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

Abstract

A vast body of evidence suggests that nanoparticles function as potent immune-modulatory agents. We have previously shown that Merck proprietary Lipid NanoParticles (LNPs) markedly boost B-cell and T-cell responses to sub-unit vaccine antigens in mice. To further evaluate the specifics of vaccine delivery and dosing regimens in vivo, we performed immunogenicity studies in BALB/c and C57BL/6 mice using two model antigens, Hepatitis B Surface Antigen (HBsAg) and Ovalbumin (OVA), respectively. To assess the requirement for co-administration of antigen and LNP for the elicitation of immune responses, we evaluated immune responses after administering antigen and LNP to separate limbs, or administering antigen and LNP to the same limb but separated by 24 h. We also evaluated formulations combining antigen, LNP, and aluminum-based adjuvant amorphous aluminum hydroxylphosphate sulfate (MAA) to look for synergistic adjuvant effects. Analyses of antigen-specific B-cell and T-cell responses from immunized mice revealed that the LNPs and antigens must be co-administered—both at the same time and in the same location—in order to boost antigen-specific immune responses. Mixing of antigen with MAA prior to formulation with LNP did not impact the generation of antigen-specific B-cell responses, but drastically reduced the ability of LNPs to boost antigen-specific T-cell responses. Overall, our data demonstrate that the administration of LNPs and vaccine antigen together enables their immune-stimulatory properties.

Lipid Nanoparticle Acts as a Potential Adjuvant for Influenza Split Vaccine without Inducing Inflammatory Responses

“…In addition, we demonstrated that SV plus LNP can protect against influenza virus challenge as efficiently as SV plus alum ( Figure 5 ), suggesting the usefulness of the LNP as an adjuvant for influenza vaccines. Our results support those of other recent studies that have highlighted the effectiveness of LNPs as vaccine adjuvants [ 23 , 24 , 25 ]. However, it is not clear whether our LNP can be used with other types of antigens because it does not enhance antigen-specific antibody responses and T-cell responses when rHA is used as an antigen ( Figure 6 and Figure 7 ).…”

“…For vaccine application, LNPs containing mRNA coding for protein antigens have been used to induce strong immune responses, such as antigen-specific antibody responses and T-cell responses in mice and rhesus macaques [ 18 , 19 ]. In addition, there is increasing evidence of the usefulness of LNPs as efficient antigen-delivery vehicles [ 20 , 21 , 22 , 23 , 24 , 25 ]. For example, by using protein antigens from dengue virus and hepatitis B virus, it has been shown that specific LNPs can enhance co-administered antigen-specific antibody responses, CD4 + T-cell responses, and CD8 + T-cell responses in mice, guinea pigs, and non-human primates without the addition of immunomodulatory adjuvant molecules [ 23 , 24 , 25 ], although the precise mechanism of adjuvanticity of specific LNPs remains unclear.…”

Lipid-Based Nanoparticles for Delivery of Vaccine Adjuvants and Antigens: Toward Multicomponent Vaccines

“…When examining the effect of combining LNPs and aluminum in a single formulation, they observed an enhanced B-cell response but a reduced T-cell response. 114 Similar studies by Swaminathan et al demonstrated that LNPs coadministered with a synthetic TLR9 agonist, immune-modulatory oligonucleotides, IMO-2125 (IMO), significantly enhanced immune responses to HBsAg and OVA in comparison to IMO alone. 115 Previous work by Yanasarn et al showed that protein antigens admixed with DOPA-based negatively charged liposomes induced strong, functional antibody responses.…”

A Solution with Ginseng Saponins and Selenium as Vaccine Diluent to Increase Th1/Th2 Immune Responses in Mice

“…For instance, De Gregorio et al reported that the adjuvant effect was often lost when the antigen and alum were administered at separate locations [71]. Thoryk et al demonstrated that lipid nanoparticles (LNPs) must be coadministered with antigens to exert adjuvant property [72]. However, Rivera et al observed that ginseng improved antibody response to porcine parvovirus (PPV) antigen regardless of that the ginseng and antigen were coinjected or not [73].…”