Mucosal prime-boost immunization with live murine pneumonia virus-vectored SARS-CoV-2 vaccine is protective in macaques

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Abstract

Immunization via the respiratory route is predicted to increase the effectiveness of a SARS-CoV-2 vaccine. Here, we evaluate the immunogenicity and protective efficacy of one or two doses of a live-attenuated murine pneumonia virus vector expressing SARS-CoV-2 prefusion-stabilized spike protein (MPV/S-2P), delivered intranasally/intratracheally to male rhesus macaques. A single dose of MPV/S-2P is highly immunogenic, and a second dose increases the magnitude and breadth of the mucosal and systemic anti-S antibody responses and increases levels of dimeric anti-S IgA in the airways. MPV/S-2P also induces S-specific CD4 ⁺ and CD8 ⁺ T-cells in the airways that differentiate into large populations of tissue-resident memory cells within a month after the boost. One dose induces substantial protection against SARS-CoV-2 challenge, and two doses of MPV/S-2P are fully protective against SARS-CoV-2 challenge virus replication in the airways. A prime/boost immunization with a mucosally-administered live-attenuated MPV vector could thus be highly effective in preventing SARS-CoV-2 infection and replication.

Abstract

Immunization via the respiratory route is predicted to increase the effectiveness of SARS-CoV-2 vaccines. Here, Kaiser et al. describe a murine pneumonia virus vectored vaccine expressing spike protein, and show that intranasal immunization of male rhesus macaques provides good mucosal and systemic immunogenicity and efficacy.

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Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Daniel Wrapp, Nianshuang Wang, Kizzmekia S. Corbett … (2020)

Structure of the nCoV trimeric spike The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryo–electron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV. Science, this issue p. 1260

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Virological assessment of hospitalized patients with COVID-2019

Roman Wölfel, Victor M Corman, Wolfgang Guggemos … (2020)

Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.

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Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates

Kizzmekia S. Corbett, Barbara Flynn, Kathryn Foulds … (2020)

Abstract Background Vaccines to prevent coronavirus disease 2019 (Covid-19) are urgently needed. The effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines on viral replication in both upper and lower airways is important to evaluate in nonhuman primates. Methods Nonhuman primates received 10 or 100 μg of mRNA-1273, a vaccine encoding the prefusion-stabilized spike protein of SARS-CoV-2, or no vaccine. Antibody and T-cell responses were assessed before upper- and lower-airway challenge with SARS-CoV-2. Active viral replication and viral genomes in bronchoalveolar-lavage (BAL) fluid and nasal swab specimens were assessed by polymerase chain reaction, and histopathological analysis and viral quantification were performed on lung-tissue specimens. Results The mRNA-1273 vaccine candidate induced antibody levels exceeding those in human convalescent-phase serum, with live-virus reciprocal 50% inhibitory dilution (ID50) geometric mean titers of 501 in the 10-μg dose group and 3481 in the 100-μg dose group. Vaccination induced type 1 helper T-cell (Th1)–biased CD4 T-cell responses and low or undetectable Th2 or CD8 T-cell responses. Viral replication was not detectable in BAL fluid by day 2 after challenge in seven of eight animals in both vaccinated groups. No viral replication was detectable in the nose of any of the eight animals in the 100-μg dose group by day 2 after challenge, and limited inflammation or detectable viral genome or antigen was noted in lungs of animals in either vaccine group. Conclusions Vaccination of nonhuman primates with mRNA-1273 induced robust SARS-CoV-2 neutralizing activity, rapid protection in the upper and lower airways, and no pathologic changes in the lung. (Funded by the National Institutes of Health and others.)

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Author and article information

Contributors

Ursula J. Buchholz:

ORCID: http://orcid.org/0000-0002-2329-3198

ubuchholz@niaid.nih.gov

Cyril Le Nouën:

ORCID: http://orcid.org/0000-0002-5719-4112

lenouenc@niaid.nih.gov

Journal

Journal ID (nlm-ta): Nat Commun

Journal ID (iso-abbrev): Nat Commun

Title: Nature Communications

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-1723

Publication date (Electronic): 26 April 2024

Publication date PMC-release: 26 April 2024

Publication date Collection: 2024

Volume: 15

Electronic Location Identifier: 3553

Affiliations

[1 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, RNA Viruses Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

[2 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, T-Lymphocyte Biology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

[3 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Experimental Primate Virology Section, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Poolesville, MD USA

[4 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Comparative Medicine Branch, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

[5 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Division of Pathology, Emory National Primate Research Center, , Emory University, ; Atlanta, GA USA

[6 ]Division of Assurances, Office of Laboratory Animal Welfare, National Institutes of Health, ( https://ror.org/01cwqze88) Bethesda, MD USA

[7 ]GRID grid.189967.8, ISNI 0000 0001 0941 6502, Emory National Primate Research Center, Environmental Health and Safety Office, , Emory University, ; Atlanta, GA USA

[8 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Tuberculosis Imaging Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

[9 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

[10 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Medical Virology Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

[11 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, SARS-CoV-2 Virology Core, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Bethesda, MD USA

Author information

Christine E. Nelson http://orcid.org/0000-0003-3879-9105

Hong-Su Park http://orcid.org/0000-0002-8423-2188

Cindy Luongo http://orcid.org/0000-0002-3830-3803

Shirin Munir http://orcid.org/0000-0002-8493-0728

Peter D. Kwong http://orcid.org/0000-0003-3560-232X

Kennichi Dowdell http://orcid.org/0000-0002-7034-711X

Hanh Nguyen http://orcid.org/0000-0002-0080-8312

Laura E. Via http://orcid.org/0000-0001-6074-9521

Daniel L. Barber http://orcid.org/0000-0001-7008-7509

Ursula J. Buchholz http://orcid.org/0000-0002-2329-3198

Cyril Le Nouën http://orcid.org/0000-0002-5719-4112

Article

Publisher ID: 47784

DOI: 10.1038/s41467-024-47784-6

PMC ID: 11053155

PubMed ID: 38670948

SO-VID: d3b1a7dd-838a-4b4b-9395-1568539aec30

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 19 August 2023

Date accepted : 11 April 2024

Funding

Funded by: FundRef https://doi.org/10.13039/100006492, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (Division of Intramural Research of the NIAID);

Award ID: ZIA AI001298-01

Award ID: 1ZIAAI001294-04

Award Recipient : Daniel L. Barber Ursula J. Buchholz

Funded by: Vaccine Research Center, NIAID, NIH

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ScienceOpen disciplines: Uncategorized

Keywords: viral infection,live attenuated vaccines,preclinical research,sars-cov-2

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ScienceOpen disciplines: Uncategorized

Keywords: viral infection, live attenuated vaccines, preclinical research, sars-cov-2

Mucosal prime-boost immunization with live murine pneumonia virus-vectored SARS-CoV-2 vaccine is protective in macaques

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Novel Coronavirus Disease COVID-19

Most cited references 38

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Virological assessment of hospitalized patients with COVID-2019

Evaluation of the mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates

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