Novel virus-like nanoparticle vaccine effectively protects animal model from SARS-CoV-2 infection

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Abstract

The key to battling the COVID-19 pandemic and its potential aftermath is to develop a variety of vaccines that are efficacious and safe, elicit lasting immunity, and cover a range of SARS-CoV-2 variants. Recombinant viral receptor-binding domains (RBDs) are safe vaccine candidates but often have limited efficacy due to the lack of virus-like immunogen display pattern. Here we have developed a novel virus-like nanoparticle (VLP) vaccine that displays 120 copies of SARS-CoV-2 RBD on its surface. This VLP-RBD vaccine mimics virus-based vaccines in immunogen display, which boosts its efficacy, while maintaining the safety of protein-based subunit vaccines. Compared to the RBD vaccine, the VLP-RBD vaccine induced five times more neutralizing antibodies in mice that efficiently blocked SARS-CoV-2 from attaching to its host receptor and potently neutralized the cell entry of variant SARS-CoV-2 strains, SARS-CoV-1, and SARS-CoV-1-related bat coronavirus. These neutralizing immune responses induced by the VLP-RBD vaccine did not wane during the two-month study period. Furthermore, the VLP-RBD vaccine effectively protected mice from SARS-CoV-2 challenge, dramatically reducing the development of clinical signs and pathological changes in immunized mice. The VLP-RBD vaccine provides one potentially effective solution to controlling the spread of SARS-CoV-2.

Author summary

Both mRNA-based and viral vector-based vaccines are currently being distributed to curtail the COVID-19 pandemic. Continued development of more varieties of SARS-CoV-2 vaccines will help battle the many variants of SARS-CoV-2. Here we have developed a virus-like particle (VLP) vaccine that combines the effectiveness of virus-based vaccines and safety of protein-based vaccines. Using the lumazine synthase nanoparticle protein as the structural scaffold and 120 copies of SARS-CoV-2 receptor-binding domain as the surface immunogen, this VLP vaccine induced high-titer neutralizing antibody responses in mice that lasted >2 months and potently inhibited SARS-CoV-2, SARS-CoV-1, and their variants. The VLP vaccine also protected mice from high-titer SARS-CoV-2 challenge. The novel VLP vaccine may contribute to the protection of the human population from SARS-CoV-2 and its variants.

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Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

Chaolin Huang, Yeming Wang, Xingwang Li … (2020)

Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.

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A pneumonia outbreak associated with a new coronavirus of probable bat origin

Peng Zhou, Xing-Lou Yang, Xian-Guang Wang … (2020)

Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.

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Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus–Infected Pneumonia

Qun Li, Xuhua Guan, Peng Wu … (2020)

Abstract Background The initial cases of novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP. Methods We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number. Results Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9). Conclusions On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.)

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Author and article information

Contributors

Qibin Geng:

ORCID: https://orcid.org/0000-0003-4872-2400

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Writing – review & editing

Wanbo Tai: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Writing – review & editing

Victoria K. Baxter:

ORCID: https://orcid.org/0000-0003-0916-360X

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: ValidationRole: Writing – review & editing

Juan Shi: Role: Data curationRole: Formal analysisRole: Validation

Yushun Wan: Role: Data curationRole: Formal analysisRole: ValidationRole: Writing – review & editing

Xiujuan Zhang:

ORCID: https://orcid.org/0000-0002-5312-0909

Role: Data curationRole: Formal analysisRole: Validation

Stephanie A. Montgomery:

ORCID: https://orcid.org/0000-0001-8012-5302

Role: Data curationRole: Formal analysis

Sharon A. Taft-Benz: Role: Data curationRole: Formal analysis

Elizabeth J. Anderson:

ORCID: https://orcid.org/0000-0001-7877-1639

Role: Data curationRole: Formal analysis

Audrey C. Knight:

ORCID: https://orcid.org/0000-0002-8009-8081

Role: Data curationRole: Formal analysis

Kenneth H. Dinnon III:

ORCID: https://orcid.org/0000-0002-8942-1551

Role: Data curationRole: Formal analysis

Sarah R. Leist:

