Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination
Modern, subunit-based vaccines have so far failed to induce significant T cell responses, contributing to ineffective vaccination against many pathogens. Importantly, while today’s adjuvants are designed to trigger innate and non-specific immune responses, they fail to directly stimulate the adaptiv...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Pharmacology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1029636/full |
| _version_ | 1811178228048461824 |
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| author | Timothy W. Phares Jing Huang Jing Huang Vinayaka Kotraiah Mary J. Hauser Arban Domi Sreenivasa Oruganti Cecille D. Browne Peter Buontempo Marc Mansour James Pannucci Moriya Tsuji Moriya Tsuji Gabriel M. Gutierrez |
| author_facet | Timothy W. Phares Jing Huang Jing Huang Vinayaka Kotraiah Mary J. Hauser Arban Domi Sreenivasa Oruganti Cecille D. Browne Peter Buontempo Marc Mansour James Pannucci Moriya Tsuji Moriya Tsuji Gabriel M. Gutierrez |
| author_sort | Timothy W. Phares |
| collection | DOAJ |
| description | Modern, subunit-based vaccines have so far failed to induce significant T cell responses, contributing to ineffective vaccination against many pathogens. Importantly, while today’s adjuvants are designed to trigger innate and non-specific immune responses, they fail to directly stimulate the adaptive immune compartment. Programmed cell death 1 (PD-1) partly regulates naïve-to-antigen-specific effector T cell transition and differentiation by suppressing the magnitude of activation. Indeed, we previously reported on a microbial-derived, peptide-based PD-1 checkpoint inhibitor, LD01, which showed potent T cell-stimulating activity when combined with a vaccine. Here we sought to improve the potency of LD01 by designing and testing new LD01 derivatives. Accordingly, we found that a modified version of an 18-amino acid metabolite of LD01, LD10da, improved T cell activation capability in a malaria vaccine model. Specifically, LD10da demonstrates improved antigen-specific CD8+ T cell expansion when combined prophylactically with an adenovirus-based malaria vaccine. A single dose of LD10da at the time of vaccination is sufficient to increase antigen-specific CD8+ T cell expansion in wild-type mice. Further, we show that LD10 can be encoded and delivered by a Modified Vaccinia Ankara viral vector and can enhance antigen-specific CD8+ T cell expansion comparable to that of synthetic peptide administration. Therefore, LD10da represents a promising biologic-based immunomodulator that can be genetically encoded and delivered, along with the antigen, by viral or other nucleic acid vectors to improve the efficacy and delivery of vaccines for ineradicable and emerging infectious diseases. |
| first_indexed | 2024-04-11T06:16:08Z |
| format | Article |
| id | doaj.art-2f258d42010d4ee08731503892bc8c93 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T06:16:08Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-2f258d42010d4ee08731503892bc8c932022-12-22T04:41:03ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-12-011310.3389/fphar.2022.10296361029636Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccinationTimothy W. Phares0Jing Huang1Jing Huang2Vinayaka Kotraiah3Mary J. Hauser4Arban Domi5Sreenivasa Oruganti6Cecille D. Browne7Peter Buontempo8Marc Mansour9James Pannucci10Moriya Tsuji11Moriya Tsuji12Gabriel M. Gutierrez13Thunder Biotech, Provo, UT, United StatesThe Aaron Diamond AIDS Research Center, New York, NY, United StatesDepartment of Medicine, Columbia University Irving Medical Center, New York, NY, United StatesLeidos Life Sciences, Leidos Inc., Frederick, MD, United StatesGeoVax Inc., Atlanta, GA, United StatesGeoVax Inc., Atlanta, GA, United StatesGeoVax Inc., Atlanta, GA, United StatesThermo Fisher Scientific, San Diego, CA, United StatesThe MITRE Corporation, McLean, VA, United StatesMM Scientific Consultants Inc., Halifax, NS, CanadaThe MITRE Corporation, McLean, VA, United StatesThe Aaron Diamond AIDS Research Center, New York, NY, United StatesDepartment of Medicine, Columbia University Irving Medical Center, New York, NY, United StatesHibiscus Biotechnology, LLC, Rockville, MD, United StatesModern, subunit-based vaccines have so far failed to induce significant T cell responses, contributing to ineffective vaccination against many pathogens. Importantly, while today’s adjuvants are designed to trigger innate and non-specific immune responses, they fail to directly stimulate the adaptive immune compartment. Programmed cell death 1 (PD-1) partly regulates naïve-to-antigen-specific effector T cell transition and differentiation by suppressing the magnitude of activation. Indeed, we previously reported on a microbial-derived, peptide-based PD-1 checkpoint inhibitor, LD01, which showed potent T cell-stimulating activity when combined with a vaccine. Here we sought to improve the potency of LD01 by designing and testing new LD01 derivatives. Accordingly, we found that a modified version of an 18-amino acid metabolite of LD01, LD10da, improved T cell activation capability in a malaria vaccine model. Specifically, LD10da demonstrates improved antigen-specific CD8+ T cell expansion when combined prophylactically with an adenovirus-based malaria vaccine. A single dose of LD10da at the time of vaccination is sufficient to increase antigen-specific CD8+ T cell expansion in wild-type mice. Further, we show that LD10 can be encoded and delivered by a Modified Vaccinia Ankara viral vector and can enhance antigen-specific CD8+ T cell expansion comparable to that of synthetic peptide administration. Therefore, LD10da represents a promising biologic-based immunomodulator that can be genetically encoded and delivered, along with the antigen, by viral or other nucleic acid vectors to improve the efficacy and delivery of vaccines for ineradicable and emerging infectious diseases.https://www.frontiersin.org/articles/10.3389/fphar.2022.1029636/fullvaccinePD1immunomodulatorCD8+viral deliveryinfectious disease |
| spellingShingle | Timothy W. Phares Jing Huang Jing Huang Vinayaka Kotraiah Mary J. Hauser Arban Domi Sreenivasa Oruganti Cecille D. Browne Peter Buontempo Marc Mansour James Pannucci Moriya Tsuji Moriya Tsuji Gabriel M. Gutierrez Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination Frontiers in Pharmacology vaccine PD1 immunomodulator CD8+ viral delivery infectious disease |
| title | Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination |
| title_full | Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination |
| title_fullStr | Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination |
| title_full_unstemmed | Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination |
| title_short | Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination |
| title_sort | viral delivery of a peptide based immunomodulator enhances t cell priming during vaccination |
| topic | vaccine PD1 immunomodulator CD8+ viral delivery infectious disease |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1029636/full |
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