Preclinical development of HIvax: Human survivin highly immunogenic vaccines

Our plain-English summary of Preclinical development of HIvax: Human survivin highly immunogenic vaccines, by P.R. Hoffmann, M. Panigada, E. Soprana, et al (Human Vaccines & Immunotherapeutics, 2015).

The study

• Authors: P.R. Hoffmann, M. Panigada, E. Soprana, F. Terry, I.S. Bandar, A. Napolitano, A.H. Rose, F.W. Hoffmann, L.C. Ndhlovu, M. Belcaid, L. Moise, A.S. De Groot, M. Carbone, G. Gaudino, T. Matsui, A. Siccardi, P. Bertino
• Journal: Human Vaccines & Immunotherapeutics
• Published: 2015;11(7):1585-95
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Our previous work involved the development of a recombinant fowlpox virus encoding survivin (FP-surv) vaccine that was evaluated for efficacy in mesothelioma mouse models. Results showed that FP-surv vaccination generated significant immune responses, which led to delayed tumor growth and improved animal survival. We have extended those previous findings in the current study, which involves the pre-clinical development of an optimized version of FP-surv designed for human immunization (HIvax). Survivin-derived peptides for the most common haplotypes in the human population were identified and their immunogenicity confirmed in co-culture experiments using dendritic cells and T cells isolated from healthy donors. Peptides confirmed to induce CD8(+) and CD4(+) T cells activation in humans were then included in 2 transgenes optimized for presentation of processed peptides on MHC-I (HIvax1) and MHC-II (HIvax2). Fowlpox vectors expressing the HIvax transgenes were then generated and their efficacy was evaluated with subsequent co-culture experiments to measure interferon-γ and granzyme B secretion. In these experiments, both antigen specific CD4(+) and CD8(+) T cells were activated by HIvax vaccines with resultant cytotoxic activity against survivin-overexpressing mesothelioma cancer cells. These results provide a rationale for clinical testing of HIvax1 and HIvax2 vaccines in patients with survivin-expressing cancers.

In plain English

This was a laboratory (preclinical) study developing two survivin-based vaccines for human use, building on the authors' earlier fowlpox-survivin vaccine tested in mesothelioma mouse models. The human survivin protein was screened computationally with the EpiMatrix algorithm, and seven peptides (Hsurv1-7) were synthesised and tested in co-cultures of dendritic cells and T cells from 10 HLA-typed healthy donors, each with a different haplotype. All peptides except Hsurv4 (survivin 20-28) induced interferon-gamma-producing CD3+ T cells; Hsurv4 activated CD8+ T cells in only one of 10 subjects. MHC-II peptides activated CD4+ T cells in 90% of donors and MHC-I peptides Hsurv5, 6, 7 activated CD8+ T cells in 100% of donors. Hsurv4 was excluded, and two fowlpox vectors were built, HIvax1 (class I epitopes) and HIvax2 (class II epitopes). In two donors, HIvax1 activated CD8+ T cells; HIvax2 activated CD4+ T cells in one. HIvax-stimulated T cells released granzyme B against survivin-overexpressing ADA mesothelioma cells but not autologous fibroblasts. The authors concluded this supports clinical testing.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: preclinical laboratory study: in silico epitope prediction followed by in vitro human dendritic cell/T cell co-culture experiments and construction of recombinant fowlpox vaccine vectors
• Who was studied: Human survivin protein sequence; dendritic cells and T cells from 10 HLA-typed healthy volunteer blood donors, each with a different haplotype (study approved by the University Hawaii Committee on Human Subjects Institutional Review Board); the human malignant mesothelioma cell line ADA and primary autologous skin fibroblasts
• Exposure: Seven synthetic survivin-derived peptides (Hsurv1-7) and two fowlpox-vectored multi-epitope vaccines, HIvax1 (MHC-I epitopes Hsurv5, 6, 7) and HIvax2 (MHC-II epitopes Hsurv1, 2, 3), with empty fowlpox vector (FP-ctrl) as control
• Main results:
  • Of 134 overlapping 9-mers screened, more than 50 EpiMatrix hits were found; 4 class I sequences were selected for testing
  • All peptides except Hsurv4 produced significant interferon-gamma-positive CD3+ T cell responses in the donors
  • MHC-II-designed peptides activated CD4+ T cells in 90% of donors; MHC-I-designed peptides Hsurv5, 6 or 7 activated CD8+ T cells in 100% of donors
  • Hsurv4 (survivin 20-28) activated CD8+ T cells in only 1 of 10 donors and was excluded from the vaccine
  • In peptide-pool experiments with cells from 4 donors, the pool lacking Hsurv4 gave CD4+ and CD8+ responses in 75% of experiments versus 50% for the pool containing all 7 peptides
  • In the two donors tested with the vaccines, HIvax1 induced CD8+ T cell interferon-gamma responses in both, while HIvax2 induced CD4+ responses in one donor and not in the other
  • T cells activated by the combined HIvax vaccines released significantly more granzyme B when co-cultured with survivin-overexpressing ADA mesothelioma cells, but not with primary fibroblasts
• The authors' conclusion: The authors concluded that their findings give a rationale and framework for clinical testing of HIvax1 and HIvax2 in patients with survivin-expressing cancers
• Limitations the authors state:
  • The authors stated the sample size was too small for definitive conclusions when comparing predictions with observed T cell responses
  • The authors stated the number of donors was insufficient to define whether Hsurv4 is immunostimulatory or immunosuppressive
  • The authors stated that further clinical investigation is needed to know whether patients respond as healthy donor cells did in vitro

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma.

Related studies

• Fowlpox-based survivin vaccination for malignant mesothelioma therapy — P. Bertino, M. Panigada, et al. (2013)
• Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma — M. Meerang, K. Bérard, et al. (2016)
• BIRC5 promoter SNPs do not affect nuclear survivin expression and survival of malignant pleural mesothelioma patients — J. Hmeljak, N. Erčulj, et al. (2011)
• Is survivin expression prognostic or predictive in malignant pleural mesothelioma? — J. Hmeljak, N. Erčulj, et al. (2013)
• Serum Survivin Levels and Outcome of Chemotherapy in Patients with Malignant Mesothelioma — K. Goričar, V. Kovač, et al. (2015)
• Survivin is a negative prognostic factor in malignant pleural effusion — E. Arellano-Orden, B. Romero-Romero, et al. (2018)

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