Intradermal injection of a Tat Oyi-based therapeutic HIV vaccine reduces of 1.5 log copies/mL the HIV RNA rebound median and no HIV DNA rebound following cART interruption in a phase I/II randomized controlled clinical trial

Abstract

Background: A Tat Oyi vaccine preparation was administered with informed consent to 48 long-term HIV-1 infected volunteers whose viral loads had been suppressed by antiretroviral therapy (cART). These volunteers were randomized in double-blind method into four groups (n = 12) that were injected intradermally with 0, 11, 33, or 99 µg of synthetic Tat Oyi proteins in buffer without adjuvant at times designated by month 0 (M0), M1 and M2, respectively. The volunteers then underwent a structured treatment interruption between M5 and M7.

Results: The primary outcomes of this phase I/IIa clinical trial were the safety and lowering the extent of HIV RNA rebound after cART interruption. Only one undesirable event possibly due to vaccination was observed. The 33 µg dose was most effective at lowering the extent of HIV RNA and DNA rebound (Mann and Whitney test, p = 0.07 and p = 0.001). Immune responses against Tat were increased at M5 and this correlated with a low HIV RNA rebound at M6 (p = 0.01).

Conclusion: This study suggests in vivo that extracellular Tat activates and protects HIV infected cells. The Tat Oyi vaccine in association with cART may provide an efficient means of controlling the HIV-infected cell reservoir.

Keywords: ART interruption; Clinical trial; HIV; Tat; Vaccine.

Fig. 1

EVATAT flow diagram. This flow diagram was constructed according to CONSORT recommendation [41]

Fig. 2

Design of the study and HIV RNA Rebound. HIV-1 infected volunteers (n = 46) were randomized into four groups having at month 0 (M0), M1 and M2 double blinded intradermal injections with respectively 0 (n = 12-black square), 11 µg (n = 12-black circle), 33 µg (n = 12-white square) or 99 µg (n = 10-white circle) of a synthetic protein called Tat Oyi in a saline buffer without adjuvant. The volunteers stopped their antiviral treatment between M5 and M7. Volunteers had undetectable HIV RNA since at least 1 year before vaccination and treatment interruption. HIV RNA rebound is displayed as the median for each group on a logarithm scale. Four volunteers did not resume ART at M6 in the 33 µg group while only two volunteers resumed ART in the other groups. HIVRNA at M7 is depicted for volunteers who resumed ART at M6 (n = 36) and at M7 (n = 10)

Fig. 3

HIV RNA at M6 for each volunteer. The HIV RNA level (copies/mL) is displayed on a logarithmic scale. For each group, the median is shown as a grey line

Fig. 4

Levels of CD4 and CD8 lymphocytes. a Median CD4 count for each group. b Median CD8 count for each group. Group 1 is depicted as a black square, group 2 as a black circle, group 3 as a white square and group 4 as a white circle

Fig. 5

HIV DNA in peripheral blood. HIV DNA medians for each group are shown from M0 to M12. Volunteers with undetectable HIV DNA (<20 copies/10⁶ PBMC) were counted as having respectively 19 copies, which is 1.3 log copies/ml (dashed line). The placebo group is depicted as a black square, the 11 µg group as a black circle, the 33 µg group as a white square and the 99 µg group as a white circle. Median decreases in HIVDNA levels were observed at doses of 99 µg (n = 10) from 1.8 (TR 1.3–2.5) to 1.3 (TR 1.3–2.6) log copies HIV DNA/10⁶ PBMC between M0 and M4 and is due to six volunteers with HIV DNA copies <20. The absence of HIVDNA rebound at M6 with the 33 µg group is highly significant in a Mann and Whitney test (p = 0.001). At M12, the 33 µg group has a median of 1.4 log copies/ml that is very close of the undetectable level. However, this difference is not significant (p > 0.1) compared to M0

Fig. 6

Evolution of the IgG anti Tat immune response in ELISA test. Data are shown before vaccination (D-15), after vaccination at M5 (just before ART interruption) and at M12 (5 months after ART was resumed). The volunteers were classified in four categories: The white bar corresponds to no recognition of Tat variants. The different shades of grey correspond to the capacity for volunteers to recognize one (low responder), two (moderate responder) or three to six (high responder) Tat variants. a Evolution of the Tat immune response for all volunteers (n = 46). b Evolution of the Tat immune response in the placebo group (n = 12). c Evolution of the Tat immune response in the 11 µg group (n = 12). d Evolution of the Tat immune response in the 33 µg group (n = 12). e Evolution of the Tat immune response in the 99 µg group (n = 10)