Abstract
Immunization with HIV AIDSVAX gp120 vaccines in the phase III VAX003 and VAX004 trials did not confer protection. To understand the shortcomings in antibody (Ab) responses induced by these vaccines, we evaluated the kinetics of Ab responses to the V1V2 and V3 regions of gp120 and the induction of Ab-mediated antiviral functions during the course of 7 vaccinations over a 30.5-month period. Plasma samples from VAX003 and VAX004 vaccinees and placebo recipients were measured for ELISA-binding Abs and for virus neutralization, Ab-dependent cellular phagocytosis (ADCP), and Ab-dependent cellular cytotoxicity (ADCC). Ab responses to V1V2 and V3 peaked after 3 to 4 immunizations and declined after 5 to 7 immunizations. The deteriorating responses were most evident against epitopes in the underside of the V1V2 β-barrel and in the V3 crown. Correspondingly, vaccinees demonstrated higher neutralization against SF162 pseudovirus sensitive to anti-V1V2 and anti-V3 Abs after 3 or 4 immunizations than after 7 immunizations. Higher levels of ADCP and ADCC were also observed at early or mid-time points as compared with the final time point. Hence, VAX003 and VAX004 vaccinees generated V1V2- and V3-binding Abs and functional Abs after 3 to 4 immunizations, but subsequent boosts did not maintain these responses.
Highlights
Development of a prophylactic HIV vaccine has faced tremendous challenges
Many VAX004 participants had declining anti-V3 Ab responses, but the decrease did not reach statistical significance. These results demonstrate that, while total Ab responses to gp[120] were stable in all vaccinees during the entire immunization period of the VAX003 and VAX004 trials, Ab responses to V1V2 and V3 decreased in some vaccine recipients after 5 or more vaccine doses
This study highlights a significant impediment in the induction of Ab response by VAX003 and VAX004 AIDSVAX gp[120] vaccines that was not appreciated previously
Summary
Development of a prophylactic HIV vaccine has faced tremendous challenges. For most currently licensed vaccines, antibodies (Abs) or Ab-mediated functions induced by vaccines are immune correlates and surrogates of protection[1]. While chronic HIV infection leads to production of high levels of both V3 ladle- and cradle-type Abs, VAX003 and VAX004 vaccine recipients generated only cradle-type Abs, and their levels 2 weeks after the final boost were considerably low[22]. These findings raise the question of how Ab responses to these different epitopes on V1V2 and V3 were stimulated during the immunization period and whether stronger responses were induced at earlier time points but declined with additional boosts. Virus neutralization, ADCP, and ADCC activities induced at early time points waned after the final immunization
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