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).

Infant immunization is the most cost-effective strategy to prevent infectious diseases in childhood, but is limited by immaturity of the immune system. To define strategies to improve vaccine immunogenicity in early life, the role of genetic and environmental factors in the control of vaccine responses in infant twins was studied. Immune responses to BCG, polio, hepatitis B, diphtheria, pertussis and tetanus vaccines were measured at 5 months of age in 207 Gambian twin pairs recruited at birth. Intrapair correlations for monozygous and dizygous pairs were compared to estimate the environmental and genetic components of variation in responses. High heritability was observed for antibody (Ab) responses to hepatitis B (77%), oral polio (60%), tetanus (44%) and diphtheria (49%) vaccines. Significant heritability was also observed for interferon-g and interleukin-13 responses to tetanus, pertussis and some BCG vaccine antigens (39-65%). Non-HLA genes played a dominant role in responses to Ab-inducing vaccines, whereas responses to BCG were predominantly controlled by genes within the HLA class II locus. Genetic factors, particularly non-HLA genes, significantly modulate immune responses to infant vaccination. The identification of the specific genes involved will provide new targets for the development of vaccines and adjuvants for young infants that work independently of HLA.

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BackgroundAlmost 30% of children in Southern Africa are HIV exposed but uninfected (HEU) and experience exposures that could increase vulnerability to infectious diseases compared to HIV unexposed (HU) children. The mechanisms of HEU infant vulnerability remain ill-defined. This review seeks to appraise the existing clinical evidence of the pattern of HEU infant infectious morbidity to aid understanding of the potential mechanism of susceptibility.MethodsA systematic search was conducted of scientific literature databases and conference proceedings up to December 2015 for studies comparing adequately defined HEU (in whom HIV-infection had been excluded through age-appropriate testing) and HU infants for all-cause mortality, all-cause hospitalization, or an infection-related morbidity. The systematic review was complemented by a narrative review of additional studies detailing the pattern of infectious morbidity experienced by HEU children without comparison to HU children or without conclusive exclusion of HIV-infection in HIV-exposed infants.ResultsOnly 3 of 22 eligible identified studies were designed to primarily compare HEU and HU infants for infectious morbidity. Fourteen were conducted prior to 2009 in the context of limited antiretroviral interventions. Three patterns emerge: (1) causes of morbidity and mortality in HEU infants are consistent with the common causes of childhood morbidity and mortality (pneumonia, diarrheal disease, and bacterial sepsis) but occur with greater severity in HEU infants resulting in higher mortality, more frequent hospitalization, and more severe manifestations of disease; (2) the greatest relative difference between HEU and HU infants in morbidity and mortality occurs beyond the neonatal period, during mid-infancy, having waned by the second year of life; and (3) HEU infants are at greater risk than HU infants for invasive streptococcal infections specifically Group B Streptococcus and Streptococcus pneumonia.ConclusionTo definitively understand HEU infant infectious morbidity risk, substantially larger prospective studies with appropriate HU infant comparison groups are necessary. HEU children would benefit from collaboration among researchers to achieve the quality of evidence required to improve HEU infant outcomes globally. HEU infant health and well-being, beyond avoiding HIV-infection, deserves a more prominent position in the local and international HIV research agendas.