Mutable Vaccines for Emerging Infectious Threats
Abstract
The proposed research will explore an entirely novel concept for design and application of a vaccine, the mutable vaccine. The mutable vaccine was conceived as an approach to attacking microorganisms like human immunodeficiency virus (HIV) and hepatitis C that mutate or change rapidly after infection, evading control by the immune system. The research addresses the Fiscal Year 2017 Peer Reviewed Medical Research Program topic areas of “Vaccine Development for Infectious Disease” and Areas of encouragement of "development of a therapeutic vaccine to achieve HIV remission." The research is also pertinent to the topic of hepatitis C. HIV infection does provoke an immune response, but the immune response inevitably fails to eradicate HIV. The reasons immunity fails to control HIV is that HIV (and hepatitis C) is a "moving target" -- it undergoes rapid genetic changes (i.e., it mutates), creating many divergent HIV viruses, some of which lack key targets of the immune response. Moreover, even when by chance immunity potentially can attack the HIV, most HIV targets are hidden during much of the virus life cycle and over time HIV (and hepatitis C) erodes the set of anti-virus immune cells, creating a condition of immune suppression or tolerance. The mutable vaccine overcomes these problems through several paradigm-shifting innovations. First, instead of trying to hit the "moving target" of HIV, the mutable vaccine itself mutates using some of the same pathways and at the same rate as HIV and, in this way, anticipates some of the genetic changes of HIV before they happen. Second, the vaccine attaches an immune stimulator (C3d) to viral "immunogens," hastening and amplifying the immune response to viral variants. Third, the mutable vaccine accomplishes mutation and production of variants in quantity because it is put directly into specialized immune cells, called B cells, which unlike all other cells have enzymes capable of generating mutations as fast as HIV and which have apparatus that responds to inflammation and that produces and secretes large amounts of protein (in this case the viral immunogens). The mutable vaccine is inserted directly into B cells with a novel "B cell targeting vector" devised for this purpose. Fourth, the mutable vaccine platform could be readily modified to attack hepatitis C or newly emerging infections, and, with modification of the approach to delivery to B cells, the mutable vaccine might be considered for use in prevention of infection. This application proposes the first testing of the mutable vaccine. The tests will be conducted in mice. The research will determine how fast the vaccine mutates and how diverse its products are. The research will also determine how much immunity the mutant products generate and whether that immunity mimics the types of immunity thought potentially to control of HIV. Although the scope of the research program does not permit actual treatment of infection in nonhuman primates or humans, the results would offer compelling support for applications to fund such trials.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810721
Entities
People
- Marilia Cascalho
Organizations
- United States Army
- University of Michigan