnolence progressing to coma. The prognosis appears to be rather poor, with death, permanent cognitive deficits, and recovery each occurring in one-third of cases. The pathologic changes are characterized by vascular congestion and brain petechiae. The pathogenesis probably involves the effects of anoxia and increased venous pressure in the brain caused by the severe cough. Interestingly, intravenous injection of toxin does not appear to cause neurologic complications.
Pertussis vaccine has dramatically decreased the burden of disease in vaccinated populations; it declined from about 200,000 cases in the United States in the mid-1930s to a nadir of 1,010 cases in 1976, with a subsequent increase to about 8,000 cases occurring in 2000 for unclear reasons. The original vaccine consisted of inactivated whole bacterial cells. Whole-cell vaccine is “reactogenic,” causing painful local injection-site reactions and fever. The latter can lead to febrile seizures in children, who are especially susceptible. This reaction triggered reports of severe neurologic illnesses following pertussis vaccination which likely were related in many cases to the fever alone.
To ascertain the risk of neurologic illness attributable to pertussis vaccine, an active survey of encephalopathic illnesses was performed in all British children from July 1976 to June 1979 in the National Childhood Encephalopathy Study (NCES). A comparison was made of rates of vaccination in those with or without encephalopathy. A small excess of patients with encephalopathy was found following vaccination. All vaccines with a pertussis component, for example, pure pertussis vaccination, DPT vaccination, and diphtheria-pertussis (DT) vaccination, were counted as pertussis vaccination. The study’s methodology has been criticized, and it is likely that other concurrent diseases in part explained the neurologic problems. In particular, some severe epileptic encephalopathies (Dravet syndrome), due to mutations in sodium channels, manifest themselves at the same age that pertussis vaccine is given. Furthermore, there were problems with choice of controls, blinding of investigators, misclassification of cases, and uncertainties regarding the onset of disease. These questions about the conduct of the study have been elaborated in published critiques and these risk estimates are no longer used by the British legal system as a basis for estimating liability. A large case-control study was performed in the United States with the intent of avoiding the methodologic difficulites of NCES, and did not find any increased risk of onset of serious acute neurologic illness in the 7 days after DTP vaccine exposure for young children.
A new acellular vaccine consisting only of a subset of antigenic components of the bacterial cell was introduced in 1996 and appears to be much less reactogenic.
Tetanus
Tetanus is a neurologic disease caused by Clostridium tetani , which is present ubiquitously in soil. The organism has two toxins carried on a plasmid: tetanospasmin, the neurotoxic component, and tetanolysin, which is a hemolysin. Tetanospasmin is elaborated locally and transported to the CNS in the blood and via local axonal transport. It interferes with release of the presynaptic inhibitory neurotransmitters glycine and γ-aminobutyric acid (GABA), causing inappropriate disinhibition of spinal cord reflex arcs, with resultant greatly increased tone in the muscles and intermittent painful spasms. Respiratory compromise may lead to death. The toxin is very potent, a lethal dose being only 2.5 ng/kg. The case fatality ratio of the untreated disease is 25 to 70 percent overall and 100 percent at the extremes of age; with intensive care, the mortality rate decreases to 10 to 20 percent.
Tetanus toxoid consists of formalin-treated tetanospasmin, which induces an immune response that provides good protection lasting around 10 years. Adverse events are rare and are mostly anecdotal. Brachial plexopathy occurs in 1:100,000 vaccinees within 1 month of vaccination, and there may be a slightly increased risk of GBS (0.4 per million doses). One person had an illness resembling GBS on each of three vaccinations with tetanus toxoid. There is some evidence that tetanus toxoid may decrease the risk of multiple sclerosis.
