Dataset Information

Single dose, dual antigen RNA vaccines protect against lethal Crimean-Congo haemorrhagic fever virus infection in mice.

ABSTRACT:

Background

Crimean-Congo Haemorrhagic Fever Virus is a tick-borne bunyavirus prevalent across Asia, Africa, the Middle East, and Europe. The virus causes a non-specific febrile illness which may develop into severe haemorrhagic disease. To date, there are no widely approved therapeutics. Recently, we reported an alphavirus-based replicon RNA vaccine which expresses the CCHFV nucleoprotein (repNP) or glycoprotein precursor (repGPC) and is protective against lethal disease in mice.

Methods

Here, we evaluated engineered GPC constructs to find the minimal enhancing epitope of repGPC and test two RNA vaccine approaches to express multiple antigens in vivo to optimize protective efficacy of our repRNA.

Findings

Vaccination with repNP and a construct expressing just the Gc antigen (repGc-FL) resulted in equivalent immunogenicity and protective efficacy compared to original repNP + repGPC vaccination. This vaccine was protective when prepared in either of two vaccine approaches, a mixed synthesis reaction producing two RNAs in a single tube and a single RNA expressing two antigens.

Interpretation

Overall, our data illustrate two vaccine approaches to deliver two antigens in a single immunization. Both approaches induced protective immune responses against CCHFV in this model. These approaches support their continued development for this and future vaccine candidates for CCHFV and other vaccines where inclusion of multiple antigens would be optimal.

Funding

This work was supported by the Intramural Research Program, NIAID/NIH, HDT Bio and MCDC Grant #MCDC2204-011.

SUBMITTER: Leventhal SS

PROVIDER: S-EPMC10885550 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Publications

Single dose, dual antigen RNA vaccines protect against lethal Crimean-Congo haemorrhagic fever virus infection in mice.

Leventhal Shanna S SS Meade-White Kimberly K Shaia Carl C Tipih Thomas T Lewis Mathew M Mihalakakos Evan A EA Hinkley Troy T Khandhar Amit P AP Erasmus Jesse H JH Feldmann Heinz H Hawman David W DW

EBioMedicine 20240220

<h4>Background</h4>Crimean-Congo Haemorrhagic Fever Virus is a tick-borne bunyavirus prevalent across Asia, Africa, the Middle East, and Europe. The virus causes a non-specific febrile illness which may develop into severe haemorrhagic disease. To date, there are no widely approved therapeutics. Recently, we reported an alphavirus-based replicon RNA vaccine which expresses the CCHFV nucleoprotein (repNP) or glycoprotein precursor (repGPC) and is protective against lethal disease in mice.<h4>Meth ...[more]

PMID: 38382314

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Project description:Crimean-Congo hemorrhagic fever (CCHF), caused by Crimean-Congo hemorrhagic fever virus (CCHFV), is on the World Health Organizations' list of prioritized diseases and pathogens. With global distribution, high fatality rate, and no approved vaccine or effective treatment, CCHF constitutes a threat against global health. In the current study, we demonstrate that vaccination with nucleoside-modified mRNA-lipid nanoparticles (mRNA-LNP), encoding for the CCHFV nucleoprotein (N) or glycoproteins (GcGn) protect IFNAR-/- mice against lethal CCHFV infection. In addition, we found that both mRNA-LNP induced strong humoral and cellular immune responses in IFNAR-/- and immunocompetent mice and that neutralizing antibodies are not necessary for protection. When evaluating immune responses induced by immunization including CCHFV Gc and Gn antigens, we found the Gc protein to be more immunogenic compared with the Gn protein. Hepatic injury is prevalent in CCHF and contributes to the severity and mortality of the disease in humans. Thus, to understand the immune response in the liver after infection and the potential effect of the vaccine, we performed a proteomic analysis on liver samples from vaccinated and control mice after CCHFV infection. Similar to observations in humans, vaccination affected the metabolic pathways. In conclusion, this study shows that a CCHFV mRNA-LNP vaccine, based on viral nucleo- or glycoproteins, mediate protection against CCHFV induced disease. Consequently, genetic immunization is an attractive approach to prevent disease caused by CCHFV and we believe we have necessary evidence to bring this vaccine platform to the next step in the development of a vaccine against CCHFV infection. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is a zoonotic pathogen causing Crimean-Congo hemorrhagic fever (CCHF), a severe fever disease. CCHFV has a wide distribution and is endemic in several areas around the world. Cases of CCHF are also being reported in new areas, indicating an expansion of the disease, which is of high concern. Dispersion of the disease, high fatality rate, and no approved vaccine makes CCHF a threat to global health. The development of a vaccine is thus of great importance. Here we show 100% protection against lethal CCHFV infection in mice immunized with mRNA-LNP encoding for different CCHFV proteins. The vaccination showed both robust humoral and cellular immunity. mRNA-LNP vaccines combine the ability to induce an effective immune response, the safety of a transient carrier, and the flexibility of genetic vaccines. This and our results from the current study support the development of a mRNA-LNP based vaccine against CCHFV.

Dataset Information

Single dose, dual antigen RNA vaccines protect against lethal Crimean-Congo haemorrhagic fever virus infection in mice.

Background

Methods

Findings

Interpretation

Funding

Publications

Single dose, dual antigen RNA vaccines protect against lethal Crimean-Congo haemorrhagic fever virus infection in mice.

Similar Datasets

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