Vaccination
Joel Alcantara
Ronald G. Lanfranchi
Since the first edition of this textbook, the seriousness of the issues and controversies surrounding the vaccination program in the United States and globally has not waned. During the preparation of this chapter, a vaccine to a novel influenza A (H1N1) virus (commonly referred to as swine flu) was being offered worldwide to address a pandemic of febrile respiratory illness associated with the disease. According to the World Health Organization (WHO), there were laboratory-confirmed cases of swine flu in nine countries on April 29, 2009. Due to the rapid spread of the disease (primarily through person-to-person transmission), some 6 weeks later (June 11, 2009), there were reported cases in 74 countries. By July 1, 2009, there were confirmed cases in 120 countries and territories. Laboratory analysis demonstrated that the H1N1 virus was genetically and antigenically different from other influenza viruses circulating among people. Clinically, a very severe form of primary viral pneumonia not typically seen during seasonal influenza was identified. This type of pneumonia progressed rapidly and was frequently fatal. Children >5 years of age and/or people with chronic medical conditions were considered at an increased risk for complications and death from this type of influenza (1,2,3). According to the Centers for Disease Control and Prevention (CDC) (4), by August 8, 2009, there were 477 deaths in the United States associated with the H1N1 pandemic. Of the 477 deaths 36 involved children >18 years of age. Of the 36 deaths, 7 (19%) involved children >5 years of age and 24 (67%) had one or more pre-existing high-risk medical condition. By April 26, 2009, the cumulative pediatric deaths in the United States attributed to the H1N1 virus numbered 305 (5). The CDC’s Advisory Committee on Immunization Practices (ACIP) recommended that individuals in certain high-risk groups get the 2009 H1N1 swine flu vaccine such as pregnant women, household contacts and caregivers for children younger than 6 months of age, health care and emergency medical services personnel, all people from 6 months through 24 years of age, children from 6 months through 18 years of age and young adults 19 through 24 years of age, as well as persons aged 25 through 64 years who have preexisting health conditions associated with a higher risk of medical complication from influenza (6). By October 2009, there were concerns that not enough of the vaccine would be available for all Americans who fit into the above five category groups. In an article published on October 29, 2009, entitled, “Sebelius: Feds Knew H1N1 Vaccine Supply Was Not Enough to Cover At-Risk Americans—Still May Donate Doses to Foreign Countries.” the Department of Health and Human Services Secretary Kathleen Sebelius was quoted as saying, “We knew from the outset—everybody knew from the outset—we would not have enough to immunize the 150 million Americans who fit into those five priority groups” (7). Vaccine production was hampered, in part, by the finding that the virus necessary for vaccine production grew much more slowly than expected and larger than anticipated quantities of the virus were necessary to produce an acceptably potent vaccine. In a study conducted by the RAND corporation surveying a nationally representative sample of US adults (n = 2,067) via the Internet between May 26th and June 8th, 2009, Maurer et al. (8) found a vaccination rate of only 49.6% for H1N1, which corresponds to roughly 115 million adult vaccinations. Moreover, vaccination intentions with the H1N1 vaccine were strongly associated with seasonal influenza vaccinations, suggesting common attitudinal barriers to both vaccines. In a survey study of 2,255 health care workers (i.e., doctors, nurses, etc.) at 31 hospital departments of internal medicine, pediatrics, and emergency medicine under the Hong Kong Hospital Authority, only 47.9% among health care workers were willing to accept the H1N1 vaccine. The most common reasons for an intention to accept the vaccine was a “wish to be protected” and “following health authority’s advice.” The major barriers to vaccination were identified as fear of side effects and
doubts about efficacy (9). Despite the possible risk of death associated with the swine flu and strong recommendations by health authorities, many parents were not enthusiastic about the swine flu vaccine for their children. In a national survey conducted by the University of Michigan’s C.S. Mott Children’s Hospital, of 1,678 parent responders, only 40% indicated that they would vaccinate their children against the H1N1 virus. Over half of the “non-vaccinating” parents cited concerns about vaccine side effects as a reason for not vaccinating (10). With respect to government-mandated vaccinations, the State of New York mandated vaccinations against seasonal and H1N1 influenza for health care workers who had direct contact with patients or who may expose patients to disease (11). The New York State Health Commissioner Richard Daines argued that the only way to achieve high rates of staff immunity is by mandatory vaccination. He argued that, “high levels of staff immunity confer protection on those patients who cannot be or have not been effectively vaccinated … while also allowing the institution to remain more fully staffed” (12). Some health care workers argued that mandatory vaccination violated their individual rights and public health policy. Stewart (11) provides an excellent review of the legal arguments for and against mandatory vaccination, particularly in the context of the mandated H1N1 vaccination by the State of New York. According to Stewart, “Health care workers have a profound effect on patients’ health. Although they have the same rights as all private citizens, it is likely that courts will continue to make the health and safety of patients the priority in permitting exceptions to individual rights.”
doubts about efficacy (9). Despite the possible risk of death associated with the swine flu and strong recommendations by health authorities, many parents were not enthusiastic about the swine flu vaccine for their children. In a national survey conducted by the University of Michigan’s C.S. Mott Children’s Hospital, of 1,678 parent responders, only 40% indicated that they would vaccinate their children against the H1N1 virus. Over half of the “non-vaccinating” parents cited concerns about vaccine side effects as a reason for not vaccinating (10). With respect to government-mandated vaccinations, the State of New York mandated vaccinations against seasonal and H1N1 influenza for health care workers who had direct contact with patients or who may expose patients to disease (11). The New York State Health Commissioner Richard Daines argued that the only way to achieve high rates of staff immunity is by mandatory vaccination. He argued that, “high levels of staff immunity confer protection on those patients who cannot be or have not been effectively vaccinated … while also allowing the institution to remain more fully staffed” (12). Some health care workers argued that mandatory vaccination violated their individual rights and public health policy. Stewart (11) provides an excellent review of the legal arguments for and against mandatory vaccination, particularly in the context of the mandated H1N1 vaccination by the State of New York. According to Stewart, “Health care workers have a profound effect on patients’ health. Although they have the same rights as all private citizens, it is likely that courts will continue to make the health and safety of patients the priority in permitting exceptions to individual rights.”
As exemplified with the swine flu and unlike vaccine-induced immunity, the issues revolving the vaccination program do not wane with time. The issues involving access to and compliance with required vaccinations, the individuals’ rights to accept or reject government-mandated vaccinations, and concerns about the adverse events associated with vaccines (13) are universal. Given the width and breath of the topic of vaccines and the issues and controversies involved, it is beyond the scope of this chapter to address each and every vaccine for a child. Consider that it is recommended that a child from age 0 to 6 years should receive vaccinations for hepatitis A & B, rotavirus, diphtheria, tetanus pertussis, Haemophilus influenzae type b, pneumococcal, inactivated poliovirus, influenza, measles, mumps, rubella (MMR), varicella, hepatitis A, and meningococcal. From age 7 to 18 years, it is recommended that they get a second vaccination with the aforementioned vaccines in addition to the human papillomavirus (HPV). We will therefore address only a few of the vaccines in the context of and reflective of the issues and controversies involved from a chiropractic perspective.
MEASLES VIROLOGY
The measles virus belongs to the paramyxovirus group of the Morbillivirus genus. It is considered a large virus with pleomorphic and spherical morphology composed of an outer lipoprotein envelope and an internal helical nucleocapsid composed of RNA and protein. The RNA genome is a negative-sense single-strand RNA, and the virus replicates via an RNA-dependent RNA polymerase. The genome of the Edmonston strain encodes for six major structural proteins. Two types of transmembrane proteins are found in the envelope: the hemagglutinin protein (H) and the fusion (F) protein. An M protein is found on the inner surface of the virion envelope and functions for the successful generation of new viral particles (14).
