Background
A safe and effective vaccine for the prevention of human immunodeficiency virus type 1 (HIV-1) infection is a global priority. We tested the efficacy of a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine regimen in persons at increased risk for HIV-1 infection in the United States.
Methods
At 21 sites, we randomly assigned 2504 men or transgender women who have sex with men to receive the DNA/rAd5 vaccine (1253 participants) or placebo (1251 participants). We assessed HIV-1 acquisition from week 28 through month 24 (termed week 28+ infection), viral-load set point (mean plasma HIV-1 RNA level 10 to 20 weeks after diagnosis), and safety. The 6-plasmid DNA vaccine (expressing clade B Gag, Pol, and Nef and Env proteins from clades A, B, and C) was administered at weeks 0, 4, and 8. The rAd5 vector boost (expressing clade B Gag-Pol fusion protein and Env glycoproteins from clades A, B, and C) was administered at week 24.
Results
In April 2013, the data and safety monitoring board recommended halting vaccinations for lack of efficacy. The primary analysis showed that week 28+ infection had been diagnosed in 27 participants in the vaccine group and 21 in the placebo group (vaccine efficacy, −25.0%; 95% confidence interval, −121.2 to 29.3; P = 0.44), with mean viral-load set points of 4.46 and 4.47 HIV-1 RNA log10 copies per milliliter, respectively. Analysis of all infections during the study period (41 in the vaccine group and 31 in the placebo group) also showed lack of vaccine efficacy (P = 0.28). The vaccine regimen had an acceptable side-effect profile.
Conclusions
The DNA/rAd5 vaccine regimen did not reduce either the rate of HIV-1 acquisition or the viral-load set point in the population studied. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00865566.)
A HIV-1 DNA prime-recombinant Adenovirus Type 5 (rAd5) boost vaccine
failed to protect from HIV-1 acquisition. We studied the nature of the
vaccine-induced antibody (Ab) response to HIV-1 envelope (Env). HIV-1-reactive
plasma Ab titers were higher to Env gp41 than gp120, and repertoire analysis
demonstrated that 93% of HIV-1-reactive Abs from memory B cells was to
Env gp41. Vaccine-induced gp41-reactive monoclonal antibodies (mAbs) were
non-neutralizing, and frequently polyreactive with host and environmental
antigens including intestinal microbiota (IM). Next generation sequencing of an
IGHV repertoire prior to vaccination revealed an Env-IM cross-reactive Ab that
was clonally-related to a subsequent vaccine-induced gp41-reactive Ab. Thus,
HIV-1 Env DNA-rAd5 vaccine induced a dominant IM-polyreactive, non-neutralizing
gp41-reactive Ab repertoire response that was associated with no vaccine
efficacy.
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