Development of a multi-antigenic SARS-CoV-2 vaccine candidate using a synthetic poxvirus platform

Chiuppesi, Flavia; Salazar, Marcela d’Alincourt; Contreras, Heidi; Nguyen, Vu H.; Martinez, Joy; Park, Yoonsuh; Nguyen, Jenny; Kha, Mindy; Iniguez, Angelina; Zhou, Qiao; Kaltcheva, Teodora; Levytskyy, Roman; Ebelt, Nancy D.; Kang, Tae Hyuk; Wu, Xiwei; Rogers, Thomas F.; Manuel, Edwin R.; Shostak, Yuriy; Diamond, Don J.; Wussow, Felix

doi:10.1038/s41467-020-19819-1

Cited by 83 publications

(97 citation statements)

References 61 publications

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“…At present, MVA serves as an advanced vaccine technology platform for developing new vector vaccines against infectious disease and cancer including emerging viruses (15). In response to the ongoing pandemic, the MVA vector vaccine platform allows rapid generation of experimental SARS-CoV-2specific vaccines (16). Previous work from our laboratory addressed the development of an MVA candidate vaccine against MERS with immunizations in animal models demonstrating the safety, immunogenicity and protective efficacy of MVA-induced MERS-CoV S-antigen specific immunity (17)(18)(19)(20).…”

Section: Introductionmentioning

confidence: 99%

Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA SARS 2 S in preclinical vaccination

Tscherne

Schwarz²,

Rohde

et al. 2021

Preprint

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The severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) has emerged as the infectious agent causing the pandemic coronavirus disease 2019 (COVID-19) with dramatic consequences for global human health and economics. Previously, we reached clinical evaluation with our vector vaccine based on vaccinia virus MVA against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes an infection in humans similar to SARS and COVID-19. Here, we describe the construction and preclinical characterization of a recombinant MVA expressing full-length SARS-CoV-2 spike (S) protein (MVA-SARS-2-S). Genetic stability and growth characteristics of MVA-SARS-2-S, plus its robust synthesis of S antigen, make it a suitable candidate vaccine for industrial scale production. Vaccinated mice produced S antigen-specific CD8+ T cells and serum antibodies binding to S glycoprotein that neutralized SARS-CoV-2. Prime-boost vaccination with MVA-SARS-2-S protected mice sensitized with a human ACE2-expressing adenovirus from SARS-CoV-2 infection. MVA-SARS-2-S is currently being investigated in a phase I clinical trial as aspirant for developing a safe and efficacious vaccine against COVID-19.Significance StatementThe highly attenuated vaccinia virus MVA is licensed as smallpox vaccine, and as vector it is a component of the approved Adenovirus-MVA-based prime-boost vaccine against Ebola virus disease. Here we provide results from testing the COVID-19 candidate vaccine MVA-SARS-2-S, a poxvirus-based vector vaccine that proceeded to clinical evaluation. When administered by intramuscular inoculation, MVA-SARS-2-S expresses and safely delivers the full-length SARS-CoV-2 spike (S) protein, inducing balanced SARS-CoV-2-specific cellular and humoral immunity, and protective efficacy in vaccinated mice. Substantial clinical experience has already been gained with MVA vectors using homologous and heterologous prime-boost applications, including the immunization of children and immunocompromised individuals. Thus, MVA-SARS-2-S represents an important resource for developing further optimized COVID-19 vaccines.

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Section: Introductionmentioning

confidence: 99%

Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA SARS 2 S in preclinical vaccination

Tscherne

Schwarz²,

Rohde

et al. 2021

Preprint

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“…This article is a US Government work. It is not subject to copyright under 17 USC The copyright holder for this preprint this version posted January 1, 2021. ; https://doi.org/10.1101/2020.12.30.424878 doi: bioRxiv preprint 5 (18), but animal protection studies have not yet been reported. However, protection has been obtained with related MVA-based SARS CoV-1 and MERS in animals (19)(20)(21)(22) and a MVA MERS vaccine was shown to be safe and immunogenic in a phase 1 clinical trial (23).…”

Section: Introductionmentioning

confidence: 99%

“…Other vaccines, including ones based on vesicular stomatitis virus (15), an alphavirus-derived replicon RNA (16), and an inactivated recombinant New Castle Disease virus (17) have shown protection in animal models. Immunogenicity in mice was found for a modified VACV Ankara (MVA)-based CoV-2 vaccine, (18), but animal protection studies have not yet been reported. However, protection has been obtained with related MVA-based SARS CoV-1 and MERS in animals (19–22) and a MVA MERS vaccine was shown to be safe and immunogenic in a phase 1 clinical trial (23).…”

Section: Introductionmentioning

confidence: 99%

MVA Vector Vaccines Inhibit SARS CoV-2 Replication in Upper and Lower Respiratory Tracts of Transgenic Mice and Prevent Lethal Disease

