New England Journal of Medicine
November 28, 2013  Vol. 369 No. 22
http://www.nejm.org/toc/nejm/medical-journal

Perspective
The Quest for an HIV-1 Vaccine — Moving Forward
Dan H. Barouch, M.D., Ph.D.
N Engl J Med 2013; 369:2073-2076November 28, 2013DOI: 10.1056/NEJMp131271

Excerpt
Vaccines have historically been the most effective biomedical interventions for controlling global infectious diseases. The development of a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) is therefore a critical research priority. Although other HIV-1 prevention efforts based on behavioral risk reduction, male circumcision, topical microbicides, preexposure prophylaxis, and treatment as prevention have had substantial effects on HIV-1 transmission rates, it is likely that a vaccine will be required to end the global HIV-1 epidemic.

The challenges in the development of a prophylactic HIV-1 vaccine, however, are unprecedented in the history of vaccinology. First, HIV-1 exhibits tremendous global genetic diversity as well as mutational capacity that can evade both humoral and cellular immune responses. The generation of vaccine antigens that will elicit immunologically relevant and broadly cross-reactive immune responses thus represents a major challenge. Second, HIV-1 rapidly integrates into the host genome and establishes a latent reservoir that cannot be eliminated by conventional antiretroviral drugs or virus-specific immune responses. A vaccine will therefore most likely need to induce potent and functional virus-specific antibodies that block establishment of initial infection, in addition to high levels of T lymphocytes for virologic control. Third, there are no known examples of spontaneous immune-mediated clearance of HIV-1 infection indicative of natural immunity, and thus the precise types of immune responses that need to be induced by a vaccine are not well understood. Fourth, although a series of broad and potent neutralizing monoclonal antibodies have recently been discovered, such antibodies are induced only in a subgroup of HIV-1–infected persons after several years of infection and typically exhibit extensive somatic hypermutation. No method currently exists to induce such antibodies by vaccination…

Original Article
Efficacy Trial of a DNA/rAd5 HIV-1 Preventive Vaccine
Scott M. Hammer, M.D., Magdalena E. Sobieszczyk, M.D., M.P.H., Holly Janes, Ph.D., Shelly T. Karuna, M.D., Mark J. Mulligan, M.D., Doug Grove, M.S., Beryl A. Koblin, Ph.D., Susan P. Buchbinder, M.D., Michael C. Keefer, M.D., Georgia D. Tomaras, Ph.D., Nicole Frahm, Ph.D., John Hural, Ph.D., Chuka Anude, M.D., Ph.D., Barney S. Graham, M.D., Ph.D., Mary E. Enama, M.A., P.A.-C., Elizabeth Adams, M.D., Edwin DeJesus, M.D., Richard M. Novak, M.D., Ian Frank, M.D., Carter Bentley, Ph.D., Shelly Ramirez, M.A., Rong Fu, M.S., Richard A. Koup, M.D., John R. Mascola, M.D., Gary J. Nabel, M.D., Ph.D., David C. Montefiori, Ph.D., James Kublin, M.D., M.P.H., M. Juliana McElrath, M.D., Ph.D., Lawrence Corey, M.D., and Peter B. Gilbert, Ph.D. for the HVTN 505 Study Team
N Engl J Med 2013; 369:2083-2092November 28, 2013DOI: 10.1056/NEJMoa1310566
http://www.nejm.org/doi/full/10.1056/NEJMoa1310566

Abstract
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.)