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. 2018 Jan 17;92(3):e01190-17.
doi: 10.1128/JVI.01190-17. Print 2018 Feb 1.

Single-Dose Trivalent VesiculoVax Vaccine Protects Macaques from Lethal Ebolavirus and Marburgvirus Challenge

Demetrius Matassov  1 , Chad E Mire  2   3 , Theresa Latham  4 , Joan B Geisbert  2   3 , Rong Xu  5 , Ayuko Ota-Setlik  5 , Krystle N Agans  2   3 , Dean J Kobs  6 , Morgan Q S Wendling  6 , Amanda Burnaugh  6 , Thomas L Rudge Jr  6 , Carol L Sabourin  6 , Michael A Egan  5 , David K Clarke  4 , Thomas W Geisbert  2   3 , John H Eldridge  4   5
Affiliations

Single-Dose Trivalent VesiculoVax Vaccine Protects Macaques from Lethal Ebolavirus and Marburgvirus Challenge

Demetrius Matassov et al. J Virol. .

Abstract

Previous studies demonstrated that a single intramuscular (i.m.) dose of an attenuated recombinant vesicular stomatitis virus (rVSV) vector (VesiculoVax vector platform; rVSV-N4CT1) expressing the glycoprotein (GP) from the Mayinga strain of Zaire ebolavirus (EBOV) protected nonhuman primates (NHPs) from lethal challenge with EBOV strains Kikwit and Makona. Here, we studied the immunogenicities of an expanded range of attenuated rVSV vectors expressing filovirus GP in mice. Based on data from those studies, an optimal attenuated trivalent rVSV vector formulation was identified that included rVSV vectors expressing EBOV, Sudan ebolavirus (SUDV), and the Angola strain of Marburg marburgvirus (MARV) GPs. NHPs were vaccinated with a single dose of the trivalent formulation, followed by lethal challenge 28 days later with each of the three corresponding filoviruses. At day 14 postvaccination, a serum IgG response specific for all three GPs was detected in all the vaccinated macaques. A modest and balanced cell-mediated immune response specific for each GP was also detected in a majority of the vaccinated macaques. No matter the level of total GP-specific immune response detected postvaccination, all the vaccinated macaques were protected from disease and death following lethal challenge with each of the three filoviruses. These findings indicate that vaccination with a single dose of attenuated rVSV-N4CT1 vectors each expressing a single filovirus GP may provide protection against the filoviruses most commonly responsible for outbreaks of hemorrhagic fever in sub-Saharan Africa.IMPORTANCE The West African Ebola virus Zaire outbreak in 2013 showed that the disease was not only a regional concern, but a worldwide problem, and highlighted the need for a safe and efficacious vaccine to be administered to the populace. However, other endemic pathogens, like Ebola virus Sudan and Marburg, also pose an important health risk to the public and therefore require development of a vaccine prior to the occurrence of an outbreak. The significance of our research was the development of a blended trivalent filovirus vaccine that elicited a balanced immune response when administered as a single dose and provided complete protection against a lethal challenge with all three filovirus pathogens.

Keywords: Ebola virus vaccine; Marburg virus vaccine; attenuation; challenge; glycoprotein; nonhuman primates; protection; rVSV vector; trivalent; vaccine.

