Monday, 9th of February 2015 |
- Author Affiliations
1. 1 Immunisation Department, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK. 2. 2 Statistics Unit, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK. 3. 3 Immunisation and Diagnosis Unit, Health Protection Agency Centre for Infections, 61 Colindale Avenue, London NW9 5EQ, UK.Excerpts below; full text, with tables, is at http://ije.oxfordjournals.org/content/36/6/1334.full.pdf+html
Background When measles vaccines were widely introduced in the 1970s, there were concerns that they might cause subacute sclerosing panencephalitis (SSPE): a very rare, late-onset, neurological complication of natural measles infection. Therefore, SSPE registries and routine measles immunization were established in many countries concurrently. We conducted a comprehensive review of the impact of measles immunization on the epidemiology of SSPE and examined epidemiological evidence on whether there was any vaccine-associated risk.
Methods Published epidemiological data on SSPE, national SSPE incidence, measles incidence and vaccine coverage, reports of SSPE in pregnancy or shortly post partum were reviewed. Potential adverse relationships between measles vaccines and SSPE were examined using available data.
Results Epidemiological data showed that successful measles immunization programmes protect against SSPE and, consistent with virological data, that measles vaccine virus does not cause SSPE. Measles vaccine does not: accelerate the course of SSPE; trigger SSPE or cause SSPE in those with an established benign persistent wild measles infection. Evidence points to wild virus causing SSPE in cases which have been immunized and have had no known natural measles infection. Perinatal measles infection may result in SSPE with a short onset latency and fulminant course. Such cases are very rare. SSPE during pregnancy appears to be fulminant. Infants born to mothers with SSPE have not been subsequently diagnosed with SSPE themselves.
Conclusions Successful measles vaccination programmes directly and indirectly protect the population against SSPE and have the potential to eliminate SSPE through the elimination of measles. Epidemiological and virological data suggest that measles vaccine does not cause SSPE.
Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder caused by persistent measles virus infection. Initial symptoms of SSPE typically occur some years after natural measles infection and are usually subtle, with intellectual decline and behavioural changes, which may only be recognized as symptoms in retrospect. Most patients proceed over months or years to generalized convulsions, dementia, coma and death. Death usually occurs within 1–3 years, although there are reports of prolonged spontaneous remission.1 SSPE is confirmed when there is a recognized clinical course accompanied by one or more of the following: measles antibody detected in the cerebrospinal fluid; a characteristic pattern on electroencephalography; typical histological findings in brain biopsy material or tissue obtained by post-mortem examination.2 There is no proven effective therapy for the treatment of SSPE.3
SSPE was originally described as three different neuropathological conditions in the 1930s and 1940s.4 A viral aetiology was suggested when the condition was first described in 1933, but it was not until 1967–69 that measles viruses were established as the cause. When live measles vaccine became available in the early 1960s, the aetiology of SSPE was therefore unknown. Once the association between measles virus and SSPE was established there were concerns that measles vaccine virus might also cause this condition; particularly as SSPE had been associated with milder natural infection.5 National SSPE registries were therefore established shortly after measles vaccine introduction in a number of countries.
In this article, we review the impact of measles immunization on the epidemiology of SSPE using comprehensive published and unpublished data. Four areas are reviewed: background SSPE epidemiology world-wide; recent trends of SSPE epidemiology in countries where measles has been eliminated or markedly reduced; available evidence on different theoretical adverse relationships between measles vaccine and SSPE; congenital and neonatal measles and SSPE. Virological sequence information and genotyping6 are a crucial part of the available data and have been reviewed as part of this study.
Relevant published articles were found using the search terms SSPE and epidemiology and also subacute sclerosing panencephalitis and epidemiology in Pubmed. Abstracts, where available, were used to identify 113 relevant papers, including 23 non-English references. A further 19 papers were found through referenced articles. A review matrix was used to decide which papers contained original data on SSPE epidemiology or risk factors. Papers that did not contain original data, were not of direct relevance, were ad hoc case reports or repeated data in other references were rejected.
A separate literature search was conducted using the search terms pregnancy and measles and SSPE and also pregnancy and measles vaccine and SSPE. In this way, case reports of SSPE onset in pregnant women were identified, together with case reports of neonatal or in utero measles exposure leading to SSPE. To identify published viral sequences, a search of GenBank was also conducted using the search terms measles and SSPE.
