To facilitate NIAID?s strategic plan for the development of a universal influenza vaccine, PAR-19-248 solicits ?Research Projects to Improve the Predictive Value of Animal Models in Recapitulating Human Immunity to Influenza Infection and Vaccination?. Here, we address some of the major research needs identified in PAR-19- 248 by continuing our development of golden Syrian hamsters (hereafter referred to as hamsters) as an animal model for influenza virus research. This is based on our previous findings that the composition of influenza virus receptors in the respiratory tract of hamsters is similar to that in the respiratory tract of humans, and that human influenza A viruses replicate in the respiratory tract of hamsters, including recent human H3N2 influenza viruses, which do not replicate efficiently in mice.
In Specific Aim 1, we plan to establish an influenza virus aerosol exposure platform for hamsters. Currently, most influenza virus infection studies entail intranasal virus inoculation, which is not the natural route of infection (i.e., aerosol exposure). By establishing an aerosol exposure platform for hamsters, we are addressing a key topic of PAR-19-248.
In Specific Aim 2, we will assess the predictive value of hamsters in simulating the impact of the first exposure to influenza viruses on subsequent exposures (imprinting). With few exceptions, influenza virus infection and vaccination studies have been conducted in nave animals, thus not reflecting the immune status of most humans who have been exposed to multiple influenza viruses through infections and/or vaccinations. Here, we will sequentially infect hamsters (via intranasal infection or aerosol exposure) with the same human influenza viruses that caused the first and second infections in a child (based on clinical samples that we have obtained from a pediatric cohort study). Hamster and human sera will then be compared for B cell responses to the first and second infections.
In Specific Aim 3, we will assess the predictive value of hamsters in simulating human immune responses to multiple infections, vaccination, and challenge. Hamsters will be sequentially infected with two different influenza viruses, and subsequently vaccinated with an inactivated vaccine. The B cell responses elicited will be compared to those of human samples obtained before and after vaccination with the same vaccine strain that will be used to vaccinate the hamsters. In another study, hamsters will be sequentially infected with two different influenza viruses, and subsequently vaccinated with an investigational (potentially broadly protective) vaccine and challenged with a heterologous virus. The B cell immune responses elicited will be compared with those from a Phase 2a clinical trial that used the same investigational vaccine and challenge viruses. By leveraging our preliminary data and our access to human samples, we will address several key topics of PAR-19-248, including the assessment of novel animal models, the assessment of aerosol exposure and pre-exposure to influenza viruses on immune responses, and the recapitulation of immune mechanisms such as imprinting and back-boosting in animal models.
Our research seeks to further establish Syrian hamsters as a model for influenza virus research that could be used to test novel, potentially broadly protective influenza vaccines. The establishment of improved animal models for influenza virus research is an urgent task that has prompted the National Institute of Allergy and Infectious Diseases to call for research proposals that address this topic.
