Chapter 104 Neurologic Complications of Immunization
Immunization programs are undoubtedly cost-effective public health measures that protect against infectious disease. Recommendations on immunization schedules are made by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention to the Surgeon General. New recommendations of the ACIP are published in Morbidity and Mortality Weekly Report, and they are the standard of care for immunization practices (Table 104-1). Vaccination programs have proved successful in eradicating diseases worldwide, best exemplified by smallpox, which was eradicated in 1980. A World Health Organization-sponsored polio eradication program, which targeted India and Nigeria, fell short of accomplishing its goal. The failure to eradicate polio in India was due in part to the strain prevalent in India (strain 1 was eradicated but strains 2 and 3 are still prevalent) and to living conditions. Distrust of vaccines by the central government of Nigeria led them to boycott vaccination efforts [Kapp, 2004].
Table 104-1 Schedule of Routine Immunization of Healthy Infants and Children
| Recommended Age | Immunizations |
|---|---|
| Birth | HBV |
| 2 months | DTaP, HBV, Hib, eIPV, PCV, RV |
| 4 months | DTaP, Hib, eIPV, PCV, RV |
| 6 months | DTaP, HBV, Hib, PCV, RV |
| 12–15 months | DTaP, Hib, MMR, eIPV, Var, PCV, Influenza (yearly), HepA (2 doses) |
| 4–6 years | DTaP, eIPV, MMR, Var |
| 11–12 years | DT, MMR, MCV4, HPV (3 doses), and Var if not given at or after 12 months |
DT, diphtheria-tetanus; DTaP, pertussis vaccine combined with diphtheria and tetanus toxoids; eIPV, enhanced-potency trivalent inactivated polio vaccine; HBV, hepatitis B virus; HepA, hepatitis A virus; Hib, Haemophilus influenzae type b; HPV, human papillomavirus; MCV4, meningococcal conjugate vaccine; MMR, measles, mumps, and rubella vaccine; OPV, oral polio vaccine; PCV, pneumococcal conjugated vaccine; Var, live-attenuated varicella vaccine; RV, rotavirus.
(From www.cdc.gov/vaccines/recs/schedules)
Vaccine mistrust is not just a problem in developing countries. Antivaccine movements are gaining strength in the United States and other industrialized countries. For instance, the United States has pertussis rates that are 10–100 times higher than rates in countries without such antivaccine movements and which enjoy high levels of vaccination (e.g., Hungary) [Gangarosa et al., 1998]. Such behaviors diminish herd immunity, thus increasing rates of infection. Witness events in Europe, where antivaccine movements, perhaps fueled by misleading measles/mumps/rubella (MMR) and autism data [Wakefield et al., 1998], have resulted in the area becoming a hotbed of measles [Muscat et al., 2009]; this reverses the historical trend by which infectious diseases previously eradicated in the United States were imported primarily from underdeveloped countries [CDC, 2008]. Similar resistance in the United States at the time of this writing also appears to be affecting efforts to vaccinate vulnerable populations with the H1N1 vaccine and may hinder efforts to contain the epidemic. The antivaccine movements have potential for harming children by not affording them the protection they need against infections at a biologically vulnerable age. Antivaccine movements are fueled by ignorance, lack of scientic scrutiny of the Internet, anecdotal reports, and frustration among parents relating to the lack of well-defined causes to explain neurologic or developmental disorders (e.g., autism) that may coincide temporally with vaccination. The high complication rates of earlier vaccines (e.g., rabies) may also contribute to this mistrust.
Assessing Causality
Clinical trials and epidemiologic population-based studies are more robust in assessing links between vaccines and adverse outcomes. Clinical trials, not usually employed to assess vaccine safety and efficacy in the United States, compare adverse outcomes in an exposed (i.e., vaccinated) and an unexposed (i.e., not vaccinated, or vaccinated with a different preparation) group of randomly selected individuals. Findings resulting from such studies are valid, but they are limited by their relatively small sample size, which precludes the identification of associations with rare outcomes. Population-based studies are useful, especially if large, because they can assess even rare outcomes. The risk of adverse outcomes in one population can then be compared with risk among the nonvaccinated populations or rates of the naturally occurring disease. However, causality cannot be determined with certainty, only suspected, unless there is a biologic marker. Further complicating the assigning of causality is the administration of several vaccines at one time [Fenichel, 1999; Howe et al., 1997].
