Abstract
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 prime-boost 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 conserved-region T cell immunogens with a high global HIV-1 match. Each of the two mosaic vaccines was individually immunogenic. When administered together in heterologous prime-boost 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/106 splenocytes, which were plurifunctional, broadly specific, and cross-reactive. These results support further development of this vaccine concept.
Highlights
Vaccine protection against infection/disease requires targeting the causative microorganisms at their most vulnerable sites by robust and timely immune responses.[1,2] Robustness broadly sums the overall magnitude of responses and effectiveness of their protective functions, which have to be exerted at the right anatomical localization at the right time.[3,4] To blunt immune attacks, highly variable microorganisms evolved multiple evasive strategies, of which perhaps the most common employs so-called decoy epitopes.[5,6] These are accessible, highly immunogenic determinants that do not stop the microbes when targeted
The mosaic pairs of vaccines were delivered by heterologous regimens combining lentivirus vectors, simian adenovirus, and poxvirus modified vaccinia virus Ankara (MVA) (Figure 1B)
IFN-g, tumor necrosis factor (TNF)-a, and interleukin (IL)-2 pro- immunogens, we demonstrated the role of the ZVex-vectored duction and degranulation, the equivalent of killing measured by sur- vaccines in priming responses for ChAdOx1 and MVA, which was face expression of CD107a, was assessed using a polychromatic flow most obvious for the immunodominant pool P4 (Figure 4C)
Summary
Vaccine protection against infection/disease requires targeting the causative microorganisms at their most vulnerable sites by robust and timely immune responses.[1,2] Robustness broadly sums the overall magnitude of responses and effectiveness of their protective functions, which have to be exerted at the right anatomical localization at the right time.[3,4] To blunt immune attacks, highly variable microorganisms evolved multiple evasive strategies, of which perhaps the most common employs so-called decoy epitopes.[5,6] These are accessible, highly immunogenic determinants that do not stop the microbes when targeted. This is because the most exposed decoy sites are in protein regions non-essential for survival, structure, or function and are, mutated to render the mounted responses ineffective.[7,8,9] In contrast, structurally and functionally important regions are frequently subdominant.[7,8,9,10,11,12,13] This is true for antibody and cytotoxic T lymphocyte (CTL) responses
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