Frequent Development of Broadly Neutralizing Antibodies in Early Life in a Large Cohort of Children With Human Immunodeficiency Virus

Abstract

Background: Recent studies have indicated that broadly neutralizing antibodies (bnAbs) in children may develop earlier after human immunodeficiency virus (HIV) infection compared to adults.

Methods: We evaluated plasma from 212 antiretroviral therapy-naive children with HIV (1-3 years old). Neutralization breadth and potency was assessed using a panel of 10 viruses and compared to adults with chronic HIV. The magnitude, epitope specificity, and immunoglobulin (Ig)G subclass distribution of Env-specific antibodies were assessed using a binding antibody multiplex assay.

Results: One-year-old children demonstrated neutralization breadth comparable to chronically infected adults, whereas 2- and 3-year-olds exhibited significantly greater neutralization breadth (P = .014). Likewise, binding antibody responses increased with age, with levels in 2- and 3-year-old children comparable to adults. Overall, there was no significant difference in antibody specificities or IgG subclass distribution between the pediatric and adult cohorts. It is interesting to note that the neutralization activity was mapped to a single epitope (CD4 binding site, V2 or V3 glycans) in only 5 of 38 pediatric broadly neutralizing samples, which suggests that most children may develop a polyclonal neutralization response.

Conclusions: These results contribute to a growing body of evidence suggesting that initiating HIV immunization early in life may present advantages for the development of broadly neutralizing antibody responses.

Keywords: antibodies; broad neutralization; pediatric HIV.

Figure 1.

Human immunodeficiency virus (HIV)-1 Env-specific total immunoglobulin (Ig)G. Total IgG for select HIV-1 Env epitopes were measured by binding antibody multiplex assay in adult and pediatric cohorts. Epitopes include gp120 (a), variable loops (b), gp140/gp41 (c), and peptides (d). Significant difference between adult and pediatric cohorts by Wilcoxon as noted.

Figure 2.

Human immunodeficiency virus (HIV)-1 Env-specific immunoglobulin (Ig)G subclass. Individual IgG subclasses for select HIV-1 Env epitopes were measured by binding antibody multiplex assay in adult and pediatric cohorts. Significant difference between adult and pediatric cohorts by Wilcoxon as noted.

Figure 3.

Neutralization potency in adults versus. children. The neutralization titers of the pediatric samples were calculated for each virus and compared with data from the historical adult cohort. Children demonstrated higher neutralization potency against 4 of 10 viruses, and adults demonstrated higher neutralization potency against 1 of 10 viruses. Statistical significance determined by Wilcoxon test as noted. ID50, 50% inhibitory dilution.

Figure 4.

Neutralization score in adults versus children. Neutralization score was determined as the area under the curve of the neutralization curve for all tested viruses (a). Overall, the neutralization score was greater in children than in chronically infected adults (P = .014, Wilcoxon) (b). Neutralization score increased with age (P = .014, median regression analysis) (c). The neutralization score of the 1-year-old (yo) cohort was comparable to that of adults (P = .44, Wilcoxon) (d). Magnitude-breadth curve comparing adults versus children. The average 50% inhibitory dilution (ID50) value for the pediatric cohort was significantly greater than that of the adult cohort (P = .013, Mann-Whitney U) as indicated by the vertical arrows, whereas a similar proportion of viruses were neutralized in the 2 cohorts as indicated by the horizontal arrow.