In determining causality, biologic mechanisms (formerly defined as biologic plausibility) should first be taken into account (i.e., whether there is a plausible mechanism by which the vaccine could cause the complication or disease in question). For example, a measles vaccine cannot elicit vaccine-associated polio. Next, the method of vaccine preparation should be considered. Four types of vaccines are available: vaccines composed of whole-killed organisms, vaccines composed of live-attenuated viruses, vaccines composed of components of organisms, and recombinant vaccines (Box 104-1). Adverse events should be congruent with the vaccine preparation. For example, vaccines made of components of organisms cannot cause the disease being vaccinated against, but live-attenuated viruses can do so in the right host (e.g., vaccine-associated polio).
Vaccine Injury Compensation Program
The U.S. Vaccine Injury Compensation Program (VICP), effective since 1988, is a federal no-fault system designed to compensate individuals or families of individuals who have been injured by childhood vaccines. Vaccines covered under the VICP are diphtheria, tetanus, and pertussis (DTP, DTaP, DT, TT, or Td); measles, mumps, and rubella (MMR or any components); polio (OPV or IPV); hepatitis B; Haemophilus influenzae type b; varicella (chickenpox); rotavirus; pneumococcal conjugate, influenza virus, meningococcal tetravalent vaccine, and human papillomavirus. Vaccines are covered, whether administered individually or in combination. VICP further includes a provision to cover any new vaccine recommended by the Centers for Disease Control and Prevention for routine administration to children, after publication by the Secretary of the Department of Health and Human Services of a notice of coverage. The list of vaccines and covered complications are shown in Table 104-2.
| Vaccine | Adverse Event | Time Interval |
|---|---|---|
| Tetanus toxoid-containing vaccines (DTaP, Tdap, DTP-Hib, DT, Td, TT) | A. Anaphylaxis or anaphylactic shock | 0–4 hours |
| B. Brachial neuritis | 2–28 days | |
| C. Any acute complication or sequela (including death) of above events | Not applicable | |
| Pertussis antigen-containing vaccines (DTaP, Tdap, DTP, P, DTP-Hib) | A. Anaphylaxis or anaphylactic shock | 0–4 hours |
| B. Encephalopathy (or encephalitis) | 0–72 hours | |
| C. Any acute complication or sequela (including death) of above events | Not applicable | |
| Measles, mumps, and rubella virus-containing vaccines in any combination (MMR, MR, M, R) | A. Anaphylaxis or anaphylactic shock | 0–4 hours |
| B. Encephalopathy (or encephalitis) | 5–15 days | |
| C. Any acute complication or sequela (including death) of above events | Not applicable | |
| Rubella virus-containing vaccines (MMR, MR, R) | A. Chronic arthritis | 7–42 days |
| B. Any acute complication or sequela (including death) of above event | Not applicable | |
| Measles virus-containing vaccines (MMR, MR, M) | A. Thrombocytopenic purpura | 7–30 days |
| B. Vaccine-strain measles viral infection in an immunodeficient recipient | 0–6 months | |
| C. Any acute complication or sequela (including death) of above events | Not applicable | |
| Polio live virus-containing vaccines (OPV) | A. Paralytic polio | |
| In a non-immunodeficient recipient | 0–30 days | |
| In an immunodeficient recipient | 0–6 months | |
| In a vaccine-associated community case | Not applicable | |
| B. Vaccine-strain polio viral infection | ||
| In a non-immunodeficient recipient | 0–30 days | |
| In an immunodeficient recipient | 0–6 months | |
| In a vaccine-associated community case | Not applicable | |
| C. Any acute complication or sequela (including death) of above events | Not applicable | |
| Polio inactivated-virus containing vaccines (e.g., IPV) | A. Anaphylaxis or anaphylactic shock | 0–4 hours |
| B. Any acute complication or sequela (including death) of above event | Not applicable | |
| Hepatitis B antigen-containing vaccines | A. Anaphylaxis or anaphylactic shock | 0–4 hours |
| B. Any acute complication or sequela (including death) of above event | Not applicable | |
DT, diphtheria-tetanus vaccine; DTaP, acellular pertussis vaccine combined with diphtheria and tetanus toxoids; DTP-Hib, Diptheria, tetanus pertussis and hemophilus influenza type b; Hib, Haemophilus influenzae type b; IPV, inactivated polio vaccine; MMR, measles, mumps, and rubella vaccine; MR, mumps and rubella vaccine; OPV, oral polio vaccine; P, pertussis; Td, tetanus and diphtheria toxoid; Tdap, tetanus and reduced dose of diptheria and pertussis (for older children > 11 years); TT, tetanus toxoid.