Influenza
Influenza is an acute, febrile, debilitating viral infection of the upper respiratory tract that causes significant work and school absences each year. It can be complicated by pneumonia and, rarely, by ADEM. In children, the complications of influenza or its treatment include encephalopathies such as Reye syndrome as well as a toxic encephalopathy of unclear nature, possibly related to cytokine production in the course of disease. The virus was first isolated in 1933. In 1935, neutralizing antibodies were detected in subjects given subcutaneous injections of influenza virus. The first trial of an influenza vaccine demonstrated some degree of protection in 1936. The virus at the time was grown in a suspension of mouse lung and then injected into children. Further studies of influenza vaccination using inactivated virus were carried out by the military in the early 1940s with clear benefit, leading to the licensing of influenza vaccines in the United States in 1945. In 1947, a dramatic failure of the vaccine during an influenza epidemic led to the discovery that the vaccine produced immunity to the vaccine virus but not to the epidemic strain as a result of antigenic change in influenza virus. Such change can be of two types: (1) antigenic drift, in which the accumulation of mutations in the genes coding for the surface antigens of the virus renders it sufficiently different from the previous strains so that it can cause disease despite exposure to the previous virus, and (2) antigenic shift, in which there is reassortment of genes coding for the surface proteins from viruses circulating between birds and pigs. This experience led to the establishment of worldwide sentinel centers by the World Health Organization, which monitor for new strains of influenza virus every year so that the new strains can be incorporated into the updated vaccine. The recent circulation of the H5N1 strain in Southeast Asia is of great concern because of the highly lethal nature of the disease and its potential for human-to-human transmission.
Current vaccines are of two types. An inactivated vaccine uses two strains of influenza A and one influenza B virus, all grown in embryonated chicken eggs and inactivated with β-propiolactone. A cold-adapted attenuated vaccine, containing two influenza A and one influenza B attenuated strains, has been introduced and is given as a nasal spray.
In 1975, a fatal case of swine flu in a military recruit prompted the institution of a national swine flu vaccination program because of the fear that the outbreak would resemble the 1918 influenza epidemic that caused such widespread mortality. The vaccine was produced, and 45 million doses were administered by mid-December 1976. In late November and early December 1976, cases of GBS were reported to local health departments and prompted an investigation of the relationship to the flu vaccine. The results of an active surveillance of all such cases reported during the period of vaccination, prompted by reports of a possible causal connection and requested by a court in which a lawsuit had been filed, uncovered 1,300 possible cases, of which 944 could be evaluated. There were 504 cases in vaccinees and 440 cases in nonvaccinees. Although the data were insufficient to diagnose GBS definitively, the cases could be classified by the extent of involvement into “extensive” and “limited” paresis. When the distribution of cases was plotted as a function of time since vaccination, the “extensive” cases followed a typical log-normal epidemic curve, whereas cases of limited paresis did not, implying a causal relationship between vaccination and GBS in a small number of cases. The effect of the vaccine lasted 6 to 8 weeks, and the actual risk of GBS attributable to vaccine was 4.8 to 5.9 per million vaccinees. Interestingly, no such increased risk was found in England and the Netherlands, as well as in 1.7 million US military personnel who received a double dose. Furthermore, there was no increased risk of GBS following influenza vaccination in other subsequent seasons. The threat of severe influenza pandemics remains, and antigenic shifts are likely to challenge us with high-morbidity pandemics.
In the late 1990s, an H5N1 outbreak among chickens in Hong Kong led to a number of human deaths, although the virus was not easily transmissible to humans. Since then, the virus has appeared in many other countries but has not led to many human infections, which is fortunate since the case fatality rate is high in both humans and birds.
Despite a theoretical concern for the safety of influenza vaccines in patients with a history of multiple sclerosis and central demyelination, it appears to be quite safe. There was no increase in the onset or relapses of multiple sclerosis in a retrospective study following swine flu vaccine. There were also no increases in relapse rate in a double-blind trial involving 66 patients with multiple sclerosis. Non–swine influenza vaccines are safe to use in multiple sclerosis, and a case-control study of influenza vaccine performed by the Vaccine Safety Datalink Study Group demonstrated no association with either multiple sclerosis or optic neuritis. The same study also showed no association between vaccination against hepatitis B, tetanus, measles, or rubella and either multiple sclerosis or optic neuritis. The Immunization Safety Review Committee of the Institute of Medicine concluded that there was sufficient evidence to reject any causal relationship between such relapses and influenza vaccination.
