Extract from report of GACVS meeting of 1-2 December 2005, published in the WHO Weekly epidemiological Record on 13 January 2006

The Committee reviewed the epidemiology of subacute sclerosing panencephalitis (SSPE) and the purported relationship between measles immunization and the occurrence of SSPE. The deliberations were considerably helped by a commissioned report presented by experts from the Health Protection Agency (HPA) of the United Kingdom. The meeting was joined by experts from the Division of Viral and Rickettsial Diseases, CDC National Center for Infectious Diseases (NCID), who agreed with the general conclusions and recommendations from the HPA experts. Evidence was provided that the true incidence of SSPE is approximately 4–11 cases per 100 000 cases of measles, although with measles infection acquired very early in life the risk may be higher (18 per 100 000 cases). A risk as high as 27.9 SSPE cases per 100 000 cases of measles has been cited. In many countries with good measles control, an increasing age at onset of SSPE has been observed attributable to cases that acquired measles infection at a time when the disease was more prevalent.

Available epidemiological data are consistent with a directly protective effect of vaccine against SSPE mediated by preventing measles. In countries with good measles control through vaccination, a decline in new SSPE cases is seen a few years after the decline in measles incidence. However, given the latency of SSPE following natural measles infection, it would take at least 5 years before an impact on SSPE incidence is seen, and more than 10 years before a large decrease is seen. Even with the elimination of measles, cases of SSPE may still occur 20 to 30 years after the last measles cases because of the skew of the latency distribution. Re-emergence of SSPE cases has been seen after outbreaks of measles following a period of good measles control. Available epidemiological data, in line with virus genotyping data, do not suggest that measles vaccine virus can cause SSPE. Furthermore, epidemiological data do not suggest that the administration of measles vaccine can accelerate the course of SSPE or trigger SSPE in an individual who would have developed the disease at a later time without immunization. Neither can the vaccine lead to the development of SSPE where it would not otherwise have occurred in a person who has already a benign persistent wild measles infection at the time of vaccination.

For situations where cases of SSPE occur in vaccinated individuals who have no previous history of natural measles infection, the available evidence points to natural measles infection as the cause of SSPE, not vaccine.

Full report of GACVS meeting of 1-2 December 2005, published in the WHO Weekly epidemiological Record on 13 January 2006

Extract from report of GACVS meeting of 9-10 June 2005, published in the WHO Weekly Epidemiological Record on 15 July 2005

The WHO Regional Office for Europe requested GACVS to review the risk of measles vaccine strains causing subacute sclerosing panencephalitis (SSPE). The United States Institute of Medicine (IOM) statements in its 1994 and 2001 reviews refer to absent or inadequate evidence either to reject or accept any causal relationship between measles-containing vaccines and SSPE in immunocompetent individuals. It is uncertain whether there is enough evidence from viral RNA sequencing and classification to warrant any modification of the IOM conclusions. However, GACVS noted that: (i) all reports published since the IOM review in 2001 containing information on measles virus classification in SSPE-immunocompetent patients indicate the presence of wild (not vaccine) measles strains; and (ii) in countries where measles has been controlled, SSPE has either declined substantially or no longer occurs. These findings do not suggest an association between measles vaccines and SSPE. GACVS will commission a review of the epidemiology of SSPE in relation to measles vaccine, the results of which will be considered at its December 2005 meeting.

Full report of GACVS meeting of 9-10 June 2005, published in the WHO Weekly Epidemiological Record on 15 July 2005

The Committee commissioned a systematic review and meta-analysis to identify and synthesize evidence about the safety, immunogenicity and efficacy of measles vaccination in children infected with HIV. A total of 8 electronic databases were searched for studies published until February 2009 relating to measles vaccination in HIV-positive children. Altogether, 723 articles were identified, of which 25 studies with comparison groups (involving 4519 vaccinated children) and 1 case-report were eligible for inclusion. Another 13 studies without comparison groups (involving 690 vaccinated children) were also examined for data on adverse events. Studies should be conducted to investigate remaining concerns. These include studies to determine the etiology of pneumonia in HIV-positive infants (no studies have examined for measles virus as the etiological agent of pneumonia in HIV-positive children), to compare morbidity and mortality among HIV-positive children with and without measles vaccination, to determine the immunogenicity of measles vaccine in HIV-positive children on HAART, and to evaluate the duration of immunity and whether there is an added benefit in administering a second dose of measles vaccine to HIV-positive children.

