tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A. 2014 Jun 9. pii: 201402766. [Epub ahead of print]
Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection.
Mallajosyula VV1, Citron M2, Ferrara F3, Lu X2, Callahan C2, Heidecker GJ2, Sarma SP1, Flynn JA2, Temperton NJ3, Liang X4, Varadarajan R5.
Author information
Abstract
Influenza hemagglutinin (HA) is the primary target of the humoral response during infection/vaccination. Current influenza vaccines typically fail to elicit/boost broadly neutralizing antibodies (bnAbs), thereby limiting their efficacy. Although several bnAbs bind to the conserved stem domain of HA, focusing the immune response to this conserved stem in the presence of the immunodominant, variable head domain of HA is challenging. We report the design of a thermotolerant, disulfide-free, and trimeric HA stem-fragment immunogen which mimics the native, prefusion conformation of HA and binds conformation specific bnAbs with high affinity. The immunogen elicited bnAbs that neutralized highly divergent group 1 (H1 and H5 subtypes) and 2 (H3 subtype) influenza virus strains in vitro. Stem immunogens designed from unmatched, highly drifted influenza strains conferred robust protection against a lethal heterologous A/Puerto Rico/8/34 virus challenge in vivo. Soluble, bacterial expression of such designed immunogens allows for rapid scale-up during pandemic outbreaks.
KEYWORDS:
Escherichia coli; cross-protection; hemagglutinin stalk; pandemic preparedness; stabilization
PMID:
24927560
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24927560
Influenza hemagglutinin stem-fragment immunogen elicits broadly neutralizing antibodies and confers heterologous protection.
Mallajosyula VV1, Citron M2, Ferrara F3, Lu X2, Callahan C2, Heidecker GJ2, Sarma SP1, Flynn JA2, Temperton NJ3, Liang X4, Varadarajan R5.
Author information
Abstract
Influenza hemagglutinin (HA) is the primary target of the humoral response during infection/vaccination. Current influenza vaccines typically fail to elicit/boost broadly neutralizing antibodies (bnAbs), thereby limiting their efficacy. Although several bnAbs bind to the conserved stem domain of HA, focusing the immune response to this conserved stem in the presence of the immunodominant, variable head domain of HA is challenging. We report the design of a thermotolerant, disulfide-free, and trimeric HA stem-fragment immunogen which mimics the native, prefusion conformation of HA and binds conformation specific bnAbs with high affinity. The immunogen elicited bnAbs that neutralized highly divergent group 1 (H1 and H5 subtypes) and 2 (H3 subtype) influenza virus strains in vitro. Stem immunogens designed from unmatched, highly drifted influenza strains conferred robust protection against a lethal heterologous A/Puerto Rico/8/34 virus challenge in vivo. Soluble, bacterial expression of such designed immunogens allows for rapid scale-up during pandemic outbreaks.
KEYWORDS:
Escherichia coli; cross-protection; hemagglutinin stalk; pandemic preparedness; stabilization
PMID:
24927560
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24927560