Abstract
Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding has been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens.
Highlights
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There are five major antibody isotypes, IgM, IgG, IgA, IgD, and IgE, which are classified based on their unique Fc fragments and each of which interacts with distinct Fc receptors (FcRs)
Summary
Given the capacity of ICs for enhancing antigen uptake, MHC presentation, and APC maturation, ICs have been investigated and developed as vaccine immunogens in order to improve the immunogenicity and efficacy of vaccines against several human and animal pathogens. YIC immunization decreased IL-17A expression in patients throughout the study, indicating the lowered therapeutic efficacy of twelve YIC doses, compared to six, attributed to immune fatigue [27] This phase III trial demonstrated that merely increasing the dosage of YIC could not enhance its therapeutic efficacy and that further investigations would be needed to improve the YIC immunogenicity, especially in terms of induction of effective cell-mediated immune responses. Bursaplex IC vaccine protected 100% of animals from clinical symptoms and mortality after IBDV challenge; still resulted in bursal atrophy and bursal lesions Both neutralizing and lysis-mediating antibodies elicited against respective glycoproteins, along with priming of EHV-1-specific local and systemic T cell proliferative responses 35% reduction of virus load in turbinates of mice immunized with glycoprotein D, but not of mice immunized with glycoprotein C. Immunomodulatory benefits of IC vaccine attributed to FcR targeting on mucosal [35]
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