Available data on national (or regional) SSPE incidence, measles incidence and vaccine coverage was collated to assess the impact of vaccination on SSPE incidence. For inclusion in this analysis, SSPE cases had to have been reported to a sentinel surveillance system that covered a geographical population. Data from the European Sero-Epidemiology Network (ESEN2)7 was used for measles incidence and vaccine coverage in some countries. This enabled the construction of figures showing SSPE incidence (by onset), vaccine coverage and measles incidence over time. Data from as many different countries as possible were included without applying standardized measures of quality because of the limited availability of these three datasets. Due to the many differences between countries in measles epidemiology, vaccine policy and SSPE registers it was not possible to perform any formal meta-analysis.
The countries were grouped according to the measles control in the available follow-up period:
Comparison of reported SSPE cases relating to 5-year periods with high measles incidence (low vaccine coverage) and low measles incidence (high vaccine coverage) was undertaken for six countries that had good measles control or control with outbreaks. The 5 years of high measles incidence were chosen to correspond to the first 5 years of SSPE reporting. The 5 years of low measles incidence (high coverage) were chosen to correspond to the most recent 5 years of SSPE data available, with the exception of the USA and Bulgaria where different periods were chosen to avoid outbreaks.
In addition to looking at time trends, the vaccination status, measles history and risk estimates per measles case or vaccinated case were sought. Further analysis of the SSPE register for England and Wales was undertaken as this database was available to the authors.
Potential adverse relationships between measles-containing vaccine and SSPE are considered below. The last three theoretical relationships would be consistent with the identification of wild measles virus, rather than vaccine virus, in the brain of such putative cases.
The decline in SSPE associated with the introduction and increased coverage of measles vaccine has been observed in many countries, as already discussed. This is consistent with a protective effect of vaccine but also a lower risk of vaccine-attributable cases. In the pre-vaccine era, when all children got measles, the risk of SSPE following measles was similar to the total SSPE cases per year divided by the birth cohort (assuming a stable population size). Post–vaccination, this estimate is less straightforward since the number of measles cases each year is required along with total SSPE cases for those infected that year (which is only complete many years later). Modelling by Farrington allowed an estimate of this risk by age at measles infection in England and Wales.73 The overall risk was four cases of SSPE per 100 000 measles cases. Data from the USA for the epidemic 1989–91 gave a similar risk.9
The estimated risk of SSPE after vaccination is often erroneously quoted as 0.14 per 100 000 based on Farringtons 1991 paper.73 Estimates of the risk from measles vaccination, consistently much lower than the risk from the disease, assume that SSPE came from vaccine if a child had vaccine and no recorded measles, therefore representing the worst case scenario for vaccine risk. Virological evidence does not support the suggestion that measles vaccine virus can cause SSPE. Natural measles virus has consistently been isolated in SSPE brain biopsy material,74–78 even in cases that were vaccinated and had no history of natural infection.8,,9,79–82 This is in keeping with the fact that natural measles infection can be very mild and is often undiagnosed.83
Although measles virus has only one serotype, significant diversity of the genome exists, eight clades (A–H) and 23 genotypes are recognized, based on the sequence of the carboxyl region of the N gene, or the full sequence of the H gene.6 All measles vaccine strains are genotype A.84 There have been no cases of SSPE in whom measles vaccine virus has been isolated, and reviewing the published N or H sequences (or with genotype information; Table 4), genotype A has been identified in only two cases (Halle, Horta-Babosa and Mantooth are almost certainly the same isolate passaged in different labs, with the published Halle sequence representing laboratory contamination85). No further information is available on Mantooth/Horta-Babosa, but the sequence differs from vaccine strains. Similarly, MVs/Belfast1.UNK/1956-SSPE differs from vaccine sequence and was from a child that acquired clinical measles in 1955 and was never vaccinated.79
A total of 23 cases detailed in Table 4 had a history of vaccination, but vaccine strain or genotype A was not identified in any of them. Instead, a wide range of virus genotypes have been identified, reflecting the diversity of wild-type genotypes.
Papers looking at virological features have come from different countries, including North and South America, Western and Eastern Europe, Japan and Papua New Guinea, where different measles vaccine virus strains are used. All measles vaccine strains are genotype A and from the same genetic lineage and, therefore, would be expected to be the same in terms of any theoretical risk of SSPE.
