Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection

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Abstract

Intranasal vaccination represents a promising approach for preventing disease caused by respiratory pathogens by eliciting a mucosal immune response in the respiratory tract that may act as an early barrier to infection and transmission. This study investigated immunogenicity and protective efficacy of intranasally administered messenger RNA (mRNA)–lipid nanoparticle (LNP) encapsulated vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Syrian golden hamsters. Intranasal mRNA-LNP vaccination systemically induced spike-specific binding [immunoglobulin G (IgG) and IgA] and neutralizing antibodies. Intranasally vaccinated hamsters also had decreased viral loads in the respiratory tract, reduced lung pathology, and prevented weight loss after SARS-CoV-2 challenge. Together, this study demonstrates successful immunogenicity and protection against respiratory viral infection by an intranasally administered mRNA-LNP vaccine.

Abstract

SARS-CoV-2 intranasal mRNA-LNP vaccine is immunogenic and protects against respiratory viral infection in an animal model.

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Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Fernando P Polack, Stephen J. Thomas, Nicholas R.E. Kitchin … (2023)

Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)

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Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Lindsey Baden, Hana El Sahly, Brandon Essink … (2020)

Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)

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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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Author and article information

Contributors

Gabriela Baldeon Vaca:

ORCID: https://orcid.org/0000-0003-2465-7157

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Michelle Meyer:

ORCID: https://orcid.org/0000-0002-9704-205X

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Ana Cadete:

ORCID: https://orcid.org/0009-0004-1967-3827

Role: ConceptualizationRole: Data curationRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing

Chiaowen Joyce Hsiao:

ORCID: https://orcid.org/0000-0001-8961-7522

Role: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: Writing - original draft

Anne Golding: Role: Formal analysisRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Albert Jeon: Role: InvestigationRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Eric Jacquinet: Role: ConceptualizationRole: Data curationRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Emily Azcue:

ORCID: https://orcid.org/0000-0002-1088-8854

Role: InvestigationRole: Resources

Chenxia Monica Guan: Role: Project administrationRole: ResourcesRole: SupervisionRole: Validation

Xavier Sanchez-Felix: Role: Investigation

Colette A. Pietzsch:

ORCID: https://orcid.org/0000-0002-0759-3983

Role: Investigation

Chad E. Mire:

ORCID: https://orcid.org/0000-0001-7596-1808

Role: InvestigationRole: Project administrationRole: Writing - review & editing

Matthew A. Hyde:

ORCID: https://orcid.org/0000-0002-7932-2699

Role: InvestigationRole: Resources

Margaret E. Comeaux:

ORCID: https://orcid.org/0009-0003-8323-7395

Role: InvestigationRole: Resources

Julie M. Williams: Role: InvestigationRole: ResourcesRole: Validation

Jean C. Sung: Role: ConceptualizationRole: SupervisionRole: Writing - review & editing

Andrea Carfi: Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: Validation

Darin K. Edwards: Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: Writing - original draft

Alexander Bukreyev:

ORCID: https://orcid.org/0000-0002-0342-4824

Role: ConceptualizationRole: Data curationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Visualization

Kapil Bahl:

ORCID: https://orcid.org/0000-0002-0276-6443

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draft

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: 22 September 2023

Publication date (Electronic, pub): 22 September 2023

Volume: 9

Issue: 38

Electronic Location Identifier: eadh1655

Affiliations

[ ¹ ]Moderna Inc., Cambridge, MA, USA.

[ ² ]Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA.

[ ³ ]Galveston National Laboratory, Galveston, TX, USA.

[ ⁴ ]Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.

Author notes

[* ]Corresponding author. Email: kapil.bahl@ 123456modernatx.com (K.B.); alexander.bukreyev@ 123456utmb.edu (A.B.)

[†]

These authors contributed equally to this work.

[‡]

Present address: Orbital Therapeutics, Inc., Cambridge, MA, USA.

Author information

Gabriela Baldeon Vaca https://orcid.org/0000-0003-2465-7157

Michelle Meyer https://orcid.org/0000-0002-9704-205X

Ana Cadete https://orcid.org/0009-0004-1967-3827

Chiaowen Joyce Hsiao https://orcid.org/0000-0001-8961-7522

Emily Azcue https://orcid.org/0000-0002-1088-8854

Colette A. Pietzsch https://orcid.org/0000-0002-0759-3983

Chad E. Mire https://orcid.org/0000-0001-7596-1808

Matthew A. Hyde https://orcid.org/0000-0002-7932-2699

Margaret E. Comeaux https://orcid.org/0009-0003-8323-7395

Alexander Bukreyev https://orcid.org/0000-0002-0342-4824

Kapil Bahl https://orcid.org/0000-0002-0276-6443

Article

Publisher ID: adh1655

DOI: 10.1126/sciadv.adh1655

PMC ID: 10516494

PubMed ID: 37738334

SO-VID: 3951537a-50b2-4daf-a537-1aeebc742861

Copyright © Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 16 February 2023

Date accepted : 23 August 2023

Funding

Funded by: Moderna, Inc.;

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Intranasal mRNA-LNP vaccination protects hamsters from SARS-CoV-2 infection

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Novel Coronavirus Disease COVID-19

Most cited references 49

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Virological assessment of hospitalized patients with COVID-2019

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Cited by 8

Most referenced authors 1,797