Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2024

Exploiting the Clec9A targeting vaccine platform to develop a safe and effective DENV vaccine   (#161)

Geraldine Nadya Putri 1 2 3 , Yee Hwa Wong 4 , Julien Lescar 4 , Mireille Lahoud 5 , Sylvie Alonso 1 2 3
  1. Department of Microbiology & Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  2. Immunology programme, Life Sciences Institute, National University of Singapore, Singapore
  3. Infectious Diseases Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  4. Institute of Structural Biology, Nanyang Technological University, Singapore
  5. Monash Biomedicine Discovery Institute, Monash University, Melbourne, Australia

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 manifestation in 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.

DENV envelope domain III (EDIII) has been a leading subunit dengue vaccine candidate, shown to induce strongly neutralising and predominantly serotype-specific antibodies, thereby minimising the risk of ADE. However, EDIII weak immunogenicity has represented a major bottleneck in the development of EDIII-based vaccines.  

We have explored a dendritic cell-targeting vaccine approach to deliver EDIII to the cDC1 dendritic cell subset. cDC1s are highly efficient in processing antigens to present them on both MHC I and MHC II, thereby inducing potent and sustained cellular and humoral immune responses. The vaccine construct consists of a rat anti-mouse Clec9A antibody fused with EDIII at the C-terminus of each heavy chain. Clec9A is a C-type lectin receptor that is specifically expressed on cDC1 . We show that a homologous prime-boost immunization regimen  induced 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. These promising results hence support that the Clec9A targeting approach may overcome the weak immunogenicity of EDIII vaccine antigen and advance its clinical development. .