Safe and effective two-in-one replicon-and-VLP minispike
vaccine for COVID-19: Protection of mice after a single
immunization

J 2021

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization

HENNRICH, A.A., B. SAWATSKY, B. SANTOS-MANDUJANO, D.H. BANDA, M. OBERHUBER et. al.

Basic information

Original name

Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization

Authors

HENNRICH, A.A., B. SAWATSKY, B. SANTOS-MANDUJANO, D.H. BANDA, M. OBERHUBER, A. SCHOPF, V. PFAFFINGER, K. WITTWER, C. RIEDEL, C.K. PFALLER and K.K. CONZELMANN

Edition

PLOS PATHOGENS, 2021, 1553-7366

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10606 Microbiology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 7.464

RIV identification code

RIV/00216224:14740/21:00124507

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1371/journal.ppat.1009064

UT WoS

000643934700002

Keywords in English

VESICULAR STOMATITIS-VIRUSCRYO-EM STRUCTURERABIES VIRUSMATRIX PROTEINGLYCOPROTEININFECTIONCORONAVIRUSPARTICLESSPIKEVISUALIZATION

Abstract

V originále

Abstract Vaccines of outstanding efficiency, safety, and public acceptance are needed to halt the current SARS-CoV-2 pandemic. Concerns include potential side effects caused by the antigen itself and safety of viral DNA and RNA delivery vectors. The large SARS-CoV-2 spike (S) protein is the main target of current COVID-19 vaccine candidates but can induce non-neutralizing antibodies, which might cause vaccination-induced complications or enhancement of COVID-19 disease. Besides, encoding of a functional S in replication-competent virus vector vaccines may result in the emergence of viruses with altered or expanded tropism. Here, we have developed a safe single round rhabdovirus replicon vaccine platform for enhanced presentation of the S receptor-binding domain (RBD). Structure-guided design was employed to build a chimeric minispike comprising the globular RBD linked to a transmembrane stem-anchor sequence derived from rabies virus (RABV) glycoprotein (G). Vesicular stomatitis virus (VSV) and RABV replicons encoding the minispike not only allowed expression of the antigen at the cell surface but also incorporation into the envelope of secreted non-infectious particles, thus combining classic vector-driven antigen expression and particulate virus-like particle (VLP) presentation. A single dose of a prototype replicon vaccine complemented with VSV G, VSV Delta G-minispike-eGFP (G), stimulated high titers of SARS-CoV-2 neutralizing antibodies in mice, equivalent to those found in COVID-19 patients, and protected transgenic K18-hACE2 mice from COVID-19-like disease. Homologous boost immunization further enhanced virus neutralizing activity. The results demonstrate that non-spreading rhabdovirus RNA replicons expressing minispike proteins represent effective and safe alternatives to vaccination approaches using replication-competent viruses and/or the entire S antigen. Author summary Two critical problems are associated with replicating paramyxo- and rhabdovirus vaccines expressing SARS-CoV-2 spike (S) protein such as VSV Delta G(S). One is eliciting of potentially disease-enhancing non-neutralizing antibodies, the other the S-mediated spread in humans. In view of the multi-organ tropism of SARS-CoV-2 in humans, their pathogenic outcome is not predictable. Here, we address and resolve both issues. We describe an innovative VSV vaccine, which is safe both in terms of virus propagation and immune response, as it is a non-spreading single round replicon vector, and the immunogen is limited to the spike's receptor binding domain (RBD), which emerged as the antigen eliciting the desired virus-neutralizing antibodies in humans. An excellent protective immune response in animals is achieved by the design of a chimeric RBD-minispike, which allows a combined "2-in-1" approach, meaning that the optimized antigen is simultaneously presented on cells and on noninfectious virus-like particles (VLPs). With such enhanced RBD antigen presentation it is thus not necessary to use replication-competent virus or entire S antigen.

Links

90127, large research infrastructures

Name: CIISB II

Citovat

HENNRICH, A.A., B. SAWATSKY, B. SANTOS-MANDUJANO, D.H. BANDA, M. OBERHUBER, A. SCHOPF, V. PFAFFINGER, K. WITTWER, C. RIEDEL, C.K. PFALLER and K.K. CONZELMANN. Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization. PLOS PATHOGENS. 2021, vol. 17, No 4, p. 1-25. ISSN 1553-7366. Available from: https://dx.doi.org/10.1371/journal.ppat.1009064.

