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...

The immune response to repeated antigenic stimtflation differs in a number of respects from the response to the initial exposure to immunogen. For example, several weeks (or even years) after the first injection, a second exposure to the immunogen often evokes an unusually vigorous response: the serum antibody concentration typically increases rapidly to reach and remain at a level higher than that attained after the primary stimulus (1-4). In addition, the antibodies produced in the secondary response often form more stable complexes with antigen than those formed at a comparable time after the first injection (5-9). Recent studies of antibodies isolated from serum at various intervals after immunization with 2,4-dinitrophenylated proteins have shown that the affinity of these antibodies for simple dinitrophenyl haptens (expressed as the average intrinsic association constant) is greater the longer the period between immunization and bleeding, and the smaller the dose of immunogen (10). These properties of the serum antibodies are the direct result of a sequential change in the nature of the antibodies synthesized by lymph node cells (11). It seemed possible, therefore, that the affinity of the antibodies formed at any time after a single injection of antigen is inversely related to the amount of antigen remaining in the animal. Accordingly, we wished to determine the effect on antibody affinity of a second injection of antigen, given when the animal is already forming high affinity antibody in response to the initial stimulus. In experiments reported here, it is demonstrated that the typical response to a second injection of antigen is a burst of synthesis of antibodies with much greater a/~ity for the dinitrophenyl group than those formed at a comparable time after the primary immunization with the same dose of immunogen. Indeed, the earliest antibodies formed after restimulation are already high in affinity. *A preliminary report of some of this work was presented at an annual meeting of the American

Given a dose of antigen, an organism may or may not respond by producing specific antibody. The contending theories disagree on almost every detail of the mechanism set in motion; they are one in assuming that whatever is or fails to be produced, is specific. Against the background of this tacit assumption any qualitative failure of the antibody response stands out as a major paradox. Thus it has been known for over 10 yr now that humans vaccinated against influenza produce antibodies against the immunlzhag antigen, but produce antibodies of higher titer against the antigen that was their first childhood experience of influenza, even if that strain happened to be absent from the vaccine-hence the name Original Antigenic Sin (1). The phenomenon rests on solid experimental foundations (2-11), and has been reproduced in laboratory animals (10, 12, 13). The evidence is incompatible with either of the reigning immunological theories in their simplest form. On an instructive model the antibody molecule would be moulded on the antigen and hence, by definition, must be more complementary to it than to any other antigen. On a selective model

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 "original antigenic sin " phenomenon (OAS) 1 challenges the dogma of the specificity of the immunological memory: when there is sequential infection with two different but antigenically related strains of influenza A virus, the antibody stimulated by the second infection reacts more strongly with the primary virus than with the one actually eliciting the response (1-3). This phenomenon is now well documented with many viral and nonviral cross-reacting antigens (4-8). However, its study with influenza antigens is of special interest because of its wide implications in the sero-epidemiology of influenza and the response to vaccination. In the accompanying paper (9) we have shown that purified hemagglutinin (HA) extracted from related influenza viruses share cross-reacting antigenic determinants, but differ in strain-specific determinants. We have now analyzed the antibody response to each of these groups of determinants after sequential exposure of mice to two related HA's, and have carried out cell-transfer experiments in an attempt to elucidate the cellular mechanisms responsible for the aberrant immunological recall of the OAS phenomenon.

Response to vaccine depends not only on the nature of the antigen itself but also on the immunological history of the recipient. The trivial case is the difference between primary and secondary experience of the same antigen. The situation is more complex when the secondary vaccine is related to rather than identical with the first. The response here is, strictly speaking, inadequate: the antibodies produced react better with the primary vaccine than with the one that stimulated their appearance. Current theories do not cover t~is contingency which demands not only immunological memory of a sort, but also some mechanism whereby the second antigen is prevented from setting off a standard primary response and instead a particular subpopulation of cross-reacting antibodies is made to appear in quantity. A hypothesis accounting for the observations on human sera has been developed in the companion paper (1), and it is our task here to test its implications experimentally. In particular, we sought to determine whether the response to a related but hitherto not experienced vaccine was of secondary type, and whether there existed a mechanism deflecting

The finding that the sera of humans 70 or more years of age in 1958 exhibited a unique frequency and concentration of antibody reacting with the 1963 strain.q of horse influenza has been amply confirmed (1-4). In the discussion of the primary data, it was pointed out that the antibody pattern described probably delineated a period of past prevalence of equine-2/63-1ike viruses in man extending from about 1880 to 1890. That interpretation was based on the demonstration that episodes in the succession of major antigenic variants of influenza viruses can be reconstructed by ascertaining the age distribution of antibodies to prototype strains currently found in the sera of humans (5, 6). However, it was recognized that the phenomenon observed then with equine-2/63 virus might be alternatively explained as the consequence of accumulated experience with the minor antigens of influenza A viruses, or less likely, might reflect the sporadic cross-species transmission of a respiratory virus from horses to humans (1). To resolve these questions and if possible to delineate more precisely the

The results of studies on the age distribution of antibodies, on the range of antibody response to monovalent vaccines by age, and on the age-specific characteristics of antibody demonstrated by serum adsorption tests, have indicated that periods of past prevalence of strains closely related antigenicalIy to swine and Asian strains can be identified. Thus a swine-like virus is thought to have been involved in the pandemic of 1918 and an Asian-fike one in the pandemic of 1889-90. A basic tenet of these serologic recapitulations is that the major antigens of the initial infections of childhood orient antibody formation throughout the rest of life. Upon subsequent exposures to antigenically different yet related strains, the level of the primary antibody is reinforced (1-9). The relevance of this thesis has been questioned by others who take the position that the presence of age-specific antibody patterns cannot be used as a basis for identification of the primary infections because after repeated experiences, minor antigenic components of infecting strains may induce antibody