China
Africa
Explore chapters and articles related to this topic
Order Nodamuvirales
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
Next, the great Annette Schneemann and her team demonstrated that the display of fragments from the influenza virus hemagglutinin (HA) stem region on the insect-cells produced FHV VLPs resulted in the induction of cross-reactive anti-HA antibodies (Schneemann et al. 2012). The 20-aa residue A-helix of the HA2 chain was selected as an epitope and displayed in 180 copies on the chimeric FHV VLPs. Figure 23.5 illustrates the structural outcome of this delicate structural design. As shown, the structure of helix-turn-helix protein B2 (PDB 2AZ2 and 2AZ0) was spliced first into the structure of the FHV capsid subunit in place of the 206 or 264 loops. The residues near the B2 termini in the best locations to start and end the inserts (i.e., unstructured polypeptide) while maintaining exposure and structure of the B2 helical segments were identified. To display the antigenic helix identified in the structures of the antibody CR6261-HA complexes (PDB 3GBN and 3GBM) (Ekiert et al. 2009), a portion of the long helix in B2 (residues 40–59) was then replaced with the HA2 A-helix (residues 39–58) from the human 1918 H1N1 pandemic virus (A/South Carolina/1/1918, PDB 3GBN). The A-helix was specifically oriented within the B2 helical turns so that residues in contact with the CR6261 antibody had maximum solvent exposure on the surface.
Development of broadly reactive influenza vaccines by targeting the conserved regions of the hemagglutinin stem and head domains
Published in Expert Review of Vaccines, 2020
Nina M.C. De Jong, Aafke Aartse, Marit J. Van Gils, Dirk Eggink
Stem directed broadly neutralizing antibodies have been isolated both from humans and mice. One of the first human stem directed antibodies, CR6261 [14], was isolated using phage display. CR6261 was selected because of its binding capacity to the HA of H5N1. Besides binding to H5N1, CR6261 was also able to bind several group 1 viruses and neutralized subtype human H1 and avian H2, H6, H8, and H9, when tested in a microneutralization assay [14]. It also showed protection against highly pathogenic avian H5N1 challenge in ferrets [15]. One year later, the broadly group 1 neutralizing antibody F10 was described by Sui et al [16]. This antibody was also generated using a human phage display. F10 was able to neutralize viruses from group 1 subtypes H1, H2, H5, H6, H8, and H9 in a microneutralization assay. The discovery of CR6261 and F10 resulted in the first crystal structure of HA complexed with a broadly neutralizing stem antibody, confirming the location of the epitope on the stem [14,16,17]. Other human broadly group 1 binding stem antibodies isolated from human bone marrow or PBMCs include the antibodies A06 [18,19], 3.1 [20], PN-SIA49 [21], and S9-3-37 [22,23]. These antibodies were isolated via phage display vector system, phage display, Epstein-Barr Virus (EBV) transformation of B cell-lines, or the hybridoma technique, respectively, and all exhibit similar broad group 1 reactivity to the aforementioned CR6261 and F10.
Call for a paradigm shift in the design of universal influenza vaccines by harnessing multiple correlates of protection
Published in Expert Opinion on Drug Discovery, 2020
The identification of broadly neutralizing antibodies in humans afforded the promising prospect of developing prophylactic and therapeutic interventions that provide broad effects against diverse influenza viruses [60]. These antibodies demonstrated broadly neutralizing activities against antigenically diverse group 1 H1, H2, H5, H6, H8, and H9 IAVs, and the most potent antibody, CR6261, protected mice against lethal challenge with H1N1 and H5N1 influenza viruses. Subsequent studies mapped the epitope of CR6261 to the HA stalk and demonstrated that the antibody prevented pH-induced conformational changes to HA and blocked HA-mediated membrane fusion, defining the mode of viral neutralization by HA stalk antibodies [61,62]. Further studies have identified a series of CR6261-like broadly neutralizing antibodies from humans [63–65]. The most promising was an HA stalk antibody that recognized all 16 subtypes and neutralized both group 1 and 2 IAVs, demonstrating in vivo cross-protection in mice and ferrets [64]. These promising results have invigorated collaborative efforts to design rational vaccine strategies that are able to induce HA stalk antibodies, such as headless HA or chimeric HA [66,67]. Initial animal studies showed that chimeric HA vaccines provided broad protection within groups, and the protection was attributed to the neutralizing activity of stalk antibodies, as passive transfer of vaccine-induced antisera provided cross-protection in mice [40,41]. Sequential vaccination with chimeric H1 (group 1) HAs protected mice against H5N1 challenge, but the in vitro neutralizing activity of vaccine-induced sera against H5N1 was not determined [40]. An analogous study in a mouse model showed that sequential vaccination with chimeric HA vaccines bearing H3 (group 2) stalks provided broad protection against both H3 and H7 influenza virus challenges [41]. However, the in vitro neutralizing activity of the vaccine-induced antisera was only confirmed against H3 pseudovirus, and not against H7 strains, although cross-reactive binding of the antisera to the H7 virus was demonstrated. Subsequent studies have explored the vaccine potency and breadth of chimeric HAs expressed in various formulations, such as virus-vectored vaccines, inactivated influenza vaccines, and live-attenuated influenza vaccines, suggesting that HA stalk antibodies provided broad protection in animal models through viral neutralizing activity [68–70].