Data from England and Wales showed that the actual number of cases of SSPE between 1992 and 2002 were consistent with the assumption that no cases were vaccine attributable.22 This period of continued SSPE decline included the introduction of MMR in 1988 and mass MR immunization of school-aged children in 1994. An Israeli study examined the expected number of SSPE cases in vaccinated individuals born between 1966 and 1971 using coverage rates and estimates of vaccine effectiveness.10 All four vaccinated cases of SSPE observed in this cohort could be accounted for by the fact that the vaccine was not 100% effective.
Dodson et al.98 described a patient who developed SSPE after early measles infection but rapidly deteriorated when immunized against measles 1 year after the onset of SSPE symptoms. They suggested that the vaccine may have led to the acceleration of symptoms (within 3 weeks of immunization) in what would have otherwise been a slowly evolving case of SSPE.
Given the average age at onset of symptoms of SSPE and the age at which immunization occurs in most countries, the situation in which an individual with ongoing symptoms of SSPE is immunized is likely to be relatively rare. In 1978, nine patients on the US National Registry with confirmed SSPE had been given measles vaccine (live and/or inactivated) subsequent to the onset of symptoms of SSPE.99 Four of the nine had died at an average of 3.6 years (2.4–6.5 years) after symptom onset, whilst the five who were still alive had survived an average of 10.5 years (7.3–12.2 years). This compared with 149 fatal SSPE cases, where average interval from onset to death ranged from 9 to 30 months, depending on age at onset. These data do not support the suggestion that measles vaccine accelerates the clinical progression of SSPE.
The possibility that measles-containing vaccine could stimulate the expression of a latent infection was first suggested in 1974.100 If measles vaccine acted as a trigger for SSPE it would be expected to bring forward the age at which SSPE develops in those immunized before onset compared with unimmunized individuals.
Whilst there are sporadic reports of SSPE onset shortly after vaccination these do not by themselves constitute evidence of a vaccine trigger effect. US data from 1960 to 1974 identified 44 patients, of 292 confirmed cases with a history of measles infection, who had received live measles vaccine subsequent to the natural infection.56 There was no difference in the mean interval from measles to onset of SSPE for those who received live measles vaccine (6.9 years) and those who did not (7.1 years). Further, there were 58 patients with no history of natural infection of whom 40 had been immunized. Of these, 35 cases had a known date of vaccination and the time period between vaccination and onset of SSPE ranged from 1 month to 9 years (3.3 years mean). Age at vaccination ranged from 12 months to 10 years and there was no apparent association with vaccination at any age.
In Turkey, there was no evidence that immunization status affected either age at onset or latency in cases with a history of measles (Table 5).51
The mean interval between measles infection and onset of SSPE, and the mean age at onset of SSPE in Israel, USA and the UK were virtually identical.10 In contrast, the mean interval between measles immunization and SSPE onset was longer in Israel than in the USA or UK. Thus, whilst an association between measles infection and SSPE was consistent, there was no such consistency in the relationship between immunization and SSPE. In this Israeli study, it was also found that the median age of onset was 97 months in the 11 vaccinated compared with 99 months in the 23 unvaccinated cases of SSPE among children born from 1965 to 1971.
In England and Wales around 7 million children aged 5–16 years were immunized in the mass MR immunization campaign in November 1994. An increase in observed compared with expected cases of SSPE might have been anticipated from about 1998 onwards if the trigger theory was true but this was not the case.22
The trigger hypothesis was further tested using the data available from the SSPE register for England and Wales. Of the 342 cases with onsets between 1962 and 2001, 42 had a history of a measles-containing vaccine, 274 were unvaccinated and the vaccination status of the remaining 26 was unknown. The age at onset in those who had a measles vaccine did not differ from those who were unvaccinated (difference after adjusting for year of birth was 0.14 years younger in the vaccinated with 95% CI 1.82 years younger–1.55 years older). If measles vaccine triggers SSPE then age of onset should be significantly younger in vaccinated cases.
Wakefield suggested that, based on Japanese studies, persistent infection of the brain with measles virus may not be that uncommon (depending on different variables, e.g. age at infection) but usually without any clinical problem.101 He theorized that, in the presence of a benign persistent wild measles infection, re-exposure to measles virus via immunization would boost the immune system leading to an attack on persistently infected cells and the triggering of SSPE in an individual who would not otherwise develop it.
