A nucleoside-modified mRNA vaccine forming rabies virus-like particle elicits strong cellular and humoral immune responses against rabies virus infection in mice

Aug 12, 2024Emerging microbes & infections

Modified mRNA vaccine creating rabies virus-like particles triggers strong immune responses against rabies infection in mice

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Abstract

RABV and VLP/N mRNA vaccines induced significantly higher neutralizing antibody titres than inactivated rabies vaccines.

The rabies virus glycoprotein is crucial for eliciting neutralizing antibody responses, with its conformation being closely linked to antibody levels.
Virus-like particles formed by the co-expression of RABV glycoprotein and matrix protein enhance immune responses through better antigen presentation.
Nucleoside-modified RABV mRNA vaccines encoding various forms of glycoprotein were developed to improve immune response.
Mice vaccinated with VLP and VLP/N mRNA vaccines demonstrated complete protection against rabies when challenged intracerebrally.
Single doses of VLP and VLP/N mRNA vaccines triggered protective antibody responses significantly higher than those from inactivated vaccines at day 7.
These vaccines also effectively promoted long-lasting immune cell responses, which are associated with durable antibody production.

AI simplified

Rabies is a lethal zoonotic disease that threatens human health. As the only viral surface protein, the rabies virus (RABV) glycoprotein (G) induces main neutralizing antibody () responses; however, Nab titre is closely correlated with the conformation of G. Virus-like particles () formed by the co-expression of RABV G and matrix protein (M) improve retention and antigen presentation, inducing broad, durable immune responses. RABV nucleoprotein (N) can elicit humoral and cellular immune responses. Hence, we developed a series of nucleoside-modified RABV mRNA vaccines encoding wild-type G, soluble trimeric RABV G formed by an artificial trimer motif (tG-MTQ), membrane-anchored prefusion-stabilized G (preG). Furthermore, we also developed RABV VLP mRNA vaccine co-expressing preG and M to generate VLPs, and VLP/N mRNA vaccine co-expressing preG, M, and N. The RABV mRNA vaccines induced higher humoral and cellular responses than inactivated rabies vaccine, and completely protected mice against intracerebral challenge. Additionally, the IgG and Nab titres in RABV preG, VLP and VLP/N mRNA groups were significantly higher than those in G and tG-MTQ groups. A single administration of VLP or VLP/N mRNA vaccines elicited protective Nab responses, the Nab titres were significantly higher than that in inactivated rabies vaccine group at day 7. Moreover, RABV VLP and VLP/N mRNA vaccines showed superior capacities to elicit potent germinal centre, long-lived plasma cell and memory B cell responses, which linked to high titre and durable Nab responses. In summary, our data demonstrated that RABV VLP and VLP/N mRNA vaccines could be promising candidates against rabies.

Key numbers

2.4×

Increase in IgG titres

Compared to G group after vaccination with preG mRNA vaccine.

>0.5 IU/mL

titre protection level

All RABV mRNA vaccines achieved this level after vaccination.

1.7×

Increase in titres

titres compared to G group after vaccination.

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A nucleoside-modified mRNA vaccine forming rabies virus-like particle elicits strong cellular and humoral immune responses against rabies virus infection in mice

Abstract

Key numbers

Full Text

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