Abstract
BackgroundThe Step trial raised the possibility that uncircumcised men with pre-existing Ad5 neutralizing antibodies carried an increased risk of HIV infection after vaccination. Thus, understanding Ad seropositivity in humans is important to the development of an AIDS vaccine. Here, we analyze the impact of different Ad5-specific neutralizing antibodies on immune function and clinical outcome.Methods and FindingsAd seropositivity in the Step trial volunteers was analyzed using chimeric rAd5/35 vectors to characterize their specificity for Ad5 fiber and non-fiber external (capsid) proteins. Immune responses and HIV seropositivity were correlated with the specificity of Ad5-neutralizing antibodies. Neutralizing antibodies induced by the vaccine in Ad5 seronegative subjects were directed preferentially to Ad5 capsid proteins, although some fiber-neutralizing antibodies could be detected. Pre-vaccination Ad5 serostatus did not affect the capsid-directed response after three vaccinations. In contrast, anti-fiber antibody titers were significantly higher in volunteers who were Ad5 seropositive prior to vaccination. Those Ad5 seropositive subjects who generated anti-capsid responses showed a marked reduction in vaccine-induced CD8 responses. Unexpectedly, anti-vector immunity differed qualitatively in Ad5 seropositive participants who became HIV-1 infected compared to uninfected case controls; Ad5 seropositive participants who later acquired HIV had lower neutralizing antibodies to capsid. Moreover, Ad35 seropositivity was decreased in HIV-infected subjects compared with uninfected case controls, while seroprevalence for other serotypes including Ad14, Ad28 and Ad41 was similar in both groups.ConclusionsTogether, these findings suggest that the case subjects were less immunologically responsive prior to infection. Subjects infected during the Step trial had qualitative differences in immunity that increased their risk of HIV-1 infection independent of vaccination.
Highlights
The Step study was a phase IIB clinical trial designed to test a recombinant adenovirus 5 based HIV vaccine in 3000 participants who were seronegative or seropositive for pre-existing Ad5 neutralizing antibodies
Subjects infected during the Step trial had qualitative differences in immunity that increased their risk of HIV-1 infection independent of vaccination
Analysis of sera from participants in the HVTN 204 trial has shown that the distribution of individual capsid-specific neutralizing antibodies varies among these sera, and the pre-existing fiber-specific neutralizing antibodies correlated with both a reduced response rate and the magnitude of anti-Gag T-cell responses induced by DNA prime and recombinant adenovirus 5 (rAd5) boost HIV vaccines [5]
Summary
The Step study was a phase IIB clinical trial designed to test a recombinant adenovirus 5 (rAd5) based HIV vaccine in 3000 participants who were seronegative or seropositive for pre-existing Ad5 neutralizing antibodies. RAd5 F35 vectors were used to detect neutralizing antibodies to Ad5 capsid and rAd35 F5 vectors were used to detect anti-Ad5 fiber neutralizing antibodies The properties of these reporter vectors reflect those found on the native Ad serotypes and can be used to detect the specificity and function of the respective viral components and analyze anti-Ad immunity in humans [5]. Analysis of sera from participants in the HVTN 204 trial has shown that the distribution of individual capsid-specific neutralizing antibodies varies among these sera, and the pre-existing fiber-specific neutralizing antibodies correlated with both a reduced response rate and the magnitude of anti-Gag T-cell responses induced by DNA prime and rAd5 boost HIV vaccines [5]. We analyze the impact of different Ad5-specific neutralizing antibodies on immune function and clinical outcome
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