LAUSR

The Ebola virus (EBOV) epidemic in West Africa that devastated Guinea, Liberia, and Sierra Leone from 2013 to 2016 became a global public health crisis and claimed over 11,000 human lives [1]. There were no licensed vaccines and therapeutics against EBOV disease available at the time of the epidemic, but several experimental vaccine approaches were accelerated into human clinical trials starting in October 2014 [2]. Among these a replication competent vesicular stomatitis virus (VSV) vector expressing the EBOV glycoprotein (GP) in place of the VSV glycoprotein (VSV-EBOV, also known as rVSV-ZEBOV) met with single-dose success, a success that was demonstrated using a ring vaccination strategy [3]. This vaccine is moving toward licensure in the United States and Europe, but has already been licensed as a combination vaccine in Russia [4]. However, VSV-EBOV has disadvantages. As it was developed as an emergency vaccine, it is fast-acting due to its replication competence in the vaccinated individual, but can cause mild adverse events similar to those observed by Yellow fever vaccination, for example, pain at injection site and fever [5]. In addition, a single study showed that the VSV-EBOV vaccine requires long-term storage conditions at −70°C and has limited stability at 4°C and 25°C [6], although the manufacturer’s are currently working toward a lyophilized formulation. If multiple doses of the VSV-EBOV have to be administered to achieve complete protection its use would be limited as the vaccine doses require a stable cold-chain for long-term storage which is challenging in Africa; however, as a single-dose vaccine, its stability is appropriate for where it is most needed in the developing world during outbreaks. However, several other experimental vaccine approaches have been developed to support a population-based vaccine effort against EBOV for the endemic areas in Africa [2]. Among the most promising candidates are adenovirus-based and modified vaccinia Ankara (MVA)-based vaccines [2]. Adenovirus (Ad)-based vectors have frequently been developed for emerging viral diseases; however, the high seropositivity in humans for human Ads limited their use. Chimpanzee adenovirus (ChAd)-EBOV was developed to circumvent these preexisting immunity complications associated with particularly human Ad5-based vaccines [2]. However, the ChAd-EBOV vaccine by itself as a single high-dose vaccine only elicits short-lived protective immune responses and requires a boost vaccination [7]. Studies in NHPs have shown that a ChAd-EBOV prime together with a boost of MVA-based vaccines expressing the EBOV GP is effective in mediating longterm protective immunity and has been analyzed in several clinical trials [2]. A single dose of this MVA-EBOV GP vaccine was also not protective in NHPs [7], which is not unexpected considering previous approaches with a vaccinia virus-based vaccine resulted in partial protection in guinea pigs and failed to protect NHPs [8]. However, does MVA have the potential to being developed as an effective single dose vaccine against EBOV? MVA is a highly attenuated vaccinia virus first produced in Germany in 1975 as a ‘safer smallpox vaccine’ for immunocompromised individuals considered to be at risk for the standard vaccinia inoculation [9,10]. Attenuation was accomplished by 570 serial passages in chicken embryo fibroblasts resulting in a virus that has lost about 30,000 bases of a wildtype vaccinia virus genome, particularly affecting genes important for virulence and immune evasion [8]. While MVA replicates well in avian cells, it undergoes an abortive infection in primates [11]. Despite its abortive infection in primates, MVA has retained desirable features of its vaccinia parent: the elicitation of durable T cell and antibody (Ab) responses [12], the ability to be stored as a lyophilized product at ambient temperature (www.ClinicalTrials.gov; NCT00914732), and the ability to be used without an adjuvant. Due to its large genome size and the amount of coding capacity lost during adaptation (~20%), MVA can be used as a vector to express multiple vaccine antigens [13], a characteristic that readily supports the construction of recombinant MVAs expressing foreign virus-like particles (VLPs) [14–16]. Recently, promise for a safer and more stable vaccine has been demonstrated using MVA to express EBOV-like particles to achieve singledose protection in nonhuman primates [14]. The advantage of this particular MVA vector compared to previously used vectors only expressing EBOV GP is that it expresses two EBOV antigens – the GP and the matrix protein VP40. Expression of both EBOV proteins from a MVA-infected cell leads to EBOVlike particle formation and the generation of a protective immune response [14,15]. The single-dose protection in nonhuman primates recently reported in Nature’s Scientific Reports reflects this ‘first in class’ VLP vaccine benefitting