A formalin-inactivated respiratory syncytial virus vaccine was used to immunize infants in the mid1960s ; when these children later were naturally infected by the virus they developed markedly accentuated disease, and two died. For the present work, a new batch of vaccine was prepared using the original formula. Administration of either the old or new vaccines resulted in enhanced lesions in immunized cotton rats subsequently challenged with live virus, although administration of the vaccine reduced virus replication by 90 %. Animals primed with formalin-inactivated virus and challenged developed markedly accentuated lesions of the same type as in animals undergoing primary or secondary infection. In addition, the animals with the vaccine-enhanced disease developed alveolitis and interstitial pneumonitis, which appear to be specific markers for the vaccine enhancement. The newly prepared vaccine appears suitable as a reference standard for studying the mechanism of vaccine-enhanced disease caused by this virus. Additionally, we reviewed the lesions in the lungs of the two humans who died with the vaccine-enhanced disease in 1967, and found that they were similar to, but more severe than those seen in the cotton rats.

Parenteral treatment of an experimental respiratory syncytial virus (RSV) infection in a cotton rat model with a monoclonal antibody directed against the viral F protein resulted in the clearance of infectious virus within 24 h but had no effect on the pulmonary pathology at 24 h and only a small effect on the pulmonary pathology at 72 h. Treatment with parenteral triamcinolone acetonide dramatically reduced the pathologic lesions of viral bronchiolitis and pneumonia but resulted in the delayed clearance of the virus. The combination of the monoclonal antibody given in a single dose 72 h after infection, combined with 3 daily doses of the corticosteroid starting 72 h after infection, demonstrated both the loss of infectivity and the disappearance of lesions. No rebound of lesions or infectivity was noted. Combined antiviral and anti-inflammatory therapy for RSV disease appears promising.Respiratory syncytial virus (RSV), the leading cause of infectious pulmonary disease in infants and children worldwide (reviewed in [1]), is increasingly recognized as a cause of serious disease in adults, particularly the elderly [2] and in immunocompromised persons [3]. Vaccine development programs spanning 4 decades have yet to result in a safe and effective RSV vaccine [4]. A major breakthrough in RSV prophylaxis has been the development and licensure both of polyclonal and monoclonal immunoglobulin products for use in high-risk infants (RespiGam [RSVIg] and Synagis [palivizumab]; MedImmune, Gaithersburg, MD). Although highly effective and apparently cost-effective in the targeted population, these products have not been widely used in persons at normal risk owing to the cost. Since most hospital admissions for RSV are among normal-risk patients, there is a pressing need for an effective RSV therapeutic [5].More than a decade has elapsed since the licensure by the US Food and Drug Administration (FDA) of ribavirin (Virazole; ICN Pharmaceuticals, Costa Mesa, CA) as an RSV therapeutic. Initial enthusiasm for this drug, however, has gradually been replaced by increasing resistance to its use, as concerns over efficacy, cost, and ease of use have grown [6].The use of RSV immunoglobulin in a therapeutic setting was first suggested in studies in cotton rats. Immunoglobulin given to RSV-infected animals reduced pulmonary virus titers 100-fold within 6 h [7], a level of reduction far greater than that seen with ribavirin in the same animal model [8]. This observation led to a series of therapeutic clinical trials of RSV immunoglobulin formulations, including generic human IgG given parenterally [9] or via aerosol [10,11], RSVIg given parenterally [12,13], and palivizumab given parenterally [14]. Although these studies showed immunoglobulin therapy to be safe, thus overturning a long-standing dogma [15], and monitored virus titers showed a reduction in immunoglobulintreated patients, none resulted in a clinically beneficial outcome.Although the goal of the clinician in treating an infectious disease has long been the elimination of th...

