Abstract
Influenza’s propensity for antigenic drift and shift, and to elicit predominantly strain specific antibodies (Abs) leaves humanity susceptible to waves of new strains with pandemic potential for which limited or no immunity may exist. Subsequently new clinical interventions are needed. To identify hemagglutinin (HA) epitopes that if targeted may confer universally protective humoral immunity, we examined plasmablasts from a subject that was immunized with the seasonal influenza inactivated vaccine, and isolated a human monoclonal Ab (mAb), KPF1. KPF1 has broad and potent neutralizing activity against H1 influenza viruses, and recognized 83% of all H1 isolates tested, including the pandemic 1918 H1. Prophylactically, KPF1 treatment resulted in 100% survival of mice from lethal challenge with multiple H1 influenza strains and when given as late as 72 h after challenge with A/California/04/2009 H1N1, resulted in 80% survival. KPF1 recognizes a novel epitope in the HA globular head, which includes a highly conserved amino acid, between the Ca and Cb antigenic sites. Although recent HA stalk-specific mAbs have broader reactivity, their potency is substantially limited, suggesting that cocktails of broadly reactive and highly potent HA globular head-specific mAbs, like KPF1, may have greater clinical feasibility for the treatment of influenza infections.
Highlights
A licensed influenza vaccine has been available for over seventy years, influenza infections still remain a major public health concern
Peripheral blood plasmablasts (CD19 + IgD-CD38 + CD27++) were single cell sorted from a healthy subject seven days after immunization with the 2014–2015 seasonal inactivated quadrivalent influenza vaccine
Subsequent deep sequencing of the B cell immunoglobulin repertoire at the same time point identified additional members of this lineage, including members with intermediate levels of somatic hypermutation, and those that had acquired additional mutations (Fig. 1c), suggesting the KPF1 Human mAbs (hmAbs) developed after an extensive affinity maturation process
Summary
A licensed influenza vaccine has been available for over seventy years, influenza infections still remain a major public health concern. Human mAbs (hmAbs) have been isolated that have the ability to neutralize diverse influenza strains These all target the hemagglutinin (HA) protein expressed on the surface of the virion and include, for instance hmAbs such as 5J821, 1F122 and CH6523, which bind multiple H1 isolates; hmAbs such as F1024 and CR626125, which recognize all group 1 viruses; hmAbs such as CR802026 and 2F0427 which recognize most group 2 viruses; hmAbs FI6/MEDI885228,29, 2B0627, S6-B0127, 3I1430, and VS14031, which each recognize both group 1 (e.g. H1, H2, H5) and group 2 (e.g. H3, H7) viruses; or hmAb CR911432, which recognizes both type A and type B viruses. KPF1 binds with high affinity to a novel conserved epitope region of the HA globular head, which is different than other previously described cross-reactive H1 mAbs, and represents an excellent option for the development of antiviral therapies based on Ab cocktails with broadly reactive and highly potent HA globular head-specific hmAbs for the treatment of H1 influenza infections in humans
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
