Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities—workshop report

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Abstract

On November 7th and 8th, 2022, The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), The Coalition for Epidemic Preparedness Innovation (CEPI), The Bill & Melinda Gates Foundation (BMGF), The Biomedical Advanced Research and Development Authority (BARDA), and the Wellcome Trust hosted a virtual workshop entitled “Mucosal Vaccines for SARS-CoV-2: Scientific Gaps and Opportunities.” During the workshop, researchers and vaccine developers from around the world discussed the potential of mucosal vaccines to block SARS-CoV-2 transmission and reviewed the status of SARS-CoV-2 mucosal vaccine research. Here, we summarize key challenges and opportunities in basic, translational, and clinical research that were highlighted during the meeting. We also provide recommendations to advance the field and accelerate the development of mucosal vaccines for SARS-CoV-2.

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Most cited references 58

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SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis

Muge Cevik, Matthew C. Tate, Ollie Lloyd … (2020)

Background Viral load kinetics and duration of viral shedding are important determinants for disease transmission. We aimed to characterise viral load dynamics, duration of viral RNA shedding, and viable virus shedding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in various body fluids, and to compare SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) viral dynamics. Methods In this systematic review and meta-analysis, we searched databases, including MEDLINE, Embase, Europe PubMed Central, medRxiv, and bioRxiv, and the grey literature, for research articles published between Jan 1, 2003, and June 6, 2020. We included case series (with five or more participants), cohort studies, and randomised controlled trials that reported SARS-CoV-2, SARS-CoV, or MERS-CoV infection, and reported viral load kinetics, duration of viral shedding, or viable virus. Two authors independently extracted data from published studies, or contacted authors to request data, and assessed study quality and risk of bias using the Joanna Briggs Institute Critical Appraisal Checklist tools. We calculated the mean duration of viral shedding and 95% CIs for every study included and applied the random-effects model to estimate a pooled effect size. We used a weighted meta-regression with an unrestricted maximum likelihood model to assess the effect of potential moderators on the pooled effect size. This study is registered with PROSPERO, CRD42020181914. Findings 79 studies (5340 individuals) on SARS-CoV-2, eight studies (1858 individuals) on SARS-CoV, and 11 studies (799 individuals) on MERS-CoV were included. Mean duration of SARS-CoV-2 RNA shedding was 17·0 days (95% CI 15·5–18·6; 43 studies, 3229 individuals) in upper respiratory tract, 14·6 days (9·3–20·0; seven studies, 260 individuals) in lower respiratory tract, 17·2 days (14·4–20·1; 13 studies, 586 individuals) in stool, and 16·6 days (3·6–29·7; two studies, 108 individuals) in serum samples. Maximum shedding duration was 83 days in the upper respiratory tract, 59 days in the lower respiratory tract, 126 days in stools, and 60 days in serum. Pooled mean SARS-CoV-2 shedding duration was positively associated with age (slope 0·304 [95% CI 0·115–0·493]; p=0·0016). No study detected live virus beyond day 9 of illness, despite persistently high viral loads, which were inferred from cycle threshold values. SARS-CoV-2 viral load in the upper respiratory tract appeared to peak in the first week of illness, whereas that of SARS-CoV peaked at days 10–14 and that of MERS-CoV peaked at days 7–10. Interpretation Although SARS-CoV-2 RNA shedding in respiratory and stool samples can be prolonged, duration of viable virus is relatively short-lived. SARS-CoV-2 titres in the upper respiratory tract peak in the first week of illness. Early case finding and isolation, and public education on the spectrum of illness and period of infectiousness are key to the effective containment of SARS-CoV-2. Funding None.

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SARS-CoV-2 infection of the oral cavity and saliva

Ni Huang, Paola Perez, Takafumi Kato … (2021)

Despite signs of infection-including taste loss, dry mouth and mucosal lesions such as ulcerations, enanthema and macules-the involvement of the oral cavity in coronavirus disease 2019 (COVID-19) is poorly understood. To address this, we generated and analyzed two single-cell RNA sequencing datasets of the human minor salivary glands and gingiva (9 samples, 13,824 cells), identifying 50 cell clusters. Using integrated cell normalization and annotation, we classified 34 unique cell subpopulations between glands and gingiva. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral entry factors such as ACE2 and TMPRSS members were broadly enriched in epithelial cells of the glands and oral mucosae. Using orthogonal RNA and protein expression assessments, we confirmed SARS-CoV-2 infection in the glands and mucosae. Saliva from SARS-CoV-2-infected individuals harbored epithelial cells exhibiting ACE2 and TMPRSS expression and sustained SARS-CoV-2 infection. Acellular and cellular salivary fractions from asymptomatic individuals were found to transmit SARS-CoV-2 ex vivo. Matched nasopharyngeal and saliva samples displayed distinct viral shedding dynamics, and salivary viral burden correlated with COVID-19 symptoms, including taste loss. Upon recovery, this asymptomatic cohort exhibited sustained salivary IgG antibodies against SARS-CoV-2. Collectively, these data show that the oral cavity is an important site for SARS-CoV-2 infection and implicate saliva as a potential route of SARS-CoV-2 transmission.

