Immunization strategies against henipaviruses

Abstract

Hendra virus and Nipah virus are recently discovered and closely related emerging viruses that now comprise the genus henipavirus within the sub-family Paramyxoviridae and are distinguished by their broad species tropism and in addition to bats can infect and cause fatal disease in a wide variety of mammalian hosts including humans. The high mortality associated with human and animal henipavirus infections has highlighted the importance and necessity of developing effective immunization strategies. The development of suitable animal models of henipavirus infection and pathogenesis has been critical for testing the efficacy of potential therapeutic approaches. Several henipavirus challenge models have been used and recent successes in both active and passive immunization strategies against henipaviruses have been reported which have all targeted the viral envelope glycoproteins.

Fig. 1

Hendra virus soluble G glycoprotein subunit vaccine. The recombinant HeV-sG glycoprotein subunit vaccine candidate is the entire predicted ectodomain (residues 76–604). Here, HeV-sG is shown as the dimer, with secondary structure and surface exposed elements modeled. HeV-sG dimer has been the purified form of HeV-sG used in all vaccine studies to date. One monomer in the dimer is colored cyan and the other is green. The secondary structure elements of the two globular head domains (cyan and green) are derived from the crystal structure of the HeV G head domain, which also revealed that all five predicted N-linked glycosylation sites (N306, N378, N417, N481 and N529) were occupied by carbohydrate moieties (Xu et al. 2012). The N-linked carbohydrate modifications are illustrated as gray sticks, but N378 was not modeled in the figure due to weak electron density. The G glycoprotein head domain folds as a six-bladed β-propeller. The structure of the entire HeV G stalk domain (residues 71–173) has not been determined, but here the stalk regions (residues 77–136) of each monomer are modeled (Kelley and Sternberg 2009) and are not a continuous helix (labeled helix break). There are two helical ranges, Thr-77 to Lys-95 and Thr-98 to Ser-135. The hydrophobic residues distribution (most hydrophobic side chains point to the same direction) suggests a bundling tendency. The HeV-sG stalk residues 98–135 appear equivalent to the HN glycoprotein stalk helix domain of the recently reported NDV structure (Yuan et al. 2011). Here, the position of HeV sG head dimer and stalks are oriented based on the alignment to the NDV structure. The ephrin receptor binding face of the cyan monomer is facing out and that of the green monomer is facing left. The ephrin receptor binding region is colored red in the cyan globular head, and an overlay of the ephrin-B2 G-H loop is shown in yellow

Fig. 2

HeV sG subunit vaccine protection against HeV challenge in the ferret. Immunohistochemical analysis using a NiV nucleoprotein (N) specific rabbit polyclonal antibody following lethal HeV challenge: lung tissue (a, b) and lymph node tissue (c, d) in a ferret immunized with recombinant HeV-sG glycoprotein prior to challenge (left panel) and a control ferret (right panel) (Pallister et al. 2011b). Scale bar (a, b) = 100 μm, scale bar (c, d) = 50 μm

Fig. 3

Passive Immunotherapy against HeV challenge in the African green monkey. Localization of HeV antigen by immunohistochemical stain in the brain stem (a, b) and lower lung (c, d) of m102.4 treated subject (72 h/d5; left panels) or control subject (right panels). Sections were stained with a NiV nucleoprotein (N) specific rabbit polyclonal antibody and images were obtained at an original magnification of at 20X. Figure is modified and reproduced from original data previously published, with permission (Bossart et al. 2011)