One of the most challenging aspects of new vaccine development for viruses, bacteria and parasites is overcoming problems associated with antigenic variation. In the picornavirus family, antigenic variation is promoted through genetic instability and the evolution of immunodominant, highly variant epitopes within the capsid structure. Immune responses to these epitopes result in isolate-, strain- or serotype-specific antibody and appear to inhibit responses to neighboring, more conserved epitopes. The long-term objective of this proposal is to test the feasibility of immune dampening as a strategy to refocus the immune responses away from immunodominant, non- protective or serotype-restricted epitopes and towards more broadly protective epitopes which were previously antigenically weak or silent. Foot and Mouth Disease Virus (FMDV) is to be used as a proof of concept model for studying human rhinovirus infection as there is no useful animal model for human Rhinovirus infection. FMDV and human rhinoviruses share many similarities in immune responses. genetic organization, and structural characteristics. In the proposed study, the FMDV VP1 GH-loop will be immune-dampened by various approaches and expressed in bacterial or insect cell systems within the context of the 70S self-assembling empty capsid polyprotein. A series of the VP1 modified FMDV antigens will be adjuvented and tested for immunogenicity and for homologous and heterologous virus neutralization. In addition, acute phase sera will be used to fine map immune responses. Immune dampening technology offers a new approach to circumvent the issues of antigenic variation and could lead to the creation of more broadly protective vaccines against a variety of bacterial, viral and parasitic diseases of man and animals.
The commercial application of this technology may allow for the development of an effective FMDV vaccine for worldwide use in cattle, sheep and swine. As this viral agent is listed as a high threat to U.S. security, a FMDV vaccine would be stockpiled in the United States as a counter measure for agriculture bioterrorism. In addition, vaccines against a wide variety of viruses, bacteria and parasites in both humans and animals for which no vaccines exist to date could be made using this approach.
| Tobin, Gregory J; Trujillo, Jessie D; Bushnell, Ruth V et al. (2008) Deceptive imprinting and immune refocusing in vaccine design. Vaccine 26:6189-99 |