CLINICAL FEATURES
Measles infection in a compromised host results in an acute, febrile, and exanthematous illness. The primary site of infection is the respiratory epithelium of the nasopharynx. Transmission of the virus occurs via respiratory secretions, and the virus undergoes multiplication in the epithelium and lymphatic tissue of the upper respiratory tract. During the multiplicative phase, the virus disseminates to the various lymphoid tissues after viremia. After incubation for a period of 10 to 12 days, viral replication in the upper respiratory tract occurs, resulting in the prodromal symptoms characterized by coryza, conjunctivitis, dry cough, sore throat, headache, low-grade fever, and enanthem or Koplik spots (bluishwhite spots on a red background). Toward the end of the prodromal stage, a second viremic phase occurs with the virus disseminating to the skin and lymphoid tissue. This results in the characteristic maculopapular rash associated with the measles. The rash is initially maculopapular but becomes confluent and disappears within 5 to 7 days in order of appearance. Substantial quantities of the virus are shed in respiratory secretions, tears, and urine during the prodromal stage before any symptoms appear, and the diagnosis of measles may be made from cell cultures of the virus. However, this is often difficult, and more conventional diagnosis of measles involves assays for the measles antibodies such as complement fixation, immunofluorescence, neutralization, hemagglutination inhibition, and last but most popularly used, enzyme immunoassays that are commercially available (15,16).
MEASLES VACCINE
In 1954, Enders and Peebles isolated the measles virus in human and kidney cell cultures. Shortly thereafter, a number of attenuated vaccine strains were prepared
from a measles isolate obtained from an infected child named Edmonston (17). Attenuation and derivation of the vaccine strains involve the multiple passages of the virus through foreign host cell cultures (i.e., chick embryo cells, human diploid cells [HDCs]) and different incubation temperatures. The Edmonston B strain was licensed in 1963 and widely used until 1975. A second measles vaccine (formalin-inactivated measles) was also licensed in 1963 but was not ideal and was withdrawn in 1967. Individuals vaccinated with the formalin-inactivated strain developed only short-lived immunity while some were predisposed to developing atypical measles when exposed to the wild-type measles (18). Other attenuated vaccine strains have been developed from the Edmonston strain such as the Schwarz and the Edmonston-Zagreb (EZ) strains (which are commonly used outside the United States) and the Moraten strain, used exclusively in the United States (19). The trivalent MMR vaccine was licensed in the United States in 1971. Other measles vaccines are developed from strains isolated from Russia (vaccine Leningrad-16), China (vaccine Shanghai 191), and Japan (vaccine CAM-70).
from a measles isolate obtained from an infected child named Edmonston (17). Attenuation and derivation of the vaccine strains involve the multiple passages of the virus through foreign host cell cultures (i.e., chick embryo cells, human diploid cells [HDCs]) and different incubation temperatures. The Edmonston B strain was licensed in 1963 and widely used until 1975. A second measles vaccine (formalin-inactivated measles) was also licensed in 1963 but was not ideal and was withdrawn in 1967. Individuals vaccinated with the formalin-inactivated strain developed only short-lived immunity while some were predisposed to developing atypical measles when exposed to the wild-type measles (18). Other attenuated vaccine strains have been developed from the Edmonston strain such as the Schwarz and the Edmonston-Zagreb (EZ) strains (which are commonly used outside the United States) and the Moraten strain, used exclusively in the United States (19). The trivalent MMR vaccine was licensed in the United States in 1971. Other measles vaccines are developed from strains isolated from Russia (vaccine Leningrad-16), China (vaccine Shanghai 191), and Japan (vaccine CAM-70).
SUCCESS AND FAILURES OF MEASLES CONTROL
Efficacy
According to the medical community, the efficacy of the measles vaccine has been demonstrated within the United States and around the world by the decrease in the incidence of the disease. Serious childhood diseases such as measles have either been eradicated or have become negligible disease entities as a result of massive immunization programs and routine immunizations of infants and children.
Worldwide, mortality attributed to measles infection reduced by 74%, from 750,000 deaths in 2000 to 197,000 in 2007 (20). Almost 80% of this global reduction in measles mortality was due to a 90% reduction in the Eastern Mediterranean and an 89% reduction in the African regions. Based on coverage estimates by the WHO and UNICEF in 2007, global coverage had reached an all-time high from 72% in 2000 to 82% in 2007 (21). As a result of improved routine coverage and mass vaccination campaigns globally, approximately 11 million measles deaths were prevented between 2000 and 2007. The vaccination campaign vaccinated 578 million children between the ages of 9 months and 15 years, averting approximately 3.6 million deaths worldwide (21).
According to Hinman et al. (22), 10 major lessons can be gleaned from efforts to eliminate measles in the United States. First, elimination requires very high vaccinationcoverage levels in children of age 2 years. Second, school immunization requirements ensure high coverage rates among schoolchildren. Third, a second dose of measles vaccine is needed to achieve satisfactory levels of immunity. Fourth, school immunization requirements ensure delivery of a second dose. Fifth, coverage assessment is crucial. Sixth, measles surveillance is critical for developing, evaluating, and refining elimination strategies. Seventh, surveillance requires laboratory backup to confirm a diagnosis. Eighth, tracking measles virus genotypes is critical to determining if an endemic strain is circulating. Ninth, once endemic transmission has been interrupted, internationally imported measles cases will continue and will cause small outbreaks. Tenth, collaborative efforts with other countries are essential to reduce imported measles cases.
VACCINE FAILURES
After 1983, major outbreaks occurred, especially among highly vaccinated school-age populations. Measles cases reached a peak of 6,282 cases in 1986 and more than 14,000 cases in 1989 (23,24). The sustained outbreaks in highly vaccinated populations were attributed primarily to vaccine failures. Vaccine failures can be divided into two major types: primary, which is due to lack of seroconversion (i.e., failure to develop immunity to the vaccine) and secondary, defined as loss of immunity after initial seroconversion (i.e., waning immunity). Since seroconversion is rarely checked or established after immunization, it is difficult to distinguish the two causes. Field trial conditions according to some studies show primary vaccine failure rates to be >5% (25,26,27). According to others, secondary vaccine failures do not play a significant role in measles outbreaks (23,28). Interestingly, 5% of those vaccinated experience seroconversion some 10 years after vaccination (29). Cases of secondary vaccine failures have been documented (30,31,32), and important questions remain unanswered regarding the role and effect of waning immunity as a factor for measles eradication. Questions such as the ability to transmit the virus after secondary vaccine failure and successful revaccination and its sustainability after secondary vaccine failure remain unanswered (32).
In 1978, the CDC set out to eradicate measles within 5 years. Although this goal was overly ambitious and not achieved, the incidence of measles decreased by 90% (33). The pattern of reasoning was to eliminate the measles virus like that of smallpox. However, the eradication of measles posed a far more substantial obstacle than did smallpox (34,35). For the 10 years from 1979 to 1988, an average of fewer than four deaths from measles occurred annually. This trend was altered in 1983 when the number of reported measles cases doubled for all age groups over the next 5 years, and in 1989 to 1990,
the United States experienced the worst epidemic of measles in nearly 20 years with more than 46,000 cases by 1991. The measles vaccine efficacy in the 1989 to 1990 epidemic is similar to those in previous years and indicates that this measles epidemic occurred despite high vaccine effectiveness (36).
the United States experienced the worst epidemic of measles in nearly 20 years with more than 46,000 cases by 1991. The measles vaccine efficacy in the 1989 to 1990 epidemic is similar to those in previous years and indicates that this measles epidemic occurred despite high vaccine effectiveness (36).
Measles outbreaks in the United States include the following reported incidents. Between March 3 and April 18, 1984, an outbreak of measles occurred in a high school in Massachusetts with a documented school immunization level of 98% (37). According to Nkowane et al. (37), vaccine failures may perpetuate an outbreak even in highly vaccinated population, depending on how they are dispersed in the population and the extent of exposure. A case of more than a dozen outbreaks among students in junior and senior high schools occurred despite >95% documented immunization on or after their first birthday. In 1985, at Corpus Christi, Texas, a measles outbreak occurred, even though vaccination requirements were fully enforced for school attendance. According to Gustafson et al. (38), outbreaks occurred even though more than 99% of the students had been vaccinated. From January 4 to May 13, 1985, an outbreak of 137 cases of measles occurred in children in Montana despite a 98.7% vaccination coverage of the students (39). Between January 1 and September 1, 1986, a sustained outbreak of 235 cases of measles-like rash illness occurred in Dade County, Wisconsin (40). The mean age of persons with measles was 13 years. An audit of 13 of the 30 schools where measles occurred showed that more than 96% of the enrolled students had prior measles vaccination. According to Edmonson et al. (40), the paradox of supposedly high measles vaccine efficacy and occurrence of measles outbreak in a highly vaccinated population can be explained in two ways. One, “the measles virus is so contagious, particularly because of airborne spread from point sources that measles elimination will require that both vaccine efficacy and vaccination coverage be higher than previously estimated. Second, cases of measles outbreak must take into account the occurrence of secondary measles vaccine failure (i.e., waning immunity).” However, a meta-analysis of published studies documenting secondary vaccine failures was performed by Anders et al. (41) and found that the estimated rate of secondary failure was 0.02%. The majority of vaccine failures are attributed to primary vaccine failures. Epidemics in the United States from 1989 to 1991 estimated the vaccine failure (i.e., mostly primary) to range from 2% to 12%, depending on the year (42,43,44,45). Overall, and depending on the year involved (1989 to 1991), it is said that 20% to 40% of the measles cases involved individuals previously immunized with measles (46).
