Influenza B viruses (IBV) primarily infect humans, causing seasonal epidemics. The absence of an animal reservoir limits pandemic concern, but IBV infections may cause severe respiratory disease, predominantly in young children and the elderly. The IBV disease burden is largely controlled by seasonal influenza vaccination; however, immunity due to vaccination is sometimes incomplete, a feature linked to antigenic mismatches. Thus, understanding the features that contribute to disease pathogenesis is important, particularly immune-mediated versus virus-mediated outcomes. Unexpectedly, C57BL/6 (B6) mice intranasally infected with a low multiplicity of infection of B/Florida/04/2006 developed substantial morbidity and mortality. To address the cause, B6 mice were treated daily with dexamethasone to dampen the immune and pro-inflammatory response to IBV infection, allowing the determination of whether the responses were immune- and/or virus-associated. As expected, dexamethasone (DEX)-treated mice had a lower pro-inflammatory response and reduced lung pathology despite the presence of high viral lung titers, but mortality was comparable to PBS-treated mice, indicating that mortality may be linked to lung virus replication. The results showed that the immune response to IBV is the major cause of morbidity, mortality, lung pathology, and viral clearance. Importantly, the results suggest that a robust lung CTL response and associated leukocyte influx contribute to disease.

The respiratory syncytial virus (RSV) causes significant respiratory disease in young infants and the elderly. Immune prophylaxis in infants is currently limited to palivizumab, an anti-RSV fusion (F) protein monoclonal antibody (mAb). While anti-F protein mAbs neutralize RSV, they are unable to prevent aberrant pathogenic responses provoked by the RSV attachment (G) protein. Recently, the co-crystal structures of two high-affinity anti-G protein mAbs that bind the central conserved domain (CCD) at distinct non-overlapping epitopes were solved. mAbs 3D3 and 2D10 are broadly neutralizing and block G protein CX3C-mediated chemotaxis by binding antigenic sites γ1 and γ2, respectively, which is known to reduce RSV disease. Previous studies have established 3D3 as a potential immunoprophylactic and therapeutic; however, there has been no similar evaluation of 2D10 available. Here, we sought to determine the differences in neutralization and immunity to RSV Line19F infection which recapitulates human RSV infection in mouse models making it useful for therapeutic antibody studies. Prophylactic (24 h prior to infection) or therapeutic (72 h post-infection) treatment of mice with 3D3, 2D10, or palivizumab were compared to isotype control antibody treatment. The results show that 2D10 can neutralize RSV Line19F both prophylactically and therapeutically, and can reduce disease-causing immune responses in a prophylactic but not therapeutic context. In contrast, 3D3 was able to significantly (p < 0.05) reduce lung virus titers and IL-13 in a prophylactic and therapeutic regimen suggesting subtle but important differences in immune responses to RSV infection with mAbs that bind distinct epitopes.