Neutralizing polyclonal antibody to respiratory syncytial virus (RSV) has been shown to be an effective prophylactic agent when administered intravenously in high-risk infants. This study describes the generation of a humanized monoclonal antibody, MEDI-493, that recognizes a conserved neutralizing epitope on the F glycoprotein of RSV. The affinity of MEDI-493 was found to be equal to or slightly better than an isotype-matched chimeric derivative of the parent antibody. In plaque reduction, microneutralization, and fusion-inhibition assays, MEDI-493 was significantly more potent than the polyclonal preparation. Broad neutralization of a panel of 57 clinical isolates of the RSV A and B subtypes was demonstrated. Pretreatment of cotton rats with MEDI-493 resulted in 99% reduction of lung RSV titers at a dose of 2.5 mg/kg, corresponding to a serum concentration of 25-30 microg/mL. Further, MEDI-493 did not induce increased RSV infection or pathology in either a primary or a secondary challenge.

Development of a Humanized Monoclonal Antibody (MEDI-493) with Potent In Vitro and In Vivo Activity against Respiratory Syncytial Virus

In order to develop a dose-response model for SARS coronavirus (SARS-CoV), the pooled data sets for infection of transgenic mice susceptible to SARS-CoV and infection of mice with murine hepatitis virus strain 1, which may be a clinically relevant model of SARS, were fit to beta-Poisson and exponential models with the maximum likelihood method. The exponential model (k= 4.1 x l0(2)) could describe the dose-response relationship of the pooled data sets. The beta-Poisson model did not provide a statistically significant improvement in fit. With the exponential model, the infectivity of SARS-CoV was calculated and compared with those of other coronaviruses. The does of SARS-CoV corresponding to 10% and 50% responses (illness) were estimated at 43 and 280 PFU, respectively. Its estimated infectivity was comparable to that of HCoV-229E, known as an agent of human common cold, and also similar to those of some animal coronaviruses belonging to the same genetic group. Moreover, the exponential model was applied to the analysis of the epidemiological data of SARS outbreak that occurred at an apartment complex in Hong Kong in 2003. The estimated dose of SARS-CoV for apartment residents during the outbreak, which was back-calculated from the reported number of cases, ranged from 16 to 160 PFU/person, depending on the floor. The exponential model developed here is the sole dose-response model for SARS-CoV at the present and would enable us to understand the possibility for reemergence of SARS.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1539-6924.2010.01427.x

Development of a dose-response model for SARS coronavirus

The cotton rat is susceptible to respiratory synctial virus infection in both the upper and lower portions of the respiratory tract. Virus replicates to high titer in the nose and lungs and to relatively low titer in the trachea. Immunofluorescence studies demonstrated viral antigen in the nasal epithelium and the bronchial and bronchiolar epithelium but not in the trachea or the alveolar cells of the lungs. Histopathologic changes included a desquamative, exudative rhinitis of moderate severity and a mild proliferative bronchiolitis. Serum neutralizing antibody developed in all animals by the ninth day after infection, reaching extremely high titer in several instances. Unlike the previously described response of experimentally infected infant ferrets, cotton rats are uniformly susceptible to pulmonary infection throughout life, thereby offering a model for long-term pulmonary studies heretofore not available.

The pathogenesis of respiratory syncytial virus infection in cotton rats.

Respiratory syncytial virus.

The battle against RSV has been long and littered with setbacks and disappointments. Improvements in the management of infant bronchiolitis and pneumonia have reduced mortality but the virus remains a major cause of serious, distressing and, occasionally fatal, disease in the very young. Painstaking work in many hospitals and laboratories has built up a detailed picture of the virus and its epidemiology but its pathogenesis and prevention remain enigmatic. The stage is now set for dramatic advances against this important disease of man and animals in which the powerful new techniques in immunology and biotechnology must be the principal players.

Respiratory syncytial virus. Brief review.

The infant ferret is susceptible to respiratory syncytial virus infection in both the upper and lower respiratory tracts. In the nose, viral replication is restricted to the surface respiratory epithelium in the nasal passages and turbinates. In the lungs, viral replication is of a lower order of magnitude and is localized in the alveolar cells. The pattern of viral replication in nasal tissues is independent of the age of the animal at infection, whereas the pattern in lung tissues shows a striking age dependence, with viral replication progressively decreasing as a function of age. Thes age dependence appears to be due to an intrinsic age-related mechanism yet to be defined. We feel that the infant ferret is an acceptable model for the study of respiratory syncytial virus disease and that the study of age dependence observed in ferrets may allow elucidation of the mechanisms involved in the age dependence seen in humans.

D. D. Porter

Papers

The pathogenesis of respiratory syncytial virus infection in infant ferrets.