Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract disease in infants and the elderly, but no safe and effective RSV vaccine is yet available. For reasons that are not well understood, RSV is only weakly immunogenic, and reinfection occurs throughout life. This has complicated the search for an effective live attenuated viral vaccine, and past trials with inactivated virus preparations have led to enhanced immunopathology following natural infection. We have tested the hypothesis that weak stimulation of innate immunity by RSV correlates with ineffective adaptive responses by asking whether expression of the fusion glycoprotein of RSV by Newcastle disease virus (NDV) would stimulate a more robust immune response to RSV than primary RSV infection. NDV is a potent inducer of both alpha/beta interferon (IFN-␣/␤) production and dendritic cell maturation, while RSV is not. When a recombinant NDV expressing the RSV fusion glycoprotein was administered to BALB/c mice, they were protected from RSV challenge, and this protection correlated with a robust anti-F CD8 ؉ T-cell response. The effectiveness of this vaccine construct reflects the differential abilities of NDV and RSV to promote dendritic cell maturation and is retained even in the absence of a functional IFN-␣/␤ receptor. Respiratory syncytial virus (RSV), a Pneumovirus of the familyParamyxoviridae, infects the majority of individuals in their first year of life. RSV is the major cause of bronchiolitis and pneumonia in infants and young children and accounts for approximately 85,000 pediatric hospitalizations per year in the United States alone (48). Many pediatric viral diseases have been eradicated or lessened in severity by successful vaccination programs, but no safe and effective vaccine yet exists for RSV despite exploitation of multiple approaches (12, 13). Difficulties in RSV vaccine development relate to (i) the poor immunogenicity of RSV (reinfection occurs throughout life [26]) and (ii) the ability of viral proteins to elicit a Th2, or allergic-type, memory response in some contexts (23,28,32,46,61). Although primary infection with RSV promotes Th1 cell differentiation, early trials of an inactivated viral vaccine (FI-RSV) led to incomplete immunity and exacerbated eosinophilic disease in vaccinated children after natural infection (10,16,35,36). These results have led RSV researchers to proceed with caution and to look beyond conventional methods and adjuvants in exploring new RSV vaccine strategies (27,45).We have hypothesized that poor stimulation of innate immune defenses by RSV might be the basis for the inadequate adaptive immune response to this infection.

Respiratory syncytial virus (RSV) is the major cause of severe lower airway disease in infants and young children, but no safe and effective RSV vaccine is yet available. The difficulties involved in RSV vaccine development were recognized in an early vaccine trial, when children immunized with a formalin-inactivated virus preparation experienced enhanced illness after natural infection. Subsequent research in animal models has shown that the vaccine-enhanced disease is mediated at least in part by memory cells producing Th2 cytokines. Previously we had observed enhanced, eosinophilic lung pathology during primary infection of IFN-deficient STAT1−/− mice that are incapable of generating Th1 CD4+ cells. To determine whether these effects depended only on Th2 cytokine secretion or involved other aspects of IFN signaling, we infected a series of 129SvEv knockout mice lacking the IFN-αβR (IFN-αβR−/−), the IFN-γR (IFN-γR−/−), or both receptors (IFN-αβγR−/−). Although both the IFN-γR−/− and the IFN-αβγR−/− animals generated strong Th2 responses to RSV-F protein epitopes, predominantly eosinophilic lung disease was limited to mice lacking both IFNRs. Although the absolute numbers of eosinophils in BAL fluids were similar between the strains, very few CD8+ T cells could be detected in lungs of IFN-αβγR−/− animals, leaving eosinophils as the predominant leukocyte. Thus, although CD4+ Th2 cell differentiation is necessary for the development of allergic-type inflammation after infection and appears to be unaffected by type I IFNs, innate IFNs clearly have an important role in determining the nature and severity of RSV disease.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in infants and the elderly. While the primary infection is the most serious, reinfection of the upper airway throughout life is the rule. Although relatively little is known about either RSV infection of the upper respiratory tract or host mucosal immunity to RSV, recent literature suggests that RSV is the predominant viral pathogen predisposing to bacterial otitis media (OM). Herein, we describe mouse and chinchilla models of RSV infection of the nasopharynx and Eustachian tube. Both rodent hosts were susceptible to RSV infection of the upper airway following intranasal challenge; however, the chinchilla proved to be more permissive than the mouse. The chinchilla model will likely be extremely useful to test the role of RSV in bacterial OM and the efficacy of RSV vaccine candidates designed to provide mucosal and cytotoxic T-lymphocyte immunity. Ultimately, we hope to investigate the relative ability of these candidates to potentially protect against viral predisposal to bacterial OM.Many factors contribute to the prevalence of middle ear infections in children as well as to the chronic or recurrent nature of otitis media (OM). These include immunological immaturity, existence of other infections, anatomic positioning of the Eustachian tube (ET), and genetic predisposition (10,14,22). However, whereas the multifactorial nature of OM is well known, it has only recently become fully appreciated that both acute and chronic OM are truly polymicrobial infections, involving any of several upper respiratory tract (URT) viruses and one or more of three bacterial pathogens.There is now ample epidemiological evidence and data generated by PCR-based assays, immunoassays, and direct culture to support the association of URT viruses with acute bacterial OM (2, 3, 15, 16, 39, 46-50, 55, 60, 64, 67-69). Moreover, peak incidence of OM occurs in concert with peak periods of viral isolation (38,56,64). Importantly, exposure to URT viruses (primarily via day care attendance or association with siblings) is a significant risk factor and/or predictor for early onset, frequent, or recurrent OM (51, 58). In a prospective study of 596 infants, Daly et al. (20) found that exposure to URT viruses is indisputably the single most important predictor for early acute OM. While the crucial role of URT viruses in the pathogenesis of bacterial OM is now firmly established (24, 32-36, 64, 65), we do not yet have a complete understanding of the mechanisms involved.Nearly all respiratory tract viruses can predispose to bacterial OM, but different viruses, and even different strains of the same virus, can differ in their relative ability to do so. The degree to which a particular virus compromises the airway, particularly the ET, has a tremendous influence on the occurrence and severity of OM (28,77). Whereas the cited studies describe intrastrain variability in the ability of influenza virus to predispose to OM, there are also ample data to suggest that othe...

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