To further define measles epidemiology in the United States and explore possible reasons why measles has not been eliminated, Markowitz et al. (23) analyzed outbreaks that occurred in 1985 and 1986. They examined measles outbreaks among preschool-age, school-age, and post-school-age persons. A large majority of the outbreaks occurred in school-age children. Outbreaks are attributed to primary and secondary vaccine failures, but they also challenge the concept of “herd immunity.” Herd immunity is the resistance of a group to infectious attack by microbes due to immunity by a large proportion of its members. Mathematical modeling asserts that vaccine efficacy of 95% to 97% is required to interrupt measles transmission and to prevent outbreaks should the measles virus be introduced to the population. One of the models assumes a contact rate of 14 to 18 persons; that is, an infected person would come into contact with an average of 14 to 18 susceptible people. In school settings, the contact rate may be much higher. Airborne transmission (47), if it is a factor, may also increase the contact rate. An increased contact rate in the mathematical modeling would require higher vaccination levels than that which presently exists. The authors of this chapter question whether such high vaccination levels (i.e., 95% to 97%) is possible to achieve and at what cost. We will shortly discuss the role of genotypic changes in the measles virus itself and antigenic drift and its role in countering vaccine efficacy but consider that human genetics alone may be enough to thwart the needed vaccine efficacy of 95% to 97% to interrupt measles transmission and prevent outbreaks. In 1991, a study of the communities of Rochester, Minnesota, Northern Newfoundland and Labrador, Canada, demonstrated, on average, negative antibody level rate among schoolchildren of approximately 10% despite a high rate of uptake of measles vaccine. Furthermore, in those cases involving low antibody titers, there was a high number of siblings. This discovery suggested that primary vaccine failure may be inheritable (48). To further investigate the role of heredity, twins were studied following MMR vaccination. Tan et al. found that the genetic variance, the variance in antibody levels presumably due to genetic effects, was 0.49 for measles, 0.54 for mumps, and 0.13 for rubella. Heritability, the ratio of genetic variance to total variance, was 88.5% for measles, with the lower bound of a one-sided 95% confidence interval equal to 52.4%. The heritability was, for mumps, 38.8% with a lower bound of 1.60%. The heritability for rubella was 45.7% with a lower bound of 4.94%. The authors concluded that genetic influences play a substantial role in the variation of antibody levels following immunization against measles and, to a lesser extent, mumps and rubella. (49). This further places into question the efficacy of herd immunity as part of the vaccination strategy. As Fine and Zell (50) commented, herd immunity thresholds for disease eradication are based on the assumption that immune and susceptible
individuals are randomly distributed. Fine and Zell (50) assert that vaccines (and hence immune individuals) are not randomly distributed. Additionally, vaccine failures are not randomly distributed and susceptible individuals may be clustered, isolating them from indirect protection by immune members of the population. Socioeconomics may also be a factor; infection may be introduced into communities with poor nutrition, lack of hygiene, health care, etc. at a higher rate than those into higher socioeconomic communities with better nutrition and health care. Measles outbreaks are not exclusive to the United States. From 2000 to 2005, 27 adult measles patients were admitted to a regional hospital in Novosibirsk, Russia despite high vaccination coverage for the region. Half of the vaccinated patients demonstrated evidence of secondary vaccine failures (51). In March to May 2006, the highest incidence of measles in New South Wales, Australia occurred. There were 33 notified cases of measles in children aged 1 to 14 years. Six of these children had a confirmed history of vaccination with at least one dose of MMR (52).
individuals are randomly distributed. Fine and Zell (50) assert that vaccines (and hence immune individuals) are not randomly distributed. Additionally, vaccine failures are not randomly distributed and susceptible individuals may be clustered, isolating them from indirect protection by immune members of the population. Socioeconomics may also be a factor; infection may be introduced into communities with poor nutrition, lack of hygiene, health care, etc. at a higher rate than those into higher socioeconomic communities with better nutrition and health care. Measles outbreaks are not exclusive to the United States. From 2000 to 2005, 27 adult measles patients were admitted to a regional hospital in Novosibirsk, Russia despite high vaccination coverage for the region. Half of the vaccinated patients demonstrated evidence of secondary vaccine failures (51). In March to May 2006, the highest incidence of measles in New South Wales, Australia occurred. There were 33 notified cases of measles in children aged 1 to 14 years. Six of these children had a confirmed history of vaccination with at least one dose of MMR (52).
CHANGING VIRUS GENOTYPE AND ANTIGENIC VARIABILITY
One of the lessons learned from efforts to eliminate measles in the United States was tracking the measles virus genotypes as a critical means to determining if an endemic strain was circulating. A potential factor in the resurgence of measles in the United States and globally may be due to genetic changes in the wild-type virus. As a result of virus genotyping, complete shifts in the measles virus genotype have been documented, replacing the predominant circulating genotype with a new genotype. Reasons for this may include a superior fitness of the “new” virus strain compared to the “old” virus circulating in the population as well as chance, the importation of viruses entering a population and vaccination. Nojiri et al. (53) developed a stochastic model of the transmission dynamics of measles simulating the effects of different levels of migration, vaccination coverage, and importation of new genotypes on patterns in the persistence and replacement of indigenous genotypes. Complete replacement in the genotype of the strain circulating in populations may occur because of chance alone but the rapid replacement of the indigenous genotype was unlikely to occur if the vaccination coverage was low. However, the rapidity of replacement occurred as the vaccination coverage increased. Several strains of wild-type measles viruses have genetic and antigenic variability (54,55,56,57,58,59). In Germany, new genotypes of the measles virus have been discovered replacing the previously circulating strain (60). Genetic and antigenic characterization of 14 wild-type measles viruses isolated from four provinces in the People’s Republic of China during 1993 and 1994 found a new genetic group in 13 of 14 Chinese viruses based on the sequence analyses of the hemagglutinin (H) and nucleoprotein (N) genes (61). In the United States, between 1993 and 2001, measles virus sequences obtained from 41 outbreak and 51 sporadic cases were representative of only 12 of 22 genotypes recognized by WHO at that time (62). Furthermore, during this time period, sequences identical to the vaccine were found in persons showing rash and fever as well as being unvaccinated (63).
Tamin et al. (64) performed an analysis of current wild-type and vaccine strains of the measles virus and showed that recent strains of wild type had antigenic changes detectable by monoclonal antibodies. The degree of antigenic shift correlated well with predicted amino acid substitutions in the H protein. The study also showed that the new and modified epitopes on the wild-type strains are not present in the vaccine strains. Although the wild-type strains may currently be neutralized by vaccine-induced antibodies, genotypic changes resulting in antigenic shift, when combined with vaccine failures, may increase infection and transmission within highly vaccinated populations. Bellini et al. (65) analyzed the genetic sequences of the H, F, and N genes of the Edmonston-derived vaccine strains and vaccine strains derived from independent isolates of the measles virus. Their findings showed that even though the vaccine viruses had a diverse geographic origin and different attenuation procedures, their sequences differed by no more than 0.5% to 0.6% at the nucleotide levels. The F gene was very stable but the degree of variability was greater in the vaccine strains compared with the wild type. This was attributed to cell culture adaptation and/or attenuation. The N sequences were highly conserved in the vaccine strains and highly variable in the wild types. The H gene was most susceptible to positive selective pressures during cell culture adaptation and/or attenuation in the vaccine strains. Analysis of wild-type isolates of their N, H, P, and M genes indicate distinct lineage. According to Bellini et al. (65), isolated measles virus strains from the United States contain the greatest number of overall genetic diversity to date. From 1954 to 1989, the average rate of nucleotide change in the H gene is 0.08% per year, whereas the wild-type isolates from 1977 to 1989, are 0.13% per year. The accelerated rates for the more recent isolates are within an order of magnitude of the rates calculated for the Influenza type A virus, a virus that evolves in response to immunologic pressure (66). Sera from recently infected individuals neutralize the current wild-type viruses four to eight times better than they neutralized the vaccine strains. Again, possible differences may exist between the wild-type strains of the measles virus and vaccine strains. The wild type may have at least one unique
or sufficiently modified region on the H protein that is immunodominant than that in the vaccine strain.
or sufficiently modified region on the H protein that is immunodominant than that in the vaccine strain.