Liu

Americo

Cotter

et al. 2021

Preprint

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Replication-restricted modified vaccinia virus Ankara (MVA) is a licensed smallpox vaccine and numerous clinical studies investigating recombinant MVAs (rMVAs) as vectors for prevention of other infectious diseases have been completed or are in progress. Two rMVA COVID-19 vaccine trials are at an initial stage, though no animal protection studies have been reported. Here, we characterize rMVAs expressing the S protein of CoV-2. Modifications of full length S individually or in combination included two proline substitutions, mutations of the furin recognition site and deletion of the endoplasmic retrieval signal. Another rMVA in which the receptor binding domain (RBD) flanked by the signal peptide and transmembrane domains of S was also constructed. Each modified S protein was displayed on the surface of rMVA-infected human cells and was recognized by anti-RBD antibody and by soluble hACE2 receptor. Intramuscular injection of mice with the rMVAs induced S-binding and pseudovirus-neutralizing antibodies. Boosting occurred following a second homologous rMVA but was higher with adjuvanted purified RBD protein. Weight loss and lethality following intranasal infection of transgenic hACE2 mice with CoV-2 was prevented by one or two immunizations with rMVAs or by passive transfer of serum from vaccinated mice. One or two rMVA vaccinations also prevented recovery of infectious CoV-2 from the lungs. A low amount of virus was detected in the nasal turbinates of only one of eight rMVA-vaccinated mice on day 2 and none later. Detection of subgenomic mRNA in turbinates on day 2 only indicated that replication was abortive in immunized animals.SignificanceVaccines are required to control COVID-19 during the pandemic and possibly afterwards. Recombinant nucleic acids, proteins and virus vectors that stimulate immune responses to the CoV-2 S protein have provided protection in experimental animal or human clinical trials, though questions remain regarding their ability to prevent spread and the duration of immunity. The present study focuses on replication-restricted modified vaccinia virus Ankara (MVA), which has been shown to be a safe, immunogenic and stable smallpox vaccine and a promising vaccine vector for other infectious diseases and cancer. In a transgenic mouse model, one or two injections of recombinant MVAs that express modified forms of S inhibited CoV-2 replication in the upper and lower respiratory tracts and prevented severe disease.

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“…Vaccines based on mRNA and adenovirus vectors have demonstrated promising results in clinical trials and have received emergency regulatory approval (11)(12)(13)(14). Other candidate CoV-2 vaccines, including ones based on vesicular stomatitis virus (15), an alphavirusderived replicon RNA (16), an inactivated recombinant Newcastle Disease virus (17), and modified VACV Ankara (MVA) (18,19) are at early stages of evaluation.…”

mentioning

confidence: 99%

One or two injections of MVA-vectored vaccine shields hACE2 transgenic mice from SARS-CoV-2 upper and lower respiratory tract infection

Liu

Americo

Cotter

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Modified vaccinia virus Ankara (MVA) is a replication-restricted smallpox vaccine, and numerous clinical studies of recombinant MVAs (rMVAs) as vectors for prevention of other infectious diseases, including COVID-19, are in progress. Here, we characterize rMVAs expressing the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Modifications of full-length S individually or in combination included two proline substitutions, mutations of the furin recognition site, and deletion of the endoplasmic retrieval signal. Another rMVA in which the receptor binding domain (RBD) is flanked by the signal peptide and transmembrane domains of S was also constructed. Each modified S protein was displayed on the surface of rMVA-infected cells and was recognized by anti-RBD antibody and soluble hACE2 receptor. Intramuscular injection of mice with the rMVAs induced antibodies, which neutralized a pseudovirus in vitro and, upon passive transfer, protected hACE2 transgenic mice from lethal infection with SARS-CoV-2, as well as S-specific CD3+CD8+IFNγ+ T cells. Antibody boosting occurred following a second rMVA or adjuvanted purified RBD protein. Immunity conferred by a single vaccination of hACE2 mice prevented morbidity and weight loss upon intranasal infection with SARS-CoV-2 3 wk or 7 wk later. One or two rMVA vaccinations also prevented detection of infectious SARS-CoV-2 and subgenomic viral mRNAs in the lungs and greatly reduced induction of cytokine and chemokine mRNAs. A low amount of virus was found in the nasal turbinates of only one of eight rMVA-vaccinated mice on day 2 and none later. Detection of low levels of subgenomic mRNAs in turbinates indicated that replication was aborted in immunized animals.

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Development of a multi-antigenic SARS-CoV-2 vaccine candidate using a synthetic poxvirus platform

Cited by 83 publications

References 61 publications

Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA SARS 2 S in preclinical vaccination

Immunogenicity and efficacy of the COVID-19 candidate vector vaccine MVA SARS 2 S in preclinical vaccination

MVA Vector Vaccines Inhibit SARS CoV-2 Replication in Upper and Lower Respiratory Tracts of Transgenic Mice and Prevent Lethal Disease

One or two injections of MVA-vectored vaccine shields hACE2 transgenic mice from SARS-CoV-2 upper and lower respiratory tract infection

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