Comparative Effects of Two Neutralizing Anti-Respiratory Syncytial Virus (RSV) Monoclonal Antibodies in the RSV Murine Model: Time versus Potency

Abstract

Respiratory syncytial virus (RSV) is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants and young children worldwide. We have previously shown in the mouse model that treatment with an anti-RSV neutralizing monoclonal antibody (MAb) against the F glycoprotein of RSV, palivizumab, decreased lung inflammation, airway obstruction, and postmethacholine airway hyperresponsiveness. MEDI-524, or Numax, is a new MAb derived from palivizumab with enhanced neutralizing activity against RSV. We compared the effects of these two MAbs on different markers of disease severity using the murine model of RSV infection. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or MEDI-524 was administered once at either 24 h before or 48 h after RSV inoculation. Regardless of the time of administration, all treated mice showed significantly decreased RSV loads in bronchoalveolar lavage samples measured by plaque assay. Only MEDI-524 given at ؊24 h significantly decreased lung RSV RNA loads on days 5 and 28 after RSV inoculation. Pulmonary histopathologic scores, airway obstruction, and postmethacholine airway hyperresponsiveness were significantly reduced in mice treated with MEDI-524 at 24 h before inoculation, compared with untreated controls and the other regimens evaluated. MEDI-524 was superior to palivizumab on several outcome variables of RSV disease assessed in the mouse model: viral replication, inflammatory and clinical markers of acute disease severity, and long-term pulmonary abnormalities.Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract disease in infants and young children worldwide. Although certain populations, such as children with chronic lung disease, congenital heart disease, prematurity, or immunodeficiency, are at increased risk for severe RSV disease, most infants hospitalized for RSV infection are previously healthy and have no known risk factors (3). Palivizumab (Pvz) (Synagis; MedImmune, Gaithersburg, MD) is a humanized neutralizing immunoglobulin G1 (IgG1) monoclonal antibody (MAb) directed against the F protein of RSV and is currently approved for prevention of severe RSV infection in high-risk children (13). Although this preventive strategy has dramatically reduced the number of hospitalizations due to RSV in the target populations (11, 13), there are still a small number of breakthrough hospitalizations. These hospitalizations do not appear to be related to the emergence of palivizumab-resistant mutants (10). Thus, the development of anti-RSV antibodies with more potent neutralizing activities, longer half-lives, or more favorable pharmacokinetic profiles and distribution characteristics has the potential to improve outcomes in patients with RSV disease. Potential benefits could be achieved not only for acute disease but also for the long-term consequences of RSV infection, such as recurrent wheezing and airway hyperresponsiveness (25,27).MEDI-524 (Numax) is a novel recombinant humanized IgG1 MAb derived from palivizumab, with m...

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

“…Although one would consider this type of correlation obvious, it is not always the case. Notably, the anti-F protein monoclonal antibody palivizumab significantly reduces viral load but does not improve lung histopathology and lung inflammation in the cotton rat RSV model [30]. In the same study, Numax showed better antiviral activity and improvement in lung histopathology than palivizumab.…”

Effects of Anti-G and Anti-F Antibodies on Airway Function after Respiratory Syncytial Virus Infection

“…Neutralizing antibodies can directly block these interactions and lead to reduced numbers of airway infiltrating cells (15,19,27,28). Airway inflammation, initiated either by innate immune responses or neurogenic responses, contribute to development of AHR (29).…”

Aberrant T cell immunity triggered by human Respiratory Syncytial Virus and human Metapneumovirus infection

“…31,38,39 In addition, antibody-mediated immunity is relevant for protection against both viruses. 40,41 For example, Palivizumab, an IgG1 humanized anti-F monoclonal antibody, is safe and effective when given in a prophylactic manner to children at risk of severe hRSV infection. 42 Thus, the ideal vaccine for either hRSV or hMPV should provide both antibody and T cell-mediated immune protection.…”