@article{1845735,
   author = {Hennrich, A.A. and Sawatsky, B. and SantosandMandujano, B. and Banda, D.H. and Oberhuber, M. and Schopf, A. and Pfaffinger, V. and Wittwer, K. and Riedel, C. and Pfaller, C.K. and Conzelmann, K.K.},
   article_number = {4},
   doi = {http://dx.doi.org/10.1371/journal.ppat.1009064},
   keywords = {VESICULAR STOMATITIS-VIRUSCRYO-EM STRUCTURERABIES VIRUSMATRIX PROTEINGLYCOPROTEININFECTIONCORONAVIRUSPARTICLESSPIKEVISUALIZATION},
   language = {eng},
   issn = {1553-7366},
   journal = {PLOS PATHOGENS},
   title = {Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization},
   url = {https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009064},
   volume = {17},
   year = {2021}
}

TY  - JOUR
ID  - 1845735
AU  - Hennrich, A.A. - Sawatsky, B. - Santos-Mandujano, B. - Banda, D.H. - Oberhuber, M. - Schopf, A. - Pfaffinger, V. - Wittwer, K. - Riedel, C. - Pfaller, C.K. - Conzelmann, K.K.
PY  - 2021
TI  - Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization
JF  - PLOS PATHOGENS
VL  - 17
IS  - 4
SP  - 1-25
EP  - 1-25
SN  - 15537366
KW  - VESICULAR STOMATITIS-VIRUSCRYO-EM STRUCTURERABIES VIRUSMATRIX PROTEINGLYCOPROTEININFECTIONCORONAVIRUSPARTICLESSPIKEVISUALIZATION
UR  - https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1009064
N2  - Abstract Vaccines of outstanding efficiency, safety, and public acceptance are needed to halt the current SARS-CoV-2 pandemic. Concerns include potential side effects caused by the antigen itself and safety of viral DNA and RNA delivery vectors. The large SARS-CoV-2 spike (S) protein is the main target of current COVID-19 vaccine candidates but can induce non-neutralizing antibodies, which might cause vaccination-induced complications or enhancement of COVID-19 disease. Besides, encoding of a functional S in replication-competent virus vector vaccines may result in the emergence of viruses with altered or expanded tropism. Here, we have developed a safe single round rhabdovirus replicon vaccine platform for enhanced presentation of the S receptor-binding domain (RBD). Structure-guided design was employed to build a chimeric minispike comprising the globular RBD linked to a transmembrane stem-anchor sequence derived from rabies virus (RABV) glycoprotein (G). Vesicular stomatitis virus (VSV) and RABV replicons encoding the minispike not only allowed expression of the antigen at the cell surface but also incorporation into the envelope of secreted non-infectious particles, thus combining classic vector-driven antigen expression and particulate virus-like particle (VLP) presentation. A single dose of a prototype replicon vaccine complemented with VSV G, VSV Delta G-minispike-eGFP (G), stimulated high titers of SARS-CoV-2 neutralizing antibodies in mice, equivalent to those found in COVID-19 patients, and protected transgenic K18-hACE2 mice from COVID-19-like disease. Homologous boost immunization further enhanced virus neutralizing activity. The results demonstrate that non-spreading rhabdovirus RNA replicons expressing minispike proteins represent effective and safe alternatives to vaccination approaches using replication-competent viruses and/or the entire S antigen. Author summary Two critical problems are associated with replicating paramyxo- and rhabdovirus vaccines expressing SARS-CoV-2 spike (S) protein such as VSV Delta G(S). One is eliciting of potentially disease-enhancing non-neutralizing antibodies, the other the S-mediated spread in humans. In view of the multi-organ tropism of SARS-CoV-2 in humans, their pathogenic outcome is not predictable. Here, we address and resolve both issues. We describe an innovative VSV vaccine, which is safe both in terms of virus propagation and immune response, as it is a non-spreading single round replicon vector, and the immunogen is limited to the spike's receptor binding domain (RBD), which emerged as the antigen eliciting the desired virus-neutralizing antibodies in humans. An excellent protective immune response in animals is achieved by the design of a chimeric RBD-minispike, which allows a combined "2-in-1" approach, meaning that the optimized antigen is simultaneously presented on cells and on noninfectious virus-like particles (VLPs). With such enhanced RBD antigen presentation it is thus not necessary to use replication-competent virus or entire S antigen.
ER  -

HENNRICH, A.A., B. SAWATSKY, B. SANTOS-MANDUJANO, D.H. BANDA, M. OBERHUBER, A. SCHOPF, V. PFAFFINGER, K. WITTWER, C. RIEDEL, C.K. PFALLER and K.K. CONZELMANN. Safe and effective two-in-one replicon-and-VLP minispike vaccine for COVID-19: Protection of mice after a single immunization. \textit{PLOS PATHOGENS}. 2021, vol.~17, No~4, p.~1-25. ISSN~1553-7366. Available from: https://dx.doi.org/10.1371/journal.ppat.1009064.

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