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

• Published in: PLoS pathogens Vol. 17; no. 4; p. e1009064
• Main Authors: Hennrich, Alexandru A, Sawatsky, Bevan, Santos-Mandujano, Rosalía, Banda, Dominic H, Oberhuber, Martina, Schopf, Anika, Pfaffinger, Verena, Wittwer, Kevin, Riedel, Christiane, Pfaller, Christian K, Conzelmann, Karl-Klaus
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2021; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Antibodies; Antibodies, Neutralizing - blood; Antibodies, Neutralizing - immunology; Antibodies, Viral - blood; Antibodies, Viral - immunology; Antigens; Biology and life sciences; Cell culture; Complications; Coronaviruses; COVID-19; COVID-19 - immunology; COVID-19 - prevention & control; COVID-19 - virology; COVID-19 vaccines; COVID-19 Vaccines - administration & dosage; Disease transmission; Engineering and Technology; Female; Genetic aspects; Genetic engineering; Genetic vectors; Glycoproteins; HEK293 Cells; Herd immunity; Humans; Immunization; Immunization - methods; Infections; Medicine and Health Sciences; Methods; Mice; Mice, Inbred C57BL; Morbidity; Mutation; Organoids; Pandemics; Peptides; Proteins; Rabies; Risk groups; S gene; SARS-CoV-2 - immunology; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Spike protein; Vaccines; Vaccines, Virus-Like Particle - administration & dosage; Viral diseases; Viral proteins; Virus research; Viruses; Germany
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1009064

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, VSVΔG-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.