mRNA - lipid nanoparticle (LNP) vaccines developed against SARS-CoV-2 are a transformative technology and saved millions of lives during the COVID-19 pandemic. In this vaccine platform, LNPs function as both a delivery agent and a powerful adjuvant. However, the relationship between LNP composition and adjuvanticity is not fully understood, hindering future vaccine design.
In this study, we focus on the impact of the Polyethylene-glycol conjugated lipid (PEG-lipid) which is one of the four standard lipids used to make LNPs. PEG-lipids are known to give stability to nanoparticles in solution, control particle size, and impact circulation half-life. We designed mRNA-LNP vaccines that encode SARS-CoV-2 spike as a model antigen, and we modulate the amount of PEG-lipid within the LNP. A comparative vaccination study was performed using BALB/c mice.
We demonstrate that the amount of PEG-lipid used in the LNP formulation has a significant impact on humoral immune responses to mRNA-LNP vaccines in mice and can impact memory B cell responses.
These findings support the rational design of novel LNPs to create more tailored and effective mRNA vaccines against both existing and emerging infectious pathogens.
NIAID, R01AI153064
Vaccines and Immunotherapy (VAC)
Emily F. Daley, Máté Vadovics, F. Coirada et al.· Journal of Immunology· 0 citations
Aberrant activation of Wnt signaling results in unregulated accumulation of cytosolic β-catenin, which subsequently enters the nucleus and promotes transcription of genes that contribute to cellular proliferation and malignancy. Here, we sought to eliminate pathogenic β-catenin from the cytosol using designer ubiquibodies (uAbs), chimeric proteins composed of an E3 ubiquitin ligase and a target-binding domain that redirect intracellular proteins to the proteasome for degradation. To accelerate uAb development, we leveraged a protein language model–driven algorithm called SaLT&PepPr to computationally design “guide” peptides with affinity for β-catenin, which were subsequently fused to the catalytic domain of a human E3 called carboxyl terminus of Hsp70-interacting protein. Expression of the resulting peptide-guided uAbs in colorectal cancer cells led to the identification of several designs that greatly reduced the abnormally stable pool of free β-catenin in the cytosol and nucleus while preserving the normal membrane–associated subpopulation. This selective knockdown of pathogenic β-catenin suppressed Wnt/β-catenin signaling and impaired tumor cell survival and proliferation. Furthermore, one of the best degraders selectively decreased cytosolic but not membrane-associated β-catenin levels in livers of BALB/c mice following delivery as a lipid nanoparticle–encapsulated mRNA. Collectively, these findings reveal the unique ability of uAbs to selectively deplete abnormal proteins in vitro and in vivo and open the door to peptide-programmable biologic modulators of other disease-causing proteins.
Tianzheng Ye, A. Alamgir, C. Robertus et al.· Science Advances· 0 citations
Dengue virus (DENV) remains a major global health burden, with four antigenically distinct serotypes (DENV-1–4) posing a significant challenge for vaccine development. Dengue non-structural protein 1 (NS1) has been associated with additional protection and reduced disease severity, supporting its inclusion in vaccine design. In this study, we designed a consensus NS1 (cNS1) antigen by integrating sequence elements from all four DENV serotypes (78–89% amino acid identity) to enhance cross-serotype antigenic coverage. The cNS1 sequence was encoded as a nucleoside-modified mRNA and formulated in lipid nanoparticles (mRNA–LNPs). Immunization of BALB/c mice with a low dose (0.2 µg) of cNS1 mRNA–LNP induced broadly reactive NS1-specific IgG responses that recognized NS1 proteins from all four serotypes. In addition, the vaccine elicited interferon-γ (IFN-γ)–producing T cell responses against peptide pools derived from multiple DENV serotypes, indicating the activation of cross-reactive cellular immunity. While broad immune recognition was achieved, this was accompanied by lower serotype-specific response magnitudes as a trade-off. In conclusion, the cNS1 mRNA vaccine induces cross-serotype humoral and cellular immune responses in mice, highlighting the potential of consensus antigen design to broaden immune recognition of DENV NS1. These findings support the further development of NS1-based immunogens as complementary components of next-generation dengue vaccines aimed at achieving broad and effective protection.
Kittipan Tharakhet, E. Prompetchara, Chirayus Khawsang et al.· PLoS ONE· 0 citations
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