Graphical Abstract Highlights d NK cell-activating antibodies are selectively transferred across the placenta d Digalactosylated Fc glycans are preferentially transferred across the placenta d Digalactosylated antibodies bind more effectively to FcRn and FCGR3A d Although immature, neonatal NK cells are highly responsive to immune complexes SUMMARY Despite the worldwide success of vaccination, newborns remain vulnerable to infections. While neonatal vaccination has been hampered by maternal antibody-mediated dampening of immune responses, enhanced regulatory and tolerogenic mechanisms, and immune system immaturity, maternal pre-natal immunization aims to boost neonatal immunity via antibody transfer to the fetus. However, emerging data suggest that antibodies are not transferred equally across the placenta. To understand this, we used systems serology to define Fc features associated with antibody transfer. The Fc-profile of neonatal and maternal antibodies differed, skewed toward natural killer (NK) cell-activating antibodies.This selective transfer was linked to digalactosylated Fc-glycans that selectively bind FcRn and FCGR3A, resulting in transfer of antibodies able to efficiently leverage innate immune cells present at birth. Given emerging data that vaccination may direct antibody glycosylation, our study provides insights for the development of next-generation maternal vaccines designed to elicit antibodies that will most effectively aid neonates. Antibodies against pertussis derived filamentous hemagglutinin (FHA), pertactin (PTN), fimbriae (FIM), and pertussis toxin (PTX) antigens were compared in 14 mother:cord pairs. (A) The flow cytometric plots depict the gating strategy for antibody dependent cellular phagocytosis (ADCP). (B) The connected dot-plot shows the phagocytic activity across mother:cord pairs. (C) The box-and-whisker plot shows the transfer ratio of ADCP. The dotted line indicates a 100% transfer efficiency (equivalent levels across both compartments). (D) The flow plots highlight the gating strategy for antibody dependent neutrophil phagocytosis (ADNP). (E) The dot-plot shows the relationship between ADNP activity across mother:cord pairs for each antigen-specificity. (F) The whisker plots show the transfer ratio for ADNP. (G) The flow plots highlighting the gating strategy for the NK cell activation assay. (H-J) The dot-line plots show NK-dependent degranulation plotted as the percentage of NK cells positive for CD107a (H), IFNg (I), and MIP-1b (J). (K-M) The whisker plots depict the transfer ratio across the three NK cell activation markers, CD107a (K), IFNg (L), and MIP-1b (M).

While the development of a protective HIV vaccine is the ultimate goal of HIV research, to date only one HIV vaccine trial, the RV144, has successfully induced a protective response. The 31% protection from infection achieved in the RV144 trial was linked to the induction of non-neutralizing antibodies, able to mediate ADCC, suggestive of an important role of Fc-mediated functions in protection. Likewise, Fc-mediated antiviral activity was recently shown to play a critical role in actively suppressing the viral reservoir, however, the Fc-effector mechanisms within tissues that provide protection from or after infection are largely unknown. Here we aimed to define the landscape of effector cells and Fc-receptors present within vulnerable tissues. We found negligible Fc-receptor expressing NK cells in the female reproductive and gastrointestinal mucosa. Conversely, Fc-receptor expressing macrophages were highly enriched in most tissues, but neutrophils mediated superior antibody-mediated phagocytosis. Modifications in Fc domain of VRC01 antibody increased phagocytic responses in both phagocytes. These data suggest that non-ADCC mediated mechanisms, such as phagocytosis and neutrophil activation, are more likely to play a role in preventative vaccine or reservoir-eliminating therapeutic approaches.

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BackgroundHepatitis B virus (HBV) affects up to 400 million people worldwide and accounts for approximately one million deaths per year from liver pathologies. Current treatment regimens are effective in suppressing viremia but usually have to be taken indefinitely, warranting research into new therapeutic approaches. Acute HBV infection in adults almost universally results in resolution of viremia, with the exception of immunocompromised persons, suggesting that the immune response can functionally cure or even eradicate HBV infection.MethodsBecause immunophenotypic and functional studies have implicated a role for Natural Killer (NK) cells in HBV clearance during acute infection, we hypothesized that a distinct NK-cell profile exists in acute HBV infection that could provide information for the mechanism of HBV clearance. Using multivariate flow cytometry, we evaluated the expression of key activating and inhibitory receptors on NK cells, and their ability to respond to classic target cell lines.ResultsMultivariate analysis revealed selective perturbation of the CD56dim NK-cell subset during acute infection, displaying low levels of NKp46+, NKp30+, CD160+ and CD161+ cells. Intriguingly, the CD56dim NK-cell profile predicted time to HBV surface antigen (HBsAg) clearance from the blood, and distinct NK-cell profiles predicted early (NKp30, CD94, CD161) and late clearance (KIR3DL1, CD158a, perforin, NKp46). Finally, functional analysis demonstrated that early and late clearance tracked with elevated degranulation (CD107a) or IFNγ production, respectively, in response to ADCC-mediated activation.ConclusionThe cytolytic CD56dim NK-cell subset is selectively activated in acute HBV infection and displays distinct phenotypic and functional profiles associated with efficient and early control of HBV, implicating antibody-mediated cytolytic NK-cell responses in the early control and functional cure of HBV infection.

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