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Figures

FIG 1
FIG 1
Genetic organization of attenuated rVSV filovirus vaccine vectors and GP expression. (A) Vectors of the rVSV-N4CT1 FiloGP1 design contained a filovirus GP gene(s) in position 1, an N gene translocation (N4), and a truncated G gene (CT1). (B) Vectors of the rVSV-N4CT1 FiloGP3 design contained a filovirus GP gene(s) in position 3, an N gene translocation (N4), and a truncated G gene (CT1). (C) rVSV-N1CT1 FiloGP3 vectors retained the VSV N gene in position 1, a filovirus GP gene(s) at position 3, and a truncated form of the VSV G gene at position 6. (D) The rVSV-N4CT1 HIVgag1 vector contained the HIV-1 gag gene in position1, an N gene translocation (N4), and a truncated G gene (CT1). The numbers designate genome positions. Virus leader (Le), trailer (Tr), and intergenic regions are shown in black. The stippled regions represent deletions in the VSV G gene. (E to G) Expression of the EBOV (E), SUDV (F), and MARV (G) GPs by Western blotting.
FIG 2
FIG 2
Mouse study design comparing immunogenicities of trivalent vaccine designs. (A) Study design. (B) Study schedule.
FIG 3
FIG 3
Filovirus GP-specific IgG ELISA titer responses in BALB/c mice immunized with trivalent vaccine. At study weeks 0 and 4 (arrows), BALB/c mice were immunized i.m. with 3 × 107 PFU of trivalent rVSV/filovirus vaccines. At study weeks 0, 2, 4, 6, and 10, sera were collected and tested for EBOV GP-specific (A), SUDV GP-specific (B), and MARV GP-specific (C) IgG responses by ELISA. The data represent the average log-transformed filovirus GP-specific IgG endpoint titers, with the standard errors of the means indicated by the error bars. *, statistically significant difference (P < 0.05) between trivalent rVSV-N4CT1 pan-FiloGP1 and trivalent rVSV-N4CT1 pan-FiloGP; #, statistically significant difference (P < 0.05) between trivalent rVSV-N4CT1 pan-FiloGP3 and trivalent rVSV-N1CT1 pan-FiloGP3.
FIG 4
FIG 4
Filovirus GP-specific IFN-γ ELISpot responses in BALB/c mice immunized with trivalent vaccine. At study weeks 1, 5, and 10, splenocytes were collected and tested for EBOV GP, SUDV GP, and MARV GP peptide pool-specific IFN-γ secretion by ELISpot assay. The data represent the average total filovirus-specific IFN-γ ELISpot responses, with the standard errors of the mean indicated by the error bars. *, statistically significant (P < 0.05) difference relative to trivalent rVSV-N4CT1 pan-FiloGP3 and trivalent rVSV-N1CT1 pan-FiloGP3; **, statistically significant (P < 0.05) difference relative to trivalent rVSV-N4CT1 pan-FiloGP3.
FIG 5
FIG 5
Filovirus GP-specific IFN-γ ELISpot titer responses in BALB/c mice immunized with monovalent and trivalent rVSV-N4CT1 FiloGP1 vaccines. At study weeks 1, 5, and 10, splenocytes were collected and tested for EBOV GP, SUDV GP, and MARV GP peptide pool-specific IFN-γ secretion by ELISpot assay. The data represent the average total filovirus-specific IFN-γ ELISpot responses, with the standard errors of the mean indicated by the error bars. *, statistically significant difference (P < 0.05) between the monovalent rVSV-N4CT1 FiloGP1- and trivalent rVSV-N4CT1 pan-FiloGP1-immunized mice.
FIG 6
FIG 6
Filovirus GP-specific IgG ELISA titer responses in BALB/c mice immunized with monovalent and trivalent rVSV-N4CT1 FiloGP1 vaccines. At study weeks 0 and 4 (arrows), BALB/c mice were immunized i.m. with 1 × 107 PFU of each monovalent rVSV-N4CT1 FiloGP1 vaccine or with 3 × 107 PFU of the trivalent rVSV-N4CT1 pan-FiloGP1 vaccine. At study weeks 0, 2, 6, and 10, sera were collected and tested for EBOV GP-specific (A), SUDV GP-specific (B), and MARV GP-specific (C) IgG responses by ELISA. The data represent the average log-transformed filovirus GP-specific IgG endpoint titers, with the standard errors of the mean indicated by the error bars. *, statistically significant difference (P < 0.05) between the monovalent rVSV-N4CT1 FiloGP1- and trivalent rVSV-N4CT1 pan-FiloGP1-immunized mice.
FIG 7
FIG 7
NHP study design to assess immunogenicity and protective efficacy of a trivalent rVSV-N4CT1 pan-FiloGP1 panfilovirus vaccine. (A) Study design. (B) Study schedule of events.
FIG 8
FIG 8
Filovirus GP-specific IgG ELISA titers and IFN-γ ELISpot responses in macaques immunized with the trivalent rVSV-N4CT1 pan-FiloGP1 vaccine. At study day 0, macaques were immunized i.m. with 3 × 107 PFU of the trivalent rVSVN4CT1 pan-FiloGP1 vaccine. As a control, macaques were immunized with 3 × 107 PFU of rVSV N4CT1gag1. (A) At study days 0, 10, and 14, sera were collected and tested for EBOV GP-, SUDV GP-, and MARV GP-specific IgG responses by ELISA. The data represent the average log-transformed filovirus GP-specific IgG concentrations, with the standard errors of the mean indicated by the error bars. (B) At study day 10, PBMCs were collected and tested for EBOV GP, SUDV GP, and MARV GP peptide pool-specific IFN-γ secretion by ELISpot assay. The data represent the individual NHP total filovirus-specific IFN-γ ELISpot responses. *, antigen-specific IFN-γ ELISpot response of ≥25 SFC/106 PBMCs.
FIG 9
FIG 9
Postchallenge survival of cynomolgus macaques immunized with the trivalent rVSV-N4CT1 pan-FiloGP1 vaccine. At study day 0, macaques were immunized i.m. with 3 × 107 PFU of the trivalent rVSV-N4CT1 pan-FiloGP1 vaccine. As a control, macaques were immunized with 3 × 107 PFU of an rVSV-N4CT1gag1 vector. At study day 28, the macaques were challenged i.m. with 1,000 PFU 7U EBOV Kikwit (A), SUDV Gulu (B), or MARV Angola (C).
FIG 10
FIG 10
Filovirus viremia in trivalent rVSV-N4CT1 pan-FiloGP1-vaccinated cynomolgus macaques challenged i.m. with EBOV, SUDV, or MARV. Trivalent rVSV-N4CT1 pan-FiloGP1- or control rVSV-vaccinated macaques were challenged i.m. with 1,000 PFU 7U EBOV Kikwit (A and B), SUDV Gulu (C and D), or MARV Angola (E and F). Postchallenge viremia was monitored by RT-qPCR (A, C, and E) or by infectious plaque assay (B, D, and F).
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