Simulation of B Cell Affinity Maturation Explains Enhanced Antibody Cross-Reactivity Induced by the Polyvalent Malaria Vaccine AMA1

Abstract

Polyvalent vaccines use a mixture of Ags representing distinct pathogen strains to induce an immune response that is cross-reactive and protective. However, such approaches often have mixed results, and it is unclear how polyvalency alters the fine specificity of the Ab response and what those consequences might be for protection. In this article, we present a coarse-grain theoretical model of B cell affinity maturation during monovalent and polyvalent vaccinations that predicts the fine specificity and cross-reactivity of the Ab response. We stochastically simulate affinity maturation using a population dynamics approach in which the host B cell repertoire is represented explicitly, and individual B cell subpopulations undergo rounds of stimulation, mutation, and differentiation. Ags contain multiple epitopes and are present in subpopulations of distinct pathogen strains, each with varying degrees of cross-reactivity at the epitope level. This epitope- and strain-specific model of affinity maturation enables us to study the composition of the polyclonal response in granular detail and identify the mechanisms driving serum specificity and cross-reactivity. We applied this approach to predict the Ab response to a polyvalent vaccine based on the highly polymorphic malaria Ag apical membrane antigen-1. Our simulations show how polyvalent apical membrane Ag-1 vaccination alters the selection pressure during affinity maturation to favor cross-reactive B cells to both conserved and strain-specific epitopes and demonstrate how a polyvalent vaccine with a small number of strains and only moderate allelic coverage may be broadly neutralizing. Our findings suggest that altered fine specificity and enhanced cross-reactivity may be a universal feature of polyvalent vaccines.

Optimal immunization cocktails can promote induction of broadly neutralizing Abs against highly mutable pathogens

“…Luo and Perelson (36) subsequently reported that, during the coevolution of viral strains and Ab responses after infection, Ab breadth increased with the number of variant Ags and the mutational distances separating them. This result likely reflects the fact that, like Chaudhury et al (33), Luo and Perelson (36) assume that there is one conserved epitope shared by all Ags, different Ags contain distinct epitopes composed of variable residues only, and B cells target either the conserved epitope or a variable epitope. The authors considered broadly cross-reactive Abs to be those with high affinity for the conserved epitope.…”

“…Chaudhury et al (33) studied the generation of protective and cross-reactive Abs against diverse strains of malaria on immunization with a few strains. The malaria apical membrane has a cluster of conserved epitopes (binding targets for B cells) and a cluster of highly variable ones.…”

“…Notice that, in the model used in ref. 33, which may be realistic for malaria, epitopes are composed of either purely conserved residues or variable residues.…”

The evolution within us

“…Broadly neutralizing antibodies can be thought of as having, on average, more available antigen than narrowly neutralizing antibodies. The idea that antibodies to abundant antigens, such as conserved epitopes, should proliferate more than antibodies to specific epitopes has been used to explain patterns of immunodominance in response to malaria [135] and is consistent with basic principles of population growth. However, the subdominance of anti-stalk antibodies in influenza suggests that structure complicates simple assessments of antigen availability.…”

Competitive exclusion by autologous antibodies can prevent broad HIV-1 antibodies from arising

“…With the exception of occasional mutations, the conserved epitope is common to all viruses. A similar approach has been used to model a malaria vaccine antigen (24). The binding between an epitope and an antibody is determined by the length of the longest common substring between their string representations (25,26) in the absence of any occluding structures, a quantity we call the match length.…”