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.
Whole-Cell Pertussis Vaccine
Whole-cell pertussis vaccine has been combined routinely with diphtheria and tetanus toxoids (DTwP). The endotoxin contained in the whole-cell vaccine causes fever and pain at the injection site. Whole-cell pertussis immunization also has been associated with febrile seizures within a day of vaccination and hypotonic hyporesponsiveness in about 1 case per 1750 doses, and with a rare (0–10.5 cases per 1 million doses administered) acute encephalopathy, characterized by persistent crying [Cody et al., 1981]. The Institute of Medicine review of combined pertussis vaccine (DwPT) concluded that the evidence, although not probative, was consistent with a causal relationship between DwPT and an acute encephalopathy in the children who experience a serious acute neurologic illness within 7 days after receiving DwPT vaccine [Institute of Medicine, 1994]. Several detailed reviews of available studies by a number of countries, including those by the U.S. Institute of Medicine, have concluded that the data did not support a causal relationship between DTwP and chronic nervous dysfunction [American Academy of Pediatrics, 1996; Cowan et al., 1993].
Hepatitis A Vaccine
Hepatitis A vaccine is composed of an inactivated whole-virus vaccine that is derived from an attenuated strain of hepatitis A virus grown in human diploid cell lines. Licensed for use in 1995, the vaccine initially was recommended for use in communities with high prevalence of hepatitis A. In 2006, it was recommended for use in all children aged 1 year or older [CDC, 2006a]. Hepatitis A vaccine has also been proven to be as effective as immune globulin in post-exposure prophylaxis [Victor et al., 2007]. No adverse neurological events have been attributed to hepatitis A vaccine.
Vaccines Composed of Live-Attenuated Viruses
Measles: Rubeola
Measles vaccinations have been in use since 1963. Before routine vaccinations, approximately 3–4 million cases of measles and 450 deaths occurred annually in the United States, where currently no endemic measles exists. Most reported measles cases in the United States are imported, though outbreaks occasionally have occurred in populations that refuse vaccination (e.g., communities in Utah and Nevada, Christian Scientist schools in Missouri and Illinois). Global plans to eradicate measles by 2010 have failed to succeed, given the high rate of infection in some parts of Europe, where many children go unvaccinated because of strong antivaccine movements. In 2006–2007, five countries accounted for over 80 percent of the more than 12,000 measles cases in Europe: Romania, Germany, the United Kingdom, Switzerland, and Italy [Muscat et al., 2009]. In 2008, measles cases in the United States, about half of which were imported from Europe, were at their highest since 1996. The number of cases was higher because of transmission after importation, as unvaccinated school-age children became infected [CDC, 2008].
The licensed measles vaccine uses the Edmonton B measles virus, attenuated by prolonged passage in chick embryo cell culture, and is combined with mumps and rubella vaccines (MMR). Children who receive live-attenuated measles vaccines are expected to develop an asymptomatic case of measles. Some children develop fever, rash, and conjunctivitis in the second week after immunization (i.e., the incubation period is at least 5 days). The main neurologic complication of measles immunization, shown in multiple studies, is a 2- to 6-fold elevated risk of febrile seizures in the second week after immunization [Barlow et al., 2001; Griffin et al., 1991; Vestergaard et al., 2004; Ward et al., 2007]; these are often complex (i.e., prolonged) [Ward et al., 2007]. Measles vaccine is not associated with increased risk of afebrile seizures or epilepsy [Barlow et al., 2001], even among high-risk children [Vestergaard et al., 2004]. Rare cases of measles encephalitis with neurologic sequelae have been reported to the VICP [Fenichel, 1982]. Although children with vaccine-induced measles can develop any of the known complications of natural infection, the vaccine does not cause subacute sclerosing panencephalitis, a chronic form of measles encephalitis. The isolated cases of subacute sclerosing panencephalitis reported among measles vaccinees have been in countries where measles is endemic, suggesting prior subclinical measles infection [Bonthius et al., 2000]. Studies that have characterized genetically the viral material from brains of patients with subacute sclerosing panencephalitis have all reported wild type of measles sequences [Barrero et al., 2003; Jin et al., 2002]. Furthermore, cases of subacute sclerosing panencephalitis in individuals who did not recall having measles all have identified the wild type of measles. In developed countries with scant or no endemic measles, subacute sclerosing panencephalitis has disappeared in tandem with the disappearance of measles [Bloch et al., 1985; CDC, 1982; Campbell et al., 2007].
