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Division of Infectious Diseases, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina
The study by Bellini et al. [1] in this issue of the Journal of Infectious Diseases provides a reassuring affirmation that what previously had been only a clinical/epidemiologic observation is indeed factual: measles vaccine viruses do not cause subacute sclerosing panencephalitis (SSPE). Bellini and colleagues have also revealed that the incidence of SSPE is much higher after natural measles than previously had been appreciated. Using sophisticated laboratory technology that was not available when SSPE was previously reported in the United States, these investigators examined brain tissue specimens obtained during the resurgence of measles in the United States during 19891991, confirmed the diagnosis of SSPE, and, by use of genotype analysis, established wild-type measles viruses as the responsible etiologic agents. The authors demonstrated, by use of data gathered during the measles outbreak of 19891991, as well as by use of data collected during earlier outbreaks, that the true incidence of SSPE was 711 cases of SSPE/100,000 cases of measles, rather than the previously cited estimate of 1 case of SSPE/100,000 cases of measles.
When a live attenuated measles virus vaccine was first licensed in the United States in 1963 [2], the etiology of SSPE was unknown. It was not until 19671969 that measles viruses were demonstrated to be the etiologic agents of this rare but almost uniformly fatal disorder of the central nervous system [3, 4]. Had we been aware, in 1963, of the role played by measles virus in the etiology of SSPE, it is highly unlikely that our live measles virus vaccine would ever have been licensed. The number of vaccine recipients needed to generate a phase 34 trial with statistically significant results would have exceeded even the 650,000 vaccine recipients and 1.18 million control subjects who, in 19541955, participated in the famous field trial of inactivated poliovirus vaccine (i.e., the "Salk vaccine") conducted by Dr. Thomas Francis (and commemorated on 12 April 2005, the 50th anniversary of the trial). Fortunately, subsequent experiences with the administration of hundreds of millions of doses of live attenuated measles virus vaccine have provided the reassurance now validated virologically by Bellini et al. [1].
When measles was an inevitable childhood disease in the United States, 50 cases of SSPE were reported annually. However, with the widespread introduction of measles vaccination programs, and with the elimination of circulating measles viruses from the United States, the rare 1 or 2 cases of SSPE that are now reported each year almost always occur among recent immigrants or adoptees who come from countries where natural measles viruses are still circulating. The successes of our immunization programs in the United States have resulted in the absence of any indigenous circulating measles viruses since 1994 and in reported total case loads of <100 cases of measles each year, nearly all of which can be traced to virus importations. Drs. Rota and Bellini, who are 2 of the same US Centers for Disease Control and Prevention investigators who prepared the report discussed here, used their genotypic analysis techniques to identify the strain variants and their likely sources of origin (Japan, Germany, India, Kenya, Zimbabwe, Ethiopia, Pakistan, Korea, China, Italy, Ireland, Bangladesh, Saudi Arabia, The Philippines, Nigeria, Thailand, Malaysia, and Russia) [5].
The persistence of SSPE abroad is a clear reflection of the failure to eliminate measles from many countries, mainly those that are resource poor but, surprisingly, also some of the wealthier nations (i.e., Japan, Italy, Germany, Austria, and France). Before the availability of measles virus vaccines, the World Health Organization estimated that 8 million deaths due to measles and its associated complications occurred annually among children. By 1999, with the introduction of increasingly aggressive immunization approaches through the World Health Organization's Expanded Program of Immunization, this annual measles-associated mortality rate had been reduced to 873,000 deaths, but, nonetheless, measles has accounted for 48% of the 1.6 million deaths due to vaccine-preventable diseases occurring annually among children. Only malaria, in the absence of vaccine, was reported to be associated with a mortality rate greater than that associated with measles in children <5 years of age.
Challenged by the continued occurrence of deaths due to a vaccine-preventable disease, in 2000, the American Red Cross (reminiscent, in some respects, of Rotary International and the role it has played in the global effort toward polio eradication) mobilized a coalition that included the International Red Cross and Red Crescent societies, the United Nations Children's Fund, the United Nations Foundation, the World Health Organization, and the US Centers for Disease Control and Prevention, to form the Measles Initiative (the Partners for Measles Advocacy). This coalition pledged to reduce the number of measles-associated deaths and to extend the control and eventual elimination of measles to those nations in which the greatest numbers of such deaths have occurred. Of the 45 countries that accounted for 95% of deaths due to measles worldwide, 31 were located in sub-Saharan Africa. Therefore, the initial Measles Initiative programs (through 2004) have involved extensive campaigns in Botswana, Zimbabwe, Namibia, Tanzania, Kenya, Uganda, Cameroon, Benin, Ghana, Burkina Faso, Guinea, Senegal, Central African Republic, Ethiopia, Angola, Zambia, Sierra Leone, The Gambia, and Guinea-Bissau. In great part as a result of these campaigns, in March 2005, the World Health Organization was able to announce jubilantly that the number of measles-associated deaths globally had "plummeted by 39%, from 873,000 in 1999 to an estimated 530,000 in 2003" [6]. Nations that have been considered to be "priority countries" for a reduction in the number of measles-associated deaths in the next 5 years (i.e., 20062010) include Bangladesh, Pakistan, India, Vietnam, Indonesia, and Yemen, among others.
The extraordinary communicability and infectivity of measles virus provide challenges even greater than those faced by the global program to eradicate polio. Just as the polio eradication effort has been hampered recently by the temporary cessation of polio vaccination in northern Nigeria (from December 1993 through August 2004) and by the resultant spread of wild polioviruses to at least 15 nations that had previously been polio free (in some instances, for as long as 10 years), measles eradication programs have faced a similar challenge, with vaccine refusal leading to major outbreaks of disease in the same area of northern Nigeria and the subsequent spread of disease to neighboring regions. If measles is to be controlled, there must be a sustained political, financial, and societal commitment to this challenge. Donor fatigue and participant fatigue are major concerns for such global programs. The success of smallpox eradication is the Holy Grail of disease eradication to which these other programs aspire, but the challenges associated with measles control and eradication are greater, and the likelihood of success more distant.
References
1. Bellini WJ, Rota JS, Lowe LE, et al. Subacute sclerosing panencephalitis: more cases of this disease are prevented by measles immunization than was previously recognized. J Infect Dis 2005; 192:168693 (in this issue). First citation in article
2. Enders JF, Katz SL, Milovanovic MB, Holloway A. Studies on an attenuated measles-virus vaccine. I. Development and preparations of the vaccine: technics for assay of effects of vaccination. N Engl J Med 1960; 263:1539. First citation in article
3. Payne FE, Baublis JV, Itabashi HH. Isolation of measles virus from cell cultures of brain from a patient with subacute sclerosing panencephalitis. N Engl J Med 1969; 281:5859. First citation in article
4. Horta-Barbosa L, Fucillo DA, Sever JL, Zenan W. Subacute sclerosing panencephalitis: isolation of measles virus from a brain biopsy. Nature 1969; 221:974. First citation in article
5. Rota PA, Bellini WJ. Update on the global distribution of genotypes of wild type measles viruses. J Infect Dis 2003; 187(Suppl 1):S2706. First citation in article
6. Joint World Health Organization/United Nations Childrens Fund. News release. 3 March 2005. First citation in article