Lipid nanoparticles (LNPs) are at the forefront of scientific thought due to the SARS-CoV-2 pandemic. While mRNA-LNPs have been studied for years, there is still much to be learned about their uses in translational medicine. Here, we expand the application of this technology for prophylactic viral vaccines and study factors that impact the immunogenicity of mRNA-LNP vaccines.

First, we discuss the prospects for vaccines against the tumor-associated Kaposi sarcoma-associated herpesvirus (KSHV) using knowledge obtained from previous herpesvirus studies. We highlight the need for immune responses in addition to neutralizing antibodies, such as antibodies with effector functions and cellular immunity. We apply LNPs as an adjuvant for a protein-based vaccine against KSHV using virus-like vesicles (VLVs), noninfectious viral particles that present viral envelope proteins. We find that adjuvanted VLVs generate KSHV-specific antibody and T cell responses in mice. Importantly, we highlight an important role of antibodies that target the complement control protein ORF4 for complement-dependent neutralization of KSHV. This forms a basis for LNP-adjuvanted KSHV VLVs to be developed as a vaccine.

We next studied the impacts of type I interferons (IFN-I) on the immunogenicity of mRNA-LNPs. Using genetic knockout and antibody blockade of IFN-I in mice, we find antigen-specific alterations in immunogenicity against three viral antigens delivered by mRNA-LNPs: influenza hemagglutinin (HA), SARS-CoV-2 Spike receptor binding domain (RBD), and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). HA antibody responses are largely unaffected by IFN-I, but T cells responding to inactivated viruses are deficient without IFN-I. Antibody responses to RBD appear strain-dependent, but IFN-I is necessary for T cell responses. Finally, RdRp-specific T cell responses are unchanged or enhanced when IFN-I is not present. These results highlight the need for antigen-specific studies to better understand the role of IFN-I in immunogenicity of mRNA-LNPs.

Finally, we study whether mRNA-LNPs that target the highly conserved SARS-CoV-2 RdRp can protect against infection. The RdRp mRNA-LNP is immunogenic in wildtype and transgenic mice, but there was minimal protection conferred by RdRp immunization against high dose SARS-CoV-2 infection of K18-hACE2 transgenic mice. Further studies are necessary to elucidate whether RdRp is a promising candidate for next-generation SARS-CoV-2 vaccines.