Lessons from IAVI-006, a Phase I clinical trial to evaluate the safety and immunogenicity of the pTHr.HIVA DNA and MVA.HIVA vaccines in a prime-boost strategy to induce HIV-1 specific T-cell responses in healthy volunteers

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

“…The cultured IFN-g ELISPOT assay detected five times more vaccine-induced responses in study participants as compared with the classical ELISPOT. 51,52 The proliferation assay used in our study and the cultured IFN-g ELISPOT assay used to evaluate the IAVI-006 trial have, in common, several days of incubation in the presence of antigen, suggesting that an expansion step may be required to reveal specific responses otherwise undetectable. The polychromatic CFSE-based proliferation assay simultaneously assessing functional markers and proliferative capacity represents, therefore, an innovative and sensitive immunoassay, well suited to reveal concealed effects of immunological interventions that are undetectable using simple IFN-gbased ICS as in the original study 4 or complex polychromatic ICS without prolonged stimulation periods.…”

Deletion of the Vaccinia Virus N2L Gene Encoding an Inhibitor of IRF3 Improves the Immunogenicity of Modified Vaccinia Virus Ankara Expressing HIV-1 Antigens

“…Numerous MVA vectors expressing different HIV-1 antigens have been produced and tested in human clinical trials (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25), revealing that MVA vectors are safe and elicit humoral and cellular immune responses to HIV-1 antigens (for reviews, see references 3, 6, and 7), regardless of its limited replication in human and most mammalian cell types. However, MVA still contains several immunomodulatory VACV genes that counteract the host antiviral innate immune response, particularly those genes encoding proteins that inhibit the Toll-like receptor (TLR) signaling pathway (26), an important route that plays a fundamental role in the defense against pathogens through the induction of proinflammatory cytokines and type I interferon (IFN) but also in modeling adaptive immune responses to patho-gens (27)(28)(29).…”

Deletion of Specific Immune-Modulatory Genes from Modified Vaccinia Virus Ankara-Based HIV Vaccines Engenders Improved Immunogenicity in Rhesus Macaques

“…Toward this goal, we have conducted the current study with the aim of improving the immunogenicity of HIV vaccines derived from modified vaccinia virus Ankara (MVA), a safe and highly attenuated orthopoxvirus that is actively being developed as an AIDS vaccine (22,26,35,46,61,66,69,83).…”

“…However, MVA-based HIV vaccines have exhibited variable, but generally limited, immunogenicity in clinical evaluations, particularly when utilized as a single modality (22,34,35,46,47,61,66,83). Several known factors contribute to this suboptimal immunogenicity profile of MVA vectors.…”