This paper argues that immunological memory is in the same class of associative memories as Kanerva's Sparse Distributed Memory, Albus's Cerebellar Model Arithmetic Computer, and Marr's Theory of the Cerebellar Cortex. This class of memories derives its associative and robust nature from a sparse sampling of a huge input space by recognition units (B and T cells in the immune system) and a distribution of the memory among many independent units (B and T cells in the memory population in the immune system). Keywords: Immunological Memory, Associative Memory, Cross-Reactive Memory, Original Antigenic Sin, Sparse Distributed Memory. 1 Introduction Cowpox vaccination, used to protect humans from smallpox, was the first known deliberate use of associative recall in the immune response (Jenner, 1798). The modern investigation of associative recall began with the observation that antibodies induced during an influenza infection often have greater affinity to prior strains of influenza than t...

We present a method for deriving shape space parameters that are consistent with immunological data, and illustrate the method by deriving shape space parameters for a model of cross-reactive memory. Cross-reactive memory responses occur when the immune system is primed by one strain of a pathogen and challenged with a related, but different, strain. Much of the nature of a cross-reactive response is determined by the quantity and distribution of the memory cells, raised to the primary antigen, that cross-react with the secondary antigen. B cells with above threshold affinity for an antigen lie in a region of shape space that we call a ball of stimulation. In a cross-reactive response, the intersection of the balls of stimulation of the primary and secondary antigens contains the cross-reactive B cells and thus determines the degree of cross-reactivity between the antigens. We derive formulas for the volume of intersection of balls of stimulation in different shape spaces, and show th...

We performed computer simulations to study the effects of prior infection on vaccine efficacy. We injected three antigens sequentially. The first antigen, designated the prior, represented a prior infection or vaccination. The second antigen, the vaccine, represented a single component of the trivalent influenza vaccine. The third antigen, the epidemic, represented challenge by an epidemic strain. For a fixed vaccine to epidemic strain cross-reactivity, we generated prior strains over a full range of cross-reactivities to the vaccine and to the epidemic strains. We found that, for many cross-reactivities, vaccination, when it had been preceded by a prior infection, provided more protection than vaccination alone. However, at some cross-reactivities, the prior infection reduced protection by clearing the vaccine before it had the chance to produce protective memory. The cross-reactivities between the prior, vaccine and epidemic strains played a major role in determining vaccine efficac...

The immune system is a real-time example of an evolving system that navigates the essentially infinite complexity of protein sequence space. How this system responds to disease and vaccination is discussed. Of particular focus is the case when vaccination leads to increased susceptibility to disease, a phenomenon termed original antigenic sin. A physical theory of protein evolution to explain limitations in the immune system response to vaccination and disease is discussed, and original antigenic sin is explained as stemming from localization of the immune system response in antibody sequence space. This localization is a result of the roughness in sequence space of the evolved antibody affinity constant for antigen and is observed for diseases with high year-to-year mutation rates, such as influenza. 1 1