Highly stable and immunogenic CMV T cell vaccine candidate developed using a synthetic MVA platform.
Journal
NPJ vaccines
ISSN: 2059-0105
Titre abrégé: NPJ Vaccines
Pays: England
ID NLM: 101699863
Informations de publication
Date de publication:
30 Mar 2024
30 Mar 2024
Historique:
received:
02
11
2023
accepted:
12
03
2024
medline:
31
3
2024
pubmed:
31
3
2024
entrez:
30
3
2024
Statut:
epublish
Résumé
Human cytomegalovirus (CMV) is the most common infectious cause of complications post-transplantation, while a CMV vaccine for transplant recipients has yet to be licensed. Triplex, a multiantigen Modified Vaccinia Ankara (MVA)-vectored CMV vaccine candidate based on the immunodominant antigens phosphoprotein 65 (pp65) and immediate-early 1 and 2 (IE1/2), is in an advanced stage of clinical development. However, its limited genetic and expression stability restricts its potential for large-scale production. Using a recently developed fully synthetic MVA (sMVA) platform, we developed a new generation Triplex vaccine candidate, T10-F10, with different sequence modifications for enhanced vaccine stability. T10-F10 demonstrated genetic and expression stability during extensive virus passaging. In addition, we show that T10-F10 confers comparable immunogenicity to the original Triplex vaccine to elicit antigen-specific T cell responses in HLA-transgenic mice. These results demonstrate improvements in translational vaccine properties of an sMVA-based CMV vaccine candidate designed as a therapeutic treatment for transplant recipients.
Identifiants
pubmed: 38555379
doi: 10.1038/s41541-024-00859-3
pii: 10.1038/s41541-024-00859-3
doi:
Types de publication
Journal Article
Langues
eng
Pagination
68Informations de copyright
© 2024. The Author(s).
Références
Varnum, S. M. et al. Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome. J. Virol. 78, 10960–10966 (2004).
pubmed: 15452216
pmcid: 521840
doi: 10.1128/JVI.78.20.10960-10966.2004
Kalejta, R. F. Tegument proteins of human cytomegalovirus. Microbiol. Mol. Biol. Rev. 72, 249–265 (2008).
pubmed: 18535146
pmcid: 2415745
doi: 10.1128/MMBR.00040-07
Zuhair, M. et al. Estimation of the worldwide seroprevalence of cytomegalovirus: a systematic review and meta-analysis. Rev. Med. Virol. 29, e2034 (2019).
pubmed: 30706584
doi: 10.1002/rmv.2034
Ronchi, A. et al. Evaluation of clinically asymptomatic high risk infants with congenital cytomegalovirus infection. J. Perinatol. J. Calif. Perinat. Assoc. 40, 89–96 (2020).
Britt, W. J. Congenital human cytomegalovirus infection and the enigma of maternal immunity. J. Virol. 91, e02392–16 (2017).
pubmed: 28490582
pmcid: 5512250
doi: 10.1128/JVI.02392-16
Griffiths, P. & Reeves, M. Pathogenesis of human cytomegalovirus in the immunocompromised host. Nat. Rev. Microbiol. 19, 759–773 (2021).
pubmed: 34168328
pmcid: 8223196
doi: 10.1038/s41579-021-00582-z
Azevedo, L. S. et al. Cytomegalovirus infection in transplant recipients. Clin. Sao Paulo Braz. 70, 515–523 (2015).
doi: 10.6061/clinics/2015(07)09
Volz, A. & Sutter, G. Modified vaccinia virus ankara: history, value in basic research, and current perspectives for vaccine development. Adv. Virus Res. 97, 187–243 (2017).
pubmed: 28057259
doi: 10.1016/bs.aivir.2016.07.001
Gilbert, S. C. Clinical development of Modified Vaccinia virus Ankara vaccines. Vaccine 31, 4241–4246 (2013).
pubmed: 23523410
doi: 10.1016/j.vaccine.2013.03.020
Dalton, A. F. et al. Estimated Effectiveness of JYNNEOS Vaccine in Preventing Mpox: A Multijurisdictional Case-Control Study — United States, August 19, 2022–March 31, 2023. MMWR Morb. Mortal. Wkly. Rep. 72, 553–558 (2023).
