Abstract
Analysis of breakthrough HIV-1 infections could elucidate whether prior vaccination primes relevant immune responses. Here, we measured HIV-specific antibody responses in 14 South African volunteers who acquired HIV infection after participating in phase 1/2 trials of envelope-containing immunogens. Serum samples were collected annually following HIV-1 infection from participants in trials HVTN 073 (subtype C, DNA/MVA, phase 1 trial, n = 1), HVTN 086 (subtype C, DNA/MVA/gp140 protein, phase 1 trial, n = 2), and HVTN 204 (multisubtype, DNA/adenovirus serotype 5 [Ad5], phase 2 trial, n = 7) and 4 placebo recipients. Binding and neutralizing antibody responses to Env proteins and peptides were determined pre- and post-HIV infection using an enzyme-linked immunosorbent assay and the TZM-bl cell neutralization assay, respectively. HIV-infected South African individuals served as unvaccinated controls. Binding antibodies to gp41, V3, V2, the membrane-proximal external region (MPER), and the CD4 binding site were detected from the first year of HIV-1 subtype C infection, and the levels were similar in vaccinated and placebo recipients. Neutralizing antibody responses against tier 1A viruses were detected in all participants, with the highest titers being to a subtype C virus, MW965.26. No responses were observed just prior to infection, indicating that vaccine-primed HIV-specific antibodies had waned. Sporadic neutralization activity against tier 2 isolates was observed after 2 to 3 years of HIV infection, but these responses were similar in the vaccinated and placebo groups as well as the unvaccinated controls. Our data suggest that prior vaccination with these immunogens did not alter the antibody responses to HIV-1 infection, nor did it accelerate the development of HIV neutralization breadth.IMPORTANCE There is a wealth of information on HIV-specific vaccine-induced immune responses among HIV-uninfected participants; however, data on immune responses among participants who acquire HIV after vaccination are limited. Here we show that HIV-specific binding antibody responses in individuals with breakthrough HIV infections were not affected by prior vaccination with HIV envelope-containing immunogens. We also found that these vectored vaccines did not prime tier 2 virus-neutralizing antibody responses, which are thought to be required for prevention against HIV acquisition, or accelerate the development of neutralization breadth. Although this study is limited, such studies can provide insights into whether vaccine-elicited antibody responses are boosted by HIV infection to acquire broader neutralizing activity, which may help to identify antigens relevant to the design of more effective vaccines.
Highlights
Analysis of breakthrough HIV-1 infections could elucidate whether prior vaccination primes relevant immune responses
We found that these vectored vaccines did not prime tier 2 virusneutralizing antibody responses, which are thought to be required for prevention against HIV acquisition, or accelerate the development of neutralization breadth
South African volunteers in phase 1/2 HIV vaccine trials of prime-boost regimens who became HIV infected either during or following the trial were recruited into the HVTN 404 trial (Table 1)
Summary
Analysis of breakthrough HIV-1 infections could elucidate whether prior vaccination primes relevant immune responses. Monomeric gp120 envelope (Env) proteins, aimed at inducing antibody responses, were first tested in the VAX003 and VAX004 trials but elicited neutralizing antibodies only against tier 1A viruses (which are the easiest to neutralize) [2] These vaccines did not induce broadly neutralizing antibodies (bNAbs) and failed to reduce HIV acquisition or impact the set-point viral load [3,4,5]. To further stimulate T-cell breadth, adenovirus serotype 5 (Ad5) was primed with DNA containing multisubtype HIV envelope genes and tested in the HVTN 505 trial (this vaccine was tested in the HVTN 204 trial) While this vaccine induced binding antibodies to gp and HIV gp120, CD4ϩ T-cell responses to HIV-1 Env, and tier 1A virus-neutralizing antibodies, it, too, failed to provide protection against HIV infection [10, 11]
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