A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate

L Sanchez-Felipe; T Vercruysse; S Sharma; J Ma; V Lemmens; D Van Looveren; MP Arkalagud Javarappa; R Boudewijns; B Malengier-Devlies; L Liesenborghs; SJF Kaptein; C De Keyzer; L Bervoets; S Debaveye; M Rasulova; L Seldeslachts; LH Li; S Jansen; MB Yakass; BE Verstrepen; KP Böszörményi; G Kiemenyi-Kayere; N van Driel; O Quaye; X Zhang; S Horst; N Mishra; W Deboutte; J Matthijnssens; L Coelmont; C Vandermeulen; E Heylen; V Vergote; D Schols; Zhongde Wang; W Bogers; Thijs Kuiken; E Verschoor; C Cawthorne; K Van Laere; G Opdenakker; G Velde; B Weynand; DE Teuwen; P Matthys; J Neyts; H Jan Thibaut; K Dallmeier

doi:10.1038/s41586-020-3035-9

A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate

L Sanchez-Felipe, T Vercruysse, S Sharma, J Ma, V Lemmens, D Van Looveren, MP Arkalagud Javarappa, R Boudewijns, B Malengier-Devlies, L Liesenborghs, SJF Kaptein, C De Keyzer, L Bervoets, S Debaveye, M Rasulova, L Seldeslachts, LH Li, S Jansen, MB Yakass, BE VerstrepenKP Böszörményi, G Kiemenyi-Kayere, N van Driel, O Quaye, X Zhang, S Horst, N Mishra, W Deboutte, J Matthijnssens, L Coelmont, C Vandermeulen, E Heylen, V Vergote, D Schols, Zhongde Wang, W Bogers, Thijs Kuiken, E Verschoor, C Cawthorne, K Van Laere, G Opdenakker, G Velde, B Weynand, DE Teuwen, P Matthys, J Neyts, H Jan Thibaut, K Dallmeier

Virology

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Abstract

The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response¹. Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and—concomitantly—protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model² and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.

Original language	English
Pages (from-to)	320-325
Number of pages	6
Journal	Nature
Volume	590
Issue number	7845
DOIs	https://doi.org/10.1038/s41586-020-3035-9
Publication status	Published - 11 Feb 2021

Bibliographical note

Funding Information:
Acknowledgements We thank E. Maas, J. Rymenants, T. Van Buyten, C. Collard, B. Voeten, D. Buyst and N. Cremers for the in vitro cell and virus culture and purification; K. Van den Eynde, E. Allegaert, S. Cumps and W. Versin for technical support with the preparation of specimens for histology; C. Coun, J. Paulissen, C. Sablon and N. Thys for technical assistance in cloning the different vaccine constructs and for generating serology data; J. Wouters and J. Nuyts for help with micro-computed tomography image analysis and support with imaging file processing; E. Martens for help with biomarker analysis; N. Berghmans, S. Knoops, T.-T. Pham, H. Crijns, M. Lox and N. Ongenae for help with hamster husbandry and bleeding; J. Vercruysse, C. Vansalen and N. Goris for help with large scale plasmid production; L. Close for next-generation sequencing analysis of vaccine virus stocks; D. Daelemans for access and W. Chiu for technical assistance with the high content screening platform; R. Gijsbers for helping with generation of pseudotyped viral vectors; H. Serroyen for assisting in figure design; M. A. Whitt for providing plasmids to rescue VSV-dG-GFP pseudoviruses; H. Kleine-Weber, M. Hoffmann and S. Pöhlmann for sharing L1-hybridoma supernatants and protocols for the generation of VSV pseudovirions; B. J. Bosch and W. Li for sharing SARS-CoV-2 S expression plasmids; I. Goodfellow for providing BSR-T7 cells; E. Brouwers for assistance in culturing hybridoma cells; P. Bredenbeek for providing BHK-21J and Vero E6 cells; and C. Libert for providing Ifnar1−/− mouse breeding couples. This list of people who have provided help during these exceptional times may not be complete, and the corresponding authors apologize for any accidental omissions. This project received funding from the European Union’s Horizon 2020 research and innovation programme (no. 101003627 (SCORE project) and no. 733176 (RABYD-VAX consortium)), funding from the Bill and Melinda Gates Foundation (INV-00636), the Research Foundation Flanders (FWO) under the Excellence of Science (EOS) program (VirEOS project 30981113), the FWO Hercules Foundation (Caps-It infrastructure). the KU Leuven Rega Foundation, the FWO (no. G0G4820N) and the KU Leuven/UZ Leuven COVID-19 Fund (COVAX-PREC project). J.M. and X.Z. were supported by grants from the China Scholarship Council (CSC). C.C. was supported by the FWO (FWO 1001719N). L.-H.L. was supported by a KU Leuven DBOF PhD scholarship. G.V.V. acknowledges grant support from KU Leuven Internal Funds (C24/17/061) and K.D. acknowledges grant support from KU Leuven

