Over-arching Goal:

MADI has been conceived and assembled as a translational research program that integrates the whole trajectory of vaccine-induced immunity from maternal to infant immunization. A series of coordinated and multidisciplinary studies will be conducted utilizing advanced technologies and approaches to determine how maternal immunization confers protective immunity to the mother and the young infant and recognize determinants of vaccine responses.

Learning from currently recommended vaccines, MADI’s main goal is to unravel the principles of vaccine induced immunity in the mother-infant dyad and to identify actionable targets to improve vaccine design and implementation and immune therapies (monoclonal Ab). MADI has three interconnected Specific Aims:
1. Distinguish unique features and predictors of vaccine-induced immunity during pregnancy.
2. Define the principles governing maternal antibody transfer.
3. Identify determinants of infant immunity and responses to vaccines.

Project 1 (P1)

Maternal Immunity

P1 Lead: Marcela Pasetti, Ph.D. (Professor, University of Maryland)

Tetanus, B. pertussis and seasonal influenza vaccines are recommended during pregnancy to boost production of antibodies (Ab), which are transferred to the infants via placenta and breast milk. A profound immune modulation takes place during pregnancy which is expected to influence responses to vaccines. Our preliminary data revealed differentially glycosylated serum IgG in pregnant, as compared to non-pregnant, women following seasonal flu vaccination. These changes were subtype-specific and influenced Ab functions. P1 will investigate biophysical and functional features of Ab elicited by vaccines, i.e. (TdaP) and influenza, during pregnancy. We will investigate Ab glycosylation and Fab- and Fc-mediated antimicrobial activity, in pregnant and non-pregnant women using unique and well characterized clinical specimens. We will also interrogate vaccine specific T and B cell responses and whether Ab modifications are associated with changes in cell mediated immunity. These results will complement innate immune phenotype studies by P4. Adoptive transfer of vaccine-induced Ab with distinct glycan profile will provide information on in vivo attributes and protective capacity of differential Ab glycosylation that occurs during gestation. P1 and P2 data will produce a complete serum, breast milk, and cord blood Ab profile. Understanding how pregnancy impacts vaccine responses and elucidating the molecular mechanisms involved will inform vaccine development and improve maternal immunization strategies.

Project 2 (P2)

Transferred Immunity

P2 Lead: Margaret Ackerman, Ph.D. (Professor, Dartmouth College)

Maternal antibodies (Ab) play a major role in fetal and neonatal health outcomes. P2 will test the following hypotheses: 1) that subclass, allotype, antigen specificity, glycosylation, light chain usage, affinity for individual or combinations of FcR including FcgR, C1q, and FcRn, or other antibody-intrinsic factors may impact the efficiency of transplacental antibody transport; 2) that the maternal serological antibody repertoire is statistically and biologically distinguishable from that transferred to the fetus in terms of the molecular features of Fv, including sequence and IGHV gene usage; 3) that antibody durability in plasma and efficiency of transplacental transport can be differentiated; and 4) that antibody transport across the human placenta can be enhanced by Fc engineering. Coupled to enhanced understanding of the pregnancy-associated differences in the antibody repertoire/vaccine response identified in P1, the inherited antibody repertoire’s role in protection and vaccine interference in P3, and in relation to multiomic profiling explored in P4, the enhanced understanding of the determinants of efficient or poor antibody transfer across the placenta gained in P2 will link studies of pregnant mothers with those in infants, with the potential to impact numerous facets of maternal-fetal medicine in the context of natural immunity, responses to vaccines, and antibody therapies, facilitating development of maternal interventions targeted to improve fetal/neonatal/infant health.

Project 3 (P3)

Infant Immunity

P3 Lead: Arnaud Marchant, M.D. Ph.D. (Professor, Université libre de Bruxelles)

Antibodies (Ab) transferred from the mother to the newborn provide protection against infectious pathogens but can also interfere with infant responses to vaccines. The overall aim of this P3 is to identify key biophysical and functional features of transferred maternal Ab mediating pathogen control and regulating vaccine responses. P3 combines systems serology analysis of placentally acquired maternal Ab and adoptive transfer of engineered human Ab followed by pathogen challenge and vaccination of FcgR/C1q knock-out and humanized infant mice to test the following hypotheses: 1) Specific biophysical and functional characteristics of transferred maternal Ab mediate immunity to pathogens; 2) Infant vaccination under the cover of maternal Ab stimulates a qualitatively different immune response; and 3) The biophysical characteristics of transferred maternal Ab determine the magnitude and quality of infant responses to vaccines. Together with the analysis of biophysical biases in Ab produced by vaccination during pregnancy (P1), Ab transported across the placenta and persisting in infants (P2), and with the systems immunology of the determinants in infant vaccine responses (P4), P3 will produce knowledge that can inform effective maternal immunization strategies to strengthen immunity and prevent infection in early life.

Project 4 (P4)

Systems Immunology

P4 Lead: John Tsang, Ph.D. (Professor, Yale University)

Designing effective vaccines is challenging because the rules for inducing protective immunity are poorly understood. Many factors also contribute to vaccine response variability in humans, including age, sex, genetics, and pre-existing immunity. The environment, history of exposure, and other variables can establish baseline immune “set points” that impact responses. Pregnancy adds an extra layer of complexity as it is accompanied by dynamic immunological and physiological changes that are only beginning to be defined. The impact of such changes in immune set points and subsequent innate and adaptive responses to vaccines in the mother and the resulting transferred immunity to infants represent a major knowledge gap. Similarly, in infants, postnatal immune states follow a dynamic trajectory; how maternal transferred antibodies (Ab) impact infant set points to shape vaccine responses remains unknown. For the first time, P4 will comprehensively measure the state of single peripheral immune cells before (baseline) and after vaccination during pregnancy and infancy at unprecedented resolution using multi-modal single cell profiling technologies to define baseline set point and early-response cellular predictors and determinants of serological outcomes in the maternal-infant dyad. We will use machine learning to link single-cell phenotypes to pregnancy associated vaccine Ab response identified in P1, the level and repertoire of Ab transferred from mothers to infants in P2, and the serological profiles of infants pre- (maternal in origin) and post-vaccination in P3. Ab features beyond titers such as glycosylation, subclasses, Fc receptor binding and effector functions will be included in these analyses. Parallel studies and mechanistic dissection in mouse models using single cell and spatial tissue imaging approaches will be integrated. P4 will generate knowledge to inform effective vaccine design strategies in the unique pregnancy-infancy setting.