The cotton rat was evaluated as a model for anti-inflammatory and antiviral influenza therapy. Beginning 3 days after intranasal infection with 10(7) tissue culture infectious doses-50% (TCID)(50) of an H3N2 human influenza, animals were treated topically via intranasal lavage with a range of doses of triamcinolone acetonide (1, 4, or 16 mg/kg), alone or in combination with a neuraminidase inhibitor or anti-influenza convalescent serum. Pulmonary histopathologic changes were dramatically decreased in animals treated with 4 or 16 mg/kg of triamcinolone, with little additional benefit from addition of a neuraminidase inhibitor or topical serum, agents which were much less effective when used alone. A high degree of suppression of IFN-gamma levels was observed in all combinations where 4 or 16 mg/kg of triamcinolone were used. Viral replication was not prolonged by corticosteroid therapy. Tissue damage during influenza infection may be greatly reduced by combination antiviral and anti-inflammatory therapy.

Despite the documented disease burden of respiratory syncytial virus (RSV) in the elderly, little is known about the underlying risk factors or pathogenesis of RSV in a geriatric population. This report describes an age-dependent change of RSV clearance in the lung and nose of the cotton rat. Six days postinfection with RSV, lung and nose viral titers were significantly higher in all older age groups as compared with 4- to 6-week old cotton rats (P < 0.05). When comparing the 4- to 6-week old animals to the 15- to 16-month old animals 6 days postinfection, there was over an 800- and 100-fold increase in lung and nose viral titers, respectively. The cotton rat may prove to be a useful model in eliciting mechanisms of severe RSV disease in the elderly.

Triamcinolone acetonide, methylprednisolone, and dexamethasone were each evaluated in combination with palivizumab (Synagis) for the therapy of established respiratory syncytial virus infection in the cotton rat. Triamcinolone and methylprednisolone proved to be more effective than dexamethasone in reducing lung pathology. No recurrence of viral replication or pulmonary pathology followed the cessation of therapy.The cotton rat model of respiratory syncytial virus (RSV) infection has been used for over 20 years to study the pathogenesis and potential therapy of RSV (7). This animal model was invaluable in proving the protective efficacy of anti-RSV antibody (6) and led to the development of RSV immunoglobulin (RespiGam; Medimmune, Inc., Gaithersburg, Md.) and palivizumab (Synagis; Medimmune) for the prevention of severe RSV infection of the lower respiratory tract (1, 2, 5). These preparations have been less effective when used therapeutically (9, 10). Recent experiments with cotton rats demonstrated that combined systemic therapy with palivizumab and triamcinolone acetonide, a potent glucocorticoid, greatly reduced inflammatory changes and viral replication in animals infected with RSV but that palivizumab alone reduced viral titers without altering the degree of inflammation (8). Systemic triamcinolone acetonide is rarely used in the treatment of pediatric respiratory disease, and therefore we examined the comparative efficacies of triamcinolone acetonide, methylprednisolone, and dexamethasone when each was used in combination with palivizumab in the treatment of experimental RSV infection.( Virus. A pool of the prototypic Long strain of RSV (American Type Culture Collection, Manassas, Va.) which contained 10 7.5 PFU/ml was used for all experiments. Pulmonary virus titers were determined by plaque assay as described previously (7).Monoclonal antibody and glucocorticoids. Palivizumab was provided by Medimmune, Inc. Triamcinolone acetonide (Steris Laboratories, Phoenix, Ariz.) was administered as a single daily intramuscular (i.m.) dose of 16 mg/kg of body weight, a dose previously found to be highly effective in reducing pulmonary pathology (8). Dexamethasone (Elkins-Sinn, Cherry Hill, N.J.) was administered in a single daily intraperitoneal (i.p.) dose of 0.6 or 1.2 mg/kg. Methylprednisolone (SoluMedrol; Phamacia and Upjohn, Kalamazoo, Mich.) was administered in a total daily dose of 4 or 8 mg/kg divided into four equal i.p. injections.Histopathology. Lungs were inflated to their normal volume with 10% formalin. Hematoxylin-and eosin-stained slides were prepared from coronal paraffin-embedded sections and scored for peribronchiolitis (inflammatory cells around small airways), interstitial pneumonitis (inflammatory cell infiltration and thickening of alveolar walls), and alveolitis (inflammatory cells within the alveolar spaces). Slides were scored in a blind manner by three investigators using a scale ranging from 0 (no inflammatory changes) to 100 (maximum inflammation).Statistical analysis. A viral titer was...