A genetic study by Rota et al. (58) of wild-type strains of measles virus isolated from recent epidemics showed that the greatest degree of genetic change were those from the wild-type viruses isolated from the United States, Canada, and the United Kingdom. Rota et al. (58) doubt the role of antigenic drift in the resurgence of measles during the last 5 years, but they do suggest that, “before the widespread use of measles vaccines in the 1960s, measles viruses were genetically homogenous and a single lineage of measles virus may have existed.” The vaccine pressure may have driven virus evolution a step forward and at a faster rate as demonstrated in Nojiri et al.’s (53) stochastic models. With respect to long-term effects, future variants may accumulate enough mutations that vaccine-induced immunity may no longer prevent the so-called vaccine-preventable diseases.
The WHO Measles and Rubella Laboratory Network, serving 166 countries in all WHO regions, continues to characterize the wild-type measles viruses in order to study the transmission pathways of the virus and is an essential component of laboratory-based surveillance. Specifically, the genetic data can help confirm the sources of virus or suggest a source for unknownsource cases as well as to establish links, or lack thereof, between various cases and outbreaks (67).
ADVERSE EVENTS ASSOCIATED WITH THE MEASLES VACCINE
Adverse events following measles vaccination are fever of 103°F (39.4°C) or higher in 5% to 15% of recipients and transient rash (68,69). The fever and rash can last 1 to 2 days and occur between the 5th and 12th day after vaccination. For the MMR vaccine, the frequency of adverse events may be as high as 16.3 reports per 100,000 with the most common reports describing local pain, edema, and induration. Anaphylaxis due to gelatin hypersensitivity occurs occasionally. Confirmed associations include thrombocytopenia, febrile seizures, anaphylaxis, and acute arthritis, whereas vasculitis, otitis media, conjunctivitis, optic neuritis, and Guillain-Barre syndrome (GBS) remain unconfirmed (70).
In the 1960s, formalin-inactivated measles vaccines were given, and initial reports showed high antibody titer response in immunized individuals. Several years later, these individuals presented with fever, pneumonia with pleural effusions, and severe petechial or hemorrhagic rash that had an atypical distribution over the skin during outbreaks of natural measles. In addition, some of these individuals exhibited an Arthus-type skin lesion when reimmunized with live measles vaccine (71,72).
ADVERSE REACTIONS
Soon after the administration of the measles vaccine, children began contracting a new form of measles termed atypical measles. Three hundred eighty-six Cincinnati children received three doses of the killed measles vaccine. Nine cases of atypical measles were reported. One hundred twenty-five had been exposed to the measles, and the disease developed in 54 children (73). Ten children who had received the killed measles vaccine 5 to 6 years earlier had atypical measles. Pneumonia that resisted all medical treatments developed in nine of these children (74). Despite these disturbing results, researchers published articles on the benefits of this measles vaccine (75). To this day, it is unknown whether the problem is inherent to the killed measles viruses or due to the vaccine processing (76).
Live attenuated EZ vaccine, which was developed at the Institute for Immunology in Yugoslavia and produced in HDC, was indicated to be suitable for immunization in children before the age of 9 months (77,78,79). The EZ vaccine was immunogenic at ages 4 to 6 months in several countries. In 1989, WHO recommended its use in countries where measles was a substantial cause of death before the age of 9 months (80). This recommendation was then reversed after data from three countries (Guinea-Bissau, Senegal, and Haiti) demonstrated increased mortality among children who received the high-titer vaccine compared with recipients who received the standard vaccine at 9 to 10 months of age (81). The EZ vaccine was protecting these children against the measles but they were dying of other diseases (pneumonia, diarrhea, parasitic infections) at a rate of 20% in the years to follow. Researchers cannot explain the excess mortality linked to the EZ and Schwartz’s vaccines, although they do suspect immune suppression. Compared with children who receive low-titer vaccines, high-titer recipients had a lower percentage of circulating CD4+ lymphocytes and consistently lower mitogen-induced lymphoproliferation and delayed type hypersensitivity (DHT) response (82). Following the reduced survival of recipients of the EZ vaccine in several studies (83,84,85), WHO recommended that vaccines with a titer of 104 to 107 plaque-forming units (PFUs) should no longer be used in routine immunization programs (86).
Infant mortality caused by vaccines such as the EZ vaccine is an example of just how vaccines in the market place are actually “experimental.” It may take years of close clinical observation to uncover an adverse consequence of a particular vaccine, which initially appears beneficial. Is immune suppression versus immune activation a normal course for viral infections? Scientists know very little about the measles virus (76). A prevailing observation was discovered with the EZ vaccine.
The increased mortality did not occur until the second year of life or later, a considerable time after vaccination. This is an example contrary to the arbitrary “reasonable” time of 24 to 18 hours allotted by vaccine proponents for an adverse reaction to be temporally associated to a particular vaccine. An accurate period of post-inoculation should be scientifically demonstrated for the incidence of an adverse effect of a particular vaccine. Without this period being defined, vaccine reporting systems such as the Vaccine Adverse Effects Reporting System (VAERS) will continue to be biased toward underreporting and correspondingly distorted.
The increased mortality did not occur until the second year of life or later, a considerable time after vaccination. This is an example contrary to the arbitrary “reasonable” time of 24 to 18 hours allotted by vaccine proponents for an adverse reaction to be temporally associated to a particular vaccine. An accurate period of post-inoculation should be scientifically demonstrated for the incidence of an adverse effect of a particular vaccine. Without this period being defined, vaccine reporting systems such as the Vaccine Adverse Effects Reporting System (VAERS) will continue to be biased toward underreporting and correspondingly distorted.
Since the licensure of the measles vaccine 25 years ago the number of measles cases has declined by 98% to 99% (87). In 1981, the number of reported measles cases annually in the United States averaged 3,000. However, frequent periodic outbreaks occurred among the vaccinated population. In 1986, 6,282 cases were reported (87). Between 1989 and 1991, 55,000 measles cases and 132 associated deaths occurred (88). In 1989, the CDC received reports in the first 4 months of the year of 56 outbreaks, which accounted for more than a 300% increase in the incidence of measles. Interestingly, more than half of the cases occurred in those older than 10 years of age, with 32% being college students, an abnormal age distribution for the measles (33,89). Only a minority (13%) of the measles cases appeared in unvaccinated people. An increased risk of adverse effects may exist in individuals already immune to measles and/or rubella when they receive additional doses of the antigens (90,91,92). The long-term efficacy of the vaccine is still in question.
In the first 26 weeks of 1989, 13 States reported at least 100 cases and accounted for 6,588 (89.8%) of all reported cases of measles. Again, more than half occurred among the appropriately vaccinated children. In 1985 to 1986 most of the cases occurred in persons who either had been appropriately vaccinated (60%) or in children not old enough to receive routine vaccination at 15 months of age (27%) (93,94). In 1985 and 1986, 101 outbreaks (67%) primarily occurred among vaccinated school-age children. In contrast, only 27% occurred in unvaccinated preschool children (33). Of the 256 students at Maryland State College who were evaluated, 43 (21%) were seronegative for measles alone, 13 (5%) were seronegative to rubella alone, and 5 (2%) were seronegative to both. Among those seronegative to measles, 86% were vaccinated previously (95).
