Template and natural selection theories offered different explanations for antibody specificity and the secondary response.
Direct template theories
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Instructive theories proposed that antigen enters antibody-forming cells and serves as a template for antibodies with combining sites complementary to the antigenic determinant.
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Pauling's model proposed that specificity results from folding antibody polypeptide chains into a tertiary structure fitting the antigenic determinant.
Indirect template theory
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Burnet and Fenner proposed that entry of an antigenic determinant induces a heritable change in the antibody-producing cell.
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A proposed 'genocopy' of the antigenic determinant was incorporated into the cellular genome and transmitted to progeny cells.
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The theory explained specificity and the secondary response but became untenable with advances in the molecular biology of protein synthesis.
Natural selection theory
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Jerne proposed that about a million globulin molecules formed during embryonic life cover the full range of antigenic specificities and constitute natural antibodies.
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An introduced antigen was proposed to select the globulin with the nearest complementary fit. The complex would then reach antibody-forming cells and stimulate synthesis of the same kind of antibody.
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This theory failed to explain why immunological memory resides in cells rather than serum.