An RNA Vaccine Protects against Crimean-Congo Hemorrhagic Fever Virus Infection in Mice

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) is commonly transmitted by ticks and has a wide geographic distribution, being endemic throughout southern and eastern Europe, the Middle East, Asia, and Africa. Due to climate change, this range is even expanding northward. CCHFV causes a hemorrhagic disease characterized by initial non-specific illness (fever, muscle pains, nausea) followed by severe internal and external bleeding with a case fatality rate of 5-60%. As there is no licensed therapeutics or vaccines, there is great need for highly effective countermeasures. Recently, we have developed a self-replicating RNA-based vaccine which expresses two of the viral proteins: the CCHFV nucleoprotein (repNP) and glycoprotein precursor (repGPC) and is highly protective against a lethal viral challenge in mice. We found that vaccination with this vaccine prevented disease and conferred 100% survival against a lethal CCHFV infection in mice. This vaccine significantly stimulated both antibody-producing B-cells and T-cells which kill infected cells. Our repNP vaccination primarily stimulated B-cells to produce anti-NP antibodies while repGPC primarily stimulated the T-cells. To confirm whether B-cells or T-cells are most responsible for protection, we vaccinated mice lacking B- or T-cells. While mice lacking T-cells survived, B-cell deficient mice only had ~40% survival indicating that the B-cells and antibodies are essential to confer protection. Currently, this vaccine is undergoing further preclinical testing in preparation for human clinical trials while ongoing studies are continuing to investigate how these antibodies protect against CCHFV so that we may improve additional and much needed CCHFV therapeutics. This research was funded by the Intramural Research Program, NIAID, NIH

Replicating RNA vaccination elicits an unexpected immune response that efficiently protects mice against lethal Crimean-Congo hemorrhagic fever virus challenge

Summary: Background: Crimean-Congo hemorrhagic fever virus is the cause of a severe hemorrhagic fever with cases reported throughout a wide-geographic region. Spread by the bite of infected ticks, contact with infected livestock or in the health care setting, disease begins as a non-specific febrile illness that can rapidly progress to hemorrhagic manifestations. Currently, there are no approved vaccines and antivirals such as ribavirin have unclear efficacy. Thus treatment is mostly limited to supportive care. Methods: In this report we evaluated an alphavirus-based replicon RNA vaccine expressing either the CCHFV nucleoprotein or glycoprotein precursor in a stringent, heterologous lethal challenge mouse model. Findings: Vaccination with the RNA expressing the nucleoprotein alone could confer complete protection against clinical disease, but vaccination with a combination of both the nucleoprotein and glycoprotein precursor afforded robust protection against disease and viral replication. Protection from lethal challenge required as little as a single immunization with 100ng of RNA. Unexpectedly, analysis of the immune responses elicited by the vaccine components showed that vaccination resulted in antibodies against the internal viral nucleoprotein and cellular immunity against the virion-exposed glycoproteins. Interpretation: Cumulatively this vaccine conferred robust protection against Crimean-Congo hemorrhagic fever virus and supports continued development of this vaccine candidate. Funding: This research was supported by the Intramural Research Program of the NIAID/NIH and HDT Bio