A sequence-level theory of the B cell and T cell primary response and protective memory production in response to multivalent vaccination is to be developed. This theory will be used to design vaccination strategies for viruses with high mutation rates or multiple subtypes. The theories will be applied to vaccine design for both influenza and dengue fever. Additionally, calibration of the theory will be done on the LCMV model system. The importance of Immunodominance and antagonism to vaccine design for these diseases and for hepatitis C will be studied. ? ? Methods from statistical mechanics are used to construct the theory. The theory is able to capture the sequence-level dynamics of virus mutation, the existence of multiple virus subtypes, and the variability of individual immune responses. The theory will be calibrated on influenza, dengue fever, and the model LCMV viruses. Both in vivo and in vitro predictions will be made from the model. ? ? The theory will be used to determine best strategies for design of multivalent vaccines. A phase diagram of the best vaccine composition as a function of mutation rate of the virus, number of subtypes, and level of initial exposure will be constructed. The model will allow determination of the best level of multivalent diversity in the vaccine, given the escape mechanisms evidenced by the virus. The proposed work allows investigation and determination of the qualitative and quantitative features that govern the interaction between an effective multivalent vaccine and the variability of the virus. ? ?
