The vaccinologist’s “dirty little secret”: a better understanding of structure-function relationships of viral immunogens might advance rational HIV vaccine design

Abstract

I will offer a conceptual analysis of different notions of structure and function of viral immunogens and of different structure-function relationships. My focus will then be on the mechanisms by which the desired immune response is induced and why strategies based on three-dimensional molecular antigen structures and their rational design are limited in their ability to induce the desired immunogenicity. I will look at the mechanisms of action of adjuvants (thus the wordplay with Janeway’s “immunologist’s dirty little secret”). Strategies involving adjuvants and other (more successful) vaccination strategies rely on taking into account activities and functions (“what is going on”), and not just the structures involved (“who is there”), in binding in a “lock and key” fashion. Functional patterns as well as other organizational and temporal patterns, I will argue, are crucial for inducing the desired immune response and immunogenicity. The 3D structural approach by itself has its benefits – and its limits, which I want to highlight by this philosophical analysis, pointing out the importance of structure-function relationships. Different functional aspects such as antigenicity, immunogenicity, and immunity need to be kept separate and cannot be reduced to three-dimensional structures of vaccines. Taking into account different notions of structure and function and their relationships might thus advance our understanding of the immune system and rational HIV vaccine design, to which end philosophy can provide useful tools.

Cutting edge technologies in chronic inflammation research

“…The late influential immunologist Charles Janeway called CFA "the immunologist's dirty little secret" since it is required to break T-and B-cell tolerance in healthy organisms. 29 In fact, a case report of accidental self-injection with CFA suggests that this adjuvant induces polyautoreactivity. 30 We have demonstrated that CFA can be replaced by Incomplete Freund's Adjuvant (IFA), which contains no M. tuberculosis, for the induction of multiple sclerosis (MS)-like disease in marmoset monkeys (Callithrix jacchus).…”

“…This adjuvant is not allowed for use in humans since it generates granulomas and serious discomfort. The late influential immunologist Charles Janeway called CFA “the immunologist's dirty little secret” since it is required to break T‐ and B‐cell tolerance in healthy organisms 29 . In fact, a case report of accidental self‐injection with CFA suggests that this adjuvant induces polyautoreactivity 30…”