Title: On the lines of antigen-antibody interactions in vitro and their significance for sensitive and specific antigen and antibody assays – including hybrid ELISAs – and for the possibility of more efficacious vaccines
Abstract:
The reaction in the conventional neutralization test was found to be bi-factorial, consisting of 1) an early short-lasting “over-neutralization” reaction.
In the complement-enriched neutralization test, the action by the complement component C1q is central. A significant neutralizing effect of otherwise non-neutralizing IgM antibodies could be demonstrated in blood as early as 4 days after experimental nasal infection and after 8 to 14 days in samples diluted 1:10.000 or more, illustrating an extraordinary potency of these non-neutralizing antibodies in combatting infectious agents.
Viruses are inactivated in vitro by antibodies in three different ways, 1) by the binding to neutralizing antibodies, 2) by simple aggregation of the test virus particles, and 3) by aggregation of virus-antibody complexes by the complement component C1q. Aggregation reactions are prompt and short-lasting.
The lines for elaborating very sensitive assays demonstrating antigens and antibodies, including also rapid hybrid ELISAs incorporating prompt aggregation reactions, are outlined.
The main reason for the prompt aggregation reactions are recognized but so far unexplained specific forces attracting and binding 1) antigenic determinants on the infectious agent and antigen-binding sites on their antibodies and 2) the Fc region of antibodies sensitized by being bound to their antigenic determinant on an infectious agent and binding sites on the C1q component of complement.
A vital adapted immune defense against infectious agents must take place on mucous membranes, where the secretory IgA antibodies constructed especially to promote aggregation of infectious agents predominate, and where also the C1q component of complement must be anticipated to play an important role in aggregating antigen-antibody complexes.
Vaccine producers have for decades followed a trend to make subunit vaccines giving rise to the formation of especially neutralizing antibodies but without attention to the important role of aggregation reactions demonstrated in the above-mentioned in vitro studies. Further investigations are urgently needed to clarify the formation and the effector mechanisms of the fundamental attractive binding forces defined above and of the in vivo importance of aggregation reactions, which might give new valuable information on how to produce better vaccines against infectious agents.
