Frequent development of broadly neutralizing antibodies in early life in a large cohort of HIV-infected children

Abstract

Recent studies conducted in small cohorts of children have indicated that broadly neutralizing antibodies (bnAbs) may develop earlier after HIV infection compared to adults. To define the frequency and kinetics of bnAb responses in a larger pediatric cohort, we evaluated plasma from 212 ART-naive, children living with HIV aged 1 to 3 years. Neutralization breadth and potency was assessed using a panel of 10 tier-2 viruses and compared to those of adults with chronic HIV. Further, the magnitude, epitope specificity and IgG subclass distribution of Env-specific antibodies were also assessed using a binding antibody multiplex assay. We found that 1-year-old children demonstrated neutralization breadth comparable to that of chronically-infected adults, and breadth continued to increase with age such that the pediatric cohort overall exhibited significantly greater neutralization breadth than adults (p= 0.014). Similarly, binding antibody responses increased with age, and the levels in 2 to 3 year-old children were comparable to those of adults. Overall, there was no significant difference in antibody specificities or IgG subclass distribution between the pediatric and adult cohorts. Interestingly, 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, suggesting a polyclonal neutralization response may develop in most children. These results contribute to a growing body of evidence suggesting that the early life immune system may present advantages for the development of an effective HIV vaccine. Author summaryUnderstanding the development of broadly neutralizing antibodies during natural HIV infection is critical to provide insights for the development of an effective vaccine. In this study, we used a large cohort (n=212) of HIV infected children aged 1-3 years old to define the frequency and kinetics of broad neutralization in comparison to adults with chronic HIV. We also evaluated the magnitude and epitope specificity of HIV Env-specific antibodies in children and adults. We observed that both the binding and neutralizing antibody responses increased with age. However, by one year of age, children had neutralization breadth comparable to that of chronically infected adults; and overall, 1-3 year-old children demonstrated higher neutralization breadth than adults. Only slight differences in epitope-specificity and IgG subclass distribution were observed between children and adults, suggesting that these factors are not major contributors to the observed age-related difference in neutralization breadth. The epitope specificity of the neutralizing antibodies could not be mapped in the majority of children, suggesting that their response may be polyclonal. Our study contributes to the body of work indicating a potential advantage of the early life immune system for the elicitation of broad neutralization.