Mumps
The mumps vaccine is administered with MMR vaccination. It is prepared by passage of the Jeryl Lynn strain of mumps virus in chick embryo cell culture. Mumps vaccine has eliminated natural mumps infection, including mumps encephalitis. No adverse neurologic events are associated with the mumps vaccine used in the United States. Aseptic meningitis has been associated with the mumps vaccine used in other countries that use a different viral strain [Arruda and Kondageski, 2001; Suigura and Yamada, 1991], but not the Jeryl Lynn strain [Miller et al., 2007]. A total of 10 isolated cases of sensorineural deafness has been reported after immunization with MMR [Kaga et al., 1998; Stewart and Prabhu, 1993]. Three of these cases could be explained from other causes; the remaining cases were unexplained.
Rubella
Earlier rubella vaccines that were grown in various animal kidneys were associated with high rates of neuropathy and arthritis. Since 1979, the rubella vaccine used in the United States has been prepared from human diploid cells. The immunologic response it produces parallels that of the natural infection. Up to 25 percent of people receiving the current rubella vaccine may develop transient arthralgias and paresthesias. Other chronic illnesses that have been reported after rubella vaccination include painful limb syndrome, blurred vision, fibromyalgia, and fatigue [Morton-Kute, 1985; Tingle et al., 1985]. In 1991, the Institute of Medicine reviewed the available scientific evidence and determined it to be consistent with, but not probative of, a causal relationship between rubella vaccination and chronic arthritis in women [Institute of Medicine, 1991]. Studies designed to address this question have not identified an association between chronic arthritis and rubella vaccination [Ray et al., 1997; Slater et al., 1995]. Rubella virus vaccine has been highly successful in eradicating endemic rubella and congenital rubella in the United States [CDC, 2005]. Inadvertent rubella vaccination of pregnant women has not resulted in any case of congenital rubella syndrome [Reef et al., 2007].
Oral Polio Vaccine
Sabin’s OPV, introduced in 1963, was successful in eradicating polio in the United States. As the greatest risk of contracting polio in the United States was vaccine-associated (i.e., the risk of wild polio is nil), OPV has been replaced by an eIPV. The overall risk for vaccine-associated paralytic poliomyelitis (VAPP) after OPV administration is approximately 1 case per 2.4 million doses distributed. Among immunocompetent individuals, 82 percent of cases among vaccine recipients and 65 percent of cases among contacts occur after administration of the first dose. The risk for VAPP is 1 case per 750,000 first doses of OPV distributed [Nathanson and Martin, 1979]. Immunodeficient patients, particularly those who have B-lymphocyte disorders that inhibit synthesis of immune globulins (i.e., agammaglobulinemia and hypogammaglobulinemia), are at greatest risk for VAPP (3200- to 6800-fold greater than the risk for immunocompetent OPV recipients) [Sutter and Prevots, 1994]. There is no evidence that administration of OPV or IPV increases the risk for GBS [Kinnunen et al., 1989]. A population-based study found that GBS in children was not associated with OPV vaccination, as no cases developed within a month of the vaccination. Moreover, 70 percent of cases of GBS were preceded by an intercurrent infection [Rantala et al., 1994].
