Towards a Safe, Effective Vaccine for Rift Valley Fever Virus

Abstract

Rift Valley fever virus (RVFV) is an important animal and human threat and leads to longstanding morbidity and mortality in susceptible hosts. Since no therapies currently exist to treat Rift Valley fever, it remains a public and animal health priority to develop safe, effective RVFV vaccines (whether for animals, humans, or both) that provide long-term protective immunity. In the evaluated article, Bhardwaj and colleagues describe the creation and testing of two successful vaccine strategies against RVFV, a DNA plasmid vaccine expressing Gn coupled to C3d, and an alpha-virus replicon vaccine expressing Gn protein. Both vaccines elicited strong neutralizing antibody responses, prevented morbidity and mortality in RVFV-challenged mice, and enabled protection of naive mice via passive antibody transfer from vaccinated mice. Both DNA and replicon RVFV vaccines have previously been shown to protect against RVFV challenge, but these results allow for direct comparison of the two methods and evaluation of a combined primeboost method. The results also highlight the specific humoral and cell-mediated immune responses to vaccination. Keywords Rift Valley Fever; vaccine Summary of methodsIn their study, Bhardwaj and colleagues performed experiments to directly compare DNA vaccines and alphavirus vaccines expressing Rift Valley Fever virus (RVFV) Gn, evaluate the efficacy of these DNA vaccines against Rift Valley Fever (RVF) in a mouse model, determine whether a prime-boost strategy enhances efficacy, and assess the nature of the immune response to vaccination [1]. RVFV is a member of the Phlebovirus genus, one of the five genera in the family Bunyaviridae [101]. RVFV, similar to other Bunyaviruses, has a single-stranded, tripartite-negative or ambisense-coded RNA genome, composed of the L, M and S segments encoding four structural proteins, viral polymerase (L segment), glycoproteins (M segment) and nucleocapsid protein N (S segment) [2]. RVFV is a highpriority pathogen because of its ability to cause blindness, encephalitis and life-threatening hemorrhagic fever in humans [3,102], its potential for severe economic harm to livestock [101], and its potential for nonvector aerosol spread during epizootics and epidemics [4,5].

Naturally Acquired Rift Valley Fever Virus Neutralizing Antibodies Predominantly Target the Gn Glycoprotein

“…The protective role antibodies play against RVFV infection is well documented ( Peters et al., 1988 ; LaBeaud, 2010 ; Niklasson et al., 1984 ). The structural glycoproteins displayed on the surface of RVFV, Gn and Gc, are key targets of this protective immune response, and monoclonal antibodies have been identified targeting both ( Besselaar and Blackburn, 1991 ; Besselaar-Blackburn, 1992 ; Wang et al., 2019 ).…”

“…Although protection against RVFV infection has long been associated with the induction of nAbs targeting Gn and Gc ( Dodd et al., 2013 ; Peters et al., 1988 ; LaBeaud, 2010 ), it can also arise from other mechanisms. Mice vaccinated with the immunodominant nucleoprotein (N), for example, show partial protection from RVFV challenge despite the absence of detectable nAbs ( Lopez-Gil et al., 2013 ; Jansen Van Vuren et al., 2011 ).…”

Current Status of Rift Valley Fever Vaccine Development

“…The wide distribution of competent vectors in non-endemic areas [ 31 , 32 , 33 , 34 , 35 ] coupled with the effects of climate change [ 36 ] and potential use for bioterrorism emphasizes the need for safe and efficacious vaccines. There is no licensed or commercially available vaccine for human use; and while a variety of vaccines for livestock have been developed, there are no fully licensed RVFV vaccines approved for veterinary use outside endemic areas [ 8 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. In the past decade, various strategies to develop efficacious RVFV vaccines have been undertaken by several research laboratories or groups.…”

Transmission Dynamics of Rift Valley Fever Virus: Effects of Live and Killed Vaccines on Epizootic Outbreaks and Enzootic Maintenance

“…New generation vaccines are currently under development and under clinical trials: (1) the attenuated MP12 which is derived from the virulent Egyptian strain (ZH548) and a plaque isolate of RVFV 74HB59, and (2) Clone 13 which is an avirulent candidate with no reversion owing to a large deletion in the NSs protein (that has been pointed out to be a virulence factor in animals), for instance (Ikegami and Makino, 2009 ; Pepin et al, 2010 ; Rusnak et al, 2011 ). Virus-like particle (VLP) approach and immunization with plasmids are examples of alternative approaches to develop vaccines (Ikegami and Makino, 2009 ; LaBeaud, 2010 ). Effective vaccines surely will facilitate the preparedness for prevention of an introduction of RVFV to disease-free areas and help reduce economic losses from dead and aborted ruminants.…”

“…The ideal vaccine would be one that is safe without causing any pathogenic reaction and virulence reversion and confers long-term protection within a single dose. In addition, it should provide the differentiability between naturally infected and vaccinated animals (DIVA), and should not be expensive and difficult to produce (LaBeaud, 2010 ). Although vaccines can induce immunity against RVFV, it is important to recognize that recombination of live vaccinal strains and virulent strains is possible.…”