The Effects of Pre-Existing Antibodies on Live-Attenuated Viral Vaccines

Abstract

Live-attenuated vaccines (LAVs) have achieved remarkable successes in controlling virus spread, as well as for other applications such as cancer immunotherapy. However, with rapid increases in international travel, globalization, geographic spread of viral vectors, and widespread use of vaccines, there is an increasing need to consider how pre-exposure to viruses which share similar antigenic regions can impact vaccine efficacy. Pre-existing antibodies, derived from either from maternal-fetal transmission, or by previous infection or vaccination, have been demonstrated to interfere with vaccine immunogenicity of measles, adenovirus, and influenza LAVs. Immune interference of LAVs can be caused by the formation of virus-antibody complexes that neutralize virus infection in antigen-presenting cells, or by the cross-linking of the B-cell receptor with the inhibitory receptor, FcgRIIB. On the other hand, pre-existing antibodies can augment flaviviral LAV efficacy such as that of dengue and yellow fever virus, especially when pre-existing antibodies are present at sub-neutralizing levels. The increased vaccine immunogenicity can be facilitated by antibody-dependent enhancement of virus infection, enhancing virus uptake in antigen-presenting cells, and robust induction of innate immune responses that promote vaccine immunogenicity. This review examines the literature on this topic and examines the circumstances where pre-existing antibodies can inhibit or enhance LAV efficacy. A better knowledge of the underlying mechanisms involved could allow us to better manage immunization in seropositive individuals and even identify possibilities that could allow us to exploit pre-existing antibodies to boost vaccine-induced responses for improved vaccine efficacy.

Keywords: antibody-dependent enhancement; live-attenuated vaccine; pre-existing antibodies; vaccine immune interference; vaccine immunogenicity.

Figure 1

Mechanisms by which pre-existing antibodies neutralize LAVs. Antibodies can prevent attachment and entry of the virus, either via steric hindrance or by altering the conformation of the viral protein that binds the receptor. However, antibody binding to activating FcγRs may still allow virus–antibody complex internalization via FcγR-mediated uptake, indicating that antibodies that prevent viral fusion and uncoating could be critical to ensure complete virus neutralization. High levels of antibodies can also lead to the formation of aggregates which inhibit viral entry.

Figure 2

Effects of antibody binding on B-cell activation. (a) Formation of viral immune complexes may result in cross-linking and activation of the inhibitory FcγRIIB, which in turn inhibits downstream BCR signaling. (b) Antibody binding may prevent the exposure of epitopes normally recognized by B-cells in a phenomenon known as “epitope masking”, thereby preventing B-cell activation.

Figure 3

Pre-existing antibodies can improve vaccine immunogenicity by promoting virus infection and inducing innate and adaptive immune responses. Immune complexes formed by pre-existing antibodies and viruses can engage FcγRs, resulting in increased viral uptake and fusion through the process of antibody-dependent enhancement that leads to increased vaccine viremia and antigen presentation. Activating FcγR-signaling, on the other hand, provokes greater innate immune responses and production of pro-inflammatory metabolites that can enhance innate and adaptive immune responses. In addition, the cross-linking of FcγRs causes increased expression of immune semaphorins, which are critical for antigen-presenting cell and T-cell interaction. Overall, this leads to increased T-cell proliferation and activation, which consequently improves LAV immunogenicity.

Figure 4

The impact of pre-existing antibody levels on live-attenuated vaccine immunogenicity. In the presence of high levels of pre-existing antibodies or with potently neutralizing antibodies, LAV immunogenicity is hindered due to immune interference from virus neutralization or inhibition of B-cell responses. However, at sub-neutralizing antibody titers, there is a window of augmented vaccine immunogenicity due to increased uptake into Fc receptor-bearing cells and greater induction of innate immune responses. The horizontal dotted line indicates LAV immunogenicity in the absence of pre-existing antibodies.