Broad and potent immune responses to a low dose intradermal HIV-1 DNA boosted with HIV-1 recombinant MVA among healthy adults in Tanzania

Abstract

Background We conducted a phase I/II randomized placebo-controlled trial with the aim of exploring whether priming with a low intradermal dose of a multiclade, multigene HIV-1 DNA vaccine could improve the immunogenicity of the same vaccine given intramuscularly prior to boosting with a heterologous HIV-1 MVA among healthy adults in Dar es Salaam, Tanzania. Methods Sixty HIV-uninfected volunteers were randomized to receive DNA plasmid vaccine 1 mg intradermally (id), n = 20, or 3.8 mg intramuscularly (im), n = 20, or placebo, n = 20, using a needle-free injection device. DNA plasmids encoding HIV-1 genes gp160 subtype A, B, C; rev B; p17/p24 gag A, B and Rtmut B were given at weeks 0, 4 and 12. Recombinant MVA (108 pfu) expressing HIV-1 Env, Gag, Pol of CRF01_AE or placebo was administered im at month 9 and 21. Results The vaccines were well tolerated. Two weeks after the third HIV-DNA injection, 22/38 (58%) vaccinees had IFN-γ ELISpot responses to Gag. Two weeks after the first HIV-MVA boost all 35 (100%) vaccinees responded to Gag and 31 (89%) to Env. Two to four weeks after the second HIV-MVA boost, 28/29 (97%) vaccinees had IFN-γ ELISpot responses, 27 (93%) to Gag and 23 (79%) to Env. The id-primed recipients had significantly higher responses to Env than im recipients. Intracellular cytokine staining for Gag-specific IFN-γ/IL-2 production showed both CD8+ and CD4+ T cell responses. All vaccinees had HIV-specific lymphoproliferative responses. All vaccinees reacted in diagnostic HIV serological tests and 26/29 (90%) had antibodies against gp160 after the second HIV-MVA boost. Furthermore, while all of 29 vaccinee sera were negative for neutralizing antibodies against clade B, C and CRF01 AE pseudoviruses in the TZM-bl neutralization assay, in a PBMC assay, the response rate ranged from 31% to 83% positives, depending upon the clade B or CRF01_AE virus tested. This vaccine approach is safe and highly immunogenic. Low dose, id HIV-DNA priming elicited higher and broader cell-mediated immune responses to Env after HIV-MVA boost compared to a higher HIV-DNA priming dose given im. Three HIV-DNA priming immunizations followed by two HIV-MVA boosts efficiently induced Env-antibody responses.

Comparable Antigenicity and Immunogenicity of Oligomeric Forms of a Novel, Acute HIV-1 Subtype C gp145 Envelope for Use in Preclinical and Clinical Vaccine Research

“…Additionally, antibodies elicited by CO6980v0c22 gp145 did not neutralize the homologous PV in the TZM-bl assay; however, titers of antibody to the CO6980 IMC were observed in a PBMC assay. We have observed this discrepancy between assay platforms previously when evaluating human vaccinee sera (91,92,97). The differences could be attributed to the detection of additional types of antibody-mediated viral inhibition in the PBMC assay (93), differences in cell surface HIV receptor expression (94), differences in the cell production systems, or differences in the Env cleavage state of the CO6980v0c22 gp145 protein versus the CO6980v0c22 PV.…”

“…Three additional Env antigens, 1086c gp140, 624⌬11 gp120, and 63521⌬11 gp120, were tested with the Biacore 3000 for comparison. b ND=, the antigenicity of BG505 SOSIP.665 gp140 has previously been evaluated and reported (34,92 date HIV vaccine immunogen. In the first study, unfractionated CO6980v0c22 gp145 was formulated by mixing or encapsulating the protein with three different adjuvants ( Table 3, study 1), and immunogenicity was tested with four rabbits per group at a gp145 dose of 25 g/ml given at weeks 0, 4, and 8; sera were collected at 2-week intervals, ending with the terminal bleed at week 12.…”

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).…”

Safety and Immunogenicity of DNA Prime and Modified Vaccinia Ankara Virus-HIV Subtype C Vaccine Boost in Healthy Adults

“…Anti-MVA responses do not appear to significantly impair subsequent immune responses, though immune responses tend to plateau after two immunizations (12,14,16,17). To circumvent antivector immunity and prime immune responses, the use of DNA as prime in "prime-boost" regimens with MVA, adenovirus, and other vector-based vaccines as the boost has become a common strategy (18)(19)(20)(21)(22)(23)(24)(25)(26). In these DNA prime, vector boost studies, typically polyfunctional T-cell responses, tier 1 neutralizing and nonneutralizing antibody responses, and even detection of effector T cells in the gut have been demonstrated, though responses are critically dependent on the insert, regimen, and time of sampling.…”