MVA Vectored Vaccines Encoding Rift Valley Fever Virus Glycoproteins Protect Mice against Lethal Challenge in the Absence of Neutralizing Antibody Responses

Abstract

In vitro neutralizing antibodies have been often correlated with protection against Rift Valley fever virus (RVFV) infection. We have reported previously that a single inoculation of sucrose-purified modified vaccinia Ankara (MVA) encoding RVFV glycoproteins (rMVAGnGc) was sufficient to induce a protective immune response in mice after a lethal RVFV challenge. Protection was related to the presence of glycoprotein specific CD8+ cells, with a low-level detection of in vitro neutralizing antibodies. In this work we extended those observations aimed to explore the role of humoral responses after MVA vaccination and to study the contribution of each glycoprotein antigen to the protective efficacy. Thus, we tested the efficacy and immune responses in BALB/c mice of recombinant MVA viruses expressing either glycoprotein Gn (rMVAGn) or Gc (rMVAGc). In the absence of serum neutralizing antibodies, our data strongly suggest that protection of vaccinated mice upon the RVFV challenge can be achieved by the activation of cellular responses mainly directed against Gc epitopes. The involvement of cellular immunity was stressed by the fact that protection of mice was strain dependent. Furthermore, our data suggest that the rMVA based single dose vaccination elicits suboptimal humoral immune responses against Gn antigen since disease in mice was exacerbated upon virus challenge in the presence of rMVAGnGc or rMVAGn immune serum. Thus, Gc-specific cellular immunity could be an important component in the protection after the challenge observed in BALB/c mice, contributing to the elimination of infected cells reducing morbidity and mortality and counteracting the deleterious effect of a subneutralizing antibody immune response.

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

“…Another study showed the cooperative effect of a non-neutralizing antibody improving protection in a mouse model ( Gutjahr et al., 2020 ). Perhaps more surprisingly, mice vaccinated with modified Vaccinia Ankara (MVA) expressing both Gn and Gc failed to elicit nAbs but were still protected from viral challenge ( Lopez-Gil et al., 2020 ). IgG1, the predominant subclass recognizing the RVFV glycoproteins identified here, can efficiently trigger the classical route of complement ( Vidarsson et al., 2014 ).…”

The Change P82L in the Rift Valley Fever Virus NSs Protein Confers Attenuation in Mice

“…They were equally distributed into groups of 5–7 animals and inoculated intraperitoneally with 500 plaque-forming units (pfus) of the corresponding viruses. Development of disease was evaluated over 3 weeks (18 days) in terms of mortality and morbidity, as elsewhere [ 18 ] checking for weight and development of clinical signs, such as ruffled fur, ocular discharges, hunched posture and reduced activity. Blood samples were collected in Microvette ® tubes K3 EDTA or Serum (Sarstedt, Nümbrecht, Germany) upon submandibular puncture at 72 h after infection and tested for viral RNA by RT-qPCR [ 16 , 19 ] to monitor viremia, while serum samples collected from survivor mice at the end of the experiment (day 18 pi) were used in antibody assays.…”

“…Wild-type rZH548 (red) and rZH548∆NSs::GFP (labeled as, rZH∆NSs/GFP, green) viruses were included as controls for virulence and attenuation, respectively. Animals were monitored up to18 days. (A) Survival rates and (B-E) morbidity upon challenge with the indicated viruses.…”

Naturally acquired Rift Valley fever virus neutralizing antibodies predominantly target the Gn glycoprotein

“…Another study showed the cooperative effect of a non-neutralizing antibody improving protection in a mouse model (Gutjahr et al, 2020). Perhaps more surprisingly, mice vaccinated with modified Vaccinia Ankara (MVA) expressing both Gn and Gc failed to elicit nAbs but were still protected from viral challenge (Lopez-Gil et al, 2020). IgG1, the predominant subclass recognising the RVFV glycoproteins identified here, can efficiently trigger the classical route of complement (Vidarsson et al, 2014).…”