Aiming for pan-Lassa virus neutralization.
Erica Saphire group (La Jolla Institute for Immunology)
Humans are under constant threat from emerging and
re-emerging infectious diseases. One such virus is Lassa virus, which
causes hemorrhagic fever, deafness and other lifelong health
consequences for survivors. Lassa infects hundreds of thousands
annually in West Africa with thousands of deaths. Modern case fatality
ratios in clinic range from 25-60%, but lethality is 90% in pregnant
women. There is not yet any vaccine, and development of an effective
vaccine has been hindered by the extreme challenges in eliciting a
protective antibody response. Recently, a team led by Kathryn Hastie
and Erica Ollmann Saphire of La Jolla Institute for Immunology cracked
a series of structures that explained how to achieve that elusive
neutralizing antibody response. They began by comparing structures of
effective and ineffective antibodies against the virus and discovered
that the difference between success and failure was as small as one or
two hydrogen bonds to a certain site on the viral surface. They used
this information to engineer weak antibodies into strong ones with
greater breadth of sequence recognition than before. They next used the
information on antibody recognition to engineer the viral surface
protein into a form that could be recognized by early “germline”
precursors of antibodies that are the starting point for eliciting an
immune response after vaccination. These newly crafted forms of the
viral surface molecule now provide new routes forward for vaccine
development.
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Figure: The Lassa virus
glycoprotein, GP (in gray) is shown bound to three different
neutralizing antibodies with highly quaternary epitopes. Structural
comparison of each GP-Fab complex identified key residues in the Fab
heavy chain that modulate neutralization potency and breadth (lower
inset) and glycosylation sites in the GP that “hug” the light chain of
the antibodies (right inset). Genetic removal of these glycans may
provide a critical leg up for the immune system and facilitate the
maturation of this type of neutralizing antibody. |
Citation: Hastie, KM, Cross, RF, Zandonatti, MA,
Koval, AP, Heinrich, ML, Rowland, MM, Robinson, JE, Garry, RF,
Geisbert, TW, Branco, LM, Saphire, EO, Convergent structures
reveal key residues to enhance potency and breadth for pan-Lassa virus
neutralization, Cell 178, 1004-1015(2019). DOI:
10.1016/j.cell.2019.07.020
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