Funding Information:
Internal Funds (C3/19/057 Laboratory of Excellence). G.O. and P.M. received funding from KU Leuven (C16/17/010) and from FWO–Vlaanderen. K.B. was supported by the European Union’s Marie Skłodowska-Curie Innovative Training Network HONOURs (no. 721367). We appreciate the in-kind contribution of UCB Pharma (Brussels). We thank everyone who has supported this research by donating money, organizing fundraising campaigns or helping to spread the word. Our efforts to develop a vaccine were strengthened by support from the KU Leuven COVID-19 Fund. We thank all donors and volunteers for their continued support, generosity and optimism.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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Cite this

Sanchez-Felipe, L., Vercruysse, T., Sharma, S., Ma, J., Lemmens, V., Van Looveren, D., Arkalagud Javarappa, MP., Boudewijns, R., Malengier-Devlies, B., Liesenborghs, L., Kaptein, SJF., De Keyzer, C., Bervoets, L., Debaveye, S., Rasulova, M., Seldeslachts, L., Li, LH., Jansen, S., Yakass, MB., ... Dallmeier, K. (2021). A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate. Nature, 590(7845), 320-325. https://doi.org/10.1038/s41586-020-3035-9

@article{2ba993a835e64cb3b8c886623c50834f,

title = "A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate",

abstract = "The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response1. Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and—concomitantly—protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model2 and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.",

author = "L Sanchez-Felipe and T Vercruysse and S Sharma and J Ma and V Lemmens and {Van Looveren}, D and {Arkalagud Javarappa}, MP and R Boudewijns and B Malengier-Devlies and L Liesenborghs and SJF Kaptein and {De Keyzer}, C and L Bervoets and S Debaveye and M Rasulova and L Seldeslachts and LH Li and S Jansen and MB Yakass and BE Verstrepen and KP B{\"o}sz{\"o}rm{\'e}nyi and G Kiemenyi-Kayere and {van Driel}, N and O Quaye and X Zhang and S Horst and N Mishra and W Deboutte and J Matthijnssens and L Coelmont and C Vandermeulen and E Heylen and V Vergote and D Schols and Zhongde Wang and W Bogers and Thijs Kuiken and E Verschoor and C Cawthorne and {Van Laere}, K and G Opdenakker and G Velde and B Weynand and DE Teuwen and P Matthys and J Neyts and {Jan Thibaut}, H and K Dallmeier",

note = "Funding Information: Acknowledgements We thank E. Maas, J. Rymenants, T. Van Buyten, C. Collard, B. Voeten, D. Buyst and N. Cremers for the in vitro cell and virus culture and purification; K. Van den Eynde, E. Allegaert, S. Cumps and W. Versin for technical support with the preparation of specimens for histology; C. Coun, J. Paulissen, C. Sablon and N. Thys for technical assistance in cloning the different vaccine constructs and for generating serology data; J. Wouters and J. Nuyts for help with micro-computed tomography image analysis and support with imaging file processing; E. Martens for help with biomarker analysis; N. Berghmans, S. Knoops, T.-T. Pham, H. Crijns, M. Lox and N. Ongenae for help with hamster husbandry and bleeding; J. Vercruysse, C. Vansalen and N. Goris for help with large scale plasmid production; L. Close for next-generation sequencing analysis of vaccine virus stocks; D. Daelemans for access and W. Chiu for technical assistance with the high content screening platform; R. Gijsbers for helping with generation of pseudotyped viral vectors; H. Serroyen for assisting in figure design; M. A. Whitt for providing plasmids to rescue VSV-dG-GFP pseudoviruses; H. Kleine-Weber, M. Hoffmann and S. P{\"o}hlmann for sharing L1-hybridoma supernatants and protocols for the generation of VSV pseudovirions; B. J. Bosch and W. Li for sharing SARS-CoV-2 S expression plasmids; I. Goodfellow for providing BSR-T7 cells; E. Brouwers for assistance in culturing hybridoma cells; P. Bredenbeek for providing BHK-21J and Vero E6 cells; and C. Libert for providing Ifnar1−/− mouse breeding couples. This list of people who have provided help during these exceptional times may not be complete, and the corresponding authors apologize for any accidental omissions. This project received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation programme (no. 101003627 (SCORE project) and no. 733176 (RABYD-VAX consortium)), funding from the Bill and Melinda Gates Foundation (INV-00636), the Research Foundation Flanders (FWO) under the Excellence of Science (EOS) program (VirEOS project 30981113), the FWO Hercules Foundation (Caps-It infrastructure). the KU Leuven Rega Foundation, the FWO (no. G0G4820N) and the KU Leuven/UZ Leuven COVID-19 Fund (COVAX-PREC project). J.M. and X.Z. were supported by grants from the China Scholarship Council (CSC). C.C. was supported by the FWO (FWO 1001719N). L.-H.L. was supported by a KU Leuven DBOF PhD scholarship. G.V.V. acknowledges grant support from KU Leuven Internal Funds (C24/17/061) and K.D. acknowledges grant support from KU Leuven Funding Information: Internal Funds (C3/19/057 Laboratory of Excellence). G.O. and P.M. received funding from KU Leuven (C16/17/010) and from FWO–Vlaanderen. K.B. was supported by the European Union{\textquoteright}s Marie Sk{\l}odowska-Curie Innovative Training Network HONOURs (no. 721367). We appreciate the in-kind contribution of UCB Pharma (Brussels). We thank everyone who has supported this research by donating money, organizing fundraising campaigns or helping to spread the word. Our efforts to develop a vaccine were strengthened by support from the KU Leuven COVID-19 Fund. We thank all donors and volunteers for their continued support, generosity and optimism. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = feb,

