Antigenic Variability

Abstract

Protective vaccines for hypervariable pathogens are urgently needed. It has been proposed that amputating highly variable epitopes from vaccine antigens would induce the production of broadly protective antibodies targeting conserved epitopes. However, so far, these approaches have failed, partially because conserved epitopes are occluded in vivo and partially because co-localizing patterns of immunodominance and antigenic variability render variable epitopes the primary target for antibodies in natural infection. In this Perspective, to recast the challenge of vaccine development for hypervariable pathogens, I evaluate convergent mechanisms of adaptive variation, such as intrahost immune-mediated diversification, spatiotemporally defined antigenic space, and infection-enhancing cross-immunoreactivity. The requirements of broadly protective immune responses targeting variable pathogens are formulated in terms of cross-immunoreactivity, stoichiometric thresholds for neutralization, and the elicitation of antibodies targeting physicochemically conserved signatures within sequence variable domains.

Keywords: antibody; antigenic variability; escape mutant; quasispecies; vaccine.

Figure 1

Mechanisms of adaptive variation. (A) Persistent generation of escape mutants resistant to neutralization by extant, intrahost antibodies prevents viral clearance (3). (B) Spatiotemporally defined emergence of novel antigenic variants resistant to population level immunity facilitates seasonal outbreaks (4). (C) Cross-immunoreactivity of antibodies can enhance infectivity of antibody bound virions (5). (D) Occlusion of evolutionarily constrained epitopes by variable domains limits cross-neutralization (6).

Figure 2

Reductionist model of low-affinity variance cross-nAB attenuation of antigenic cooperation. Reductionist model of antigenic altruism describes the probability that an immune response generated by variant i will be stimulated by variant j (Gj, i) and the probability that an immune response to i neutralizes j (Uj, i). Accordingly, if Gj, i < Gi, i, but > 0, and variant i preceded j, the response to j will be characterized by a variant-specific, relational immunodeficiency (antigenic cooperation) (7). However, if Uj, i ≈ Ui, i (low-affinity variance of nAB between i and j), variants j and i are equally vulnerable to neutralization to the immune response generated by i. In this case, despite j-specific immunodeficiency, variant j will be cleared with equal probability to variant i.