Adverse events were not mentioned in 20 of 39 studies. In the 19 studies that described adverse events, 17 reported no serious or severe adverse events. In 2 prospective studies that reported on adverse events and allowed comparative analysis, there was no increased risk of vaccine-related serious adverse events in HIV-positive children when compared with HIV-exposed but uninfected children or children not exposed to HIV. A total of 8 hospitalizations were reported after vaccination in 457 HIV-positive children enrolled in prospective studies, excluding those events explicitly stated by the authors to be unrelated to vaccination. There were 55 deaths in 387 HIV-positive children who had been vaccinated. Serological assessments of measles antibody titres after vaccination showed that measles vaccination at the age of 6 months resulted in similar levels of antibody in HIV-positive children and children who had not been exposed to HIV; by the age of 9 months, fewer HIV-positive children (with severity of disease ranging from no clinical signs of AIDS to groups where 71% were symptomatic) responded to measles vaccine than did children who had not been exposed to HIV. After measles vaccination at age 6 months, children who had initially tested HIV-positive owing to maternal antibodies but were subsequently found to be uninfected, were slightly more likely to have developed antibodies than children who had not been exposed to HIV. Two studies suggested that the antibody response in HIV-positive children waned faster than it did in children who were not infected with HIV. There were scant data about the effects of highly active antiretroviral treatment (HAART) on responses to measles vaccination, and the possibility of comparing vaccinated children to unvaccinated HIV-positive children was limited. Data relating to clinical efficacy against measles were also scarce.

Based on these findings the Committee drew the following conclusions.

• The evidence does not demonstrate a serious risk in using measles vaccine in HIV-positive children. Although millions of doses of measles vaccine have been administered to HIV-positive children, only 1 case report was identified that suggested possible severe adverse events following immunization. However, ascertainment of such events may be incomplete.
• The literature review documented higher mortality among HIV-positive children who received measles vaccine than among children who were not infected with HIV and who received measles vaccine. However, it seems plausible that most or all of this effect is due to HIV infection alone rather than to measles vaccination. There are many confounding factors that could explain a higher rate of death or severe adverse events following measles vaccination in this population. One possible approach to resolving this issue would be to recommend systematic follow up of children vaccinated against measles in populations with a high prevalence of HIV and to conduct case–control studies of all cases with severe adverse events following measles vaccination in order to assess the possible part played by HIV infection.
• Measles vaccine appears to be immunogenic in the majority of HIV-positive children. Important areas for further research include determining the duration of immunity and protection, and whether there is a benefit to administering a second dose of measles vaccine to HIV-positive children.
• On the basis of the literature reviewed, the Committee considers that there is no need to modify WHO’s recommendation on measles vaccination in HIV-positive children.
• The recommendation on the use of measles vaccines indicates that it is contraindicated in people who are severely immunocompromised. This reflects the risk–benefit ratio, since children with low CD4 cell counts might derive little benefit from the vaccine.
• Studies should be conducted to investigate remaining concerns. These include studies to determine the etiology of pneumonia in HIV-positive infants (no studies have examined for measles virus as the etiological agent of pneumonia in HIV-positive children), to compare morbidity and mortality among HIV-positive children with and without measles vaccination, to determine the immunogenicity of measles vaccine in HIV-positive children on HAART, and to evaluate the duration of immunity and whether there is an added benefit in administering a second dose of measles vaccine to HIV-positive children.

Full report of GACVS meeting of 17-18 June 2009, published in the WHO Weekly Epidemiological Record of 7 August 2009