day = "11",

doi = "10.1038/s41586-020-3035-9",

language = "English",

volume = "590",

pages = "320--325",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7845",

}

Sanchez-Felipe, L, Vercruysse, T, Sharma, S, Ma, J, Lemmens, V, Van Looveren, D, Arkalagud Javarappa, MP, Boudewijns, R, Malengier-Devlies, B, Liesenborghs, L, Kaptein, SJF, De Keyzer, C, Bervoets, L, Debaveye, S, Rasulova, M, Seldeslachts, L, Li, LH, Jansen, S, Yakass, MB, Verstrepen, BE, Böszörményi, KP, Kiemenyi-Kayere, G, van Driel, N, Quaye, O, Zhang, X, Horst, S, Mishra, N, Deboutte, W, Matthijnssens, J, Coelmont, L, Vandermeulen, C, Heylen, E, Vergote, V, Schols, D, Wang, Z, Bogers, W, Kuiken, T, Verschoor, E, Cawthorne, C, Van Laere, K, Opdenakker, G, Velde, G, Weynand, B, Teuwen, DE, Matthys, P, Neyts, J, Jan Thibaut, H & Dallmeier, K 2021, 'A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate', Nature, vol. 590, no. 7845, pp. 320-325. https://doi.org/10.1038/s41586-020-3035-9

