Antibody persistence and T-cell balance: two key factors confronting HIV vaccine development

Abstract

The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibody-mediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4(+) T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Env-based AIDS vaccines regardless of the mechanism of antibody-mediated protection.

Keywords: AIDS; HIV; T cell; antibody persistence; vaccine.

Fig. 1.

Dynamics of a persistent antibody response. The stylized dynamics of persistent antibody responses elicited by vaccination with the licensed vaccines in Table 2 are illustrated (adapted from figure 3 in ref. 56). Three zones of increasing antibody persistence characterized by three decay constants, α, β, and γ, are shown, along with the relative frequencies (in arbitrary units) of the short-lived plasmablasts (PB), short-lived plasma cells (PC_S), and long-lived plasma cells (PC_L) responsible for circulating antibody titers over time.

Fig. 2.

Temporal decay of protection and antibody responses in the RV144 trial on two time scales: months (A) and years (B). In A, the decay of vaccine efficacy (black line), anti-V1/V2 seropositivity (red line), and anti-gp120 (blue line) are depicted. The protection data are from a study by Robb et al. (30), and the seropositivity data are from a study by Yates et al. (26). In B, the same data are plotted on a time scale more representative of durable antibody responses elicited by the licensed vaccines in Table 2. The green line represents data for the persistence of anti-HPV antibody titers modeled by a modified power law in a study by David et al. (60). The data in A and B were plotted from tables in the study by Yates et al. (26) or digitized from the original publications (23, 30, 60) using the commercially available software DigitizeIt (www.digitizeit.de). Accordingly, the digitized data should be viewed as approximate, but this procedure should not affect the conclusions drawn from their analysis in this report.