In support of this theory, he cited the increase in SSPE cases in England and Wales and in the USA shortly after the introduction of measles vaccination. Thereafter, according to the theory, a decline would be seen as the protective effect of measles vaccine against wild infection becomes apparent. An increase in SSPE cases shortly after the introduction of vaccination with a subsequent decline has been seen in a number of countries, as already described. However, in these countries, as in the UK and USA, a SSPE register was set up at the same time as measles vaccination was introduced. It is to be expected that improving case ascertainment in the early years of the register with a real reduction a few years later due to prevention of measles infection would result in such a phenomenon.
If SSPE were induced by this second hit mechanism then there should be a higher than expected proportion vaccinated among SSPE cases with a history of measles, and in addition if the effect were acute, a younger age at onset.
An acute effect is not plausible given the consistency in age between vaccinated and unvaccinated cases already discussed.
Looking at SSPE cases in England and Wales in whom measles infection occurred under 1 year of age (before measles/MMR vaccine is offered), the proportion who were subsequently vaccinated was not greater than expected from vaccine coverage figures. In those born since 1970, 9 of 25 had been vaccinated (36%). This compares with an expected vaccine coverage of 55% (calculated using vaccine coverage and number of cases by year of birth).
More recent data have been used to look at cases that have arisen since the MR immunization campaign in England and Wales in November 1994. It was found that 8 of 19 eligible cases (42% coverage) had MR vaccine prior to onset, whereas, overall coverage for the campaign was 92%. A US case–control study showed that measles vaccine was protective; of those who had measles, 11/43 cases were vaccinated (26%) compared with 20/45 (44%) of controls.54 So, there was no evidence among those who had measles that vaccine provided an additional risk.102
There are several publications reporting the outcome of measles in pregnancy for the mother and fetus.103–110 There is general agreement in the literature that maternal measles is associated with a higher risk of complications such as pneumonia and encephalitis than in other adults. There is no convincing evidence of an increased risk of congenital abnormality in the infants of women with measles in pregnancy. Where defects have been reported, no consistent pattern has been seen suggesting that, if the virus does cross the placenta, it is not teratogenic.105,,111–113 There are papers that report an increased risk of fetal loss, intrauterine growth retardation, premature delivery and neonatal death following maternal measles, which may reflect non-specific effects of maternal infection or a specific effect of intra-uterine infection.105,,107,110
When maternal infection occurs around the time of delivery, however, perinatal infection of the infant may give rise to SSPE with a short onset latency and fulminant course. In three of the five case reports adequately described in the literature,114–117 the onset of maternal rash (which coincides with the appearance of antibody and occurs as the viraemia is declining), was 1–17 days post partum, in one case maternal fever complicated the last 3 days of pregnancy.118 Under these circumstances, maternal infection could result in transplacental or early neonatal infection of the infant in the absence of maternal antibody. It has been speculated that these circumstances combined with immaturity of the neonatal immune system predisposes towards early onset of SSPE and a fulminant course. In four of the five cases described in the literature, onset of symptoms in the infant occurred under 2 years of age.
There is considerable literature reporting cases of SSPE in pregnancy and these have all been confirmed by the usual diagnostic methods.8,,17,22,61,63,119,120 The course appears to be fulminant, for which it is speculated that immunological and hormonal consequences of pregnancy may be responsible. The fetal outcome is often unfavourable due to the obstetric consequences arising from the mothers condition, for example elective premature delivery by caesarean section. No infants who survived subsequently developed SSPE. One report of a mild newborn form of SSPE in an infant whose mother developed SSPE in pregnancy was not subsequently confirmed and the infant was developing normally at 4 years of age.20 Since viraemia does not occur in SSPE, transmission of measles virus to the infant would not be expected.
Two cases in pregnant women were identified in the England and Wales register with onset between 1990 and 2002.22 The probability of two cases diagnosed during pregnancy was calculated as only 0.004 based on the age of female cases and birth rate data.
