: These revised recommendations of the Advisory Committee on Immunization Practices (ACIP) on measles, mumps, and rubella prevention supersede recommendations published in 1989 and 1990. This statement summarizes the goals and current strategies for measles, rubella, and congenital rubella syndrome (CRS) elimination and for mumps reduction in the United States. Changes from previous recommendations include: Emphasis on the use of combined MMR vaccine for most indications; A change in the recommended age for routine vaccination to 12-15 months for the first dose of MMR and to 46 years for the second dose of MMR; A recommendation that all states take immediate steps to implement a two dose MMR requirement for school entry and any additional measures needed to ensure that all school-aged children are vaccinated with two doses of MMR by 2001; A clarification of the role of serologic screening to determine immunity; A change in the criteria for determining acceptable evidence of rubella immunity; A recommendation that all persons who work in health-care facilities have acceptable evidence of measles and rubella immunity; Changes in the recommended interval between administration of immunological and measles vaccination; and Updated information on adverse events and contraindications, particularly for persons with severe HIV infection, persons with a history of egg allergy or gelatin allergy persons with a history of thrombocytopenia, and persons receiving steroid therapy

Measles, mumps, and rubella--vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP).

The characteristic disease features of measles--fever and rash--are associated with the immune response to infection and are coincident with virus clearance. MV-specific antibody and CD4 and CD8 T cell responses are generated and contribute to virus clearance and protection from reinfection. During this same phase of immune activation immunologic abnormalities are also apparent. There is a generalized suppression of cellular immune responses that may contribute to increased susceptibility to other infections. Autoimmune disease may appear in the form of acute disseminated encephalomyelitis. If virus-specific immune responses are inadequate infection may progress with pulmonary or CNS manifestations, but without a rash. The pathogenesis of the rare disease SSPE, that occurs many years after primary infection is not clear, but immune responses show increased antibody to measles and cellular immune responses similar to those seen after uncomplicated infection.

Immune responses during measles virus infection

Measles virus causes a severe systemic illness. The rash occurs simultaneously with the onset of the effector phase of the antiviral immune response and substantial evidence of immune activation. This immune response is effective in clearing virus and in establishing long-term resistance to reinfection but is associated with immune suppression, autoimmune encephalomyelitis, and increased susceptibility to secondary infections. This apparent paradox may be explained in part by preferential long-term activation of type 2 CD4+ T cells by measles virus infection. Preferential stimulation of type 1 CD4+ T cells by inactivated virus vaccines is hypothesized to play a role in subsequent development of atypical measles.

Pathogenesis Of Measles Virus Infection: An Hypothesis For Altered Immune Responses

In 1967, infants and toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (RSV) experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. The enhanced disease was initially characterized as a "peribronchiolar monocytic infiltration with some excess in eosinophils." Decades of research defined enhanced RSV disease (ERD) as the result of immunization with antigens not processed in the cytoplasm, resulting in a nonprotective antibody response and CD4(+) T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection. In recent years, the field of RSV experienced significant changes. Numerous vaccine candidates with novel designs and formulations are approaching clinical trials, defying our previous understanding of favorable parameters for ERD. This review provides a succinct analysis of these parameters and explores criteria for assessing the risk of ERD in new vaccine candidates.

Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease

The severe disease atypical measles occurred when individuals immunized with a poorly protective inactivated vaccine contracted measles, and was postulated to be due to a lack of fusion-inhibiting antibodies. Here, rhesus macaques immunized with formalin-inactivated measles vaccine developed transient neutralizing and fusion-inhibiting antibodies, but no cytotoxic T-cell response. Subsequent infection with measles virus caused an atypical rash and pneumonitis, accompanied by immune complex deposition and an increase in eosinophils. Fusion-inhibiting antibody appeared earlier in these monkeys than in non-immunized monkeys. These data indicate that atypical measles results from previous priming for a nonprotective type 2 CD4 T-cell response rather than from lack of functional antibody against the fusion protein.

Production of atypical measles in rhesus macaques: evidence for disease mediated by immune complex formation and eosinophils in the presence of fusion-inhibiting antibody.

The clinical course of measles occurring in 17 adolescents who had previously received killed measles vaccine is described. All adolescents had a peripheral dermatitis. Fifteen had characteristic pulmonary infiltrates. Serologic study in six adolescents using immunoprecipitation of 35S-methionine-labeled measles virus antigens revealed that 5/6 acute sera lacked antibody to the hemolysin antigen whereas 5/6 sera contained antibody to hemagglutinin antigen. Skin biopsies, obtained from three patients, demonstrate a combination of an Arthus reaction and delayed hypersensitivity. The typical measles histologic complex was absent. Measles virions were seen in the deep dermal blood vessels. The serologic and histopathologic presentation of this disease indicates that killed vaccine does not adequately induce antibody to the hemolysin (F) which is necessary to prevent cell-to-cell spread of paramyxoviruses. Killed vaccine does, however, produce hemagglutinin antibody and simultaneously incites later hypersensitivity to wild virus infection, producing the unusual dermatopathologic reaction seen.

Herbert Ichinose

Papers

Atypical Measles Syndrome: Pathologic and Serologic Findings