pubmed: 37200229
pmcid: 10205167
doi: 10.15585/mmwr.mm7220a3
Rao, A. K. et al. Use of JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Nonreplicating) for preexposure vaccination of persons at risk for occupational exposure to orthopoxviruses: recommendations of the advisory committee on immunization practices — United States, 2022. MMWR Morb. Mortal. Wkly. Rep. 71, 734–742 (2022).
pubmed: 35653347
pmcid: 9169520
doi: 10.15585/mmwr.mm7122e1
Antoine, G., Scheiflinger, F., Dorner, F. & Falkner, F. G. The Complete Genomic Sequence of the Modified Vaccinia Ankara Strain: Comparison with Other Orthopoxviruses. Virology 244, 365–396 (1998).
pubmed: 9601507
doi: 10.1006/viro.1998.9123
Meisinger-Henschel, C. et al. Genomic sequence of chorioallantois vaccinia virus Ankara, the ancestor of modified vaccinia virus Ankara. J. Gen. Virol. 88, 3249–3259 (2007).
pubmed: 18024893
doi: 10.1099/vir.0.83156-0
Sutter, G. & Moss, B. Nonreplicating vaccinia vector efficiently expresses recombinant genes. Proc. Natl Acad. Sci. 89, 10847–10851 (1992).
pubmed: 1438287
pmcid: 50439
doi: 10.1073/pnas.89.22.10847
Draper, S. J., Cottingham, M. G. & Gilbert, S. C. Utilizing poxviral vectored vaccines for antibody induction—Progress and prospects. Vaccine 31, 4223–4230 (2013).
pubmed: 23746455
pmcid: 7131268
doi: 10.1016/j.vaccine.2013.05.091
Cottingham, M. G. & Carroll, M. W. Recombinant MVA vaccines: dispelling the myths. Vaccine 31, 4247–4251 (2013).
pubmed: 23523407
doi: 10.1016/j.vaccine.2013.03.021
Sylwester, A. W. et al. Broadly targeted human cytomegalovirus-specific CD4 + and CD8 + T cells dominate the memory compartments of exposed subjects. J. Exp. Med. 202, 673–685 (2005).
pubmed: 16147978
pmcid: 2212883
doi: 10.1084/jem.20050882
Wang, Z. et al. A fusion protein of HCMV IE1 exon4 and IE2 exon5 stimulates potent cellular immunity in an MVA vaccine vector. Virology 377, 379–390 (2008).
pubmed: 18538366
doi: 10.1016/j.virol.2008.04.034
Chiuppesi, F. et al. Multiantigenic modified vaccinia virus ankara vaccine vectors to elicit potent humoral and cellular immune reponses against human cytomegalovirus in mice. J. Virol. 92, e01012–e01018 (2018).
pubmed: 30045984
pmcid: 6146800
doi: 10.1128/JVI.01012-18
Wussow, F. et al. Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLoS Pathog. 10, e1004524 (2014).
pubmed: 25412505
pmcid: 4239111
doi: 10.1371/journal.ppat.1004524
Wussow, F. et al. A vaccine based on the rhesus cytomegalovirus UL128 complex induces broadly neutralizing antibodies in rhesus macaques. J. Virol. 87, 1322–1332 (2013).
pubmed: 23152525
pmcid: 3554163
doi: 10.1128/JVI.01669-12
Wang, Z. et al. Recombinant modified vaccinia virus Ankara expressing a soluble form of glycoprotein B causes durable immunity and neutralizing antibodies against multiple strains of human cytomegalovirus. J. Virol. 78, 3965–3976 (2004).
pubmed: 15047812
pmcid: 374285
doi: 10.1128/JVI.78.8.3965-3976.2004
Wang, Z. et al. Modified H5 promoter improves stability of insert genes while maintaining immunogenicity during extended passage of genetically engineered MVA vaccines. Vaccine 28, 1547–1557 (2010).
pubmed: 19969118
doi: 10.1016/j.vaccine.2009.11.056
La Rosa, C. et al. MVA vaccine encoding CMV antigens safely induces durable expansion of CMV-specific T cells in healthy adults. Blood 129, 114–125 (2017).
