Recombinant Modified Vaccinia Virus Ankara Expressing a Glycosylation Mutant of Dengue Virus NS1 Induces Specific Antibody and T-Cell Responses in Mice
The four serotypes of dengue virus (DENV1–4) continue to pose a major public health threat. The first licenced dengue vaccine, which expresses the surface proteins of DENV1–4, has performed poorly in immunologically naïve individuals, sensitising them to antibody-enhanced dengue disease. DENV non-st...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-03-01
|
| Series: | Vaccines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-393X/11/4/714 |
| _version_ | 1797603300819861504 |
|---|---|
| author | Lucas Wilken Sonja Stelz Ayse Agac Gerd Sutter Chittappen Kandiyil Prajeeth Guus F. Rimmelzwaan |
| author_facet | Lucas Wilken Sonja Stelz Ayse Agac Gerd Sutter Chittappen Kandiyil Prajeeth Guus F. Rimmelzwaan |
| author_sort | Lucas Wilken |
| collection | DOAJ |
| description | The four serotypes of dengue virus (DENV1–4) continue to pose a major public health threat. The first licenced dengue vaccine, which expresses the surface proteins of DENV1–4, has performed poorly in immunologically naïve individuals, sensitising them to antibody-enhanced dengue disease. DENV non-structural protein 1 (NS1) can directly induce vascular leakage, the hallmark of severe dengue disease, which is blocked by NS1-specific antibodies, making it an attractive target for vaccine development. However, the intrinsic ability of NS1 to trigger vascular leakage is a potential drawback of its use as a vaccine antigen. Here, we modified DENV2 NS1 by mutating an N-linked glycosylation site associated with NS1-induced endothelial hyperpermeability and used modified vaccinia virus Ankara (MVA) as a vector for its delivery. The resulting construct, rMVA-D2-NS1-N207Q, displayed high genetic stability and drove efficient secretion of NS1-N207Q from infected cells. Secreted NS1-N207Q was composed of dimers and lacked N-linked glycosylation at position 207. Prime–boost immunisation of C57BL/6J mice induced high levels of NS1-specific antibodies binding various conformations of NS1 and elicited NS1-specific CD4<sup>+</sup> T-cell responses. Our findings support rMVA-D2-NS1-N207Q as a promising and potentially safer alternative to existing NS1-based vaccine candidates, warranting further pre-clinical testing in a relevant mouse model of DENV infection. |
| first_indexed | 2024-03-11T04:28:14Z |
| format | Article |
| id | doaj.art-95158a0bb5a14b38ab736f610ede6edf |
| institution | Directory Open Access Journal |
| issn | 2076-393X |
| language | English |
| last_indexed | 2024-03-11T04:28:14Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj.art-95158a0bb5a14b38ab736f610ede6edf2023-11-17T21:40:42ZengMDPI AGVaccines2076-393X2023-03-0111471410.3390/vaccines11040714Recombinant Modified Vaccinia Virus Ankara Expressing a Glycosylation Mutant of Dengue Virus NS1 Induces Specific Antibody and T-Cell Responses in MiceLucas Wilken0Sonja Stelz1Ayse Agac2Gerd Sutter3Chittappen Kandiyil Prajeeth4Guus F. Rimmelzwaan5Research Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine (TiHo), 30559 Hannover, GermanyResearch Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine (TiHo), 30559 Hannover, GermanyResearch Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine (TiHo), 30559 Hannover, GermanyDivision of Virology, Institute for Infectious Diseases and Zoonoses, Department of Veterinary Sciences, Ludwig Maximilian University (LMU), 80539 Munich, GermanyResearch Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine (TiHo), 30559 Hannover, GermanyResearch Center for Emerging Infections and Zoonoses (RIZ), University of Veterinary Medicine (TiHo), 30559 Hannover, GermanyThe four serotypes of dengue virus (DENV1–4) continue to pose a major public