Mouse Models of Influenza Infection with Circulating Strains to Test Seasonal Vaccine Efficacy

Abstract

Influenza virus infection is a significant cause of morbidity and mortality worldwide. The surface antigens of influenza virus change over time blunting both naturally acquired and vaccine induced adaptive immune protection. Viral antigenic drift is a major contributing factor to both the spread and disease burden of influenza. The aim of this study was to develop better infection models using clinically relevant, influenza strains to test vaccine induced protection. CB6F1 mice were infected with a range of influenza viruses and disease, inflammation, cell influx, and viral load were characterized after infection. Infection with circulating H1N1 and representative influenza B viruses induced a dose-dependent disease response; however, a recent seasonal H3N2 virus did not cause any disease in mice, even at high titers. Viral infection led to recoverable virus, detectable both by plaque assay and RNA quantification after infection, and increased upper airway inflammation on day 7 after infection comprised largely of CD8 T cells. Having established seasonal infection models, mice were immunized with seasonal inactivated vaccine and responses were compared to matched and mismatched challenge strains. While the H1N1 subtype strain recommended for vaccine use has remained constant in the seven seasons between 2010 and 2016, the circulating strain of H1N1 influenza (2009 pandemic subtype) has drifted both genetically and antigenically since 2009. To investigate the effect of this observed drift on vaccine induced protection, mice were immunized with antigens from A/California/7/2009 (H1N1) and challenged with H1N1 subtype viruses recovered from 2009, 2010, or 2015. Vaccination with A/California/7/2009 antigens protected against infection with either the 2009 or 2010 strains, but was less effective against the 2015 strain. This observed reduction in protection suggests that mouse models of influenza virus vaccination and infection can be used as an additional tool to predict vaccine efficacy against drift strains.

Combination of STING Pathway Agonist With Saponin Is an Effective Adjuvant in Immunosenescent Mice

“…The rapid increase in the IgG2a antibody isotype in cGAMP/Quil-A adjuvanted groups that we observed was also consistent with a Th-1 bias of adjuvant action mode (54). We have found that in aged mice, cGAMP potentiated the protective immune response in the presence of Quil-A, while in adult mice Quil-A alone efficiently increased survival and HAI titers, and further addition of 1-5 µg cGAMP did not significantly increase the high protective efficacy of the A/California07/09 H1N1vaccine (55).…”

Membrane‐Based Approach for the Downstream Processing of Influenza Virus‐Like Particles

“…Influenza preclinical studies using mice require a dose of 1.5 µg HA and a maximum volume of injection of 100 µL . Therefore, the target concentration that should be achieved is 15 µg mL −1 .…”

High-Throughput Human Primary Cell-Based Airway Model for Evaluating Influenza, Coronavirus, or other Respiratory Virusesin vitro

“…For coronaviruses, Calu-3 or Vero E6 cells are often used for similar reasons, but again differ by species, cell source, disease state, and innate antiviral signaling pathways [12,13] compared to normal, healthy human conducting airway and alveolar epithelium [14], thus providing an insufficient model. Unfortunately, complications also exist within animal models of IAV, not only in mice, rats, and guinea pigs, but even in more human-relevant options for evaluation such as ferrets and macaques [15,16]. These models often require species-adapted viral strains, and fail to recapitulate features of human innate antiviral responses and clinical symptoms of infection [17,18].…”