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. 2016 Apr 8;8(4):94.
doi: 10.3390/v8040094.

Virus-Like Particle Vaccination Protects Nonhuman Primates From Lethal Aerosol Exposure With Marburgvirus (VLP Vaccination Protects Macaques Against Aerosol Challenges)

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Virus-Like Particle Vaccination Protects Nonhuman Primates From Lethal Aerosol Exposure With Marburgvirus (VLP Vaccination Protects Macaques Against Aerosol Challenges)

John M Dye et al. Viruses. .
Free PMC article

Abstract

Marburg virus (MARV) was the first filovirus to be identified following an outbreak of viral hemorrhagic fever disease in Marburg, Germany in 1967. Due to several factors inherent to filoviruses, they are considered a potential bioweapon that could be disseminated via an aerosol route. Previous studies demonstrated that MARV virus-like particles (VLPs) containing the glycoprotein (GP), matrix protein VP40 and nucleoprotein (NP) generated using a baculovirus/insect cell expression system could protect macaques from subcutaneous (SQ) challenge with multiple species of marburgviruses. In the current study, the protective efficacy of the MARV VLPs in conjunction with two different adjuvants: QS-21, a saponin derivative, and poly I:C against homologous aerosol challenge was assessed in cynomolgus macaques. Antibody responses against the GP antigen were equivalent in all groups receiving MARV VLPs irrespective of the adjuvant; adjuvant only-vaccinated macaques did not demonstrate appreciable antibody responses. All macaques were subsequently challenged with lethal doses of MARV via aerosol or SQ as a positive control. All MARV VLP-vaccinated macaques survived either aerosol or SQ challenge while animals administered adjuvant only exhibited clinical signs and lesions consistent with MARV disease and were euthanized after meeting the predetermined criteria. Therefore, MARV VLPs induce IgG antibodies recognizing MARV GP and VP40 and protect cynomolgus macaques from an otherwise lethal aerosol exposure with MARV.

Keywords: Marburg virus; adjuvant; aerosol; macaque; vaccine; virus-like particle.

Figures

Figure 1
Figure 1
Western blot showing identity of MARV antigens in the MARV VLP preparations used for vaccination. VLP preparations were separated on a SDS-PAGE gel, transferred to nitrocellulose and subjected to immunoblotting using MARV GP—(left sample lane), NP—(middle sample lane) and VP40—(right sample lane) specific antibodies. A molecular mass marker is located in the left most lane.
Figure 2
Figure 2
(A,B) IgG response of nonhuman primates against MARV antigens following MARV VLP vaccination. Serum titers from vaccinated macaques were measured for IgG against purified MARV GPdTM (A) or VP40 (B) by ELISA. The data are expressed as the antibody units for individual animal responses with animals receiving MARV VLP with QS-21 depicted as open squares or those receiving MARV VLPs with polyI:C depicted as closed circles or as the mean antibody units for each group (lines) at each time point the samples were drawn. Vaccination with MARV VLPs combined with either QS-21 or polyI:C exhibited similar responses to the protective GP antigens (p = 0.6006) but animals vaccinated with polyI:C had higher responses to the VP40 antigen than those vaccinated with QS-21, specifically at the later time points of days 70, 84 and 105 post vaccination (p = 0.0057).
Figure 3
Figure 3
Assessment of viremia in MARV infected macaques. Viral load in serum samples for each animal on various time points after challenge was determined using a standard plaque assay. No virus was detected in any of the MARV VLP vaccinated macaques, regardless of the adjuvant or challenge route used. Viremia of the three control macaques is represented as the values for individual monkeys on each study day after the challenge day. The limit of detection for the plaque assay (50 pfu) is depicted by the dotted line.
Figure 4
Figure 4
Photomicrographs of liver and spleen from macaques that were challenged with MARV. (A) spleen from a control animal (vaccinated with QS-21 adjuvant only and challenged subcutaneously) has a lymphoid nodule with markedly reduced numbers of lymphocytes (i.e., lymphoid depletion) and which is surrounded by pale pink deposits of fibrin in the adjacent red pulp. The center of this nodule (asterisk) has an aggregate of histiocytes and fragments of lysed lymphocytes; (B) liver from a control animal (vaccinated with QS-21 adjuvant only and aerosol challenged) has multiple foci of hepatocellular degeneration and necrosis (arrowheads). Numerous neutrophils and monocytes are present in the sinusoidal blood vessels and aggregate around necrotic hepatocytes in one area (asterisk); (C) spleen from a VLP-vaccinated animal (Poly I:C adjuvant and aerosol challenged) that survived the viral challenge. A proliferation of lymphocytes (i.e., lymphoid hyperplasia) expands a lymphoid nodule (asterisk); (D) liver from a VLP-vaccinated animal (QS-21 adjuvant and aerosol challenged) that survived the viral challenge. Tissue is normal except for a small focus of subacute inflammation (arrowhead). Magnification: 100× for panels (A) and (C); 200× for panels (B) and (D). Hematoxylin and eosin stain was used for tissue sections in all panels.

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