Genetically Modified Rabies Virus Vector-Based Rift Valley Fever Virus Vaccine is Safe and Induces Efficacious Immune Responses in Mice

Abstract

Rift Valley fever virus (RVFV), which causes Rift Valley fever (RVF), is a mosquito-borne zoonotic pathogen that causes serious morbidity and mortality in livestock and humans. RVF is a World Health Organization (WHO) priority disease and, together with rabies, is a major health burden in Africa. Here, we present the development and characterization of an inactivated recombinant RVFV and rabies virus (RABV) vaccine candidate (rSRV9-eGn). Immunization with rSRV9-eGn stimulated the production of RVFV-specific IgG antibodies and induced humoral and cellular immunity in mice but did not induce the production of neutralizing antibodies. IgG1 and IgG2a were the main isotypes observed by IgG subtype detection, and IgG3 antibodies were not detected. The ratios of IgG1/IgG2a > 1 indicated a Type 2 humoral immune response. An effective vaccine is intended to establish a long-lived population of memory T cells, and mice generated memory cells among the proliferating T cell population after immunization with rSRV9-eGn, with effector memory T cells (TEM) as the major population. Due to the lack of prophylactic treatment experiments, it is impossible to predict whether this vaccine can protect animals from RVFV infection with only high titres of anti-RVFV IgG antibodies and no neutralizing antibodies induced, and thus, protection confirmation needs further verification. However, this RVFV vaccine designed with RABV as the vector provides ideas for the development of vaccines that prevent RVFV and RABV infections.

Comparable Long-Term Rabies Immunity in Foxes after IntraMuscular and Oral Application Using a Third-Generation Oral Rabies Virus Vaccine

“…For example, a mixed type-1/type-2 and predominant type-1 response to inactivated RABV have been reported for mice and dogs, respectively [ 36 , 48 ]. Additionally, contradictory results with type-2-based immune responses with high IgG1/IgG2 ratios in mice vaccinated with live recombinant RABV vaccine have been reported [ 35 ]. Therefore, interpretation of results is difficult considering that immunogenicity is often investigated using mice as an animal model, which have a different immune system compared to most other species [ 68 ].…”

“…Notably, virus gene expression in lymphoid tissue cells after oral vaccine uptake [ 32 ] and the ensuing cytokine induction, antigen processing, and presentation are crucial for the recruitment of antigen-presenting cells (APC), in particular dendritic cells (DCs), for initiation and shaping of adaptive T- and B-cell mediated immune responses [ 33 ]. Initiation of CD4+ and CD8+ T cell responses after RABV infection independent of the virus used has been described [ 34 ], with live RABV vector vaccines able to elicit both a type 1 and 2 immune response [ 35 ]. Hence, immunization with live-attenuated vaccines is supposed to provide long-lasting rabies immunity, superior to the protection induced by inactivated vaccines [ 36 ].…”

A Bivalent Human Adenovirus Type 5 Vaccine Expressing the Rabies Virus Glycoprotein and Canine Distemper Virus Hemagglutinin Protein Confers Protective Immunity in Mice and Foxes

“…The ratio of IgG1/IgG2a almost equaled 1, suggesting that the rAd5-G-H induced both Th1 and Th2 immune responses in mice. IFN-γ is a Th1-type cytokine involved in the antiviral action of cellular immune responses, while IL-4 is mainly produced by Th2 cells and has been associated with humoral immune responses (Zhang S. et al, 2019). Notably, the rAd5-G-H induced more IFNγ + SFCs than IL-4 + SFCs 4 weeks after immunity in mice, indicating a Th1 preferred cellular-mediated immune response, which contributed to a 100% protection against RABV challenge in mice and CDV challenge in foxes.…”

An inactivated recombinant rabies virus displaying the Zika virus prM-E induces protective immunity against both pathogens

“…The RABV SRV9 strain was derived from the SAD strain by plaque purification in BHK cells, and it is nonpathogenic to dogs, rats, guinea pigs, deer, and 3-week-old mice [ 22 ]. The vector RABV SRV9, which can highly express foreign proteins, was constructed in our lab [ 22 ] and has been used in vaccine development [ 26 , 27 ]. Therefore, we chose the SRV9 strain as the vector to construct three recombinant viruses expressing ZIKV prM-E: ZI-D, ZI-E and ZI-F.…”