Enhancing protective immunity against SARS-CoV-2 with a self-amplifying RNA lipid nanoparticle vaccine

Dec 7, 2024Journal of controlled release : official journal of the Controlled Release Society

Improving COVID-19 protection with a self-boosting RNA vaccine in fat particles

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Abstract

LNP-saRNA-RBD vaccination induced a robust immune response in mice, leading to protection against SARS-CoV-2.

Self-amplifying RNA (saRNA) may enhance the intensity and duration of immune responses compared to traditional RNA vaccines.
The LNP-saRNA-RBD vaccine effectively delivered the receptor-binding domain of the SARS-CoV-2 spike protein, promoting prolonged antigen expression.
Vaccination led to the generation of antigen-specific T cells that differentiated into long-lived memory cells.
A germinal center response was initiated in draining lymph nodes, resulting in the production of anti-RBD IgG antibodies capable of neutralizing SARS-CoV-2 pseudovirus.
Prime-boost immunizations with LNP-saRNA-RBD reduced viral infection and replication in the lungs of mice, along with mitigating associated inflammatory damage.

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RNA-based vaccines against SARS-CoV-2 have demonstrated promising protective immunity against the global COVID-19 epidemic. Enhancing the intensity and duration of mRNA antigen expression is anticipated to markedly boost antiviral immune responses. Self-amplifying RNA (saRNA) represents a next-generation platform for RNA-based vaccines, amplifying transcripts in situ to augment the expression of encoded immunogens. Here, we develop a saRNA nanovaccine, formulated with a mutated saRNA encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein, encapsulated within a lipid nanoparticle (LNP-saRNA-RBD). This LNP-saRNA vaccine platform enables efficient delivery of saRNA-RBD, inducing enhanced and prolonged expression of the RBD antigen. LNP-saRNA-RBD vaccination stimulated the generation of antigen-specific T cells, promoting their differentiation into a long-lived effector memory phenotype. Immunization with LNP-saRNA-RBD induced a germinal center response in draining lymph nodes, leading to the production of anti-RBD IgG antibodies with the ability to neutralize SARS-CoV-2 pseudovirus. Furthermore, prime-boost immunizations with LNP-saRNA-RBD conferred protection to mice against SARS-CoV-2 challenge by suppressing viral infection and replication, as well as pulmonary inflammatory responses and associated damage. Taken together, these findings provide strong support for advancing the development of LNP-saRNA-RBD as a safe and efficacious vaccine candidate against SARS-CoV-2 infection.

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Enhancing protective immunity against SARS-CoV-2 with a self-amplifying RNA lipid nanoparticle vaccine

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