Background: The dual activity of the regulatory Tat protein on viral replication and immunosuppression strongly supports the use of Tat as a key component of an anti HIV-1 vaccine candidate.

Methods: A double-blind, randomized, placebo-controlled phase I/II study was conducted to evaluate the safety and immunogenicity of an HIV-1 Tat toxoid vaccine with or without adjuvant in P on stable Highly Active Antiretroviral Therapy (HAART) with VL < 50 copies/mL and CD4 ³ 300/mm3. P were randomized to receive 100 µg of Tat toxoid protein intramuscularly in diluent (n = 12) or with DC-Chol adjuvant (n = 12) or DC-Chol adjuvant alone (n = 8) at wk 0, 2, 4, 6, and 12. Local and systemic reactions were recorded. Clinical and biological safety and/ or immunogenicity evaluations were recorded at wk 0, 2, 4, 6, 12, 16 and 24. Anti-native Tat Abs (IIIb) titers (ELISA), the functionality of the Abs (transactivation assay) and the avidity of the anti-Tat Abs (by Biacore) were measured. In vivo DTH test was performed at the study end. Tat-specific proliferative responses were measured (lymphoproliferation assay) as well as Tat specific CD4⁺ and CD8⁺ T-cell responses (ELISpot).

Results: Twenty-three (23) patients (pts) experienced local reactions after any injections, in the 3 groups (5/12, 10/12, and 8/8), mostly pain (3, 10, and 8, respectively), of which 1 severe on both Tat+DC-Chol and DC-Chol arm while systemic events occurred in 7/12, 9/12, and 8/8, mostly asthenia, chills, fever, headache, myalgia, sweating, none of severe entity. No lab abnormalities were observed, nor any increase of VL. High anti-Abs Tat at wk 16 were detected in both groups receiving Tat, (6/12 vs 12/12) higher in the Tat + DC-Chol group (p < 0,05). No Ab response was noted in the placebo group. Transactivation neutralizing Abs responses were detected in both groups receiving Tat (7/11 and 9/12). In addition, Biacore analysis showed a strong avidity of the rTat induced Abs. Th2 CD4⁺ T-cell response was higher in the Tat + DChol group compared to the Tat alone group (p < 0.05) as well as the Tat specific proliferative response. Finally, the DTH test confirmed a cellular response in rTat vaccinees.

Conclusions: rTat toxoid vaccine administered with or without DC-Chol appears safe and well tolerated. Immunization with rTat induced specific neutralizing antibodies with high Tat avidity, significant proliferative responses and a Th2-biased CD4⁺ T-cell profile. DC-Chol showed an adjuvant effect on both humoral and cellular immunity responses.