Abstract
A key aspect to finding an efficacious human immunodeficiency virus (HIV) vaccine is the optimization of vaccine schedules that can mediate the efficient maturation of protective immune responses. In the present study, we investigated the effect of alternate booster regimens on the immune responses to a candidate HIV-1 clade C CN54gp140 envelope protein, which was coadministered with the TLR4-agonist glucopyranosyl lipid A-aqueous formulation. Twelve study participants received a common three-dose intramuscular priming series followed by a final booster at either 6 or 12 months. The two homologous prime-boost regimens were well tolerated and induced CN54gp140-specific responses that were observed in both the systemic and mucosal compartments. Levels of vaccine-induced IgG-subclass antibodies correlated significantly with FcγR engagement, and both vaccine regimens were associated with strikingly similar patterns in antibody titer and FcγR-binding profiles. In both groups, identical changes in the antigen (Ag)-specific IgG-subclass fingerprint, leading to a decrease in IgG1 and an increase in IgG4 levels, were modulated by booster injections. Here, the dissection of immune profiles further supports the notion that prime-boost strategies are essential for the induction of diverse Ag-specific HIV-1 responses. The results reported here clearly demonstrate that identical responses were effectively and safely induced by both vaccine regimens, indicating that an accelerated 6-month regimen could be employed for the rapid induction of immune responses against CN54gp140 with no apparent impact on the overall quality of the induced immune response. (This study has been registered at http://ClinicalTrials.gov under registration no. NCT01966900.)
Highlights
The human immunodeficiency virus (HIV) continues to infect nearly two million people every year with one million AIDSrelated deaths occurring annually [1]
IgG antibodies against the variable regions 1 and 2 (V1–V2) of HIV-1 envelope proteins correlated with a decreased risk of HIV acquisition [7] and post hoc analysis of RV144 estimated efficacy at 6 months after vaccination to be 60.5%, indicating an early protective vaccine effect that declines over time [8]
The empirical process of optimizing IM schedules is likely key to the development of an efficacious HIV vaccine, where the interval between sequential IMs can prove critical in shaping the maturation of the induced adaptive immune response [42]
Summary
The human immunodeficiency virus (HIV) continues to infect nearly two million people every year with one million AIDSrelated deaths occurring annually [1]. Two phase III trials (VAX 004/003), using monomeric AIDSVAX clade B/E gp120 proteins as immunogens, failed to show efficacy in reducing HIV acquisition [4, 5], despite induction of high antibody binding titers following an autologous prime-boost regime. IgG antibodies against the variable regions 1 and 2 (V1–V2) of HIV-1 envelope proteins correlated with a decreased risk of HIV acquisition [7] and post hoc analysis of RV144 estimated efficacy at 6 months after vaccination to be 60.5%, indicating an early protective vaccine effect that declines over time [8]. An immunecorrelates analysis of the RV144 trial identified that vaccineinduced Env V1–V2 IgG3 levels correlated with a decreased risk of HIV-1 infection and declined in line with the observed vaccine efficacy [10]. The extended hinge region equips IgG3 with a high degree of conformational flexibility, suggesting an improved potential for penetrating the protective HIV glycan shield, which could be crucial for preventing HIV immune evasion
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