Development of a New, More Effective Live-Attenuated Influenza Vaccine: An Essential Platform for Future Pandemic Protection
Abstract
Vaccination is the most cost-effective approach by which the spread of a pandemic influenza virus could be prevented, and severe disease reduced. However, current influenza vaccines have had an efficacy rate of < 50% against seasonal influenza over the past decade. The effectiveness of the current quadrivalent live-attenuated influenza vaccine (LAIV4) has been even lower than this, leading the Advisory Committee on Immunization Practices (ACIP) to make "the interim recommendation that LAIV4 should not be used" in the 2016-17 influenza season. Thus, it is very important to develop a new and more effective live-attenuated influenza vaccine (LAIV) capable of eliciting broadly cross-protective immune responses to conserved internal viral proteins, thereby providing the basis for a universal influenza vaccine. The current LAIV is both temperature sensitive (ts) -- meaning that it cannot replicate at the temperatures encountered in the febrile human lung (39 degrees Celsius) -- and attenuated (att), meaning that it is weakened with respect to its ability to cause disease in vivo. We hypothesize that by understanding the molecular basis for these properties, it will be possible to develop a new, more effective live-attenuated influenza vaccine that leverages LAIV’s superior ability to protect against infection by diverse influenza viruses. Our goal is to develop a new LAIV that (1) has greater temperature sensitivity than current LAIVs, resulting in viral replication only in the lower temperatures of the nasal cavity and extreme upper airway and (2) selectively favors virus gene expression over viral replication, resulting in abundant protein expression (and immunogenicity) but minimal production of infectious progeny virus. We are well positioned to test this hypothesis because we have developed several innovative assays to study LAIV, along with a novel mouse model of LAIV, and we have also identified a new mutation that dramatically increases the safety of LAIV, without compromising vaccine immunogenicity. We propose three specific aims. The first aim will identify the mechanisms by which mutations unique to the current LAIV vaccine affect viral polymerase function and render it temperature sensitive in human cells (i.e., unable to function at the temperatures encountered in the febrile human lung). These experiments will include assessments of virus polymerase activity and virus replication in cultured human cells, over a physiologically relevant temperature range. The second aim will identify the mechanisms by which other polymerase mutations associated with viral temperature sensitivity, including a novel mutation that we have recently identified, affect viral polymerase function. We will also examine the effects of the mutations present in a LAIV developed in Russia. This “Russian LAIV” is important not only because its hallmark mutations are completely different from the current U.S. LAIV, but also because it has been licensed to the World Health Organization for pandemic influenza preparedness in developing countries and it was safe and well tolerated in a large, recent clinical trial in young children in Bangladesh. Finally, in the third aim, we will evaluate the replication and safety of novel LAIVs containing rationally designed combinations of mutations (chosen from Aims 1 and 2), and we will also test their ability to protect against lethal influenza virus infection in vivo. The ultimate objective is to identify new and more effective LAIVs for development as candidate universal influenza vaccines. Impact: This study will impact the development and testing of a universal influenza vaccine. Short-term impacts will include (1) understanding, for the first time, at the molecular level how the currently licensed LAIV vaccine actually works (i.e., why it is temperature sensitive), creating the opportunity to improve it and (2) identifying new, more effective LAIVs capable of eliciting broadly cr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710168
Entities
People
- Stephen Dewhurst
Organizations
- United States Army
- University of Rochester