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A single-dose intranasal ChAd vaccine protects upper and lower respiratory tracts against SARS-CoV-2

Ahmed O. Hassan, Natasha Kafai, Igor Dmitriev … (2020)

Summary The Coronavirus Disease 2019 pandemic has made deployment of an effective vaccine a global health priority. We evaluated the protective activity of a chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike protein (ChAd-SARS-CoV-2-S) in challenge studies with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and mice expressing the human angiotensin-converting enzyme 2 receptor. Intramuscular dosing of ChAd-SARS-CoV-2-S induces robust systemic humoral and cell-mediated immune responses and protects against lung infection, inflammation, and pathology but does not confer sterilizing immunity, as evidenced by detection of viral RNA and induction of anti-nucleoprotein antibodies after SARS-CoV-2 challenge. In contrast, a single intranasal dose of ChAd-SARS-CoV-2-S induces high levels of neutralizing antibodies, promotes systemic and mucosal IgA and T cell responses, and virtually completely prevents SARS-CoV-2 infection in both the upper and lower respiratory tracts. Intranasal administration of ChAd-SARS-CoV-2-S is a candidate for preventing SARS-CoV-2 infection and transmission, and curtailing pandemic spread.

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Author and article information

Contributors

Jane M. Knisely:

ORCID: http://orcid.org/0000-0003-0581-0742

kniselyj@niaid.nih.gov

Journal

Journal ID (nlm-ta): NPJ Vaccines

Journal ID (iso-abbrev): NPJ Vaccines

Title: NPJ Vaccines

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2059-0105

Publication date (Electronic): 12 April 2023

Publication date PMC-release: 12 April 2023

Publication date Collection: 2023

Volume: 8

Electronic Location Identifier: 53

Affiliations

[1 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Office of the Director, , National Institute of Allergy and Infectious Diseases, National Institutes of Health, ; Bethesda, MD 20892 USA

[2 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Division of Microbiology and Infectious Diseases, , National Institute of Allergy and Infectious Diseases, National Institutes of Health, ; Bethesda, MD USA

[3 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Office of Scientific Management and Operations, , National Institute of Allergy and Infectious Diseases, National Institutes of Health, ; Bethesda, MD 20892 USA

[4 ]GRID grid.507196.c, ISNI 0000 0004 9225 0356, Coalition for Epidemic Preparedness Innovations, Skøyen Atrium, ; Askekroken 11, 0277 Oslo, Norway

[5 ]GRID grid.52788.30, ISNI 0000 0004 0427 7672, Infectious Disease, Prevention, , Wellcome Trust, UK, ; London, NW1 2BE UK

[6 ]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

[7 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, RNA Viruses Section, Laboratory of Infectious Diseases, , National Institute of Allergy and Infectious Diseases, National Institutes of Health, ; Bethesda, MD 20892 US

[8 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Division of AIDS, National Institute of Allergy and Infectious Diseases, , National Institutes of Health, ; Rockville, MD USA

[9 ]GRID grid.419681.3, ISNI 0000 0001 2164 9667, Division of Allergy, Immunology, and Transplantation, , National Institute of Allergy and Infectious Diseases, ; Rockville, MD USA

[10 ]GRID grid.418309.7, ISNI 0000 0000 8990 8592, Bill & Melinda Gates Foundation, ; Seattle, WA USA

[11 ]GRID grid.476870.a, Administration for Strategic Preparedness and Response, , Biomedical Advanced Research and Development Authority, ; 200 C Street SW, Washington, DC 20024 USA

Author information

Jane M. Knisely http://orcid.org/0000-0003-0581-0742

Rebecca Mandt http://orcid.org/0000-0001-7165-7876

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

Wolfgang W. Leitner http://orcid.org/0000-0003-3125-5922

Robert A. Seder http://orcid.org/0000-0003-3133-0849

Stig Tollefsen http://orcid.org/0000-0002-3467-2054

David W. Vaughn http://orcid.org/0000-0002-1396-1690

Article

Publisher ID: 654

DOI: 10.1038/s41541-023-00654-6

PMC ID: 10091310

PubMed ID: 37045860

SO-VID: a6703a63-c6eb-49ec-a8bb-e4d99f86bf5c

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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 9 February 2023

Date accepted : 27 March 2023

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);