A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike

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Measles virus (MeV) vaccine is one of the safest and most efficient vaccines with a track record in children. Here, we generated a panel of rMeV-based vaccines with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) S antigens inserted near 3′ of the MeV genome. The rMeV expressing a soluble stabilized, prefusion spike (preS) is much more potent in triggering SARS-CoV-2–specific neutralizing antibody than rMeV-based full-length S vaccine candidate. A single dose of rMeV-preS is sufficient to induce high levels of SARS-CoV-2 antibody in animals. Furthermore, rMeV-preS induces high levels of Th1-biased immunity. Hamsters immunized with rMeV-preS were completely protected against SARS-CoV-2 challenge. Our results demonstrate rMeV-preS is a safe and highly efficacious bivalent vaccine candidate for SARS-CoV-2 and MeV.

Abstract

The current pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights an urgent need to develop a safe, efficacious, and durable vaccine. Using a measles virus (rMeV) vaccine strain as the backbone, we developed a series of recombinant attenuated vaccine candidates expressing various forms of the SARS-CoV-2 spike (S) protein and its receptor binding domain (RBD) and evaluated their efficacy in cotton rat, IFNAR ^−/−mice, IFNAR ^−/−-hCD46 mice, and golden Syrian hamsters. We found that rMeV expressing stabilized prefusion S protein (rMeV-preS) was more potent in inducing SARS-CoV-2–specific neutralizing antibodies than rMeV expressing full-length S protein (rMeV-S), while the rMeVs expressing different lengths of RBD (rMeV-RBD) were the least potent. Animals immunized with rMeV-preS produced higher levels of neutralizing antibody than found in convalescent sera from COVID-19 patients and a strong Th1-biased T cell response. The rMeV-preS also provided complete protection of hamsters from challenge with SARS-CoV-2, preventing replication in lungs and nasal turbinates, body weight loss, cytokine storm, and lung pathology. These data demonstrate that rMeV-preS is a safe and highly efficacious vaccine candidate, supporting its further development as a SARS-CoV-2 vaccine.

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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 Novel Coronavirus from Patients with Pneumonia in China, 2019

Na Zhu, Dingyu Zhang, Wenling Wang … (2020)

Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)

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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

Journal

Journal ID (nlm-ta): Proc Natl Acad Sci U S A

Journal ID (iso-abbrev): Proc Natl Acad Sci U S A

Journal ID (hwp): pnas

Journal ID (pmc): pnas

Journal ID (publisher-id): PNAS

Title: Proceedings of the National Academy of Sciences of the United States of America

Publisher: National Academy of Sciences

ISSN (Print): 0027-8424

ISSN (Electronic): 1091-6490

Publication date (Print): 23 March 2021

Publication date (Electronic): 09 March 2021

Publication date PMC-release: 09 March 2021

Volume: 118

Issue: 12

Electronic Location Identifier: e2026153118

Affiliations

[1] ^aDepartment of Veterinary Biosciences, The Ohio State University , Columbus, OH 43210;

[2] ^bCenter for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital , Columbus, OH 43205;

[3] ^cDepartment of Microbial Infection and Immunity, College of Medicine, The Ohio State University , Columbus, OH 43210;

[4] ^dDepartment of Surgery, College of Medicine, The Ohio State University, Columbus, OH 43210;

[5] ^eTexas Biomedical Research Institute , San Antonio, TX 78227;

[6] ^fDepartment of Pediatrics, College of Medicine, The Ohio State University , Columbus, OH 43210;

[7] ^gInfectious Disease Institute, The Ohio State University, Columbus, OH 43210;

[8] ^hCenter for Retrovirus Research, The Ohio State University, Columbus, OH 43210;

[9] ⁱDepartment of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center , Kansas City, KS 66160

Author notes

²To whom correspondence may be addressed. Email: li.926@ 123456osu.edu .

Edited by Peter Palese, Icahn School of Medicine at Mount Sinai, New York, NY, and approved February 10, 2021 (received for review December 21, 2020)

Author contributions: M.L., P.D., Y.Z., S.T., A.L., O.H., X.L., M.E.P., A. Kapoor, S.N., and J.L. designed research; M.L., P.D., Y.Z., S.T., A.L., O.H., M.K.C., S.C., A.Z., A. Kenney, C.Z., C.C., C.Y., X.L., P.N.B., J.Q., L.M.-S., J.S.Y., M.E.P., A. Kapoor, S.N., and J.L. performed research; M.L., C.Y., M.S., S.-L.L., A.M., O.R., J.Q., L.M.-S., J.S.Y., M.E.P., A. Kapoor, S.N., and J.L. contributed new reagents/analytic tools; M.L., P.D., Y.Z., S.T., M.K.C., S.C., P.N.B., L.M.-S., M.E.P., A. Kapoor, S.N., and J.L. analyzed data; M.L. and J.L. wrote the paper; P.D., Y.Z., S.T., A.L., O.H., M.K.C., S.C., A.Z., A. Kenney, C.Z., C.Y., X.L., M.S., S.-L.L., A.M., O.R., P.N.B., J.Q., L.M.-S., J.S.Y., M.E.P., A. Kapoor, and S.N. edited the manuscript; and J.L. provided funding.

¹P.D., Y.Z., S.T., A.L., O.H., and M.K.C. contributed equally to this work.

Author information

Mijia Lu https://orcid.org/0000-0002-4438-980X

Piyush Dravid https://orcid.org/0000-0002-4790-9591

Mahesh KC https://orcid.org/0000-0002-5177-9566

Supranee Chaiwatpongsakorn https://orcid.org/0000-0003-3511-7359

Chuanxi Cai https://orcid.org/0000-0003-0532-7435

Prosper N. Boyaka https://orcid.org/0000-0001-6857-9088

Jianming Qiu https://orcid.org/0000-0001-9850-1695

Article

Publisher ID: 202026153

DOI: 10.1073/pnas.2026153118

PMC ID: 8000430

PubMed ID: 33688034

SO-VID: 5c6f016e-2a4f-4a57-b297-2e9673298809

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This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).

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Pages: 11

Funding

Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) 100000060

Award ID: AI090060

Award Recipient : Mark Peeples Award Recipient : Stefan Niewiesk Award Recipient : Jianrong Li

Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) 100000060

Award ID: AI112524

Award Recipient : Mark Peeples Award Recipient : Stefan Niewiesk Award Recipient : Jianrong Li

Funded by: HHS | NIH | National Human Genome Research Institute (NHGRI) 100000051

Award ID: HG008935

Award Recipient : Jianrong Li

Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) 100000060

Award ID: AI42733

Award Recipient : Mark Peeples Award Recipient : Stefan Niewiesk Award Recipient : Jianrong Li

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Keywords: sars-cov-2 vaccine,measles virus vector,prefusion spike

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Keywords: sars-cov-2 vaccine, measles virus vector, prefusion spike

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A safe and highly efficacious measles virus-based vaccine expressing SARS-CoV-2 stabilized prefusion spike

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Novel Coronavirus Disease COVID-19

Most cited references 59

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

A Novel Coronavirus from Patients with Pneumonia in China, 2019

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

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