Analyses of data from the UK and the USA have shown the true incidence of SSPE to be approximately 4–11 cases of SSPE per 100 000 cases of measles and the risk has been cited as high as 27.9 SSPE cases per 100 000 cases of measles. In many countries, reported rates of SSPE have been much lower, including earlier estimates from the USA. This suggests that there has been substantial under-ascertainment of cases of SSPE. Ideally, national registries should collate information on possible SSPE cases from different sources including neurologists, hospital episodes, laboratories and death certificate data.
With the exception of an increased risk of early measles infection, reduced likelihood of immunization against measles and a higher SSPE rate in boys, risk factors have been differentially described and are based on data of varying quality. The significance of each is thus difficult to assess and may often reflect the chance of contracting early measles infection.
When looking at cases by year of SSPE onset, changes in the mean age at onset (and latency) over time are often seen. In countries with good measles control, where incidence has been low for some time, the recent cases should be older because they reflect cases infected years ago when measles incidence was higher or because they represent cases infected when older. If measles incidence has not changed then age at onset should not change. If measles incidence declined for some years then re-emerged, then the resulting cases first seen would be young cases. In many countries with good measles control, an increasing age at onset of SSPE (and of latency) has been observed. Even in countries where good paediatric surveillance is in place, cases in older ages may not be detected because there is no routine surveillance of this age group. Whilst the sex ratio is fairly consistently reported with male predominance, there is some suggestion of a different latency (time between infection and onset) by gender. This suggestion comes from the observed differences in sex ratio through time in some countries; with the sex ratio moving towards more equal sex distribution some years after natural measles transmission has been interrupted. Therefore, some years after interruption of measles transmission, cases of SSPE that do still arise are more likely to occur at older ages and a higher proportion of these cases may arise in women than when onset occurs at younger ages.
Patterns of SSPE in individual countries reflected the epidemiology of natural measles infection. In countries with good measles control, a decline in new cases of SSPE is seen several years after the decline in measles. An epidemic of measles after a period of good control leads to increased cases of SSPE after a delay of several years. In the USA such cases were demonstrated to be virologically linked to the 1989–91 epidemic. Vaccination against measles has evidently reduced the incidence of SSPE through protection against measles. Any theoretical risk of SSPE due to vaccination is, therefore, substantially lower than that due to disease. Measles vaccine offers direct protection by preventing measles infection with its associated risk of SSPE. When coverage is high enough there is also an indirect protective effect through herd immunity, which protects the unvaccinated from infection or delays infection until a later age, when risk of SSPE is reduced. However, if coverage is not high enough to eliminate disease, vaccination can result in a resurgence of measles infection in younger children who are at increased risk of SSPE.
Of the four theoretical ways in which measles vaccine could be adversely associated with SSPE none of the available epidemiological evidence is consistent with vaccine virus directly causing (theory 1), accelerating (theory 2), triggering (theory 3) or inducing, through a second hit mechanism (theory 4), SSPE. Some papers do describe cases of SSPE with no history of wild measles infection in immunized individuals. Such cases can be erroneously attributed to vaccine.121 When individuals with such a history have been examined virologically, only wild measles virus has been found. Before such techniques were available, the estimate of vaccine-attributable risk of SSPE was calculated in England and Wales, in the worst case scenario, to be 0.14 per 100 000 based on a total of nine cases reported with onset prior to 1990.72 In cases reported since 1990, there were four vaccinated without a history of measles. Brain biopsies were obtained from two of these four cases and in both wild measles virus was identified.22 Cases of SSPE in which there is no known history of natural measles infection but measles vaccine has been administered should, therefore, not be attributed to vaccine; all available evidence points to such cases being due to undiagnosed or unrecorded natural infection, which can be very mild.
Perinatal infection of the infant, as a result of maternal measles infection around the time of delivery, may give rise to SSPE with a short onset latency and fulminant course. Such cases have been rarely reported in the literature. SSPE arising during pregnancy appears to be fulminant. The fetal outcome is often unfavourable due to the obstetric consequences arising from the mothers condition. However, no infant that has survived has been subsequently diagnosed with SSPE. There is no evidence of a link between measles vaccination in pregnancy and SSPE.
This review was undertaken on behalf of and funded by the World Health Organization Global Advisory Committee on Vaccine Safety. We would like to thank Dina Pfeifer for her contribution and support in compiling this review and Saroj Valambia, Anders Peter Hviid and Kate Manvatkar for their assistance.
Conflict of interest: None declared.
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