Following recent successes in tackling the COVID-19 pandemic, messenger RNA (mRNA) lipid nanoparticle (LNP) vaccines have been designed against a broad range of viral diseases and cancers. However, the development of mRNA-LNP vaccines targeting bacterial pathogens has lagged behind. To address this shortfall and demonstrate the potential utility of mRNA-LNP vaccines to treat patients infected with antibiotic-resistant bacterial strains, researchers at Tel Aviv University report an optimized mRNA-LNP vaccine against Yersinia pestis, the etiological agent of the bubonic plague. Their data, published in Science Advances, show that a single dose of the vaccine elicits humoral and cellular immunological responses in mice and confers rapid, full protection against a lethal Y. pestis challenge.
The F1 capsule antigen is an attractive therapeutic target
A typical Y. pestis strain contains three plasmids (pCD1, pMT1, and pPCP1), of which pMT1 encodes the highly immunogenic fraction 1 capsule antigen (F1). F1 is expressed from the caf1 operon and assembled into polymers with the assistance of the Caf1M chaperone. It is then exported to the bacterial cell surface by the Caf1A usher protein, where it forms a gel-like capsule that enables Y. pestis to evade phagocytosis. Based on its role for the bacterium, F1 is an attractive therapeutic target for a vaccine against this pathogen.
Several vaccine candidates based on F1 have demonstrated protection in animal models of plague and in clinical studies, but none of these has been approved for use in Western countries. With the emergence of antibiotic-resistant Y. pestis strains, an effective vaccine could be crucial to slowing an outbreak.
Rational mRNA design
F1 biogenesis involves the concerted expression of multiple genes from the caf1 operon. However, this biogenesis pattern is challenging to reproduce in a mammalian system. Therefore, Kon et al. based their vaccine mRNA design on a circular permutated caf1 gene encoding monomeric F1. Four mRNA sequences were synthesized, in part by TriLink, each building on the previous and incorporating features aimed at improving vaccine immunogenicity and efficacy. The first modification the scientists made was to include a signal peptide sequence originating from the human immunoglobulin kappa light chain to send the produced antigen through the secretory pathway. Second, a higher guanine and cytosine (GC) content was used to increase mRNA and protein expression. Third, a human Fc sequence was conjugated to the mRNA sequence to improve stability, half-life and immunogenicity. Finally, the researchers also tested a mRNA that had high GC content, the human Fc conjugation and removed the signal peptide to reduce undesired immunogenicity of the vaccine.
Optimized mRNA-LNPs protect against lethal Y. pestis challenge
To assess mRNA immunogenicity in vivo, each construct was encapsulated in an LNP and used to vaccinate mice prior to a lethal Y. pestis challenge. The different mRNA designs provided varying levels of protection to the pathogen. In particular, enriching the GC content from 45% to 66% elicited high antibody titers in 4 of 8 animals following three immunizations (compared to 0 animals without GC enrichment), which subsequently translated to 50% survival against a lethal dose of Y. pestis. The mRNA vaccine without the signal peptide but retaining high GC content similarly provided 50% survival protection. Finally, just a single dose of the GC-enriched construct with both the signal peptide and the human Fc conjugated sequence provided full (100%) protection against the Y. pestis challenge.
Foundation for antibacterial mRNA vaccine development
Overall, this study is a promising step towards developing mRNA-LNP vaccines that can protect against dangerous bacterial infections and provide a framework for future mRNA bacterial vaccine development. Thus, the advantages of mRNA vaccines, such as rapid and specific development, could be employed to develop vaccines against bacterial diseases, including antibiotic-resistant bacteria, and to provide urgently needed protection against life-threatening conditions like the bubonic plague.
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Article reference: Kon E, Levy Y, Elia U , et al. A single-dose F1-based mRNA-LNP vaccine provides protection against the lethal plague bacterium. Science Advances 2023; Vol. 9, No. 10.