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. 2014 Sep 1;193(5):2073-86.
doi: 10.4049/jimmunol.1401054. Epub 2014 Jul 30.

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

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Free PMC article

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

Sidhartha Chaudhury et al. J Immunol. .
Free PMC article

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.

Figures

FIGURE 1.
FIGURE 1.
Immune system model for affinity maturation. A summary of the immune system model that is used to simulate affinity maturation, including B cell stimulation, mutation and proliferation, differentiation, Ab production, and Ag clearance. The components in the model include Ags, naive B cells (N), GC B cells (B), stimulated GC B cells (B*), memory cells (M), plasma cells (P), and Abs. Subscripts denote epitope and paratope genotypes.
FIGURE 2.
FIGURE 2.
Affinity maturation simulation results for 50 independent trajectories for monovalent (upper panel) and polyvalent (lower panel) vaccinations. Median values are shown for each panel. (A) B cell populations, including GC B cells, stimulated GC B cells, memory cells, and plasma cells. (B) B cell diversity, with the number of unique genotypes that make up 25, 50, 75, and 100% of the total B cell population. B cell populations (C) and Ab levels (D) with respect to affinity to the Ag strain S1 for different levels of affinity, from low affinity (Hamming distance = 7) to high affinity (Hamming distance = 4).
FIGURE 3.
FIGURE 3.
Simulated in vitro results compared with prior experimental data. (A) The median Ab titers from the monovalent and polyvalent simulations are reported for the homologous (strain S1) and heterologous (strain S5) Ags, as well as a model chimera containing only the polymorphic (POLY) or conserved (CONS) epitope. Experimental results for monovalent (3D7) and polyvalent (QV) vaccination against homologous (strain 3D7) and heterologous (strains 7G3, M24, and 102-1) Ags, as well as recombinant POLY and CONS AMA1 chimeras. (B) Median simulated GIA reversal and experimental GIA reversal assays for the same Ags as above used for depletions. SDs are given for the simulated results; all experimental data are from Dutta et al. (47) and are derived from pooled serum samples. All differences in the simulation results between monovalent and polyvalent vaccinations were significant based on a Welch t test (p < 10−5).
FIGURE 4.
FIGURE 4.
Fine specificity and cross-reactivity of the Ab response. (A) The Ab response toward the conserved (Ep 1) and polymorphic (Ep 2) epitopes for strain S1 in the monovalent and polyvalent vaccine simulations. (B) The Ab response is further broken down with respect to reactivity across multiple Ag alleles: fully cross-reactive (cross), partially cross-reactive (partial), and strain-specific (spec) for both epitopes.
FIGURE 5.
FIGURE 5.
Monovalent, bivalent, trivalent, and tetravalent vaccine responses. (A) The Ab response toward a heterologous, non–vaccine strain is shown from simulations of monovalent, bivalent, trivalent, and tetravalent vaccinations. (B) The cross-reactive, partially cross-reactive, and strain-specific Ab response to the conserved (Ep 1) and polymorphic (Ep 2) epitopes is shown for monovalent, bivalent, trivalent, and quadvalent vaccine conditions.
FIGURE 6.
FIGURE 6.
Memory B cell response. (A) A breakdown of the memory B cell response in terms of specificity for the conserved (Ep 1) and polymorphic (Ep 2) epitopes in the monovalent (left) and polyvalent (right) vaccine simulations. (B) A sequence phylogeny tree of the 35 largest B cell clonal populations, which represent ∼30–40% of the total B cell population, colored with respect to epitope and cross-reactivity in the same scheme as in (A). The font size reflects the relative population size of that clonal line.
FIGURE 7.
FIGURE 7.
B cell cross-reactivity and proliferation rate. (A) The number of B cells with fully cross-reactive, partially cross-reactive, and strain-specific Ag specificity for monovalent (left panel) and polyvalent (right panel) vaccination conditions. (B) The growth rate of B cell populations (dB/dT) corresponding to cross-reactive, partially cross-reactive, and strain-specific B cells for monovalent (left panel) and polyvalent (right panel) conditions. (C) Epitope dose for fully conserved (Cross), partially conserved (Partial), and strain-specific (Spec) epitopes in monovalent (left panel) and polyvalent (right panel) vaccine formulations. Total Ag dose was 360 units.
FIGURE 8.
FIGURE 8.
B cell fitness landscape during affinity maturation. The fitness landscape for B cells during affinity maturation in the monovalent (left panel) and polyvalent (right panel) simulations, as a function of cross-reactivity and binding affinity. A fitness of 1 represents the highest fitness; cross-reactivity is listed as the number of strains that the B cell line is specific to, and the binding affinity is shown as low, medium, high, and max, corresponding to Hamming distances of 4, 5, 6, and 7.

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