A Tetravalent Sub-unit Dengue Vaccine Formulated with Ionizable Cationic Lipid Nanoparticle induces Significant Immune Responses in Rodents and Non-Human Primates

Abstract

Dengue virus has emerged as an important arboviral infection worldwide. As a complex pathogen, with four distinct serotypes, the development of a successful Dengue virus vaccine has proven to be challenging. Here, we describe a novel Dengue vaccine candidate that contains truncated, recombinant, Dengue virus envelope protein from all four Dengue virus serotypes (DEN-80E) formulated with ionizable cationic lipid nanoparticles (LNPs). Immunization studies in mice, Guinea pigs, and in Rhesus macaques, revealed that LNPs induced high titers of Dengue virus neutralizing antibodies, with or without co-administration or encapsulation of a Toll-Like Receptor 9 agonist. Importantly, LNPs were also able to boost DEN-80E specific CD4+ and CD8+ T cell responses. Cytokine and chemokine profiling revealed that LNPs induced strong chemokine responses without significant induction of inflammatory cytokines. In addition to being highly efficacious, the vaccine formulation proved to be well-tolerated, demonstrating no elevation in any of the safety parameters evaluated. Notably, reduction in cationic lipid content of the nanoparticle dramatically reduced the LNP’s ability to boost DEN-80E specific immune responses, highlighting the crucial role for the charge of the LNP. Overall, our novel studies, across multiple species, reveal a promising tetravalent Dengue virus sub-unit vaccine candidate.

Efficient Delivery of Dengue Virus Subunit Vaccines to the Skin by Microprojection Arrays

“…Subunit vaccine approaches based on the main target of a neutralizing antibody response, the DENV E glycoprotein, also have great potential [7]. Despite previous evidence that the DENV E protein is poorly immunogenic on its own [7,10], there are several practical advantages in the subunit vaccine approach over live-attenuated vaccines. These include safety, flexibility to adjust the antigenic dose to balance the immune response, and the ability to safely immunize infants and immunosuppressed individuals [30].…”

“…The DENV surface glycoprotein E is an ideal candidate for a subunit vaccine, given that it is the major target of a neutralizing antibody response [7][8][9]. However, ensuring a potent immune response remains a challenge for recombinant subunit vaccines, necessitating an effective adjuvant strategy [10]. Immune responses can be enhanced by targeting antigen presenting cells in the skin by intradermal injection or by use of microarray patches (MAPs), such as the nanopatch.…”

Co-Administration of Lipid Nanoparticles and Sub-Unit Vaccine Antigens Is Required for Increase in Antigen-Specific Immune Responses in Mice

“…Then, using a sterile syringe, the specified volume of vaccination mixture was retrieved and administered to mice. Our group has recently published two papers where such detailed protocols are provided [17,22]. In addition, our group’s recent publication reported our characterization of antigen and adjuvant′s physio-chemical properties and stability [17].…”

Plant‐expressed Fc‐fusion protein tetravalent dengue vaccine with inherent adjuvant properties

“…Several promising nonlive subunit dengue vaccine candidates have been reported, including DNA vaccines (Poggianella et al, 2015;Porter and Raviprakash, 2015), nanoparticle formulations (Swaminathan et al, 2016) and lipidated dengue antigens (Chiang et al, 2016). These and other preclinical candidates currently being considered are necessary for continuous feeding of the dengue vaccine pipeline until an effective vaccine strategy against this global pandemic is finally attained.…”