Immune Complex Vaccine Strategies to Combat HIV-1 and Other Infectious Diseases

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 have 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.

Broadly Neutralizing Antibody Epitopes on HIV-1 Particles are exposed after Virus Interaction with Host Cells

“…7, binding of all three V2i mAbs (697, 830A and 2158) presumably induced an allosteric effect that exposed the PG9 binding epitopes. This concurs with the published study showing that V2i 830A and 2158 increases the binding of PG9 mAb on A244 gp120 (98). However, 697 did not induce similar increased binding in case of A244 gp120 (98).…”

“…This concurs with the published study showing that V2i 830A and 2158 increases the binding of PG9 mAb on A244 gp120 (98). However, 697 did not induce similar increased binding in case of A244 gp120 (98). In contrast, the V3 mAbs, epitopes of which remain occluded on the functional Env on virions, did not alter PG9 binding and were comparable to the negative control mAb 3685.…”

“…Next, we explored the possibility if microsphere-virion coupling method had any adverse effect that may explain the inability to detect any binding to these epitopes. If that stands correct then binding of PG9 or V3 2219 mAb will remain low on virions even under conditions that are known to conformationally unmask these epitopes (97, 98). We tested this idea by pre-treating the virus with select mAbs followed by detecting the binding of V3 (2219) and V2q (PG9) mAbs.…”

“…The V3 loops are tucked beneath V1V2, thus Abs that induce any movement in the V1V2 loops such that they are displaced from their position should expose the V3 epitopes. We made the use of CD4bs mAbs: NIH45-46 that binds strongly to Env on virions, the non-neutralizing mAb 694 that is known to expose V3 loops, and the V2i mAb 830A (97, 98). Non-biotinylated 2219 and 3685 were used as controls.…”

Protein engineering strategies for rational immunogen design

“…The formation of immune complexes between antibodies and an antigen can mask epitopes; subsequent immunization with these immune complexes can sterically shield epitopes and thus bias antibody responses. This was shown for flavivirus, influenza, and HIV glycoproteins [75][76][77][78] . Recent refinement of this approach has both decreased the size of the shielding to a single chain variable fragment (scFv), or generated covalently stabilized complexes through chemical cross-linking or expression of an antigen-antibody genetic fusion [79][80][81] .…”