The side effects and adverse reactions of MMR are associated with clinical manifestations in approximately 5% to 20% of the vaccine’s recipients (96). Interestingly, although there are frequent measles outbreaks, many North American physicians have never seen a case of measles (87,97). Failure of the measles vaccine to immunize infants >12 months of age correlated serologically with the presence of maternal antibodies in the infant, which interfered with successful vaccination (57). At the time of these studies, most women of childbearing age acquired measles immunity naturally. Consequently, they exhibited a higher antibody titer. In contrast with mass vaccination today, most mothers have acquired measles artificially.
In the United States, the definition of vaccine failure has been expanded to include not only inadequate/waning immunity but also measles vaccination before the 15th month of age (98). The occurrence of measles outbreaks among the vaccinated population has stimulated interest in the mechanism of vaccine failures and the reason for inadequate immunity. Individuals vaccinated with the measles virus despite previous vaccination had a normal capacity to generate a humoral and cellular immune response to the vaccine. Vaccine failure in these individuals was said to be due to the host’s inability to generate an enhanced cellular immune response thereby increasing the vaccine recipients’ susceptibility to measles infection (99). In areas free from natural measles, antibody levels for MMR are likely to decline with advancing age. Revaccination would be needed to boost decreasing antibody titers (100), unlike natural disease, which confers life-long immunity (56).
Alterations in immune cell function can be detected in most individuals after vaccination (56,101,102,103,104,105,106,107,108). The MMR vaccine will suppress polymorphonuclear neutrophil function (109), the initial defense response of the immune system.
Vaccine-induced immunity is shorter-lived than the lifelong immunity conferred by natural disease (71,110). This raises the question as to the long-term effects in most of the population of individuals who are without any immunologic contact with the naturally occurring wild-type measles virus, a virus that increases antibody concentrations (111,112). The recommended age for initial measles vaccination has been modified twice in the United States. In 1965, the vaccination age was increased from 9 to 12 months, and in 1976 it was again increased to 15 months. These alterations were due to persistent maternal antibodies (113,114). Studies have indicated that infants vaccinated at 12 through 14 months of age may have an elevated risk of contracting measles later in childhood (115,116,117,118). Are infants more susceptible in recent years to measles because of an early decline in maternal antibodies now induced by vaccines rather than natural infection? Do vaccines deplete retinoids and/or other antioxidants thus increasing the risk of autoimmunity? The answers to these questions remain unknown and a reassessment of the measles vaccine is needed (110,111). This discussion illustrates the possibility that vaccination against measles in one generation may open a window of opportunity for infection in infants of the next generation.
One argument against vaccinating against measles is that measles is a mild disease with rarely a serious complication and negligible rate of fatalities in healthy children. More than half of the deaths occur in persons with serious chronic disease or disability (119). The degree of immunity and the length of time of “protection” still remain controversial. On the one hand, the efficacy of a single dose of measles vaccine appears to give 90% protection for at least 15 years (120). On the other hand, a properly administered vaccine will, in most cases, provide life-long immunity (121). This is assumed, not confirmed.
Several groups of central nervous system (CNS) diseases complicate measles virus infection/vaccination (122,123). The first incident of measles and/or mumps causing encephalitis or encephalopathy was a report of 23 cases of neurologic disease after measles vaccination in the United States from January 1965 to February 1967, 3 to 24 days post-inoculation. Curiously, it was concluded that, “no single clinical or epidemiological characteristic appears consistent in the reports of cases of possible neurologic sequela of measles vaccine” (124). Eighty-four cases of neurologic disorders occurring within 30 days of vaccination against measles were reported to the CDC over the 9-year period from 1963 to 1971. Fifty-nine patients with extensive neurologic disorders, which included encephalomyelitis, were reported (125). A study based in Canada reported a rate of 1.1 cases of meningitis per 100,000 doses of MMR, a statistically significant finding (126). Several reports of encephalopathy following measles vaccination can be found in VAERS between November 1990 and July 1992. Seventeen cases were suggestive of encephalopathy or encephalitis from vaccines (mostly MMR) from age 5 to 16 years of age. Encephalitis is thought to occur in one in a million doses of measles vaccine (127).
The Institute of Medicine concluded that there is inadequate evidence to accept or reject a causal relationship between measles or mumps vaccination and encephalitis or encephalopathy (128). We suggest, however, there is a literature base (as discussed above) for the biological correlation between measles vaccine and encephalopathy.
Subacute sclerosing panencephalitis (SSPE) is characterized by a long latent period after infection/vaccination. The clinical manifestations are progressive mental retardation and involuntary movements over several months or years (129,130,131). Laboratory and epidemiologic studies have linked SSPE to measles infection/vaccination. The first report of SSPE in a patient with a negative history of measles but a positive history of vaccination with live attenuated measles vaccine was reported in 1968 (132). The child received a measles vaccine 3 weeks before the onset of the symptoms and died 18 months postinoculation. Newly diagnosed cases of SSPE occurring in children identified by their medical histories as being vaccinated against measles increased approximately threefold from 1967 to 1974 (133). SSPE is a recognized sequela of measles infection, and it is biologically plausible that it could occur after administration of the live attenuated vaccine. The Institute of Medicine suggests that the issue is still in question and has concluded that the evidence is inadequate to accept or reject a causal relationship between measles vaccine and SSPE (134).
IMMUNE THROMBOCYTOPENIC PURPURA
Recent data suggest that the MMR vaccine can cause immune thrombocytopenic purpura (ITP). The United States administered an MMR similar to that used in Finland. Finnish researchers discovered 23 cases out of approximately 700,000 children immunized with MMR developed ITP in 1992. The children developed thrombocytopenic purpura between 7 and 59 days post-inoculation (135,136). On the basis of the data from Finland and Sweden, the incidence appeared to be in the order of 1:30,000 to 40,000 vaccinated children. The Institute of Medicine concluded that the evidence establishes a causal relationship between MMR vaccine and ITP (137). France et al. (138) found an attributable risk of 1 case per 40,000 doses of MMR administered in the second year of life. Since approximately 4 million children are born per year in the United States and the first dose of MMR is routinely recommended by the CDC in the second year of life, then approximately 100 cases of ITP per year would be attributable to MMR vaccination in the United States. Chronic ITP is said to occur at approximately 2 of 20 ITP cases post-MMR vaccination among children 12 to 23 months of age (139). Hemorrhages requiring blood transfusion and reports of intracranial hemorrhage or death have been reported in the literature (139,140,141,142). In a systematic review of the literature, Mantadakis et al. (143), based on 12 studies, estimated that the incidence of MMR-associated ITP ranged from 0.087 to 4 (median 2.6) cases per 100,000 vaccine doses.
Measles and mumps viruses are grown in cell cultures of chicken embryo fibroblasts. Concerns have been acknowledged regarding the safety of egg-derived vaccines in individuals who are sensitive to egg protein since there is an undefined portion of the population who are biologically sensitive to it (144). The suspected correlation between measles and mumps vaccines and anaphylaxis are based on reports following the administration of the MMR vaccine (145,146,147,148,149).
In 1981 there were reports of immediate reactions 30 minutes following the administration of a live attenuated measles vaccine in three Australian children. Fifteen reports of reactions occurring within 30 minutes of vaccination with the live attenuated measles virus
were acknowledged by the Adverse Drug Reaction Advisory Committee in Australia from February 1980 to March 1982 (150). Nine cases of possible anaphylactic reactions were reported in the United States by VAERS between November 1990 and July 1992 following administration of the MMR vaccine (144).
were acknowledged by the Adverse Drug Reaction Advisory Committee in Australia from February 1980 to March 1982 (150). Nine cases of possible anaphylactic reactions were reported in the United States by VAERS between November 1990 and July 1992 following administration of the MMR vaccine (144).
Several citations in the literature describe safe measles vaccines and MMR vaccination in patients with varying degrees (including severe reactions) of allergic symptoms to egg protein (151,152). Skin testing with the MMR vaccine itself has been evaluated. A case series of 140 children with egg hypersensitivity were evaluated. The authors of the study concluded that MMR skin testing was not helpful in predicting an adverse reaction to the MMR vaccine (153). It must be noted that these studies are limited to only Type 1 IgE-mediated reactions. The authors did not address the viability of Types II, III, and IV hypersensitivity reactions and what effects and/or reactions were plausible. The evidence establishes a causal relation between MMR and death from anaphylaxis or complications of severe thrombocytopenia (154).
