Chimeric human parainfluenza virus bearing the Ebola virus glycoprotein as the sole surface protein is immunogenic and highly protective against Ebola virus challenge

Abstract

We generated a new live-attenuated vaccine against Ebola virus (EBOV) based on a chimeric virus HPIV3/ΔF-HN/EboGP that contains the EBOV glycoprotein (GP) as the sole transmembrane envelope protein combined with the internal proteins of human parainfluenza virus type 3 (HPIV3). Electron microscopy analysis of the virus particles showed that they have an envelope and surface spikes resembling those of EBOV and a particle size and shape resembling those of HPIV3. When HPIV3/ΔF-HN/EboGP was inoculated via apical surface of an in vitro model of human ciliated airway epithelium, the virus was released from the apical surface; when applied to basolateral surface, the virus infected basolateral cells but did not spread through the tissue. Following intranasal (IN) inoculation of guinea pigs, scattered infected cells were detected in the lungs by immunohistochemistry, but infectious HPIV3/ΔF-HN/EboGP could not be recovered from the lungs, blood, or other tissues. Despite the attenuation, the virus was highly immunogenic, and a single IN dose completely protected the animals against a highly lethal intraperitoneal challenge of guinea pig-adapted EBOV.

Aerosolized Ebola vaccine protects primates and elicits lung-resident T cell responses

“…HPIV3/EboGP elicited greater levels of activated CD8 + and CD4 + T cells in lungs and blood, while in the spleen, levels were comparable between the 2 vaccines. Replication of the HPIV3/EboGP vaccine construct in the lungs of guinea pigs is attenuated by 63-to 200-fold compared with the wild-type vector (19,20), while the level of attenuation in NHPs is unknown. HPIV3/EboGP, whose replication is confined to the respiratory tract (18)(19)(20), likely stimulates antigenpresenting cells and induces T cell responses in bronchus-associated lymphoid tissues, as was demonstrated with influenza A virus in mice lacking spleens (48,49).…”

“…While aerosol particles less than 3 μM in diameter readily penetrate the small airways (26), the recipients of aerosolized HPIV3/EboGP received a 10-fold higher dose of the vaccine to account for a 10% delivery efficiency of aerosol particles to the lower respiratory tract in primate models due to small lung size and shallow breathing patterns (27,28) further exacerbated by anesthesia during vaccination (26). The VRP group was vaccinated by 2 sequential s.c. injections of 10 10 infecinto the vector particle and was functional in mediating infection of the respiratory tract, but did not alter the tropism of the vaccine virus (18)(19)(20). Rhesus macaques were protected against a lethal dose of EBOV when 2 successive liquid doses of the vaccine were administered using the combined intranasal and intratracheal (i.n./i.t.)…”

Attenuated Human Parainfluenza Virus Type 1 Expressing Ebola Virus Glycoprotein GP Administered Intranasally Is Immunogenic in African Green Monkeys

“…We previously evaluated HPIV3 (JS strain) expressing EBOV GP as an intranasal (i.n.) vaccine candidate called rHPIV3/EboGP (9,20,21). In NHPs, one i.n.…”

Ebola vaccines in clinical trial: The promising candidates

“…Since the impeding factor showed from an epidemiological investigation 60 that PEI to HPIV3 in the human adults may greatly impact the replication and immunogenicity of the vaccine, the vaccine vector was improved by deleting the HPIV3 F and HN genes, which are the main targets for the HPIV3-specific humoral immune response. 61 The new attenuated vector expressing EBOV-GP was more efficient in comparison to the previous construct. 61 One of the main advantages of the HPIV3-based vector platform is the potential for needle-free administration because of this vaccination via the respiratory route.…”

“…61 The new attenuated vector expressing EBOV-GP was more efficient in comparison to the previous construct. 61 One of the main advantages of the HPIV3-based vector platform is the potential for needle-free administration because of this vaccination via the respiratory route. Safety is another virtue of HPIV3, triggered by restriction of virus only in epithelial cells of respiratory tract, an ongoing phase I clinical trial is carried out in US last year and this is one clinical trial which is given intranasally to human beings for now (NCT02564575) ( Table 1).…”