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Nov 1st, 2018
HIV-1 vaccine design through minimizing envelope metastability
Linling He, Sonu Kumar, Joel D. Allen, Deli Huang, Xiaohe Lin, Colin J. Mann, Karen L. Saye-Francisco, Jeffrey Copps, Anita Sarkar, Gabrielle S. Blizard, Gabriel Ozorowski, Devin Sok, Max Crispin, Andrew B. Ward et al.

Overcoming envelope metastability is crucial to trimer-based HIV-1 vaccine design. Here, we present a coherent vaccine strategy by minimizing metastability. For 10 strains across five clades, we demonstrate that the gp41 ectodomain (gp41ECTO) is the main source of envelope metastability by replacing wild-type gp41ECTO with BG505 gp41ECTO of the uncleaved prefusion-optimized (UFO) design. These gp41ECTO-swapped trimers can be produced in CHO cells with high yield and high purity. The crystal structure of a gp41ECTO-swapped trimer elucidates how a neutralization-resistant tier 3 virus evades antibody recognition of the V2 apex. UFO trimers of transmitted/founder viruses and UFO trimers containing a consensus-based ancestral gp41ECTO suggest an evolutionary root of metastability. The gp41ECTO-stabilized trimers can be readily displayed on 24- and 60-meric nanoparticles, with incorporation of additional T cell help illustrated for a hyperstable 60-mer, I3-01. In mice and rabbits, these gp140 nanoparticles induced tier 2 neutralizing antibody responses more effectively than soluble trimers.

Sci Adv. 2018 Nov; 4(11): eaau6769. doi: 10.1126/sciadv.aau6769
Sciences Advances
Apr 21st, 2020
Multimeric single-domain antibody complexes protect against bunyavirus infections
Paul J Wichgers Schreur Is a corresponding author, Sandra van de Water, Michiel Harmsen, Erick Bermúdez-Méndez, Dubravka Drabek, Frank Grosveld, Kerstin Wernike, Martin Beer, Andrea Aebischer, Olalekan Daramola et al.

The World Health Organization has included three bunyaviruses posing an increasing threat to human health on the Blueprint list of viruses likely to cause major epidemics and for which no, or insufficient countermeasures exist. Here, we describe a broadly applicable strategy, based on llama-derived single-domain antibodies (VHHs), for the development of bunyavirus biotherapeutics. The method was validated using the zoonotic Rift Valley fever virus (RVFV) and Schmallenberg virus (SBV), an emerging pathogen of ruminants, as model pathogens. VHH building blocks were assembled into highly potent neutralizing complexes using bacterial superglue technology. The multimeric complexes were shown to reduce and prevent virus-induced morbidity and mortality in mice upon prophylactic administration. Bispecific molecules engineered to present two different VHHs fused to an Fc domain were further shown to be effective upon therapeutic administration. The presented VHH-based technology holds great promise for the development of bunyavirus antiviral therapies.

eLife 2020;9:e52716 DOI: 10.7554/eLife.52716
elife
Apr 28th, 2020
Synthetic antibodies built with bacterial superglue could help fight emerging viruses
Paul J Wichgers Schreur et al.

Antibody building blocks stuck together with bacterial superglue can protect against bunyaviruses, and herald a new approach to developing antibodies to fight emerging viruses.

April 28th 2020
eLife

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