In 1989, the measles case fatality rate for admissions to Goroka Base Hospital (GBH) in New Guinea was 17%, the highest level recorded in 20 years (155). It appears that measles infection changed from being a disease of apparently minor importance to a major killer of children admitted to GBH. Reviewing the history of infectious diseases there is the suggestion that viruses alter their virulence when their environment is altered. Is it possible that the practice of vaccination over the past 25 years has caused the measles virus to mutate? This appears to be a more likely explanation than spontaneously magnified virulence (see the section “Changing Virus Genotype and Antigenic Variability” above). This would be analogous to bacterial resistance selected for by antibiotic therapy.
VACCINATION CONTRAINDICATIONS
Vaccination should be postponed in individuals suffering from severe febrile illnesses; in persons who have received IG, whole blood or other antibody-containing blood products for 3 months to prevent or avoid possible seroconversion failure; to pregnant women and to people with a history of anaphylactic hypersensitivity to neomycin and eggs; to people with immunosuppressed or compromised immune responses due to illness or medication (33).
MUMPS VACCINATION
Mumps has classically been considered a disease of children and young adults, with the highest incidence in persons between the ages of 5 to 9 years. The disease is more severe in older children and adults and a single attack, clinical or subclinical, confers lifelong immunity. With vaccination, a marked decline in reported cases in all age groups has been observed with an all-time low of 2,982 cases reported in 1985. This represented a 98% decline in the disease when compared to that of 1968. In 1986 to 1987, there was a resurgence with the disease. This affected all groups but more so for children ages 10 to 19 years, showing a seven to eightfold increase compared to 1985. Provisional data from 1988 showed an incidence of 1.4 per 100,000 in states with kindergarten to grade law vaccination laws, a 1.0 per 100,000 in states with partial laws and 3.2 per 100,000 in states with no state laws regarding vaccination (156).
Mumps Virology
The mumps virus belongs to the paramyxovirus family. Its genome consists of a negative-sense single-stranded RNA contained in a helical nucleocapsid along with an RNA-dependent RNA polymerase and a nucleoprotein. The virus lipid layer is derived from the host cell wall and contains glycosylated proteins with hemagglutinating (H) and neuraminidase (N) activities and a fusion (F) protein.
Clinical Features
Infection in a susceptible host by the mumps virus occurs through the respiratory system either by droplets or droplet-spread from saliva or fomites. The incubation lasts an average of 18 days, and the virus replicates in the nasopharyngeal mucosa and regional lymph nodes. The parotid glands are distinctively involved as well as the CNS, the gonads, pancreas, mammary glands, meninges, myocardium, kidneys and, other glands.
Parotid gland enlargement is the most commonly recognized manifestation. Mumps is more severe in older children and adults. Epididymo-orchitis is the most common nonsalivary manifestation, present in 15to 29-year-old males 30% to 38% of the time (157). Testicular atrophy may occur more commonly unilaterally but sterility rarely results. Meningoencephalitis occurs commonly. CNS involvement results in headache, mental confusion, a stiff neck, and CSF lab abnormalities.
Mumps Vaccine
In 1950, a formalin-killed vaccine was introduced which was only 80% protective in outbreak situations; it produced short-lived IgG antibodies directed against the hemagglutinating and neuraminidase proteins but not against the fusion protein and required yearly booster shots (158). Mumps virus isolated from a child (Jeryl Lynn B strain) was attenuated by 17 passages through embryonated hens’ eggs and 10 passages through chick
embryo and was licensed in 1967. The vaccine is given as a trivalent along with measles and rubella vaccines known as the MMR vaccine. After administration of the vaccine, it was shown to produce protective neutralizing antibodies in 97% of children and 93% of adults. The antibody levels are lower and are produced more slowly but have been shown to have efficacy in households and schools at 95%. In other studies, they were shown to have efficacies in the order of 75% to 91% (159,160,161).
embryo and was licensed in 1967. The vaccine is given as a trivalent along with measles and rubella vaccines known as the MMR vaccine. After administration of the vaccine, it was shown to produce protective neutralizing antibodies in 97% of children and 93% of adults. The antibody levels are lower and are produced more slowly but have been shown to have efficacy in households and schools at 95%. In other studies, they were shown to have efficacies in the order of 75% to 91% (159,160,161).
Success and Failures of Mumps Control
Vaccine Efficacy In 1977, the ACIP recommended the use of the attenuated mumps vaccine along with measles and rubella (MMR) in children after the age of 12 months. A significant decline in the incidence of reported mumps cases hit an all-time low in all age groups in 1985 with 2,982 cases—a decline of 98% when compared to cases reported in 1968 (156).
Vaccine Failure In 1986 to 1987, there was a resurgence of mumps. All age categories were affected but more so for individuals 10 to 19 years of age where there was a sevento eightfold increase compared to 1985. The age group with the highest risk shifted from the 5 to 9 years of age group to older age groups. This shift to an older age group was similar but less marked than what was observed in measles and rubella cases. This raised concerns about the efficacy of the vaccine (156). In 2006, the United States experienced the largest nationwide mumps epidemic in 20 years. A total of 6,584 cases of mumps were reported, with 76% occurring between March and May. There were 85 hospitalizations, no reported deaths, and 85% of patients lived in eight contiguous Midwestern states. According to Barskey et al. (162), the unexpected elements of the outbreak included very abrupt time course (i.e., 75% of cases occurred within 90 days), geographic focality (i.e., 85% of cases occurred in eight rural Midwestern states), rapid upward and downward shift in peak age-specific attack rate (i.e., 5 to 9-year-olds to 18 to 24-year-olds, then back), and a two-dose vaccine failure. Sixty-three percent of the case-patients had received two doses of vaccination for mumps. According to Dayan et al. (163), despite a high coverage rate with two doses of mumpscontaining vaccine (i.e., the national two-dose coverage among adolescents was 87%, the highest in US history), a large mumps outbreak occurred, characterized by two-dose vaccine failure, particularly among Midwestern college-age adults who probably received the second dose as schoolchildren.
Side Effects and Adverse Reactions
Vaccine side effects have been found to be mild parotitis, fever, and rash. The vaccine has been shown to infect the placenta when given to pregnant women (164).
Mumps has been associated with aseptic meningitis. Nottingham (UK) Public Health Laboratories isolated mumps virus from the cerebral spinal fluid (CSF) of eight children following administration of Urabe-containing MMR vaccine (165). Seven of the isolates resembled the vaccine strain (the eighth sample could not be typed). The rate was virologically confirmed and suspected MMR-associated meningitis was calculated to be 1 case per 3,800 doses. The authors of the study also reviewed laboratory records for approximately a 3-year period and determined that there were excess cases of lymphocytic meningitis in the group that was recently vaccinated with MMR compared with those that were not.
In 1989 a nationwide surveillance of neurologic complications after administration of the mumps vaccine was conducted in Japan. This was based on the notification of cases and the testing of the mumps virus isolated from CSF for their relatedness to the vaccine by nucleotide sequence analysis. Among 630,157 recipients of MMR vaccine containing Urabe Am9 mumps vaccine, there were at least 311 meningitis cases (166).
In 1986, soon after the vaccination with MMR in Canada, an increase in the number of mumps meningitis cases began to appear. In a study at Montreal’s Children’s Hospital of four patients with meningitis that appeared within 19 to 26 days after receiving the Urabecontaining vaccine, mumps virus was isolated from the patients’ CSF. It was confirmed that these patients had no previous contact with any persons contracting with naturally occurring mumps virus (167,168).
