Balance of cellular and humoral immunity determines the level of protection by HIV vaccines in rhesus macaque models of HIV infection

Abstract

A guiding principle for HIV vaccine design has been that cellular and humoral immunity work together to provide the strongest degree of efficacy. However, three efficacy trials of Ad5-vectored HIV vaccines showed no protection. Transmission was increased in two of the trials, suggesting that this vaccine strategy elicited CD4+ T-cell responses that provide more targets for infection, attenuating protection or increasing transmission. The degree to which this problem extends to other HIV vaccine candidates is not known. Here, we show that a gp120-CD4 chimeric subunit protein vaccine (full-length single chain) elicits heterologous protection against simian-human immunodeficiency virus (SHIV) or simian immunodeficiency virus (SIV) acquisition in three independent rhesus macaque repeated low-dose rectal challenge studies with SHIV162P3 or SIVmac251. Protection against acquisition was observed with multiple formulations and challenges. In each study, protection correlated with antibody-dependent cellular cytotoxicity specific for CD4-induced epitopes, provided that the concurrent antivaccine T-cell responses were minimal. Protection was lost in instances when T-cell responses were high or when the requisite antibody titers had declined. Our studies suggest that balance between a protective antibody response and antigen-specific T-cell activation is the critical element to vaccine-mediated protection against HIV. Achieving and sustaining such a balance, while enhancing antibody durability, is the major challenge for HIV vaccine development, regardless of the immunogen or vaccine formulation.

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

“…Again, the similarities in Gag-specific CD4 + T cell responses of mice and human vaccinees suggest that the ISH approach may be applicable to humans, as well. Whether this approach can be extended to Th cells with non-HIV specificities needs to be explored, but the idea to avoid possibly detrimental HIV-1-specific CD4 + T cell responses is appealing (58)(59)(60)(61).…”

Breakthrough of SIV strain smE660 challenge in SIV strain mac239-vaccinated rhesus macaques despite potent autologous neutralizing antibody responses

“…Thus, it is important to consider that vaccination itself may alter the mucosal environment such that transmission is favored over protection (31,36,37). This could result from the generation and homing of vaccine-elicited CD4+ T cells to the portal of entry, which in turn mitigates the beneficial effects of the vaccine-elicited humoral immune response (38-40).…”

Antibody functional assays as measures of Fc receptor-mediated immunity to HIV - new technologies and their impact on the HIV vaccine field.

“…In these studies the CD4i specific Abs elicited are clearly protective (e.g. [41,42]). Furthermore, a recent microscopy study showed fluorescently labelled virions bound to the target cell surface displayed Env epitopes, including CD4i and CD4 binding site epitopes, although this reactivity was lost as entry progressed.…”

“…In what is a presumably more physiological repeated low dose challenge of animals vaccinated across varied FLSC/adjuvant regimens, protection from acquisition was correlated with CD4i antibody and ADCC activity, but only in individuals with low CD4 T cell responses. The negative impact of T cell activation, reminiscent of human vaccine studies [40], confounded otherwise protective levels of ADCC antibodies [41].…”