期刊
MOLECULAR THERAPY
卷 25, 期 2, 页码 494-503出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2016.12.004
关键词
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资金
- UK Medical Research Council
- UK Department for International Development (DFID) [MRC G1001757, MR/N023668/1]
- European Union Horizon Research and Innovation Programme EAVI2020 [681137]
- Immune Design Corp
- MRC [MR/N023668/1, MR/K012037/1, G1001757] Funding Source: UKRI
- Medical Research Council [MR/K012037/1, G1001757, MR/N023668/1] Funding Source: researchfish
To be effective against HIV type 1 (HIV-1), vaccine-induced T cells must selectively target epitopes, which are functionally conserved (present in the majority of currently circulating and reactivated HIV-1 strains) and, at the same time, beneficial (responses to which are associated with better clinical status and control of HIV-1 replication), and rapidly reach protective frequencies upon exposure to the virus. Heterologous primeboost regimens using virally vectored vaccines are currently the most promising vaccine strategies; nevertheless, induction of robust long-term memory remains challenging. To this end, lentiviral vectors induce high frequencies of memory cells due to their low-inflammatory nature, while typically inducing only low anti-vector immune responses. Here, we describe construction of novel candidate vaccines ZVex. tHIVconsv1 and ZVex. tHIVconsv2, which are based on an integration-deficient lentiviral vector platform with preferential transduction of human dendritic cells and express a bivalent mosaic of conservedregion T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous primeboost regimens with chimpanzee adenovirus and/or poxvirus modified vaccinia virus Ankara (MVA) vaccines to BALB/c and outbred CD1-Swiss mice, they induced a median frequency of over 6,000 T cells/10(6) splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept.
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