Disquisitions on Original Antigenic Sin I. Evidence in Man* by S. Fazekas

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 the antigen acts as mitogenic stimulus for cells predestined to form that particular antibody; once again, the response should be most complementary to the antigen which triggered the proliferation of a particular clone of cells. Our studies were prompted by this paradox, and undertaken in the hope that a satisfactory solution might also teach us something about the production of antibodies in general. The work falls into three parts: (a) reexamination of the sera on which the Doctrine of Original Antigenic Sin was founded; (b) demonstration of a basic difference between these and standard primary or secondary sera, together with a hypothesis to account for the observations; and (c) experimental tests of the new hypothesis.