Varicella
A live-attenuated varicella virus (Oka strain) vaccine was licensed in 1995 in the United States, and is currently recommended for routine childhood immunization for susceptible children between 12 and 24 months of age [American Academy of Pediatrics, 2000]. It is safe and effective in normal and immunocompromised children, and is being used to protect children with acute lymphocytic leukemia [White et al., 1991] and HIV infection (before immune suppression) [Levin et al., 2001]. The vaccine produces a mild case of chickenpox, resulting in any of the neurological complications linked to the wild-type varicella infection but at lower rates. For acute cerebellar ataxia, the vaccine-associated rate is 0.15:100,000 doses varicella zoster virus (VZV) vaccine-years, which is but 3 percent of the incidence of acute cerebellar ataxia linked to the wild type (5:100,000 VZV infections for children up to 5 years) [van der Maas et al., 2009]. For herpes zoster, the vaccine-associated incidence rate has declined to 27 per 100,000 children vaccinated [Tseng et al., 2009], which is lower than rates reported among immunocompetent children (under 20 years) with natural varicella infection (68 per 100,000 person-years) [Guess et al., 1986]. Zoster complications with Oka virus, when compared to wild-type VZV, tended to occur in younger children (about 2 years of age) and have a shorter onset after vaccination (318 vs. 588 days), and the zoster eruption was noted to correlate with the site of the vaccination in 46 percent of cases [Galea et al., 2008]. The rate of zoster among varicella vaccinees aged 10–23 years and followed for 10 years was 1 case per 1000 person-years, which is comparable to zoster rates described after wild-type VZV infection [Hambelton et al., 2008]. Encephalitis has been reported as being temporally related to varicella vaccination but, in cases where cerebrospinal fluid was examined, Oka virus was not found to be present [Galea et al., 2008]. Varicella vaccine-associated stroke from Oka virus vasculopathy has not been reported in a study that reviewed over 3 million vaccinees [Donahue et al., 2009]. No major neurological adverse effects were reported as being associated with Oka virus 42 or more days after varicella vaccination.
Smallpox
Eradicated in 1980, smallpox has again emerged as a potential risk in the wake of recent terrorist events because of its potential use as a biologic weapon. The United States has commissioned the manufacture of vaccinia vaccines in preparation for the possible intentional release of smallpox among the population. In case of an outbreak, individuals of all ages would be vaccinated. The smallpox vaccine currently is recommended only for high-risk personnel (i.e., laboratory workers and at-risk military personnel), and is contraindicated for children and individuals with cutaneous disorders and immune suppression [Wharton et al., 2004]. The smallpox vaccine is prepared from vaccinia, a live poxvirus that causes mild disease, including rash, fever, and aches. The main neurologic complication of smallpox vaccination is postvaccinal encephalomyelitis [CDC, 2003]. Neuropathologic reports describe cerebral edema and perivenular and leptomeningeal inflammation, findings that are consistent with an immune-mediated response [Perdrau, 1928]. However, vaccinia has been cultured [Angulo et al., 1964], as well as antigen recovered from affected brains [Kurata et al., 1977]. A comprehensive review, based on data collected before 1970, estimates the risk of postvaccinal encephalomyelitis to be at least 3 cases per 1 million primary vaccinations, and that of vaccinia necrosum to be 1 case per 1 million primary vaccinations [Aragon et al., 2003]. The highest risk for developing postvaccinial encephalomyelitis was among infants younger than 1 year (risk ratio = 2.80, compared with vaccinees 1 year or older). The mortality rate among patients with postvaccinial encephalomyelitis was 29 percent; among patients with vaccinia necrosum, it was 15 percent. Among re-vaccinees, the risk of postvaccinial encephalomyelitis was reduced 26-fold, the risk of generalized vaccinia was reduced 29-fold, and the risk of eczema vaccinatum was reduced 12-fold. Clinical trials of recombinant smallpox vaccine are being carried out. The recombinant smallpox vaccine was designed to be safer for patients with cutaneous disorders, and it is expected to be associated with a lower risk of postvaccinial encephalomyelitis. Compensation for smallpox vaccination complications is covered under a separate congressional act [Health Resources and Services Administration, 2003].
Rotavirus
Rotavirus (RV) vaccine is composed of a live, attenuated human G1P rotavirus. Rotavirus vaccine is recommended for routine vaccination of infants for the prevention of rotavirus gastroenteritis caused by G1 and non-G1 types (G3, G4, and G9) [Parashar et al., 2006]. Intussusception is the main side effect associated with RV vaccine [Murphy et al., 2001]. No adverse neurological side effects have been attributed to rotavirus vaccine.