health threat. The first licenced dengue vaccine, which expresses the surface proteins of DENV1–4, has performed poorly in immunologically naïve individuals, sensitising them to antibody-enhanced dengue disease. DENV non-structural protein 1 (NS1) can directly induce vascular leakage, the hallmark of severe dengue disease, which is blocked by NS1-specific antibodies, making it an attractive target for vaccine development. However, the intrinsic ability of NS1 to trigger vascular leakage is a potential drawback of its use as a vaccine antigen. Here, we modified DENV2 NS1 by mutating an N-linked glycosylation site associated with NS1-induced endothelial hyperpermeability and used modified vaccinia virus Ankara (MVA) as a vector for its delivery. The resulting construct, rMVA-D2-NS1-N207Q, displayed high genetic stability and drove efficient secretion of NS1-N207Q from infected cells. Secreted NS1-N207Q was composed of dimers and lacked N-linked glycosylation at position 207. Prime–boost immunisation of C57BL/6J mice induced high levels of NS1-specific antibodies binding various conformations of NS1 and elicited NS1-specific CD4<sup>+</sup> T-cell responses. Our findings support rMVA-D2-NS1-N207Q as a promising and potentially safer alternative to existing NS1-based vaccine candidates, warranting further pre-clinical testing in a relevant mouse model of DENV infection.https://www.mdpi.com/2076-393X/11/4/714dengue virusvaccinevectorantibodyT cell |
| spellingShingle | Lucas Wilken Sonja Stelz Ayse Agac Gerd Sutter Chittappen Kandiyil Prajeeth Guus F. Rimmelzwaan Recombinant Modified Vaccinia Virus Ankara Expressing a Glycosylation Mutant of Dengue Virus NS1 Induces Specific Antibody and T-Cell Responses in Mice Vaccines dengue virus vaccine vector antibody T cell |
| title | Recombinant Modified Vaccinia Virus Ankara Expressing a Glycosylation Mutant of Dengue Virus NS1 Induces Specific Antibody and T-Cell Responses in Mice |
| title_full | Recombinant Modified Vaccinia Virus Ankara Expressing a Glycosylation Mutant of Dengue Virus NS1 Induces Specific Antibody and T-Cell Responses in Mice |
| title_fullStr | Recombinant Modified Vaccinia Virus Ankara Expressing a Glycosylation Mutant of Dengue Virus NS1 Induces Specific Antibody and T-Cell Responses in Mice |
| title_full_unstemmed | Recombinant Modified Vaccinia Virus Ankara Expressing a Glycosylation Mutant of Dengue Virus NS1 Induces Specific Antibody and T-Cell Responses in Mice |
| title_short | Recombinant Modified Vaccinia Virus Ankara Expressing a Glycosylation Mutant of Dengue Virus NS1 Induces Specific Antibody and T-Cell Responses in Mice |
| title_sort | recombinant modified vaccinia virus ankara expressing a glycosylation mutant of dengue virus ns1 induces specific antibody and t cell responses in mice |
| topic | dengue virus vaccine vector antibody T cell |
| url | https://www.mdpi.com/2076-393X/11/4/714 |
| work_keys_str_mv | AT lucaswilken recombinantmodifiedvacciniavirusankaraexpressingaglycosylationmutantofdenguevirusns1inducesspecificantibodyandtcellresponsesinmice AT sonjastelz recombinantmodifiedvacciniavirusankaraexpressingaglycosylationmutantofdenguevirusns1inducesspecificantibodyandtcellresponsesinmice AT ayseagac recombinantmodifiedvacciniavirusankaraexpressingaglycosylationmutantofdenguevirusns1inducesspecificantibodyandtcellresponsesinmice AT gerdsutter recombinantmodifiedvacciniavirusankaraexpressingaglycosylationmutantofdenguevirusns1inducesspecificantibodyandtcellresponsesinmice AT chittappenkandiyilprajeeth recombinantmodifiedvacciniavirusankaraexpressingaglycosylationmutantofdenguevirusns1inducesspecificantibodyandtcellresponsesinmice AT guusfrimmelzwaan recombinantmodifiedvacciniavirusankaraexpressingaglycosylationmutantofdenguevirusns1inducesspecificantibodyandtcellresponsesinmice |