Maternal vaccination: moving the science forward

Abstract

Background: Infections remain one of the leading causes of morbidity in pregnant women and newborns, with vaccine-preventable infections contributing significantly to the burden of disease. In the past decade, maternal vaccination has emerged as a promising public health strategy to prevent and combat maternal, fetal and neonatal infections. Despite a number of universally recommended maternal vaccines, the development and evaluation of safe and effective maternal vaccines and their wide acceptance are hampered by the lack of thorough understanding of the efficacy and safety in the pregnant women and the offspring.

Methods: An outline was synthesized based on the current status and major gaps in the knowledge of maternal vaccination. A systematic literature search in PUBMED was undertaken using the key words in each section title of the outline to retrieve articles relevant to pregnancy. Articles cited were selected based on relevance and quality. On the basis of the reviewed information, a perspective on the future directions of maternal vaccination research was formulated.

Results: Maternal vaccination can generate active immune protection in the mother and elicit systemic immunoglobulin G (IgG) and mucosal IgG, IgA and IgM responses to confer neonatal protection. The maternal immune system undergoes significant modulation during pregnancy, which influences responsiveness to vaccines. Significant gaps exist in our knowledge of the efficacy and safety of maternal vaccines, and no maternal vaccines against a large number of old and emerging pathogens are available. Public acceptance of maternal vaccination has been low.

Conclusions: To tackle the scientific challenges of maternal vaccination and to provide the public with informed vaccination choices, scientists and clinicians in different disciplines must work closely and have a mechanistic understanding of the systemic, reproductive and mammary mucosal immune responses to vaccines. The use of animal models should be coupled with human studies in an iterative manner for maternal vaccine experimentation, evaluation and optimization. Systems biology approaches should be adopted to improve the speed, accuracy and safety of maternal vaccine targeting.

Keywords: animal model; antibody; immunology; pregnancy; vaccine.

Figure 1

Mechanisms of vaccine-induced maternal, fetal and neonatal immune protection. (A) Maternal vaccination induces innate, humoral and cell-mediated immunity that confers direct protection of the mother against infections (left panel). Vaccine-induced maternal IgG is also transferred to the fetus to confer systemic passive immunity (middle and right panels). Maternal IgG is endocytosed into villous syncytiotrophoblasts from the maternal surface (a) and binds to FcRn in the acidic environment of early endosomes (b). IgG-FcRn complexes are then either transcytosed to the fetal side of syncytiotrophoblasts (c) or recycled back to the maternal side (d). IgG dissociates from FcRn upon exposure to the neutral pH environment at the fetal side of syncytiotrophoblasts (e) and enters fetal circulation (f). FcRn on the fetal side of syncytiotrophoblasts can be retrieved back to the maternal side to participate in subsequent IgG transport (g). Maternal vaccine-induced IgD could cross trophoblasts and enter fetal circulation via an unknown mechanism (h). (B) Maternal vaccination-induced antibodies, including IgA, IgG, IgM and IgD, are also secreted into colostrum and milk. During breastfeeding, these antibodies are ingested by the neonate (left panel). IgA, IgG and IgM confer neonatal mucosal immune protection by binding to commensal and pathogenic microbes and their virulence factors to mediate immune exclusion and neutralization (middle panel). In addition, maternal IgA facilitates antigen sampling in the neonatal intestinal mucosa by crossing M cells via an unknown receptor (i) or apical-to-basolateral retro-transcytosis via polymeric Ig receptor (pIgR) (k). Besides delivering antigens to mucosal dendritic cells (DCs), IgA can interact with DCs via FcαRI, leading to either immunity against pathogenic microbes or tolerance to commensal microbes (l). IgA can also interact with Fcα/µR on DCs to mediate immune tolerance. Ingested maternal IgG can also cross epithelial cells via FcRn (m) through a mechanism similar to that in syncytiotrophoblasts. This pathway delivers antigens to, and regulates, DCs via activating or inhibitory FcγRs (n). Maternal IgG acquired during the perinatal period can be re-secreted by FcRn into the lumen to participate in mucosal immune defense (o).

Figure 2

Pregnancy-associated humoral immune alterations that can influence vaccine responses. Pregnancy is accompanied by a marked suppression of the generation of B lineage precursors from hematopoietic stem cells (HSCs) in the bone marrow (a), leading to a reduction of the size of the B cell pool. This suppression of B lymphopoiesis is likely mediated by steroid hormones, such as estrogen. However, estrogen has an opposite effect at later stages of B cell differentiation by promoting the maturation of immature B cells (b) and the generation of marginal zone (MZ) B cells (c) and follicular B cells (d). The combined effect is a reduction of the percentages of immature and transitional B cells in the reduced B cell pool. Estrogen has also been shown to promote the development of plasma cells (e), whereas estrogen and human chorionic gonadotrophin (hCG) have been shown to promote the development of regulatory B cells (B_regs) (f). In normal pregnancy, peripheral CD5⁺ B cells, which have been implicated in adverse pregnancy outcomes, are suppressed by a mechanism that is not well-known (g). This mechanism and the proper negative selection of autoreactive B cells in the bone marrow are critical to avoid the stimulation of potentially pathogenic B cells by estrogen during pregnancy. Of note, the identity of human B-1 cells is under contentious debate, and the developmental relationship between human B_regs, MZ B cells and B-1 cells is unclear.