Influenza Vaccine Research and Development

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Developing influenza vaccines that provide broader, stronger, and longer-lasting protection would help the world fight both seasonal flu and future pandemics. While current vaccines reduce the risk of symptomatic infection and severe disease, their effectiveness is limited by the continual antigenic evolution of influenza viruses. This study focuses on advancing vaccine platforms and immunization strategies that can generate sustained, broadly protective immune responses against the antigenic diversity of influenza viruses. The effectiveness of the current influenza vaccines varies and is influenced by factors such as antigenic match between vaccine and circulating viruses and the limitations around vaccine production (e.g., acquisition of mutations). The major goals of our program are to develop next-generation influenza vaccine candidates that can provide 1) supraseasonal protection from antigenically drifted seasonal influenza virus strains and 2) protection from potential pandemic virus subtypes. Moreover, the immune response elicited by our vaccine candidates should also provide durable immunity. To fulfill our research goals, we employ structure-based immunogen design and self-assembling nanoparticle display platforms. To achieve supraseasonal influenza immunity by improving vaccine-elicited breadth across homotypic and heterosubtypic viruses, we computationally designed a two-component mosaic nanoparticle immunogen. One such mosaic nanoparticle co-displayed the hemagglutinins (HAs) of the four influenza strains in the licensed 2017-2018 seasonal influenza vaccine. Vaccination of mice, ferrets, and nonhuman primates with these mosaic nanoparticles demonstrated that they were highly immunogenic, eliciting vaccine-matched immunity comparable to the current influenza vaccines. More importantly, our mosaic vaccine induced broad protection not only against vaccine-matched strains but also heterologous viruses including heterosubtypic strains. Based on these promising preclinical results, a Phase I clinical trial using a version of this quadrivalent mosaic nanoparticle was initiated to assess safety and immunogenicity. We also designed a next generation hexavalent mosaic vaccine candidate which incorporates two additional HAs from non-circulating influenza viruses and completed pre-clinical studies in mice and nonhuman primates. The hexavalent vaccine candidate was immunogenic in both animal models, and we have also enrolled healthy adults in a Phase I, open-label, dose-escalation study to assess safety, tolerability and immunogenicity. More recently, we developed a mosaic HA stem-only nanoparticle that co-displays four stabilized stem trimers derived from non-circulating influenza group 1 and 2 subtypes with pandemic potential. We have also begun evaluating whether combining an adjuvant with our stabilized stem or mosaic immunogens can enhance vaccine-induced immune responses in both preclinical models and Phase I clinical trials. Our results suggest that our vaccine candidates have the potential to be used for supraseasonal or pre-pandemic influenza. We also continue to structurally and functionally characterize the influenza surface glycoprotein neuraminidase (NA) to gain a better understanding of how it can be used as an improved vaccine candidate.