pubmed: 27760761
pmcid: 5216266
doi: 10.1182/blood-2016-07-729756
Aldoss, I. et al. Poxvirus vectored cytomegalovirus vaccine to prevent cytomegalovirus viremia in transplant recipients: a phase 2, randomized clinical trial. Ann. Intern. Med. 172, 306 (2020).
pubmed: 32040960
pmcid: 9074089
doi: 10.7326/M19-2511
La Rosa, C. et al. Hematopoietic stem cell donor vaccination with cytomegalovirus triplex augments frequencies of functional and durable cytomegalovirus‐specific T cells in the recipient: a novel strategy to limit antiviral prophylaxis. Am. J. Hematol. 98, 588–597 (2023).
pubmed: 36594185
doi: 10.1002/ajh.26824
Rashidi, A. et al. CMV triplex vaccine to enhance adaptive NK and T-cell reconstitution after autologous hematopoietic cell transplantation. Transplant. Cell. Ther. 28, 343.e1–343.e4 (2022).
pubmed: 35272066
doi: 10.1016/j.jtct.2022.03.003
Ball, C. B. et al. Human cytomegalovirus IE2 both activates and represses initiation and modulates elongation in a context-dependent manner. mBio 13, e00337–22 (2022).
pubmed: 35579393
pmcid: 9239164
doi: 10.1128/mbio.00337-22
Asmar, J., Wiebusch, L., Truss, M. & Hagemeier, C. The putative zinc finger of the human cytomegalovirus IE2 86-kilodalton protein is dispensable for DNA binding and autorepression, thereby demarcating a concise core domain in the C terminus of the protein. J. Virol. 78, 11853–11864 (2004).
pubmed: 15479827
pmcid: 523240
doi: 10.1128/JVI.78.21.11853-11864.2004
Chiuppesi, F. et al. Development of a multi-antigenic SARS-CoV-2 vaccine candidate using a synthetic poxvirus platform. Nat. Commun. 11, 6121 (2020).
pubmed: 33257686
pmcid: 7705736
doi: 10.1038/s41467-020-19819-1
Wussow, F. et al. Synthetic multiantigen MVA vaccine COH04S1 and variant-specific derivatives protect Syrian hamsters from SARS-CoV-2 Omicron subvariants. Npj Vaccines 8, 41 (2023).
pubmed: 36928589
pmcid: 10018591
doi: 10.1038/s41541-023-00640-y
Chiuppesi, F. et al. Synthetic multiantigen MVA vaccine COH04S1 protects against SARS-CoV-2 in Syrian hamsters and non-human primates. Npj Vaccines 7, 7 (2022).
pubmed: 35064109
pmcid: 8782996
doi: 10.1038/s41541-022-00436-6
Chiuppesi, F. et al. Safety and immunogenicity of a synthetic multiantigen modified vaccinia virus Ankara-based COVID-19 vaccine (COH04S1): an open-label and randomised, phase 1 trial. Lancet Microbe 3, e252–e264 (2022).
pubmed: 35287430
pmcid: 8906816
doi: 10.1016/S2666-5247(22)00027-1
Wyatt, L. S. et al. Elucidating and minimizing the loss by recombinant vaccinia virus of human immunodeficiency virus gene expression resulting from spontaneous mutations and positive selection. J. Virol. 83, 7176–7184 (2009).
pubmed: 19420086
pmcid: 2704791
doi: 10.1128/JVI.00687-09
Tischer, B. K., von Einem, J., Kaufer, B. & Osterrieder, N. Two-step red-mediated recombination for versatile high-efficiency markerless DNA manipulation in Escherichia coli. BioTechniques 40, 191–197 (2006).
pubmed: 16526409
doi: 10.2144/000112096
Tischer, B. K., Smith, G. A. & Osterrieder, N. En passant mutagenesis: a two step markerless red recombination system. in In Vitro Mutagenesis Protocols (ed. Braman, J.) vol. 634 421–430 (Humana Press, Totowa, NJ, 2010).
