Combating COVID-19: MVA Vector Vaccines Applied to the Respiratory Tract as Promising Approach Toward Protective Immunity in the Lung

Förster, Reinhold; Fleige, Henrike; Sutter, Gerd

doi:10.3389/fimmu.2020.01959

Cited by 16 publications

(15 citation statements)

References 20 publications

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“…The absence of detectable anti-S IgA in serum was in accord with the result of Hassan et al ( 13 ), who found IgA after IN but not IM vaccination with an adenovirus CoV-2 S vaccine. MVA can be administered orally, IN, and by aerosol, and the IN route has been shown to stimulate bronchus-associated lymphoid tissue and serum IgA ( 57 – 59 ). Even though IM administration of the rMVA CoV-2 S vaccines greatly reduced and rapidly eliminated virus replication in the nasal turbinates, IN administration might have a greater ability to reduce CoV-2 spread.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Poxviruses and particularly modified vaccinia virus Ankara (MVA) strain have previously demonstrated to provide protective immunity against influenza virus H5N1 in mice [ 11 ]. The MVA vaccinia virus strain has also been considered as a promising candidate for vaccine development against coronaviruses, due to their potential targeting of mucosal surfaces of the respiratory tract [ 57 ]. A synthetic MVA-based vaccine platform has been engineered by application of a unique three-plasmid system for co-expression of SARS-CoV-2 S and nucleocapsid proteins [ 46 ].…”

Section: Preclinical Studiesmentioning

confidence: 99%

Viral Vectors for COVID-19 Vaccine Development

Lundström¹

2021

Viruses

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Vaccine development against SARS-CoV-2 has been fierce due to the devastating COVID-19 pandemic and has included all potential approaches for providing the global community with safe and efficient vaccine candidates in the shortest possible timeframe. Viral vectors have played a central role especially using adenovirus-based vectors. Additionally, other viral vectors based on vaccinia viruses, measles viruses, rhabdoviruses, influenza viruses and lentiviruses have been subjected to vaccine development. Self-amplifying RNA virus vectors have been utilized for lipid nanoparticle-based delivery of RNA as COVID-19 vaccines. Several adenovirus-based vaccine candidates have elicited strong immune responses in immunized animals and protection against challenges in mice and primates has been achieved. Moreover, adenovirus-based vaccine candidates have been subjected to phase I to III clinical trials. Recently, the simian adenovirus-based ChAdOx1 vector expressing the SARS-CoV-2 S spike protein was approved for use in humans in the UK.

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“…Another point to consider is the route of administration, which can affect the ability of vaccines to prevent spread. In addition to IM and subcutaneous routes, rMVAs can be administered orally, IN and by aerosol(53)(54)(55)(56)(57)(58)(59)(60). Although IM administration of the rMVA CoV-2 S vectors greatly reduced and rapidly eliminated virus replication in the nasal turbinates, it will be of interest to determine whether IN administration would prevent replication entirely.Materials and MethodsCells.…”

mentioning

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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Combating COVID-19: MVA Vector Vaccines Applied to the Respiratory Tract as Promising Approach Toward Protective Immunity in the Lung

Cited by 16 publications

References 20 publications

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

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

Viral Vectors for COVID-19 Vaccine Development

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

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