Development of next-generation respiratory virus vaccines through targeted modifications to viral immunomodulatory genes

Abstract

Vaccines represent one of the greatest contributions of the scientific community to global health. Yet, many pathogens remain either unchallenged or inadequately hindered by commercially available vaccines. Respiratory viruses pose distinct and difficult challenges due to their ability to rapidly spread, adapt, and modify the host immune response. Considerable research has been directed to understand the role of respiratory virus immunomodulatory proteins and how they influence the host immune response. We review here efforts to develop next-generation vaccines through targeting these key immunomodulatory genes in influenza virus, coronaviruses, respiratory syncytial virus, measles virus, and mumps virus.

Keywords:

• coronavirus
• immunology
• influenza
• measles
• mumps
• next-generation vaccines
• pathogenesis
• respiratory syncytial virus
• respiratory viruses

Financial & competing interests disclosure

This work was supported by NIH grants R01AI087798 (ML Moore), U19 AI095227 (ML Moore), and T32 AI074492 (CC Stobart) and the Emory Children’s Center for Childhood Infections and Vaccines (CCIV). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Respiratory viruses continue to pose many new challenges for vaccine design and development.

• Influenza virus vaccine remains marginally effective from season to season and fails to provide broadly protective immunity. Several new immunomodulatory proteins of influenza have been identified and new techniques are being made available, which may result in a new generation of influenza vaccines.

• Despite a clear potential for pandemic disease, no vaccines remain available for coronaviruses. A number of immunomodulatory genes for coronaviruses have been identified and novel strategies including targeting viral replication fidelity represent new directions in vaccine development.

• Respiratory syncytial virus remains a major respiratory pathogen for young children and currently no prophylactic options are available for prevention. Codon deoptimization represents a potentially new strategy for respiratory syncytial virus gene modulation, which has been shown to be effective for immunomodulatory proteins NS1 and NS2. Combining this approach with alterations to changes to other key regulatory genes may provide the basis for a novel respiratory syncytial virus live-attenuated vaccine.

• Future development of respiratory virus vaccines will likely target combining changes to immunomodulatory genes with improvements in reverse genetics. Codon modifications represent a key new development that may allow catered modifications of specific immunomodulatory genes in vaccine development.