Component Vaccines
Acellular Pertussis Vaccine
Since 1997, acellular pertussis vaccines have been recommended for initial vaccination of children, beginning at 6 weeks of age [CDC, 1997]. Acellular pertussis vaccines contain substantially fewer proteins (five) and less endotoxin than whole-cell pertussis vaccines. Acellular pertussis vaccination is associated with fewer local adverse events and systemic adverse events compared with DwPT [Rosenthal et al., 1996]. Fewer rates of serious neurologic disorders are also reported following DaPT [Geier and Geier, 2004], including lower rates of febrile seizures and hypotonic unresponsive events [LeSaux et al., 2003]. No cases of encephalopathy have been identified that could be attributable to acellular pertussis after the administration of millions of doses of vaccines [Moore et al., 2004; Ray et al., 2006].
Meningococcal Conjugate Vaccine
Meningococcal conjugate vaccine (MCV4) is a tetravalent vaccine constituted by capsular polysaccharide of serotype A, C, Y, W135. It was licensed for use in January 2005 and is recommended for routine administration in adolescents 11–18 years of age. In October 2005, the Centers for Disease Control and Prevention reported five cases of GBS among recipients of MCV4 reported to VAERS [CDC, 2005a], first raising the possibility of an increased risk of GBS in association with MCV4 (within 42 days of vaccination). Findings were viewed as preliminary and the CDC made no change in vaccine recommendations. As of December 2008, there were 37 confirmed cases of GBS among MCV4 recipients of all ages reported to the VAER program, of which 33 were among 11–19-year-olds. The rate of GBS in the group of 11–19-year-olds was lower than that expected in this age group; however, the rate among 15–19-year-olds (n = 26) was slightly higher than expected (IRR 1.3; n = 19.8). Although findings did not reach significance (IRR (incidence relative risk) = 1.3; 95 percent confidence interval 0.87–1.90), data were suggestive of a small possible heightened risk of GBS with MCV4 vaccine among 15–19-year-olds [Calugar et al., 2009]. Given the limitations of the VAER system (incomplete reporting, lack of a direct comparison group), the VAER data are not designed to test vaccine safety hypotheses, but rather to generate hypotheses for subsequent studies. None the less, given that individuals with a history of GBS are at greater risk of relapse than the general population, MCV4 is now contraindicated among individuals with a history of GBS. Studies are under way to determine whether MCV4 vaccination is indeed associated with GBS (http://www.clinicaltrials.gov/ct2/show/NCT00575653).
Human Papillomavirus Vaccine
The human papillomavirus (HPV) vaccine was licensed for use in the United States in 2005. It is recommended for routine vaccination of girls aged 11–12 years. It is composed of non-infectious virus-like particles (VLPs) of the major capsid L1 protein of HPV types 6, 11, 16, and 18. In clinical trials, it has been found to be effective in preventing cervical, vulval, and vaginal dysplasia, genital warts, and cervical cancer caused by these specific HPV types [Future II, 2007]. In the United States, HPV vaccine-associated adverse effects reported to VAERS were nonserious. Ninety-three percent of side effects related to arm pain at the injection site and syncope, including convulsive syncope. A possible increased risk of venous thrombotic disease was also noted among cases reported to VAER, and this merits further study [Slade et al., 2009]. HPV vaccine was not linked to higher rates of GBS than are encountered in the general population. Five cases of central nervous system demyelination were reported within 21 days of HPV vaccination in Australia [Sutton et al., 2009]; however, the report was limited because of its referral sample and lack of control group. In the United States, CNS demyelination attributable to HPV has not been reported [Slade et al., 2009]. Vaccination is contraindicated in individuals with yeast allergies.
Tetanus and Diphtheria
Tetanus and diphtheria are toxoids that are produced by formalin inactivation of the toxins elaborated by the two organisms. Both have low rates of complications [Lloyd et al., 2003]. Tetanus toxoid is given alone to children and adults after injury or burn exposure. The only contraindication for either toxoid is a history of a neurologic or severe hypersensitivity reaction after a previous dose.
GBS associated with tetanus toxoid has been reported in one child and one adult. The adult patient developed recurrent episodes of GBS after three doses of tetanus toxoid separated by many years, and later developed chronic inflammatory demyelinating polyneuropathy without prior vaccination [Pollard and Selby, 1978]. Infants have been reported who developed brachial neuritis after DTP immunization, and in such cases, the tetanus toxoid has been implicated [Hamati-Haddad and Fenichel, 1997]. The Institute of Medicine concluded that a causal relationship exists in adults between tetanus toxoid and brachial neuritis, based on repeated reports (class III).