* Information effective as of November 20, 2009; Drawn from http://www.hrsa.gov/Vaccinecompensation/table.htm: see original table for full definition of each adverse event. No condition specified for compensation for the following vaccines: Haemophilus influenzae type b, pneumococcal, rotavirus, varicella, meningoccal tetravalent, and human papillomavirus.
Types of Vaccines
Vaccines Composed of Whole-Killed Organisms
Inactivated Polio Vaccine
As OPV is prepared with a live-attenuated virus, it is associated with a low risk of eliciting polio in healthy individuals and a larger risk in immune-suppressed people (see “Vaccines Composed of Live-Attenuated Viruses”). An enhanced-potency trivalent polio vaccine (eIPV) was licensed in the United States in 1987, and was indicated initially for immunodeficient individuals. After a successful transition from OPV, eIPV has become the vaccine used to immunize children in the United States [CDC, 1997]. It is easier to administer, and it is not associated with vaccine-associated poliomyelitis.
Influenza Virus Vaccine
Epidemic human influenza illness is caused by influenza A and B. Influenza A viruses are categorized into subtypes, based on two surface antigens: hemagglutinin (H) and neuraminidase (N). These two surface antigens of the influenza A viruses vary over time through the process of drift and shift [Murphy and Webster, 1996]. Antigenic drift is due to point mutations arising during viral replication in hemagglutinin (HA) and neuraminidase (NA), whereas antigenic shift involves major changes in RNA caused by replacement of the gene segment. New influenza virus variants result from antigenic drift [Webster, 1998], whereas antigenic shift may facilitate cross-species infection and fuel pandemics [Riedel, 2006].
In so far as all known influenza A subtypes exist in the aquatic bird reservoir, influenza eradication is not feasible; instead, the goal is geared towards prevention and control of disease outbreaks [Webster, 1998] The risk to humans arises when more virulent avian strains cross species and infect humans, such as in the pandemic scare originating in China in 2004 (avian flu H5N1). Although the cross-species infection rates were low, the mortality rate was over 60 percent [Peiris et al., 2007]. The H1N1 flu that originated in Mexico in the spring of 2009 is fueling a pandemic. Initially termed swine flu because the virus contained genes swapped from the swine influenza virus, the name has been abandoned appropriately in favor of H1N1 because the virus does not infect pigs; nor is it transmitted from pigs, rather from humans. In the Northern Hemisphere, H1N1 represents the vast majority of total influenza cases and infection rates are still on the rise. Through July 2009, a total of 43,677 laboratory-confirmed cases of influenza A pandemic (H1N1) 2009 were reported in the United States, which is likely a substantial underestimate of the true number. In models correcting for under-ascertainment, 1.8–5.7 million cases of H1N1 are estimated to have occurred, necessitating 9000–21,000 hospitalizations [Reed et al., 2009]. Confirmed pediatric deaths reported so far are few [CDC, 2009] but H1N1 disproportionately affects children with neurodevelopmental disabilities.
Every year, a new influenza vaccine is developed to protect against the prevalent virus strains that are expected to appear in the United States the following winter. Each vaccine contains three influenza viruses: one A (H3N2) virus, another A (H1N1) virus, and one B. Two types of flu vaccines are available: the inactivated flu vaccine (discussed later) and the nasal-spray flu vaccine (i.e., live-attenuated influenza vaccine [LAIV]). The LAIV is prepared from live-attenuated flu viruses that do not cause disease in humans. This nasal preparation is cold-adapted to replicate best at 25°C, and it is temperature-sensitive so that it cannot replicate in the lower airways. LAIV was licensed for use in the United States in 2003 and is approved for use in healthy people 5–49 years of age, who are not pregnant. Trials in children have found that inactivated flu vaccine and LAIV share a comparable efficacy and safety profile [Zangwill et al., 2004].
