A recombinant prime, peptide boost vaccination strategy can focus the immune response on to more than one epitope even though these may not be immunodominant in the complex immunogen

Davis, David A.; Morein, Brør; Åkerblom, Lennart; Lövgren-Bengtsson, Karin; Gils, M. E. Van; Bogers, Willy; Teeuwsen, Vera; Heeney, Jonathan L.

doi:10.1016/s0264-410x(97)00084-4

Cited by 22 publications

(12 citation statements)

References 35 publications

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“…This potentially results in a larger proportion and higher titer of nAbs. Even though the use of selected epitopes or mimotopes as vaccines to focus the immune response on neutralizing domains is still in its beginning, several examples in the last years show the successful induction of nAbs against V2 and/or V3 [65], [66], [67]. We chose to perform the boosts with five different mimotope groups, each representing a well-defined Env region (the V3 loop, the C-terminus of gp120, gp41 IDR, and separately, the KLIC motif, and MPER).…”

Section: Discussionmentioning

confidence: 99%

Inducing Cross-Clade Neutralizing Antibodies against HIV-1 by Immunofocusing

et al. 2008

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BackgroundAlthough vaccines are important in preventing viral infections by inducing neutralizing antibodies (nAbs), HIV-1 has proven to be a difficult target and escapes humoral immunity through various mechanisms. We sought to test whether HIV-1 Env mimics may serve as immunogens.Methodology/Principal FindingsUsing random peptide phage display libraries, we identified the epitopes recognized by polyclonal antibodies of a rhesus monkey that had developed high-titer, broadly reactive nAbs after infection with a simian-human immunodeficiency virus (SHIV) encoding env of a recently transmitted HIV-1 clade C (HIV-C). Phage peptide inserts were analyzed for conformational and linear homology using computational analysis; some peptides mimicked various domains of the original HIV-C Env, such as conformational V3 loop epitopes and the conserved linear region of the gp120 C-terminus. Next, we devised a novel prime/boost strategy to test the immunogenicity of such phage-displayed peptides and primed mice only once with HIV-C gp160 DNA followed by boosting with mixtures of recombinant phages.Conclusions/SignificanceThis strategy, which was designed to focus the immune system on a few Env epitopes (immunofocusing), not only induced HIV-C gp160 binding antibodies and cross-clade nAbs, but also linked a conserved HIV Env region for the first time to the induction of nAbs: the C-terminus of gp120. The identification of conserved antigen mimics may lead to novel immunogens capable of inducing broadly reactive nAbs.

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Section: Discussionmentioning

confidence: 99%

Inducing Cross-Clade Neutralizing Antibodies against HIV-1 by Immunofocusing

et al. 2008

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“…The first two immunizations at weeks 0 and 6 consisted of glycosylated Chinese hamster ovary-expressed monomeric HIV-1 SF2 gp120 (13) and p24 incorporated into ISCOMs. At weeks 6 and 16 ISCOMs covalently coupled with the synthetic peptides IRDKIQKENALFRNLC (representing the V2 region) and NNNTRKSIYIGPGRAC (representing the V3 region) coupled to PR8-Flu-ISCOMs were also administered (23). The HIV-1 gp120 specific antibody titers were determined by ELISA (24,25), and virus neutralization assays for HIV-1 SF2 and HIV-1 SF13 were performed as described (23).…”

Section: Methodsmentioning

confidence: 99%

β-Chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques

Heeney

Teeuwsen

Gils

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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One of the obstacles to AIDS vaccine development is the variability of HIV-1 within individuals and within infected populations, enabling viral escape from highly specific vaccine induced immune responses. An understanding of the different immune mechanisms capable of inhibiting HIV infection may be of benefit in the eventual design of vaccines effective against HIV-1 variants. To study this we first compared the immune responses induced in Rhesus monkeys by using two different immunization strategies based on the same vaccine strain of HIV-1. We then utilized a chimeric simian͞HIV that expressed the envelope of a dual tropic HIV-1 escape variant isolated from a later time point from the same patient from which the vaccine strain was isolated. Upon challenge, one vaccine group was completely protected from infection, whereas all of the other vaccinees and controls became infected. Protected macaques developed highest titers of heterologous neutralizing antibodies, and consistently elevated HIV-1-specific T helper responses. Furthermore, only protected animals had markedly increased concentrations of RANTES, macrophage inf lammatory proteins 1␣ and 1␤ produced by circulating CD8 ؉ T cells. These results suggest that vaccine strategies that induce multiple effector mechanisms in concert with ␤-chemokines may be desired in the generation of protective immune responses by HIV-1 vaccines.

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“…Nevertheless, there is the possibility that the peptides also boosted antibodies to a peptide whose sequence lies close to the neutralizing epitope but does not overlap with it. 26 The result indicated that this protein prime-epitope peptide boost strategy would be advantageous in eliciting more specific humoral immune response. Although both protein homologous modality and protein prime-peptide boost vaccination showed minimal adverse response, 8 a broader response will inherently provide more potential risks from a safety perspective.…”

confidence: 96%