TY - JOUR

T1 - A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate

AU - Sanchez-Felipe, L

AU - Vercruysse, T

AU - Sharma, S

AU - Ma, J

AU - Lemmens, V

AU - Van Looveren, D

AU - Arkalagud Javarappa, MP

AU - Boudewijns, R

AU - Malengier-Devlies, B

AU - Liesenborghs, L

AU - Kaptein, SJF

AU - De Keyzer, C

AU - Bervoets, L

AU - Debaveye, S

AU - Rasulova, M

AU - Seldeslachts, L

AU - Li, LH

AU - Jansen, S

AU - Yakass, MB

AU - Verstrepen, BE

AU - Böszörményi, KP

AU - Kiemenyi-Kayere, G

AU - van Driel, N

AU - Quaye, O

AU - Zhang, X

AU - Horst, S

AU - Mishra, N

AU - Deboutte, W

AU - Matthijnssens, J

AU - Coelmont, L

AU - Vandermeulen, C

AU - Heylen, E

AU - Vergote, V

AU - Schols, D

AU - Wang, Zhongde

AU - Bogers, W

AU - Kuiken, Thijs

AU - Verschoor, E

AU - Cawthorne, C

AU - Van Laere, K

AU - Opdenakker, G

AU - Velde, G

AU - Weynand, B

AU - Teuwen, DE

AU - Matthys, P

AU - Neyts, J

AU - Jan Thibaut, H

AU - Dallmeier, K

N1 - Funding Information: Acknowledgements We thank E. Maas, J. Rymenants, T. Van Buyten, C. Collard, B. Voeten, D. Buyst and N. Cremers for the in vitro cell and virus culture and purification; K. Van den Eynde, E. Allegaert, S. Cumps and W. Versin for technical support with the preparation of specimens for histology; C. Coun, J. Paulissen, C. Sablon and N. Thys for technical assistance in cloning the different vaccine constructs and for generating serology data; J. Wouters and J. Nuyts for help with micro-computed tomography image analysis and support with imaging file processing; E. Martens for help with biomarker analysis; N. Berghmans, S. Knoops, T.-T. Pham, H. Crijns, M. Lox and N. Ongenae for help with hamster husbandry and bleeding; J. Vercruysse, C. Vansalen and N. Goris for help with large scale plasmid production; L. Close for next-generation sequencing analysis of vaccine virus stocks; D. Daelemans for access and W. Chiu for technical assistance with the high content screening platform; R. Gijsbers for helping with generation of pseudotyped viral vectors; H. Serroyen for assisting in figure design; M. A. Whitt for providing plasmids to rescue VSV-dG-GFP pseudoviruses; H. Kleine-Weber, M. Hoffmann and S. Pöhlmann for sharing L1-hybridoma supernatants and protocols for the generation of VSV pseudovirions; B. J. Bosch and W. Li for sharing SARS-CoV-2 S expression plasmids; I. Goodfellow for providing BSR-T7 cells; E. Brouwers for assistance in culturing hybridoma cells; P. Bredenbeek for providing BHK-21J and Vero E6 cells; and C. Libert for providing Ifnar1−/− mouse breeding couples. This list of people who have provided help during these exceptional times may not be complete, and the corresponding authors apologize for any accidental omissions. This project received funding from the European Union’s Horizon 2020 research and innovation programme (no. 101003627 (SCORE project) and no. 733176 (RABYD-VAX consortium)), funding from the Bill and Melinda Gates Foundation (INV-00636), the Research Foundation Flanders (FWO) under the Excellence of Science (EOS) program (VirEOS project 30981113), the FWO Hercules Foundation (Caps-It infrastructure). the KU Leuven Rega Foundation, the FWO (no. G0G4820N) and the KU Leuven/UZ Leuven COVID-19 Fund (COVAX-PREC project). J.M. and X.Z. were supported by grants from the China Scholarship Council (CSC). C.C. was supported by the FWO (FWO 1001719N). L.-H.L. was supported by a KU Leuven DBOF PhD scholarship. G.V.V. acknowledges grant support from KU Leuven Internal Funds (C24/17/061) and K.D. acknowledges grant support from KU Leuven Funding Information: Internal Funds (C3/19/057 Laboratory of Excellence). G.O. and P.M. received funding from KU Leuven (C16/17/010) and from FWO–Vlaanderen. K.B. was supported by the European Union’s Marie Skłodowska-Curie Innovative Training Network HONOURs (no. 721367). We appreciate the in-kind contribution of UCB Pharma (Brussels). We thank everyone who has supported this research by donating money, organizing fundraising campaigns or helping to spread the word. Our efforts to develop a vaccine were strengthened by support from the KU Leuven COVID-19 Fund. We thank all donors and volunteers for their continued support, generosity and optimism. Publisher Copyright: © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2021/2/11

Y1 - 2021/2/11

N2 - The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response1. Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and—concomitantly—protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model2 and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.

AB - The expanding pandemic of coronavirus disease 2019 (COVID-19) requires the development of safe, efficacious and fast-acting vaccines. Several vaccine platforms are being leveraged for a rapid emergency response1. Here we describe the development of a candidate vaccine (YF-S0) for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that uses live-attenuated yellow fever 17D (YF17D) vaccine as a vector to express a noncleavable prefusion form of the SARS-CoV-2 spike antigen. We assess vaccine safety, immunogenicity and efficacy in several animal models. YF-S0 has an excellent safety profile and induces high levels of SARS-CoV-2 neutralizing antibodies in hamsters (Mesocricetus auratus), mice (Mus musculus) and cynomolgus macaques (Macaca fascicularis), and—concomitantly—protective immunity against yellow fever virus. Humoral immunity is complemented by a cellular immune response with favourable T helper 1 polarization, as profiled in mice. In a hamster model2 and in macaques, YF-S0 prevents infection with SARS-CoV-2. Moreover, a single dose conferred protection from lung disease in most of the vaccinated hamsters within as little as 10 days. Taken together, the quality of the immune responses triggered and the rapid kinetics by which protective immunity can be attained after a single dose warrant further development of this potent SARS-CoV-2 vaccine candidate.

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U2 - 10.1038/s41586-020-3035-9

DO - 10.1038/s41586-020-3035-9

M3 - Article

C2 - 33260195

SN - 0028-0836

VL - 590

SP - 320

EP - 325

JO - Nature

JF - Nature

IS - 7845

ER -

A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate

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