Guillain–barré syndrome
Increased rates of Guillain–Barré syndrome (GBS) were reported to be associated with the swine vaccine of 1976, with rates of GBS among vaccinees found to exceed the background rate of less than 10 cases per 1 million persons vaccinated. The incidence of GBS associated with the swine vaccine of 1976 ranged from 8 to 13 per million [Breman and Hayner, 1984; Marks and Halpin, 1980; Langmuir et al., 1984; Safranek et al., 1991; Schonberger et al., 1979]. Rates of GBS associated with influenza vaccine reported to the Vaccine Adverse Event Reporting System (VAERS) have fallen 4-fold, from a peak of 1.7 per million vaccinees in 1993–1994 to 0.4 in 2002–2003 [Haber et al., 2004). After 1976, no influenza season has shown a significant increase risk of GBS after influenza vaccination.
The Institute of Medicine has determined a causal relationship between GBS and influenza vaccination for 1976, but not for other years [Institute of Medicine, 2003]. Nevertheless, because individuals with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than individuals without such a history, it has been recommended that influenza vaccination be avoided among individuals with a history of GBS and who are known to have experienced GBS within 6 weeks of a previous influenza vaccination (http://www.cdc.gov/flu/protect/vaccine.htm). The role of influenza vaccination in increasing the risk for GBS is debatable. None the less, even if influenza vaccination were to increase the risk of GBS, the risk attributable to the vaccine would be only about 1 additional case per 1 million persons vaccinated, a figure that is substantially lower than the risk for severe influenza, especially among high-risk individuals. Furthermore, rates of GBS reported after natural influenza were significantly higher than following influenza vaccination, as evident in a large case-control study from the United Kingdom, where GBS cases increased more than 7-fold within 90 days and over 16-fold within 30 days following an influenza-like illness, as compared to no increase after influenza vaccine [Stowe et al., 2009]. No cases of GBS are reported in vaccinated children [Institute of Medicine, 2003].
No significant complications have been reported with the H1N1 vaccinations thus far. As the bulk of the H1N1 vaccination effort is still under way, it may be premature to comment on its rate of complications for rare disorders. As H1N1 has elements of swine influenza virus in its composition, fears have been raised that H1N1 could possibly replicate the GBS complications of the swine flu vaccine of 1976. This potential complication is unlikely to occur, given that the vaccine produced in 1976 used whole virus, while the current H1N1 vaccine uses split virus, i.e. is produced using only a subset of viral antigens needed to make it a viable vaccine. Furthermore, H1N1 vaccine has been produced according to the same methodology that is followed to produce the annual flu vaccine, which is very safe. The biggest fear surrounding the H1N1 flu vaccine in the fall of 2009 is that not enough vaccine will be delivered in time to protect vulnerable populations. Consequently, the H1N1 epidemic has been designated a national emergency in order to facilitate delivery of the vaccine. To ensure adequate ascertainment of any potential neurological complications of the H1N1 vaccine, the American Academy of Neurology is collaborating with the Centers for Disease Control and Prevention to mount a heightened safety surveillance system (AAN, 2009).
Multiple sclerosis
Although early studies suggested an association with multiple sclerosis relapse, there is no evidence that influenza vaccination increases the risk of multiple sclerosis relapse, as indicated by numerous studies [De Keyser et al., 1998], including a double-blind clinical trial [Miller et al., 1997; de Stefano et al., 2003] and a cohort study [Confavreux et al., 2001]. In one study, the rate of multiple sclerosis relapse following influenza vaccination was comparable to the base rate of relapse (5 percent), while the rate of multiple sclerosis relapse following an influenza-like illness was significantly increased (33 percent) [De Keyser et al., 1998]. More recently, a comprehensive review of the literature concluded that there was class A evidence that influenza vaccination does not induce relapse and that it should be used in affected individuals when indicated, based on risk factors [Rutschmann et al., 2002].
Rabies Vaccine
Rabies was the first manufactured vaccine to be used in humans. Early vaccines were grown in the central nervous system of animals and contained myelin basic protein [Hemachudha et al., 1987]. These vaccines (Semple vaccine), still in use in developing countries, have been associated with a high incidence of acute disseminated encephalomyelitis (ADEM) (0.15 percent), polyradiculitis, and polyneuritis [Tullu et al., 2003]. The rabies vaccine licensed for use in the United States is prepared from rabies virus grown on human diploid cells, and it has an excellent safety record [Noah et al., 1996]. Rare cases of demyelinating reactions have been reported, usually during the administration of the vaccine series or 1 week after completion, including atypical GBS [Boe and Nyland, 1980; Bernard et al., 1982; Knittel et al., 1989; Tornatore and Richert, 1990] and ADEM.
