Coordinated Fc-effector and neutralization functions in HIV-infected children define a window of opportunity for HIV vaccination

Abstract

Objectives: Antibody function has been extensively studied in HIV-infected adults but is relatively understudied in children. Emerging data suggests enhanced development of broadly neutralizing antibodies (bNAbs) in children but Fc effector functions in this group are less well defined. Here, we profiled overall antibody function in HIV-infected children. Design: Plasma samples from a cross-sectional study of 50 antiretroviral therapy-naive children (aged 1–11 years) vertically infected with HIV-1 clade A were screened for HIV-specific binding antibody levels and neutralizing and Fc-mediated functions. Methods: Neutralization breadth was determined against a globally representative panel of 12 viruses. HIV-specific antibody levels were determined using a multiplex assay. Fc-mediated antibody functions measured were antibody-dependent: cellular phagocytosis (ADCP); neutrophil phagocytosis (ADNP); complement deposition (ADCD) and natural killer function (ADNK). Results: All children had HIV gp120-specific antibodies, largely of the IgG 1 subtype. Fifty-four percent of the children exhibited more than 50% neutralization breadth, with older children showing significantly broader neutralization activity. Apart from ADCC, observed only in 16% children, other Fc-mediated functions were common (>58% children). Neutralization breadth correlated with Fc-mediated functions suggesting shared determinants of enhanced antibody function exist. Conclusions: These results are consistent with previous observations that children may develop high levels of neutralization breadth. Furthermore, the striking association between neutralization breadth and Fc effector function suggests that HIV vaccination in children could yield multifunctional antibodies. Paediatric populations may therefore provide an ideal window of opportunity for HIV vaccination strategies.

Characterization of antibody‐dependent cellular phagocytosis in patients infected with hepatitis C virus with different clinical outcomes

“…Moreover, we found that patients with anti‐E2 antibodies targeting Domain B and D that are known to be associated with effective neutralization 55–59 are also the ones that had antibodies strongly associated with high ADCP, further supporting the notion that there may be overlapping protective functions via dually acting antibodies. This is consistent with reports on HIV in which overlapping ADCP and neutralizing functions were observed, 24 and antibodies that maintain broad neutralization function against several HIV variants also possessed potent Fc receptor‐dependent effector functions including ADCP 14,17,24,25 . However, future studies aimed at defining the significance of ADCP in HCV, namely its role in viral clearance and clinical outcomes using live viruses, is warranted.…”

“…Among these effector functions, ADCP has been shown to correlate with immune protection against several RNA viruses, including HIV, 18 ebola, 19 dengue, 20 and influenza 21 . Importantly, in patients with HIV infection, antibodies that neutralize broader HIV variants 22,23 also possess potent Fc receptor‐dependent effector functions, including ADCP, 24,25 and antibodies that maintain broadly neutralizing function at later stages of the disease showed an early and stronger Fc‐receptor‐dependent effector function 14,17,26,27 . A positive relationship between neutralization and ADCP was also observed in patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) 15,28 and influenza virus 29 infections.…”

“…However, antibody‐mediated neutralization 11,12 or early CD4 + T cell functions 13 alone are not sufficient to protect against HCV infection, thus undefined immunological processes acting independently or in synergy with the beforementioned mechanisms are required for sustained and broad immune protection. In recent years, Fc‐receptor‐dependent antibody effector functions, including antibody‐dependent cellular phagocytosis (ADCP), antibody‐dependent cellular cytotoxicity (ADCC), antibody‐dependent complement deposition (ADCD), and antibody‐dependent respiratory burst (ADRB) have been recognized to play key roles in antiviral immunity 14–17 . Among these effector functions, ADCP has been shown to correlate with immune protection against several RNA viruses, including HIV, 18 ebola, 19 dengue, 20 and influenza 21 .…”

Influenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children

“…Furthermore, in HIV infection, ADCC mediating antibodies have been attributed to being moderately protective in the absence of broadly neutralizing Abs 36 and are correlated with ADCC and IgG3 34 , 37 . Furthermore, high FcR responses can be enriched in pediatric HIV non-progressors 38 . Whilst vaccine antibody breadth is associated with infection-free time from SARS-CoV-2 variants 39 , similar to pre-existing antibodies pandemic and avian influenza found here.…”

Strategies for HIV-1 vaccines that induce broadly neutralizing antibodies

“…1), and bnAbs constitute a minor component of an individual's overall HIV-1-specific antibody response [32][33][34][35][36] . Recent data suggest that in infants and children, high levels of bnAbs may develop over a shorter period of time and require fewer mutations than in adults, although the factors governing this remain unclear 37,38 .…”