Abstract
BackgroundIndividuals without prior immunity to a vaccine vector may be more sensitive to reactions following injection, but may also show optimal immune responses to vaccine antigens. To assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, we evaluated a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins, VRC-HIVADV014-00-VP, in a randomized, double-blind, dose-escalation, multicenter trial (HVTN study 054) in HIV-1-seronegative participants without detectable neutralizing antibodies (nAb) to the vector. As secondary outcomes, we also assessed T-cell and antibody responses.Methodology/Principal FindingsVolunteers received one dose of vaccine at either 1010 or 1011 adenovector particle units, or placebo. T-cell responses were measured against pools of global potential T-cell epitope peptides. HIV-1 binding and neutralizing antibodies were assessed. Systemic reactogenicity was greater at the higher dose, but the vaccine was well tolerated at both doses. Although no HIV infections occurred, commercial diagnostic assays were positive in 87% of vaccinees one year after vaccination. More than 85% of vaccinees developed HIV-1-specific T-cell responses detected by IFN-γ ELISpot and ICS assays at day 28. T-cell responses were: CD8-biased; evenly distributed across the three HIV-1 antigens; not substantially increased at the higher dose; and detected at similar frequencies one year following injection. The vaccine induced binding antibodies against at least one HIV-1 Env antigen in all recipients.Conclusions/SignificanceThis vaccine appeared safe and was highly immunogenic following a single dose in human volunteers without prior nAb against the vector.Trial RegistrationClinicalTrials.gov NCT00119873
Highlights
2.7 million persons become infected with the human immunodeficiency virus (HIV-1) each year [1]
The National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Research Center’s recombinant adenovirus 5 HIV-1 vaccine VRC-HIVADV014-00-VP was previously tested in a dose-escalation clinical trial that found local and systemic signs and symptoms increase in frequency and severity with increasing vaccine doses up to 1011 particle units (PU), but found no reactions of greater than moderate severity
The analysis was by intention to treat, modified to exclude individuals who entered in the randomization process but did not proceed with study enrollment; five such individuals were not included in the analysis
Summary
2.7 million persons become infected with the human immunodeficiency virus (HIV-1) each year [1]. In non-human primate models, gene-based immunization with viral vectors, alone or in combination with DNA plasmid vaccines, have protected against infection or disease progression following challenge with immunodeficiency retroviruses; such protection is associated with the induction of immunodeficiency virus-specific T-lymphocyte responses [3,4, 5,6,7], CD8+ T-cell responses. To assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, we evaluated a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins, VRC-HIVADV014-00-VP, in a randomized, double-blind, dose-escalation, multicenter trial (HVTN study 054) in HIV-1-seronegative participants without detectable neutralizing antibodies (nAb) to the vector.
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