A phase I trial of preventive HIV vaccination with heterologous poxviral-vectors containing matching HIV-1 inserts in healthy HIV-uninfected subjects☆☆☆

Abstract

We evaluated replication-defective poxvirus vectors (modified vaccinia Ankara [MVA] and fowlpox [FPV]) in a homologous and heterologous vector prime-boost vaccination regimen containing matching HIV inserts (MVA-HIV and FPV-HIV) given at months 0, 1, 3, 5 and 7 in 150 healthy HIV-negative vaccinia-naïve participants. FPV-HIV alone was poorly immunogenic, while the high dose (10 9 NIH Public Access Author ManuscriptVaccine. Author manuscript; available in PMC 2011 February 24.Published in final edited form as: Vaccine. 2011 February 24; 29(10): 1948-1958. doi:10.1016/j.vaccine.2010. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript boost. Thus, a heterologous poxvirus vector prime-boost regimen can induce an HIV-specific CD8+ T-cell and CD4+ T-cell responses, which may be an important feature of an optimal regimen for preventive HIV vaccination.

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

“…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.…”

HIV-specific humoral responses benefit from stronger prime in phase Ib clinical trial

“…Of note, CD4 + T cell responses dominated in this trial, which is unusual for vaccine regimens including rAd5. This enrichment of CD4 + T cell responses is likely due to the inclusion of NYVAC-B; like other poxvirus vectors, it preferentially induces this subset (7,10). CD8 + T cell responses were somewhat lower in HVTN 078 compared with those measured in HVTN 054, in which a single dose of the same rAd5 was given; this may be explained in part by the time point chosen for immunogenicity assessment.…”

“…Following the disappointing outcome of the rAd5-vectored Step Study (3) and the more promising results obtained in the RV144 trial (6) with a canarypox-containing regimen, poxvirus vectors have seen a surge in interest over the past few years. Early poxvirus vectors were poorly immunogenic in humans compared with adenovirus-based vaccines (7,8), but more recent immunogens based on New York vaccinia (NYVAC) or modified vaccinia Ankara (MVA) boosts show promising results in clinical trials (9-13). The number of participants enrolled, randomized, followed up, and analyzed is shown for placebo and treatment groups.…”