Maternal antibodies: clinical significance, mechanism of interference with immune responses, and possible vaccination strategies

Abstract

Neonates have an immature immune system, which cannot adequately protect against infectious diseases. Early in life, immune protection is accomplished by maternal antibodies transferred from mother to offspring. However, decaying maternal antibodies inhibit vaccination as is exemplified by the inhibition of seroconversion after measles vaccination. This phenomenon has been described in both human and veterinary medicine and is independent of the type of vaccine being used. This review will discuss the use of animal models for vaccine research. I will review clinical solutions for inhibition of vaccination by maternal antibodies, and the testing and development of potentially effective vaccines. These are based on new mechanistic insight about the inhibitory mechanism of maternal antibodies. Maternal antibodies inhibit the generation of antibodies whereas the T cell response is usually unaffected. B cell inhibition is mediated through a cross-link between B cell receptor (BCR) with the Fcγ-receptor IIB by a vaccine-antibody complex. In animal experiments, this inhibition can be partially overcome by injection of a vaccine-specific monoclonal IgM antibody. IgM stimulates the B cell directly through cross-linking the BCR via complement protein C3d and antigen to the complement receptor 2 (CR2) signaling complex. In addition, it was shown that interferon alpha binds to the CD21 chain of CR2 as well as the interferon receptor and that this dual receptor usage drives B cell responses in the presence of maternal antibodies. In lieu of immunizing the infant, the concept of maternal immunization as a strategy to protect neonates has been proposed. This approach would still not solve the question of how to immunize in the presence of maternal antibodies but would defer the time of infection to an age where infection might not have such a detrimental outcome as in neonates. I will review successful examples and potential challenges of implementing this concept.

Keywords: B cell receptor; FcγRIIB; cotton rat; maternal antibody; maternal immunization.

Figure 1

Model of B cell activation in the presence of maternal IgG. B cells are being stimulated through three signals, the first one is recognition of antigen by the B cell receptor (BCR), the second the interaction with T cells through CD40/CD40 ligand, and the third cytokines like type I interferon or IL-6. During vaccination in the presence of maternal antibodies T cell responses are generated and therefore the second signal is provided. (A) In the presence of maternal antibodies (IgG), the first signal is downregulated by a cross-link between BCR and FcγRIIB. If MV-specific IgG binds to MV, the constant region is bound by the receptor for the constant region (Fc) of IgG (which is FcγRIIB). FcγRIIB is the only Fc-receptor on B cells and does not bind other immunoglobulins like IgM or IgA. After juxtaposition of the BCR and FcγRIIB, the tyrosine-based inhibitory motif of FcγRIIB is in close proximity to the tyrosine-based activation motif of BCR and delivers a negative signal. (B) If MV-specific IgM binds to MV, it also binds via C3d to CD21 (complement receptor 2), which is part of the positively signaling CD21/CD19/CD83/Leu-13 complex. The opsonin C3d does not bind to IgG. (C) Interferon α (type I interferon) binds to both the interferon receptor and CD21, and the dual receptor usage leads to a strong positive signal. It stimulates antibody secretion by B cells in the presence of maternal antibodies. (D) A possible approach to vaccination in the presence of maternal antibodies is the reduction of the vaccine antigen into small units, which do form antigen–antibody complexes unable to cross-link BCR and FcγRIIB. An example of this approach is experimental vaccination against respiratory syncytial virus in the presence of maternal antibodies (138).