Taylor, J., Weinberg, R., Kawaoka, Y., Webster, R. & Paoletti, E. Protective immunity against avian influenza induced by a fowlpox virus recombinant. Vaccine 6, 504–508 (1988).
pubmed: 2854339
doi: 10.1016/0264-410X(88)90101-6
Lohr, V. et al. The avian cell line AGE1.CR.pIX characterized by metabolic flux analysis. BMC Biotechnol. 14, 72 (2014).
pubmed: 25077436
pmcid: 4124504
doi: 10.1186/1472-6750-14-72
Lohr, V. et al. Live attenuated influenza viruses produced in a suspension process with avian AGE1.CR.pIX cells. BMC Biotechnol. 12, 79 (2012).
pubmed: 23110398
pmcid: 3505166
doi: 10.1186/1472-6750-12-79
Pascolo, S. et al. HLA-A2.1-restricted education and cytolytic activity of CD8(+) T lymphocytes from beta2 microglobulin (beta2m) HLA-A2.1 monochain transgenic H-2Db beta2m double knockout mice. J. Exp. Med. 185, 2043–2051 (1997).
pubmed: 9182675
pmcid: 2196346
doi: 10.1084/jem.185.12.2043
Rohrlich, P.-S. et al. HLA-B*0702 transgenic, H-2KbDb double-knockout mice: phenotypical and functional characterization in response to influenza virus. Int. Immunol. 15, 765–772 (2003).
pubmed: 12750360
doi: 10.1093/intimm/dxg073
Kozak, M. Pushing the limits of the scanning mechanism for initiation of translation. Gene 299, 1–34 (2002).
pubmed: 12459250
pmcid: 7126118
doi: 10.1016/S0378-1119(02)01056-9
Kozak, M. An analysis of 5’-noncoding sequences from 699 vertebrate messenger RNAs. Nucleic Acids Res. 15, 8125–8148 (1987).
pubmed: 3313277
pmcid: 306349
doi: 10.1093/nar/15.20.8125
Lemonnier, F. A. The utility of H-2 class I knockout mice. Virus Res. 82, 87–90 (2001).
doi: 10.1016/S0168-1702(01)00392-6
Daftarian, P. et al. Immunization with Th-CTL fusion peptide and cytosine-phosphate-guanine DNA in transgenic HLA-A2 mice induces recognition of HIV-infected T cells and clears vaccinia virus challenge. J. Immunol. 171, 4028–4039 (2003).
pubmed: 14530323
doi: 10.4049/jimmunol.171.8.4028
Song, G.-Y. et al. An MVA vaccine overcomes tolerance to human p53 in mice and humans. Cancer Immunol. Immunother. 56, 1193–1205 (2007).
pubmed: 17219151
doi: 10.1007/s00262-006-0270-3
Birnboim, H. C. & Doly, J. A rapid alkaline extraction procedure for screening recombinant plasmid DNA. Nucleic Acids Res. 7, 1513–1523 (1979).
pubmed: 388356
pmcid: 342324
doi: 10.1093/nar/7.6.1513
Boppana, S. B., Smith, R. J., Stagno, S. & Britt, W. J. Evaluation of a microtiter plate fluorescent-antibody assay for rapid detection of human cytomegalovirus infection. J. Clin. Microbiol. 30, 721–723 (1992).
pubmed: 1313050
pmcid: 265140
doi: 10.1128/jcm.30.3.721-723.1992
White, E. A., Clark, C. L., Sanchez, V. & Spector, D. H. Small internal deletions in the human cytomegalovirus IE2 gene result in nonviable recombinant viruses with differential defects in viral gene expression. J. Virol. 78, 1817–1830 (2004).
pubmed: 14747546
pmcid: 369462
doi: 10.1128/JVI.78.4.1817-1830.2004
Britt, W. J. & Auger, D. Identification of a 65 000 dalton virion envelope protein of human cytomegalovirus. Virus Res. 4, 31–36 (1985).
pubmed: 3002068
doi: 10.1016/0168-1702(85)90018-8
Schmelz, M. et al. Assembly of vaccinia virus: the second wrapping cisterna is derived from the trans Golgi network. J. Virol. 68, 130–147 (1994).
pubmed: 8254722
pmcid: 236272
doi: 10.1128/jvi.68.1.130-147.1994