Introduction of the vaccination for MMR in Japan in 1989 coincided with reports of mumps vaccineassociated meningitis (169). There were 35 cases of aseptic meningitis within 8 weeks of vaccination with MMR. The patients had no history of contact with individuals with natural viral mumps infection. An extended nationwide survey of the neurological complications after mumps vaccine administration revealed 311 cases of vaccine-related meningitis among 630 (49%) individuals vaccinated with MMR. There is a strong biological evidence that the mumps virus could cause aseptic meningitis. The incidence appears to be one in a few thousand recipients of the Urabe strain (166). In the United States where the Jeryl Lynn strain is used, the occurrence of “atypical” mumps has developed. Symptoms include fever, loss of appetite, nausea, malaise, and a 24-hour erythematous papular rash (170). Six schools in Atlantic County, New Jersey, reported 63 cases of the mumps (a 40% increase over the previous year). Vaccination compliance was 95% and was given as not the reason for the outbreak. An outbreak in 1983 in the Egg Harbor Township school district in Atlantic City, New Jersey, represented a 40% increased incidence of the mumps compared with the previous year (171). Nineteen cases of serious neurological sequelae
possibly associated with the Jeryl Lynn mumps strain were reported in Sweden from 1982 to 1984 (172). Interestingly, the live virus mumps vaccine was licensed in 1967 but the vaccine’s presence took a decade before it was endorsed as a routine vaccine and even then it was slowly accepted. The reason for the vaccine’s deferring acceptance was due to the benign nature of mumps as well as the high cost of the vaccine (173). In lieu of its slow acceptance, mumps was on the decline. Since 1986 there has been a resurgence of mumps among middle and high school students (174). As mumps vaccination compliance increased, substantial outbreaks began to occur. Mumps is complicated by orchitis in one-fifth of all cases of mumps occurring in males after puberty (175). It appears that the age distribution of the mumps has been altered from 4- to 10-year-olds to over 10 years of age by the vaccine. Is this a cyclic change or is it possible that the advocates of vaccination, in trying to direct the natural course of the mumps, have transposed a low incidence of orchitis in childhood to a greater incidence in the prepubescent population where these complications are more devastating?
possibly associated with the Jeryl Lynn mumps strain were reported in Sweden from 1982 to 1984 (172). Interestingly, the live virus mumps vaccine was licensed in 1967 but the vaccine’s presence took a decade before it was endorsed as a routine vaccine and even then it was slowly accepted. The reason for the vaccine’s deferring acceptance was due to the benign nature of mumps as well as the high cost of the vaccine (173). In lieu of its slow acceptance, mumps was on the decline. Since 1986 there has been a resurgence of mumps among middle and high school students (174). As mumps vaccination compliance increased, substantial outbreaks began to occur. Mumps is complicated by orchitis in one-fifth of all cases of mumps occurring in males after puberty (175). It appears that the age distribution of the mumps has been altered from 4- to 10-year-olds to over 10 years of age by the vaccine. Is this a cyclic change or is it possible that the advocates of vaccination, in trying to direct the natural course of the mumps, have transposed a low incidence of orchitis in childhood to a greater incidence in the prepubescent population where these complications are more devastating?
Neurological complications occurring in children vaccinated with Jeryl Lynn or Rubini mumps strains do not appear to occur at a higher frequency compared to those who are unvaccinated (176,177).
A nationwide surveillance of neurological complications after mumps vaccine administration in Japan during 1989 revealed 311 vaccine-related cases of meningitis among the 630,157 vaccines administered (16). The incidence rates of meningitis were reported to be 1 in 2,026. A 7-year-old girl developed unilateral deafness 11 days after receiving MMR vaccine (178,179). Nineteen cases of serious neurological complications possibly associated with the Jeryl Lynn mumps strain were reported in Sweden (172).
Three cases of insulin-dependent diabetes mellitus 10 days to 2 weeks after inoculation with a mumps vaccine in a 2-, 3-, and 16-year-old, respectively, have been reported (180). One hundred twelve parents of diabetic children in Erie County, New York, were interviewed. The parents noted that 11% of those affected had received the mumps vaccine, with a median lag time of 3 years (181). Recently, Clifford et al. (182) reported on three cases of orchitis following vaccination with MMR vaccine, two with an onset within 3 days following vaccination. Orchitis is a common complication of mumps infection, particularly in post-pubertal males, and is also recognized as a very rare complication of mumps vaccination.
Vaccination Recommendations
As with the measles vaccine, our stance on informed consent, as discussed above, remains. For those who choose to vaccinate their child, the first dose of the vaccine is given to children as part of the MMR vaccine schedule. A second dose, as in measles, is recommended. Again, the second dose schedule contains much controversy. The ACIP recommends that the vaccine (MMR) should be given prior to school entry. The Committee on Infectious Diseases of the Academy of Pediatrics suggests the second dose schedule at the sixth-grade level.
Vaccination Contraindications
Vaccination should be postponed in persons who have received IG, whole blood, or other antibody-containing blood products for 3 months to prevent or avoid possible seroconversion failure—to pregnant women and to people with immunosuppressed or compromised immune responses due to illness or medication (146).
RUBELLA VACCINATION
Like mumps, rubella occurs most commonly in children 5 to 9 years of age. Prior to vaccination, rubella was seen in both epidemic and endemic forms in the United States. Clinical and subclinical entities of rubella confer lifelong immunity to the disease. However, it has been observed that reinfection is more likely to occur with vaccine-induced immunity as compared to infection with the wild-type. Rubella can be distinguished into two types, postnatal rubella which is mild and selflimiting and congenital rubella, a more severe, disseminated, and chronic disease.
Rubella Virology
The Rubella virus belongs to the genus Rubiviridae of the Togaviridae group of viruses. The virus has an outer envelope as in the measles and mumps virus and a single-stranded RNA core.
Clinical Features
Rubella is an illness characterized by a nondescript maculopapular rash of a short duration of 2 to 3 days. The incubation period for rubella is 14 to 25 days, during which time viremia results in the spread of the virus throughout the body. The prodromal stage is characterized by fever, malaise, and cervical and occipital lymphadenopathy. During this time period and for 1 to 2 days after the rash appears, the virus can be cultured from the blood. There is no pathological lesion characterized by rubella (183,184). The primary concern regarding rubella infection is in the first trimester of pregnancy which carries the highest fetal mortality due to the increased placental transmission of the
virus. Congenital rubella syndrome can be manifested by fetal death, deafness, cataracts, cardiac abnormalities, microcephaly, motor defects, thrombocytopenic purpura, hepatosplenomegaly, anemia, and low birth weight.
virus. Congenital rubella syndrome can be manifested by fetal death, deafness, cataracts, cardiac abnormalities, microcephaly, motor defects, thrombocytopenic purpura, hepatosplenomegaly, anemia, and low birth weight.
Rubella Control
Over 83 million doses of rubella have been administered since 1969 and there are still periodic upswings in incidence. Essentially, we have controlled the disease in persons 14 years of age and younger but have given a free hand in those 15 or older. The point of the rubella vaccine is not the prevention of rubella but the prevention of “congenital rubella syndrome” (185). Over 1,000 cases of rubella were reported between January and May of 1971 in Casper, Wyoming. This occurred 9 months after a rubella vaccination program in which 83% of elementary school children and 52% of pre-school children were inoculated (186).
The persistence of antibodies 10 years after rubella vaccination with three different vaccines in some 5,153 children on the islands of Kauai and Hawaii has been studied. The report demonstrated that within 4 years, the level of antibodies decreased by one-half as compared to the original levels immediately after vaccine injection (187).
Australian army recruits with confirmed lack of immunity to rubella were given the rubella (Cendevax) vaccine. The population was sent to a camp which had periodic outbreaks of rubella. Three to four months after vaccination, 80% of the men acquired rubella. Another similar trial on an institutionalized population resulted in a similar lack of immunity (188). It appears that the rubella vaccine may afford temporary protection to some but not all individuals vaccinated.
Acute arthralgia and arthritis following vaccination have been documented since the earliest studies of the rubella vaccine (189,190,191,192). These acute events have been associated to varying degrees with all rubella vaccine strains and occur more frequently in adult women than in men or prepubertal children of either sex (193). The literature suggests a causal relationship between the currently used rubella vaccine (RA 27/3) and acute arthritis (194,195).
There have been reports of numerous cases of paresthesia following rubella vaccination (196,197,198). At this time the Institute of Medicine concludes that there is insufficient evidence to indicate a causal relationship between the currently used rubella vaccine (RA 27/3) and neuropathies (199).
An investigation of vaccine failure in 13 Canadian adults was carried out. Seven of the recipients were partially immunized and six were fully immunized against rubella. These patients had a significant medical history: chronic inflammatory joint syndrome (n = 3), recurrent parotiditis (n =1), variable hypogammaglobulinemia (n =1), chronic lymphocytic chyroiditis (n =1) (200).
