Insights into the regulatory mechanism controlling the inhibition of vaccine-induced seroconversion by maternal antibodies

Abstract

The inhibition of vaccination by maternal antibodies is a widely observed phenomenon in human and veterinary medicine. Maternal antibodies are known to suppress the B-cell response. This is similar to antibody feedback mechanism studies where passively transferred antibody inhibits the B-cell response against particulate antigens because of epitope masking. In the absence of experimental data addressing the mechanism underlying inhibition by maternal antibodies, it has been suggested that epitope masking explains the inhibition by maternal antibodies, too. Here we report that in the cotton rat model of measles virus ( IntroductionMaternal antibodies of the immunoglobulin G (IgG) antibody class are transferred from mother to child and protect children against infectious diseases. Over time, passively transferred maternal antibody titers decline and are not protective any longer but interfere with successful vaccination. A well-documented example of this is measles vaccination. 1 Inoculation of seronegative children with a live-attenuated vaccine measles virus (MV) leads first to the development of antibodies specific for the nucleocapsid (MV-N) protein (which is released by infected cells) and subsequently to protective neutralizing antibodies specific for the hemagglutinin (MV-H) and fusion (MV-F) proteins. 2 Neutralizing antibodies recognize at least 15 nonoverlapping neutralizing epitopes on MV-H and 3 on MV-F. 3 Vaccination in the presence of maternal antibodies, however, does not lead to development of protective neutralizing antibodies, 4 whereas the T-cell response is readily detectable. [5][6][7][8][9][10] These findings indicate a specific inhibition of B-cell responses by maternal antibodies. In the absence of experimental data, inhibition of B cells has been postulated to be the result of physical blockage of epitopes by maternal antibodies (epitope masking 11 ). This model is based on antibody feedback mechanism studies. 11,12 In these studies, passive transfer of IgG suppresses the B-cell response against sheep red blood cells. Epitope masking leads to epitope-specific suppression at lower antibody concentrations, whereas at higher antibody concentrations also nonepitopespecific inhibition was observed and explained by steric hindrance. 13 A proposed alternate mechanism is based on the only inhibitory receptor of the IgG binding Fc receptor family, Fc␥-IIB receptor (Fc␥RIIB). On B cells, cross-linking of Fc␥RIIB to the B-cell receptor (BCR) through antigen/antibody complexes leads to inhibition of activation and antibody secretion. 12,[14][15][16] This mechanism was dismissed for the antibody feedback model because IgG is inhibitory in Fc-receptor knockout mice, 17 an IgG3 isotype antibody that in the mouse does not bind to Fc␥RIIB can be inhibitory, 18,19 and in some studies F(abЈ) 2 fragments can also inhibit B-cell responses. 17,20,21 In summary, these studies provide evidence for epitope masking as the main mechanism of inhibition of antibody responses in the antibody feedback model. Whether the...

Comparisons of the effect of naturally acquired maternal pertussis antibodies and antenatal vaccination induced maternal tetanus antibodies on infant's antibody secreting lymphocyte responses and circulating plasma antibody levels

“…Nevertheless, inhibition of B cell responses can also be mediated by binding Fc region of passive antibody-vaccine Ag complex to the B cell Fcg-receptor IIB, results in a stronger negative signal that inhibits both the proliferation 21 and the antibodies secretion of B cells. 20 In this study, we observed a 9-fold increase in plasma anti-TT-IgG at 1 wk after three doses of primary immunizations (at 1.5, 2.5 and 3.5 mo of age), while at 1 y of age, it was decreased by about 5-fold from the peak and had returned to the pre-vaccination level (Fig. 1A).…”

“…However, experimentally it has been shown that one antibody at a high concentration is less efficient in inhibiting active vaccination response than several antibodies at lower concentrations. 20 Presumably natural infection produced a more diverse array of antibodies than vaccines in the subclinical maternal pertussis infection as observed in our study. Nevertheless, inhibition of B cell responses can also be mediated by binding Fc region of passive antibody-vaccine Ag complex to the B cell Fcg-receptor IIB, results in a stronger negative signal that inhibits both the proliferation 21 and the antibodies secretion of B cells.…”

Maternal Antibodies: Clinical Significance, Mechanism of Interference with Immune Responses, and Possible Vaccination Strategies

“…Three facts argue against this hypothesis: maternal antibodies suppress not only replicating live-attenuated vaccines but also (non-replicating) protein vaccines; immunization with vector systems expressing measles virus proteins (which are not sensitive to neutralizing antibodies) are inhibited by maternal antibodies (134–136); and non-neutralizing antibodies block vaccination with a live-attenuated vaccine (114). …”

Sidestepping maternal antibody: a lesson from measles virus vaccination

“…This solution appears to be impossible to achieve in the presence of high levels of maternal antibody and an increase in vaccine dose would probably be harmful (as in the case of measles vaccination [8][9][10]). Using the cotton rat model of MV vaccination [16], we have now established that inhibition by maternal antibody is due to cross-linking of the B-cell receptor (BCR) and FcgIIB receptor by a measles virus-antibody (IgG) complex [17]. Thus, maternal antibodies trigger a regulatory mechanism of B-cell responses similar to that used by IgG antibodies after active immunization.…”

“…In an enzyme-linked immunosorbent spot assay, MV-specific IgM stimulates B cells to secrete antibody even in the presence of inhibitory IgG. After coimmunization of MV vaccine and a monoclonal IgM antibody specific for MV hemagglutinin in the presence of maternal antibodies, neutralizing antibodies were restored to approximately 20-40% of antibody levels after immunization in the absence of maternal antibodies [17]. Another approach has focused on the induction of a third signal because MV vaccine virus does not induce type I interferon secretion by dendritic cells in tissue culture, or in the bronchoalveolar lavage in cotton rats [18].…”