Hepatitis B
Hepatitis B is caused by a hepadnavirus, a partially double-stranded DNA virus, which is endemic worldwide, especially in sub-Saharan Africa and Southeast Asia. The virus is present in blood and semen and can thus be transmitted sexually and through inadequately processed blood products. The disease is usually self-limited in adults, with a clinical spectrum of asymptomatic infection to severe disease, followed by resolution and clearance of virus. However, in infants and children (80 to 90% of those infected before 1 year) as well as in some adults (approximately 5% of those infected), the acute infection is often asymptomatic but evolves into a chronic active hepatitis, with progression to cirrhosis and possibly hepatocellular cancer. In highly endemic areas such as sub-Saharan Africa and Southeast Asia, this is one of the most common cancers, leading to significant mortality.
In 1991, two cases of central demyelination were reported after receipt of the recombinant hepatitis B vaccine, one being in a patient with preexisting multiple sclerosis. A report of eight patients with disseminated central demyelination with persistent activity on imaging studies caused much controversy in France. After other cases were subsequently reported, calculations of the expected number of new cases of multiple sclerosis (1 to 3 per 100,000 annually) showed that the disease incidence in the vaccinees (0.65 per 100,000 annually) was actually less than would have been expected. A population-based retrospective cohort study of 134,698 persons compared the rate of CNS demyelination in hepatitis B vaccinees with that in nonvaccinees and found no difference. In a case-control study from British Columbia, the rates of development of multiple sclerosis in adolescents vaccinated against hepatitis B in the years 1992 to 1998 (after universal hepatitis B vaccination became standard) were compared with those not vaccinated in the years 1986 to 1992 (before the vaccine was available); no statistically significant difference was found between the two groups. A multicenter hospital-based study in France also found no evidence of an association between central demyelination and receipt of hepatitis B vaccine. There is therefore no evidence of causality between hepatitis B vaccination and multiple sclerosis. Other studies have found no evidence that hepatitis B vaccine triggers relapses in patients with established multiple sclerosis.
Poliomyelitis
Poliomyelitis, caused by poliovirus type 1, 2, or 3, usually is asymptomatic or consists of a mild febrile illness in early childhood. In older children, adolescents, or adults, the febrile illness may be accompanied by damage to the anterior horn cells in the spinal cord. The disease is spread by fecal-oral contact and caused considerable morbidity before vaccination became widely available.
Early attempts at vaccination in the 1930s were disastrous—inadequate attenuation of the virulent virus led to polio in recipients (there was no test for attenuation of viruses), different serotypes were unknown and therefore not protected against, and there were no safety precautions against injecting neurally derived material. In the Cutter incident, which was associated with the Salk inactivated vaccine, 260 vaccinees and contacts contracted polio. These cases were thought to be related to the vaccine because they occurred in just a few western states, all were injected by vaccine supplied by a single manufacturer (Cutter Laboratories), the injected extremities were disproportionately affected, and the cases were traced to lots that were found to be inadequately attenuated.
The Sabin oral vaccine consists of attenuated virus that replicates in the gut and induces immunity in both the vaccinee and contacts (because the vaccinee sheds vaccine virus). Rarely, however, the virus reverts to a virulent form and may cause vaccine-associated paralytic poliomyelitis (VAPP) in 1 per 1 million doses in vaccinees or their contacts. Because the only polio seen in North America was vaccine associated, the Sabin vaccine was withdrawn from use in 1994. It is still in use in other parts of the world and has occasionally caused small epidemics of paralytic disease, with a recently reported outbreak occurring in China in 2004.
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