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Induction of a long-term immunological memory, which can expand and defend the host upon pathogen encounter, is the ''holy grail'' of vaccinology. Here, using a sensitive cultured IFN-c ELISPOT assay, we show that 50% (15 out of 30) of healthy, HIV-1/2-uninfected volunteers who received pTHr.HIVA DNA prime-modified vaccinia virus Ankara. HIVA boost vaccine regimen 1 to 3 1/2 years ago had detectable HIV-1-specific T-cell responses. These T cells, predominantly of the CD4 1 subtype, could proliferate and produce multiple cytokines in response to in vitro peptide stimulation. Peptide mapping studies showed that the vaccine-induced CD4 1 T cells were mostly directed toward epitopes targeted in HIV-1-infected individuals. In addition, we used the same assay to re-evaluate 51 volunteers from past vaccine trial IAVI-006 and corrected the previously reported 10% of vaccine responders to 50%. Thus, we confirmed that cultured assays are a valuable tool for studying T-cell memory. These results are discussed in the context of the current state-of-affairs of the HIV-1 vaccine field.Key words: Clinical trial . DNA-MVA vaccines . HIV-1 . Memory T cells IntroductionDespite proven methods of prevention and/or decrease of transmission, all efforts to slow the rate of new HIV-1 infections are failing in most countries around the world, including the USA (http://www.unaids.org/). The best solution to control of the HIV-1 epidemic remains the development of a safe, effective and accessible preventive vaccine [1]. The aim of vaccination is induction of long-lived, pathogen-specific circulating antibodies and cellular immunological memory, which together provide a faster and more efficient defense of the host following exposure to the pathogen. A central role in both the T-and B-cell memory development is played by CD4 1 T cells [2,3], the functionality of which is tuned by the non-adaptive innate response [4]. It is the CD4 1 T-cell population that is decimated by HIV-1-infection, which eventually leads to opportunistic infections [5,6].The long-term aim of our effort is development of an effective HIV-1 vaccine. In particular, we explore strategies for eliciting HIV-1-specific T-cell responses, which could on their own, or together with vaccine-induced anti-HIV-1 antibodies, limit tissue damage during HIV-1 infection. Our first vaccine platform was designed as a heterologous DNA prime-modified vaccinia virus Ankara (MVA) boost regimen delivering a common immunogen HIVA, which consists of consensus African clade A Gag p24 and The most sensitive assay employed and validated by the IAVI-016 trial was the IFN-g ELISPOT assay combined with a prior 10-day-culture expansion of PBMC using immunogen-derived peptides and externally supplemented cytokines. This so called cultured IFN-g ELISPOT assay increased the frequencies of specific T cells more than 24-fold compared with the ex vivo assay and detected vaccine-induced HIV-1-specific responses in all (8 out of 8) IAVI-016 subjects who received the pTHr.HIVA DNA-MVA.HIVA regimen [14]. Thes...