Intradermal vaccination of HIV-infected patients with short HIV Gag p24-like peptides induces CD4 + and CD8 + T cell responses lasting more than seven years

Abstract

Background: Vacc-4x contains 4 HIV p24-like short peptides. In a previous phase II trial this immunized 90% of 38 patients on antiretroviral treatment (ART) after intradermal delivery in conjunction with local granulocyte–macrophage colony-stimulating factor (GM-CSF) as adjuvant. In this study, 22 responders were retested for cellular memory at a median 7.3 y after their last immunization. All had resumed effective ART after an interspersed ART-free median interval of 2.2 y. Methods: Vacc-4x as 15-mer overlapping by 2 amino acid panels and Vacc-4x consensus peptide sequences (4xCP) were used as antigens. Proliferation was determined as percentages of CFSE^dimHLA-DR ⁺ 7AAD ⁻ CD3+ T cells of the CD4+ and CD8+ subsets after 6 days of culture. Frequencies of specific T cells in 6-h cultures were determined by interferon-γ (IFN) ⁺ CD4+ and IFN ⁺ CD8+, as well as degranulating bifunctional CD107a ⁺ IFN ⁺ CD8 + subsets. Results: Proliferative CD4+ and CD8+ responses to Vacc-4x as well as 4xCP were still present in 95% and 68%, respectively. Proliferation correlated with the Vacc-4x delayed-type hypersensitivity test (DTH) obtained after completed immunizations (CD4+ r = 0.63 (p = 0.002) and CD8+ r = 0.47 (p = 0.03)), suggesting that they represent T cell memory recall responses. The proliferative CD8+ and possibly CD4 + subset responses to 4xCP peptides correlated with Vacc-4x (r = 0.46 (p = 0.03) and r = 0.38 (p = 0.08), respectively). Forty-one percent still had Vacc-4x-specific IFN ⁺ CD4+ T cells, which correlated to corresponding frequencies of 4xCP peptides (r = 0.50, p = 0.02). CD107a⁺ IFN ⁺ CD8+ T cell responses against Vacc-4x were found in 55%. Conclusions: Evidence of long-lasting T cell memory recall responses to a peptide-based immunotherapeutic candidate for HIV-infected patients should enhance the focus on peptide-based intradermal vaccine delivery.

Keywords::

• HIV
• vaccine
• T cells
• T cell memory
• CD107a

Acknowledgements

We thank Mette Sannes for excellent assistance and Per Bengtsson for valuable advice. The study was supported by the Research Council of Norway in the Global Health and Vaccination Research (GLOBVAC) programme (http://www.rcn.no), grant number 179389.

Declaration of interest: AL and DK had the responsibility for handling the patients, regulatory issues, and most of the data analysis. MAS, IB, and BS all have shares in Bionor Pharma ASA.