Adding a to mRNA boosted antigen-specific cellular and antibody responses in preclinical vaccine models.
Evidence
This formulation and immunogenicity study compared AD03-LNP with conventional LNP across HPV, SARS-CoV-2 Omicron spike, and influenza HA mRNAs, reporting 1.5-2.1-fold higher HPV CD8+ T cell and cytokine responses, 8-fold higher S-Omicron IgG2a endpoint titers, and 2.3-2.6-fold higher HA CD8+ T cell responses with 3.6-fold higher total IgG endpoint titers.
Caveat
The abstract reports preclinical immune-response endpoints rather than protection, tumor control, durability, or human clinical outcomes.
Simplified
UNLABELLED: N1-methylpseudouridine (N1-methyl-Ψ)-modified mRNA offers a safer alternative to unmodified mRNA-based cancer immunotherapies but induces weaker innate immune responses. This study aimed to enhance the expression of and improve innate and adaptive immune responses by incorporating a toll-like receptor (TLR) 7/8 agonist (AD7/8) into a lipid nanoparticle (LNP). AD7/8 was incorporated into by partially replacing cholesterol, and the mRNA expression efficiency of various formulations was evaluated, leading to the selection of the LNP formulation containing 0.5% AD7/8 (AD03-LNP). AD03-LNP was evaluated using mRNAs encoding human papillomavirus (HPV)16 E7 and HPV18 E6 antigens, the SARS-CoV-2 Omicron spike protein (S-Omicron), and influenza hemagglutinin (HA), and it consistently enhanced antigen-specific immune responses compared with conventional LNP. In the HPV mRNA model, antigen-specific CD8⁺ T cell and cytokine responses were significantly increased by 1.5-2.1-fold. In the S-Omicron mRNA model, IgG2a levels, indicative of a Th1-skewed response, were markedly elevated by 8-fold as measured by endpoint titers. Importantly, in the HA mRNA model, which evaluated both cellular and humoral immunity, AD03-LNP induced significantly higher CD8⁺ T cell responses by 2.3-2.6-fold, together with increased antibody production, with total IgG elevated by 3.6-fold as measured by endpoint titers. These findings demonstrate that AD03-LNP enhances both cellular and humoral immune responses across diverse antigens. These results provide insights into how -loaded LNPs influence mRNA expression and immune responses, supporting an effective formulation approach to boost the immunogenicity of mRNA-LNP vaccines. This approach may help advance the design of mRNA-based cancer immunotherapies and prophylactic vaccines that depend on strong T cell responses.
SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13036-025-00573-1.
Key numbers
1.5-2.1×
Increase in CD8⁺ T cell responses
Measured in the HPV mRNA model using AD03-LNP.
8×
Elevated IgG2a levels
Observed in the S-Omicron mRNA model.
3.6×
Increase in antibody production
Measured in the HA mRNA model with AD03-LNP.
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