Development of a novel, single-cycle replicable rift valley Fever vaccine

• Published in: PLoS neglected tropical diseases 2014-03, Vol.8 (3), p.e2746
• Main Authors: Murakami, Shin, Terasaki, Kaori, Ramirez, Sydney I, Morrill, John C, Makino, Shinji
• Format: Article
• Language: English
• Subjects: Abortion; Animal vaccines; Animals; Antibodies, Neutralizing - blood; Antibodies, Viral - blood; Arbovirus; Biology; Biomedical research; Bunyaviridae; Cloning; Disease Models, Animal; Encephalitis; Female; Fever; Infection control; Innovations; Medicine; Mice; Mosquitoes; Mutant Proteins - genetics; Mutant Proteins - metabolism; Mutation; Pharmacology, Experimental; Phlebovirus; Prevention; Proteins; Public health; Rift Valley fever; Rift Valley Fever - prevention & control; Rift Valley fever virus; Rift Valley fever virus - genetics; Rift Valley fever virus - immunology; Rift Valley fever virus - physiology; RNA polymerase; Ruminantia; Scholarships & fellowships; Sheep; Survival Analysis; Vaccines, Attenuated - administration & dosage; Vaccines, Attenuated - adverse effects; Vaccines, Attenuated - genetics; Vaccines, Attenuated - immunology; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - adverse effects; Vaccines, Synthetic - genetics; Vaccines, Synthetic - immunology; Veterinary Science; Viral Proteins - genetics; Viral Proteins - immunology; Viral vaccines; Viral Vaccines - administration & dosage; Viral Vaccines - adverse effects; Viral Vaccines - genetics; Viral Vaccines - immunology; Virus Internalization; Virus Replication
• ISSN: 1935-2735; 1935-2727; 1935-2735
• DOI: 10.1371/journal.pntd.0002746

Rift Valley fever virus (RVFV) (genus Phlebovirus, family Bunyaviridae) is an arbovirus that causes severe disease in humans and livestock in sub-Saharan African countries. Although the MP-12 strain of RVFV is a live attenuated vaccine candidate, neuroinvasiveness and neurovirulence of MP-12 in mice may be a concern when vaccinating certain individuals, especially those that are immunocompromised. We have developed a novel, single-cycle replicable MP-12 (scMP-12), which carries an L RNA, M RNA mutant encoding a mutant envelope protein lacking an endoplasmic reticulum retrieval signal and defective for membrane fusion function, and S RNA encoding N protein and green fluorescent protein. The scMP-12 underwent efficient amplification, then formed plaques and retained the introduced mutation after serial passages in a cell line stably expressing viral envelope proteins. However, inoculation of the scMP-12 into naïve cells resulted in a single round of viral replication, and production of low levels of noninfectious virus-like particles. Intracranial inoculation of scMP-12 into suckling mice did not cause clinical signs or death, a finding which demonstrated that the scMP-12 lacked neurovirulence. Mice immunized with a single dose of scMP-12 produced neutralizing antibodies, whose titers were higher than in mice immunized with replicon particles carrying L RNA and S RNA encoding N protein and green fluorescent protein. Moreover, 90% of the scMP-12-immunized mice were protected from wild-type RVFV challenge by efficiently suppressing viremia and replication of the challenge virus in the liver and the spleen. These data demonstrated that scMP-12 is a safe and immunogenic RVFV vaccine candidate.