Two cases of congenital rubella were found after previously presumed maternal immunity, one of which was vaccinated. The authors concluded that the quality of antibody produced in women where seroconversion has occurred after vaccination may be inadequate for total protection compared with natural infection. There were significant differences in rubella-specific IgG, IgA, and IgM responses on subsequent challenge with rubella vaccine between vaccinated and the naturally immune (201,202).
Side Effects from Vaccination
Side effects from vaccination may include fever, rash, and lymphadenopathy as well as depression of platelet count. Optic neuritis, transverse myelitis, arthralgia, and arthritis may also be seen, particularly in adult women after vaccination. One group of scientists has isolated rubella virus from children with long-standing arthritis long after vaccination (203).
Vaccine Recommendations and Contraindications
As discussed previously, for those who choose to have their child vaccinated, the vaccination recommendations and contraindications are generally similar to the measles and mumps vaccine as is our stance on informed consent.
Vaccines and Autism
Given the extent to which we have reviewed the individual components of the MMR vaccine, we thought it appropriate at this juncture to review the controversies associated with the MMR vaccine (and vaccines in general) and their possible association (and possible cause and effect) with Autism Spectrum Disorder and other neurodevelopmental disorders (NDs). Three specific hypotheses have been proposed in the pathophysiology of autism in relation to vaccines: (a) the combination MMR vaccine causes autism by damaging the intestinal lining, which allows the entrance of encephalopathic proteins; (b) the ethylmercury preservative thimerosal in vaccines is a CNS neurotoxin, and (c) the simultaneous administration of multiple vaccines overwhelms the immune system (204).
In 1998, Wakefield et al. (205) described 12 children (mean age 6 years, age range 3 to 10 years; 11 boys) referred to a pediatric gastroenterology unit with a history of normal development followed by loss of acquired skills, including language, together with diarrhea and
abdominal pain. The children underwent gastroenterological, neurological, and developmental assessment and review of developmental records. Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were also performed. Barium follow-through radiography was done where possible. Biochemical, hematological, and immunological profiles were examined. According to Wakefield et al., the onset of the behavioural symptoms was associated with MMR vaccination in 8 of the 12 children, with measles infection in one child, and otitis media in another, based on parental reports. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in 7, but no granulomas. Behavioral disorders included autism (n = 9), disintegrative psychosis (n =1), and possible post-viral or vaccinal encephalitis (n =2). No focal neurological abnormalities were detected, and MRI and EEG tests were normal. Wakefield postulated that MMR vaccination caused intestinal inflammation that led to translocation of usually nonpermeable peptides to the bloodstream and, subsequently, to the brain, where they affected the development. The publication by Wakefield et al. have been cited as a major reason for the low uptake of vaccines in the United Kingdom (206,207). Several groups have since published studies to debunk the “Wakefield Hypothesis” (208,209,210). Despite assurances by those in the medical community that vaccines are safe, parents continue to have concerns about the safety of the MMR vaccine (211,212).
abdominal pain. The children underwent gastroenterological, neurological, and developmental assessment and review of developmental records. Ileocolonoscopy and biopsy sampling, magnetic-resonance imaging (MRI), electroencephalography (EEG), and lumbar puncture were also performed. Barium follow-through radiography was done where possible. Biochemical, hematological, and immunological profiles were examined. According to Wakefield et al., the onset of the behavioural symptoms was associated with MMR vaccination in 8 of the 12 children, with measles infection in one child, and otitis media in another, based on parental reports. All 12 children had intestinal abnormalities, ranging from lymphoid nodular hyperplasia to aphthoid ulceration. Histology showed patchy chronic inflammation in the colon in 11 children and reactive ileal lymphoid hyperplasia in 7, but no granulomas. Behavioral disorders included autism (n = 9), disintegrative psychosis (n =1), and possible post-viral or vaccinal encephalitis (n =2). No focal neurological abnormalities were detected, and MRI and EEG tests were normal. Wakefield postulated that MMR vaccination caused intestinal inflammation that led to translocation of usually nonpermeable peptides to the bloodstream and, subsequently, to the brain, where they affected the development. The publication by Wakefield et al. have been cited as a major reason for the low uptake of vaccines in the United Kingdom (206,207). Several groups have since published studies to debunk the “Wakefield Hypothesis” (208,209,210). Despite assurances by those in the medical community that vaccines are safe, parents continue to have concerns about the safety of the MMR vaccine (211,212).
Thimerosal, functioning as antibacterial and antifungal in vaccines, is approximately 50% ethylmercury, a neurotoxin. In 1997, the U.S. Food and Drug Administration (FDA) Modernization Act mandated that mercury (Hg) in all food and drugs must not only be identified but quantified. In 1999, the FDA found that children might be receiving as much as 187.5 mg of Hg within the first 6 months of life. Further, a review by the U.S. Food and Drug Administration found that thimerosal-containing vaccines (TCVs) for infants may have exceeded the 1995 Environmental Protection Agency (EPA) guidelines for exposure to organic Hg (1 µg/kg/d vs. 3 µg/kg/d in the previous 1985 EPA guidelines) (213). In response, the American Academy of Pediatrics and the Public Health sector recommended removing Hg in vaccines (214). The effects of organic Hg on neurologic development have been studied (215,216,217). Despite the documentation that increased Hg is present in newborns following vaccination (218), several publications support the safety of TCVs (219,220,221). Some have advocated that the benefits of preventing infectious diseases through TCVs in poor countries outweigh the risk- and cost-prohibitive aspects of removing thimerosal from these vaccines (222).
Concerns regarding the simultaneous administration of multiple vaccines and its effect on the nervous system and the development of the immune system have been raised (223), particularly in light of Wakefield’s Hypothesis and recommendations of monovalent vaccines in the delivery of the MMR vaccines. Our concern here involves not only the use of multi-valent vaccines and their effects on a developing neurological system but also the use of new-generation adjuvant vaccines, particularly when these new vaccines produce strong innate responses with unknown consequences as well as the use of certain cancer vaccines (224). For example, some vaccines are based on dendritic cells pulsed with tumor antigens which carry a substantial risk for autoimmunity (225). With respect to the effects on a developing immune system, the use of multi-valent vaccines raises the concerns on their effects on the various populations of regulatory T cells that have been demonstrated to play a central role in the maintenance of peripheral homeostasis and the establishment of controlled immune responses (226). Their identification as key regulators of the immune response, particularly in peripheral tolerance to allergens has opened an important consideration not only in the prevention and treatment of autoimmune diseases but also in their pathophysiology (see Chapter 10).
Autoimmune diseases as a consequence of vaccination have been firmly established clinically and in the scientific literature. For example, Guillain-Barré syndrome was associated with the 1976 to 1977 vaccination against influenza (see H. influenzae Viruses section) and the previously discussed thrombocytopenia with the MMR vaccines. An association between the hepatitis vaccine and multiple sclerosis was raised in France after 35 cases of primary demyelinating occurred in a hospital in Paris between 1991 and 1997, within 8 weeks of vaccination to the hepatitis B vaccine injection (227,228). Half of these patients were eventually diagnosed with clinical multiple sclerosis after a mean follow-up of 3 years. Studies have since been published ruling out the association between hepatitis B vaccination and the occurrence of demyelinating events or multiple sclerosis (229,230). However, what also became apparent was that the 35 affected patients were found to be at high risk for multiple sclerosis (i.e., mostly women, mean age around 30 years, over-representation of the HLA-DR2 antigen, and a positive family history of the disease) and may represent a situation of special circumstances.
In the last decade, the incidence and prevalence of Type 1 diabetes has been on the rise (231). The possibility that childhood vaccines may act as a trigger for this disease has been raised. Blom et al. (232) examined the possibility of vaccinations resulting in childhood diabetes.
For vaccination against tuberculosis, smallpox, tetanus, whooping cough, rubella and mumps, the authors found no significant effect on odds ratio for diabetes. However, the work of Classen and Classen (233) reject this claim of safety and argue that the potential risk of the vaccines outweigh their benefits (i.e., H. influenzae
For vaccination against tuberculosis, smallpox, tetanus, whooping cough, rubella and mumps, the authors found no significant effect on odds ratio for diabetes. However, the work of Classen and Classen (233) reject this claim of safety and argue that the potential risk of the vaccines outweigh their benefits (i.e., H. influenzae
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