Adenovectors encoding RSV-F protein induce durable and mucosal immunity in macaques after two intramuscular administrations.

Respiratory Syncytial Virus (RSV) can cause severe respiratory disease, yet a licensed vaccine is not available. We determined the immunogenicity of two homologous and one heterologous intramuscular prime-boost vaccination regimens using replication-incompetent adenoviral vectors of human serotype 26 and 35 (Ad26 and Ad35), expressing a prototype antigen based on the wild-type fusion (F) protein of RSV strain A2 in adult, RSV-naive cynomolgus macaques. All regimens induced substantial, boostable antibody responses that recognized the F protein in pre- and postfusion conformation, neutralized multiple strains of RSV, and persisted for at least 80 weeks. Vaccination induced durable systemic RSV-F-specific T-cell responses characterized mainly by CD4+ T cells expressing Th1-type cytokines, as well as RSV-F-specific CD4+ and CD8+ T cells, IgG, and IgA in the respiratory tract. Intramuscular immunization with Ad26 and 35 vectors thus is a promising approach for the development of an optimized RSV vaccine expected to induce long-lasting humoral and cellular immune responses that distribute systemically and to mucosal sites.

Efficient entry inhibition of human and nonhuman primate immunodeficiency virus by cell surface-expressed gp41-derived peptides.

Membrane-anchored C-peptides (for example, maC46) derived from human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41 effectively inhibit HIV-1 entry in cell lines and primary human CD4+ cells in vitro. Here we evaluated this gene therapy approach in animal models of AIDS. We adapted the HIV gp41-derived maC46 vector construct for use in rhesus monkeys. Simian immunodeficiency virus (SIV and SHIV) sequence-adapted maC46 peptides, and the original HIV-1-derived maC46 expressed on the surface of established cell lines blocked entry of HIV-1, SIVmac251 and SHIV89.6P. Furthermore, primary rhesus monkey CD4+ T cells expressing HIV sequence-based maC46 peptides were also protected from SIV entry. Depletion of CD8+ T cells from PBMCs enhanced the yield of maC46-transduced CD4+ T cells. Supplementation with interleukin-2 (IL-2) increased transduction efficiency, whereas IL-7 and/or IL-15 provided no additional benefit. Phenotypic analysis showed that maC46-transduced and expanded cells were predominantly central memory CD4+ T cells that expressed low levels of CCR5 and slightly elevated levels of CD62L, beta7-integrin and CXCR4. These findings show that maC46-based cell surface-expressed peptides can efficiently inhibit primate immunodeficiency virus infection, and therefore serve as the basis for evaluation of this gene therapy approach in an animal model for AIDS.