ORCID: https://orcid.org/0000-0002-4989-5381

Role: Data curationRole: Formal analysis

Ralph S. Baric: Role: Funding acquisitionRole: MethodologyRole: ResourcesRole: Supervision

Jian Shang: Role: Data curationRole: Formal analysisRole: ValidationRole: Writing – review & editing

Sung-Wook Hong:

ORCID: https://orcid.org/0000-0001-9718-726X

Role: Data curationRole: Formal analysisRole: Writing – review & editing

Aleksandra Drelich: Role: Data curationRole: Formal analysis

Chien-Te K. Tseng:

ORCID: https://orcid.org/0000-0001-5726-9834

Role: Formal analysisRole: ResourcesRole: SupervisionRole: Validation

Marc Jenkins: Role: Formal analysisRole: ResourcesRole: SupervisionRole: Writing – review & editing

Mark Heise:

ORCID: https://orcid.org/0000-0001-5829-8477

Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: ValidationRole: Writing – review & editing

Lanying Du: Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – review & editing

Fang Li:

ORCID: https://orcid.org/0000-0002-1958-366X

Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draft

Kanta Subbarao: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Pathog

Journal ID (iso-abbrev): PLoS Pathog

Journal ID (publisher-id): plos

Title: PLoS Pathogens

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1553-7366

ISSN (Electronic): 1553-7374

Publication date (Electronic): 7 September 2021

Publication date Collection: September 2021

Volume: 17

Issue: 9

Electronic Location Identifier: e1009897

Affiliations

[1 ] Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, Minnesota, United States of America

[2 ] Center for Coronavirus Research, University of Minnesota, Saint Paul, Minnesota, United States of America

[3 ] Laboratory of Viral Immunology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York, United States of America

[4 ] Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America

[5 ] Division of Comparative Medicine, University of North Carolina, Chapel Hill, North Carolina, United States of America

[6 ] Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina, United States of America

[7 ] Rapidly Emerging Antiviral Drug Development Initiative, University of North Carolina, Chapel Hill, North Carolina, United States of America

[8 ] Center for Immunology, Department of Microbiology and Immunology, University of Minnesota, Minneapolis, Minnesota, United States of America

[9 ] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America

[10 ] Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America

The Peter Doherty Institute and Melbourne University, AUSTRALIA

Author notes

We have read the journal’s policy and the authors of this manuscript have the following competing interests: The University of Minnesota has filed a patent on the lumazine synthase nanoparticle-based SARS-CoV-2 RBD vaccine with F.L, Q.G., Y.W., J.S., M.J., S.H., L.D. and T.W. as inventors. Other authors have declared that no competing interests exist.

* E-mail: mark_heisem@ 123456med.unc.edu (MH); ldu@ 123456nybc.org (LD); lifang@ 123456umn.edu (FL)

Author information

Qibin Geng https://orcid.org/0000-0003-4872-2400

Victoria K. Baxter https://orcid.org/0000-0003-0916-360X

Xiujuan Zhang https://orcid.org/0000-0002-5312-0909

Stephanie A. Montgomery https://orcid.org/0000-0001-8012-5302

Elizabeth J. Anderson https://orcid.org/0000-0001-7877-1639

Audrey C. Knight https://orcid.org/0000-0002-8009-8081

Kenneth H. Dinnon III https://orcid.org/0000-0002-8942-1551

Sarah R. Leist https://orcid.org/0000-0002-4989-5381

Sung-Wook Hong https://orcid.org/0000-0001-9718-726X

Chien-Te K. Tseng https://orcid.org/0000-0001-5726-9834

Mark Heise https://orcid.org/0000-0001-5829-8477

Fang Li https://orcid.org/0000-0002-1958-366X

Article

Publisher ID: PPATHOGENS-D-21-00291

DOI: 10.1371/journal.ppat.1009897

PMC ID: 8448314

PubMed ID: 34492082

SO-VID: 50243a81-d22b-4884-a59b-18e0189d280b

License:

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 author and source are credited.

History

Date received : 7 February 2021

Date accepted : 16 August 2021

Page count

Figures: 5, Tables: 0, Pages: 20

Funding

Funded by: University of Minnesota

Award Recipient :

ORCID: https://orcid.org/0000-0002-1958-366X

Fang Li