Replicating Vector Protects Against Lethal Filovirus and Arenavirus Challenge

Aside from better and more rapid diagnostics and antivirals, the development of a protective vaccine, particularly against 'category A' VHF pathogens such as Ebola and Marburg viruses, is a priority for many countries. Recent investigations have concentrated on the use of subunit vaccines (glycoprotein, nucleoprotein) delivered by several distinct approaches including DNA vaccination or replication-deficient viruses. Many of these approaches resulted in protective efficacy in rodent models but failed to protect nonhuman primates with the exception of adenovirus-based strategies for Ebola virus.Given the partial success in generating effective vaccines in the past, we decided to investigate the utility of a replication-competent vector, such as recombinant vesicular stomatitis virus (rVSV). The potential of VSV to serve as a vaccine vector relates to the high-tittered growth in vitro, the elucidation of a strong cellular and humoral immune response in vivo, and the neglectful level of pre-existing immunity in humans. We developed rVSVs in which the VSV glycoprotein is completely replaced by a foreign transmembrane glycoprotein. The rVSVs show the characteristic rhabdovirus morphology, a slightly attenuated growth kinetic, and the tropism of the donor virus. The rVSVs expressing were studied in respect to their potential in mounting a protective immunity against lethal virus challenge. A single intramuscular injection uniformly protected nonhuman primates from disease after high-dose challenge with homologous Marburg or Ebola viruses. Back-challenge experiments demonstrated cross-protection within but not among species. Mucosal immunity could be achieved with a single dose of the Ebola vaccine in mice, guinea pigs and nonhuman primates. In mice it could be shown that the Ebola vaccine provided complete specific protection if administered 7 days before challenge and 80% protection when given 30 minutes after challenge. Effective post-exposure treatment was recently also demonstrated in the nonhyuman primate model. Vaccination with the rVSV vectors did not result in any clinical symptoms in any of the investigated animal species (mice, guinea pigs, goats, macaques). Our data suggest that this vaccine vectors are not only highly potent and safe, but induce rapid 'sterile' immunity. The potential for mucosal delivery make them potent candidates for mass immunization during outbreaks or in the event of a bioterrorist attack and also useful for application in wildlife. Furthermore, the approach might also be a promising concept for future vaccine development against other lethal VHF agents.