SBIR-STTR Award

The annual epidemics of influenza result in a substantial number of hospitalizations with an estimated 3 to 5 million cases of severe disease, and 300,000 to 500,000 deaths globally. During the 20th century, three major influenza pandemics have occurred with a total mortality of 50–100 million people. Recently, new influenza monoclonal antibodies (mAbs) have been identified that are capable of neutralizing a wide range of viruses. In the last eight years, several broadly neutralizing, stem-reactive antibodies have been identified. Of these stem antibodies, only one recognized all influenza A subtypes however this breadth of recognition was only elicited after in vitro mutagenesis. This suggests that an epitope to guide a universal vaccine strategy has yet be defined. Stem antibodies could provide universal influenza coverage since they are potentially capable of neutralizing both influenza A and B viruses. One strategy to identify neutralizing stem-specific antibodies involves immortalized B cells from immunized individuals. B cell-derived mAbs that cross react with the H5 and H7 HA subtypes have been shown to yield high affinity stem-specific mAbs that can bind to all influenza A HA subtypes. An alternative strategy, that doesn’t involve B cell cloning, starts with an antigen specific population of stem binding polyclonal antibodies (pAbs) that can then be directly sequenced by proteomic tandem mass spectrometry (MS/MS). These pAbs are a preferred source for mAb discovery since the peripheral antibody population, not the peripheral B cell population, is representative of the full humoral immune response. Direct sequencing of peripheral pAbs can rapidly mine this immune diversity to yield mAbs against novel and unique epitopes.

Public Health Relevance Statement:
Narrative The focus of this proposal is to use a new mass spectrometry-based antibody discovery technology to sequence serum antibodies that are components of the human immune response to influenza. This is intended to identify antibodies recognizing highly conserved regions of the influenza virus. There is a clear unmet need to identify broadly neutralizing influenza antibodies capable of influenza therapy. In addition, these antibodies will be invaluable in identifying components of the virus that can serve as candidate vaccines to elicit endogenous broadly neutralizing immune responses.

Project Terms:
No Project Terms available.

___(NOTE: Note: no official Abstract exists of this Phase II projects. Abstract is modified by idi from relevant Phase I data. The specific Phase II work statement and objectives may differ)___ The annual epidemics of influenza result in a substantial number of hospitalizations with an estimated 3 to 5 million cases of severe disease, and 300,000 to 500,000 deaths globally. During the 20th century, three major influenza pandemics have occurred with a total mortality of 50–100 million people. Recently, new influenza monoclonal antibodies (mAbs) have been identified that are capable of neutralizing a wide range of viruses. In the last eight years, several broadly neutralizing, stem-reactive antibodies have been identified. Of these stem antibodies, only one recognized all influenza A subtypes however this breadth of recognition was only elicited after in vitro mutagenesis. This suggests that an epitope to guide a universal vaccine strategy has yet be defined. Stem antibodies could provide universal influenza coverage since they are potentially capable of neutralizing both influenza A and B viruses. One strategy to identify neutralizing stem-specific antibodies involves immortalized B cells from immunized individuals. B cell-derived mAbs that cross react with the H5 and H7 HA subtypes have been shown to yield high affinity stem-specific mAbs that can bind to all influenza A HA subtypes. An alternative strategy, that doesn’t involve B cell cloning, starts with an antigen specific population of stem binding polyclonal antibodies (pAbs) that can then be directly sequenced by proteomic tandem mass spectrometry (MS/MS). These pAbs are a preferred source for mAb discovery since the peripheral antibody population, not the peripheral B cell population, is representative of the full humoral immune response. Direct sequencing of peripheral pAbs can rapidly mine this immune diversity to yield mAbs against novel and unique epitopes.

Public Health Relevance Statement:
Narrative The focus of this proposal is to use a new mass spectrometry-based antibody discovery technology to sequence serum antibodies that are components of the human immune response to influenza. This is intended to identify antibodies recognizing highly conserved regions of the influenza virus. There is a clear unmet need to identify broadly neutralizing influenza antibodies capable of influenza therapy. In addition, these antibodies will be invaluable in identifying components of the virus that can serve as candidate vaccines to elicit endogenous broadly neutralizing immune responses.

Project Terms:
No Project Terms available.