BoHV-4-Based Vector Single Heterologous Antigen Delivery Protects STAT1(-/-) Mice from Monkeypoxvirus Lethal Challenge

Abstract

Monkeypox virus (MPXV) is the etiological agent of human (MPX). It is an emerging orthopoxvirus zoonosis in the tropical rain forest of Africa and is endemic in the Congo-basin and sporadic in West Africa; it remains a tropical neglected disease of persons in impoverished rural areas. Interaction of the human population with wildlife increases human infection with MPX virus (MPXV), and infection from human to human is possible. Smallpox vaccination provides good cross-protection against MPX; however, the vaccination campaign ended in Africa in 1980, meaning that a large proportion of the population is currently unprotected against MPXV infection. Disease control hinges on deterring zoonotic exposure to the virus and, barring that, interrupting person-to-person spread. However, there are no FDA-approved therapies against MPX, and current vaccines are limited due to safety concerns. For this reason, new studies on pathogenesis, prophylaxis and therapeutics are still of great interest, not only for the scientific community but also for the governments concerned that MPXV could be used as a bioterror agent. In the present study, a new vaccination strategy approach based on three recombinant bovine herpesvirus 4 (BoHV-4) vectors, each expressing different MPXV glycoproteins, A29L, M1R and B6R were investigated in terms of protection from a lethal MPXV challenge in STAT1 knockout mice. BoHV-4-A-CMV-A29LgD106ΔTK, BoHV-4-A-EF1α-M1RgD106ΔTK and BoHV-4-A-EF1α-B6RgD106ΔTK were successfully constructed by recombineering, and their capacity to express their transgene was demonstrated. A small challenge study was performed, and all three recombinant BoHV-4 appeared safe (no weight-loss or obvious adverse events) following intraperitoneal administration. Further, BoHV-4-A-EF1α-M1RgD106ΔTK alone or in combination with BoHV-4-A-CMV-A29LgD106ΔTK and BoHV-4-A-EF1α-B6RgD106ΔTK, was shown to be able to protect, 100% alone and 80% in combination, STAT1(-/-) mice against mortality and morbidity. This work demonstrated the efficacy of BoHV-4 based vectors and the use of BoHV-4 as a vaccine-vector platform.

Crimean-Congo Hemorrhagic Fever Virus Subunit Vaccines Induce High Levels of Neutralizing Antibodies But No Protection in STAT1 Knockout Mice

“…Despite the absence of type I and II interferon function, STAT129 mice were shown to develop strong adaptive immune responses to virus infections (Vancott et al 2003, Franceschi et al 2015 or vaccination with experimental subunit vaccines (Vancott et al 2003, Raymond et al 2011. Although this suggests that the model is suitable for the evaluation of candidate vaccines, the high susceptibility of STAT129 mice to virus infection may result in undervaluing the vaccine potential of experimental vaccines.…”

Bovine herpesvirus 4-based vector delivering the full length xCT DNA efficiently protects mice from mammary cancer metastases by targeting cancer stem cells

“…However, BoHV-4-mxCT-transduced cells expressed mxCT, as revealed by western blotting ( Figure 1E). A virus expressing the unrelated A29 Monkeypoxvirus glycoprotein (BoHV-4-A29) 38 was used as a control.…”

BoHV-4-based vector delivering Ebola virus surface glycoprotein

“…The Zaire Ebola virus Mayinga strain glycoprotein (GP) sequence, identical to the Gabon-94 strain and highly conserved with the new isolates (accession number: KJ660346.2, KJ660347, KJ660348), was used as a template to obtain its nucleotide sequence by reverse translation, which was human codon usage adapted and tagged at the carboxy-terminal with gD106 tag peptide [10, 20] (Fig. 1a, b).…”

“…Based on previous studies, which demonstrated the ability of BoHV-4 based vectors to efficiently protect against the Category A agent Monkeypox virus [10], it can be assumed that the use of BoHV-4 vector based platform represents an effective tool to test unknown antigens and vectors for class A pathogens.…”

“…Bovine herpesvirus 4 (BoHV-4)-is a relatively new viral vector derived from bovine gammaherpesvirus . Recombinant BoHV-4s cloned as bacterial artificial chromosome (BAC), delivering ORFs coding for immune-dominant antigens from different pathogens, were shown to successfully elicit a functional immune-response in mice [9, 10], rats [11], rabbits [12], sheep [13], swine [14] and goats [15]. In the present paper, a BoHV-4-based vector platform was generated exploiting a synthetic gene approach; a recombinant BoHV-4 delivering EBOV GP ORF expression cassette was constructed and goats were successfully immunized.…”