MI2025 – Geraldine Nadya

Title:
Exploiting the Clec9A targeting vaccine platform to develop a safe and effective DENV vaccine

Abstract:
With approximately 3.8 billion people at risk of infection in tropical and sub-tropical regions, dengue ranks among the top ten threats worldwide. It is caused by dengue virus, a flavivirus with four distinct serotypes. Dengue places a large economic burden on endemic countries and has the potential for severe disease manifestationin the form of Dengue Haemorrhagic Fever (DHF) or Dengue Shock Syndrome (DSS). With no approved antivirals to treat infected patients, vaccines have been recognised to be the foundation to reduce DENV burden. However, dengue vaccine development has proven to be a challenge as an imbalanced immune response towards one serotype over the other could lead to antibody dependent enhancement (ADE) and eventual severe dengue. There are two live-attenuated dengue vaccines (Dengvaxia, Sanofi and QDENGA, Takeda Pharmaceuticals) that have been approved for human use, but only in specific age groups and have varied efficacies against the four DENV serotypes.

Our group utilises the Clec9A-targeting system to develop a subunit DENV vaccine, which involves a rat anti-mouse Clec9A antibody with a DENV2 envelope domain III (EDIII) genetically fused to the C-terminus of the heavy chain. Clec9A is a receptor that is specifically expressed in dendritic cells of the cDC1 subtype. cDC1s are highly efficient in processing antigens and cross-presentation on MHC I and MHC II, making Clec9A a promising DC surface receptor for antigen delivery. In addition, antibodies generated against EDIII are strongly neutralising and predominantly serotype-specific, minimising the risk of ADE. Optimisation of the immunisation regimen Balb/C mice immunised with a two-dose regimen of the Clec9A-EDIII construct (priming, followed by boosting one month after prime) have shown sustained anti-EDIII IgG titres and neutralising antibody titres up to 9 months post-boost. Clec9A-EDIII immunisation also generated EDIII-specific spleen Tfh cell response and poly-functional CD4+ T cells secreting IFN-γ, IL-2, and TNF-α at 1 week post boost. More work will be done to characterise the B cell responses following immunisation as well as exploring an alternative construct combining EDIII with a CD8+ DENV epitope to elicit both humoral and cellular protection.

Biography:
Geraldine is a PhD student in A/P Sylvie Alonso’s lab who is passionate about vaccinology and virology.