Recombinant Vaccines
Hepatitis B Vaccine
Hepatitis B vaccine is prepared by introducing DNA coding for the hepatitis B surface antigen into yeasts for cloning. The original plasma-derived vaccine is also safe and effective, and it is still used elsewhere in the world. Multiple sclerosis initially was associated temporally with hepatitis B vaccine in France after hepatitis B immunization became mandatory for health-care workers in that country [Gout et al., 1997]. A few cases of GBS, Bell’s palsy, acute cerebellar ataxia, and brachial plexitis have been reported after use of the plasma-derived vaccine [Deisenhammer et al., 1994; Shaw et al., 1988]. Controlled studies, however, have noted an association between hepatitis B vaccine with new-onset multiple sclerosis in adults [Ascherio et al., 2001; Verstraeten et al., 2001] or adolescents [Sadovnik and Scheifele, 2000], or with multiple sclerosis relapse [Confavreux et al., 2001]. The Institute of Medicine has determined that the evidence is insufficient to support a cause-and-effect association [Institute of Medicine, 1993].
Combination Vaccines and Additives
Mumps, Measles, and Rubella Vaccine and Autism
A major debate arose after publication of a small gastroenterology study in Britain of a link between the MMR vaccine and autism. The study of 12 patients found gastrointestinal complaints among patients with autistic regression, 8 of whom had been vaccinated with MMR, as determined retrospectively [Wakefield et al., 1998]. The authors have since retracted their conclusion of a causal link with autism [Murch et al., 2004], but not before causing broad repercussions throughout Britain and the United States. The same authors also published data identifying a persistent measles virus in the gastrointestinal tract of autistic children [Uhlmann et al., 2002], a finding that has not been replicated by other investigators in blood cells [Afzal et al., 2006; Baird et al., 2008] or in intestinal samples [Hornig et al., 2008] of autistic children. It subsequently became known that Dr. Wakefield had been contracted by lawyers representing parents of autistic children, who believed their children were harmed by MMR, a conflict of interest that was not disclosed to The Lancet or to his collaborating authors [Eggentson, 2010]. Wakefield is currently the subject of General Medical Council disciplinary hearings in London regarding his treatment of the children in his research.
Studies in Japan, where vaccine-associated aseptic meningitis resulted in suspension of MMR vaccination after 1993, have found no association between MMR and autism; rates of autism continued to increase after vaccine was discontinued [Honda et al., 2006], and there was no difference in rates of autistic regression [Uchiyama et al., 2007]. Numerous studies throughout the globe, including ecological [Kaye et al., 2001; Dales et al., 2001; Chen et al., 2004; Fombonne et al., 2006] and controlled studies [DeStefano, 2004; Madsen et al., 2002; Smeeth et al., 2004], have found that MMR is not associated with pervasive developmental delay or autistic regression. The Institute of Medicine has concluded, after a careful review of existing studies, that data do not support a causal relationship between MMR and autism [Institute of Medicine, 2004].
Thimerosal-Containing Vaccines and Developmental Disorders of Childhood
Thimerosal is an organic mercury compound preservative that has been in use since the 1930s. It was contained in more than 30 vaccines licensed and marketed in the United States, including some of the vaccines administered to infants for protection against diphtheria, tetanus, pertussis, Haemophilus influenzae type b, and hepatitis B. Thimerosal is metabolized to ethylmercury and thiosalicylate. Theoretical concerns were raised that cumulative exposure to ethylmercury, a known neurotoxin, could have developmental side effects [CDC, 1999]. In 1999, thimerosal was removed from vaccines to trace amounts (<3 μg). Several studies [Hviid et al., 2003; Verstraeten et al., 2003] have found no association between thimerosal-containing vaccines and autism. Subsequent ecologic studies reported that, after discontinuation of thimerosal-containing vaccines, rates of autism remained unchanged or increased [Madsen et al., 2003]. Other studies targeting development and cognition have failed to identify thimerosol-associated impairments [Heron et al., 2004; Thompson et al., 2007]. The Institute of Medicine has concluded that thimerosal-containing vaccines are not associated with neurodevelopmental disorders, including autism, attention-deficit hyperactivity disorder, and developmental delay [Institute of Medicine, 2004].
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