Phase 1 Safety and Immunogenicity Evaluation of a Multiclade HIV‐1 Candidate Vaccine Delivered by a Replication‐Defective Recombinant Adenovirus Vector

Andrew T. Catanzaro 2 3 Richard A. Koup 2 3 Mario Roederer 2 3 Robert T. Bailer 2 3 Mary E. Enama 2 3 Zoe Moodie 0 2 Lin Gu 0 2 Julie E. Martin 2 3 Laura Novik 2 3 Bimal K. Chakrabarti 2 3 Bryan T. Butman 1 2 Jason G. D. Gall 1 2 C. Richter King 1 2 Charla A. Andrews 2 3 Rebecca Sheets 2 3 Phillip L. Gomez 2 3 John R. Mascola 2 3 Gary J. Nabel 2 3 Barney S. Graham () 2 3 the Vaccine Research Center 2 Study Team 2 4 0 Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center , Seattle, Washington 1 GenVec, Inc., Gaithersburg, Maryland 2 Received 5 April 2006; accepted 28 June 2006; electronically published 8 November 2006. Potential conflicts of interest: G.J.N. and B.K.C. are named on patent applications for this vaccine concept. B.T.B., J.G.D.G., and C.R.K. are employees of GenVec, Inc. All other authors report no conflicts of interest. Financial support: National Institute of Allergy and Infectious Diseases in- tramural research program. Clinicaltrials.gov registry number: NCT00083330 3 Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health , Bethesda 4 Study group members are listed after the text. NIAID, NIH, 40 Convent Dr., MSC-3017, Bldg. 40, Rm. 2502, Bethesda, MD 20892- 3017 (See the editorial commentary by Robinson and Weinhold and the article by Graham et al., on pages 1625-7 and 1650-60, respectively.) Background. The development of an effective human immunodeficiency virus (HIV) vaccine is a high global priority. Here, we report the safety, tolerability, and immunogenicity of a replication-defective recombinant adenovirus serotype 5 (rAd5) vector HIV-1 candidate vaccine. Methods. The vaccine is a mixture of 4 rAd5 vectors that express HIV-1 subtype B Gag-Pol fusion protein and envelope (Env) from subtypes A, B, and C. Healthy, uninfected adults were randomized to receive 1 intramuscular injection of placebo (n p 6) or vaccine at dose levels of 109 (n p 10), 1010 (n p 10), or 1011 (n p 10) particle units and were followed for 24 weeks to assess immunogenicity and safety. Results. The vaccine was well tolerated but was associated with more reactogenicity at the highest dose. At week 4, vaccine antigen-specific T cell responses were detected in 28 (93.3%) and 18 (60%) of 30 vaccine recipients for CD4+ and CD8+ T cells, respectively, by intracellular cytokine staining assay and in 22 (73%) of 30 vaccine recipients by enzyme-linked immunospot assay. Env-specific antibody responses were detected in 15 (50%) of 30 vaccine recipients by enzyme-linked immunosorbant assay and in 28 (93.3%) of 30 vaccine recipients by immunoprecipitation followed by Western blotting. No neutralizing antibody was detected. Conclusions. A single injection induced HIV-1 antigen-specific CD4+ T cell, CD8+ T cell, and antibody responses in the majority of vaccine recipients. This multiclade rAd5 HIV-1 vaccine is now being evaluated in combination with a multiclade HIV-1 DNA plasmid vaccine. - More than 40 million people are living with HIV/AIDS. Three million deaths occur annually because of HIV/ AIDS, with 5 million new infections occurring in 2005 [1]. Development of an effective vaccine would be an important intervention to help control the expanding global pandemic. Adenovirus serotype 5 (Ad5) has been developed as a replication-defective recombinant vector (rAd5) to deliver intracellular genes via a number of routes [2]. Vaccination with rAd5 results in transient intracellular gene expression followed by rapid clearance [3]. Cellular and humoral immune responses have been induced in preclinical studies of rAd5 vaccines for HIV1, simian immunodeficiency virus (SIV), and simianhuman immunodeficiency virus (SHIV) [47]. This approach builds on previous successes with other infectious disease models, particularly for Ebola virus, against which nonhuman primates have been protected from lethal challenge [8, 9]. Recently, immunization of chimpanzees with rAd expressing hepatitis C virus (HCV) nonstructural genes resulted in T cellmediated protection against heterologous HCV challenge [10]. These preclinical studies support the concept that gene-based vaccination can induce effective immunity against viral infections in primates. The development of an HIV vaccine that is effective against multiple circulating viral clades remains a scientific priority and urgent public health need [11]. The rAd5 vaccine evaluated in the present clinical trial was designed to express an HIV-1 clade B Gag-Pol fusion protein and Env glycoproteins from HIV-1 clades A, B, and C. Here, we report the findings from the first phase 1 clinical trial of this multigene, multiclade rAd5 HIV1 candidate vaccine. SUBJECTS, MATERIALS, AND METHODS Study design. Vaccine Research Center (VRC) 006 (National Institutes of Health [NIH] 04-I-0172) was a randomized, double-blinded, placebo-controlled phase 1 trial conducted at the NIH Clinical Center (Bethesda, MD) by the VRC (National Institute of Allergy and Infectious Diseases [NIAID], NIH, Department of Health and Human Services). Enrollment began 19 July 2004, and unblinding occurred on 27 May 2005. Eligibility criteria required that volunteers be HIV uninfected, 18 44 years old, amenable to risk-reduction counseling, and in good general health as determined by medical history, physical examination, and laboratory tests. Thirty-six volunteers were enrolled into 3 dose groups of 12 study subjects and were randomized to receive vaccine or placebo at a 5:1 ratio. Vaccine doses of 109, 1010, and 1011 particle units (PUs; n p 10 subjects/ group) and injection of the final formulation buffer as placebo Table 1. Subject demographics. Category, parameter Female Vaccine recipients (n p 30) All subjects (n p 36) 20 (55.6) 16 (44.4) NOTE. Data are no. (%) of subjects, unless otherwise indicated. (n p 6 subjects) were evaluated. A 1-mL intramuscular (deltoid) injection was administered on the day of enrollment. The NIAID Data Safety and Monitoring Board completed a safety review before each dose escalation. Safety evaluations included physical examination and monitoring of laboratory parameters. Local (pain, swelling, or redness) and systemic (fever, malaise, myalgia, headache, chills, or nausea) reactogenicity symptoms after vaccination were recorded on a 5-day diary card. Adverse events were graded for severity by use of a preapproved table that incorporated a 5-point scale and were coded by use of Medical Dictionary for Regulatory Activities terminology. To address a theoretical concern about the interaction of rAd5 with a naturally acquired adenovirus, subjects experiencing upper respiratory tract infection, urinary tract infection, gastroenteritis, or conjunctivitis within 4 weeks of the study injection had a specimen collected for adenoviral cultures. Specimens were cultured for 5 days via shell vial on a human lung epithelial cell line monolayer (Diagnostic Hybrid) and were scre (...truncated)