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      Localized and Systemic Immune Responses against SARS-CoV-2 Following Mucosal Immunization

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          Abstract

          The rapid transmission of SARS-CoV-2 in the USA and worldwide necessitates the development of multiple vaccines to combat the COVID-19 global pandemic. Previously, we showed that a particulate adjuvant system, quil-A-loaded chitosan (QAC) nanoparticles, can elicit robust immunity combined with plasmid vaccines when used against avian coronavirus. Here, we report on the immune responses elicited by mucosal homologous plasmid and a heterologous immunization strategy using a plasmid vaccine and a Modified Vaccinia Ankara (MVA) expressing SARS-CoV-2 spike (S) and nucleocapsid (N) antigens. Only the heterologous intranasal immunization strategy elicited neutralizing antibodies against SARS-CoV-2 in serum and bronchoalveolar lavage of mice, suggesting a protective vaccine. The same prime/boost strategy led to the induction of type 1 and type 17 T-cell responses and polyfunctional T-cells expressing multiple type 1 cytokines (e.g., IFN-γ, TNFα, IL-2) in the lungs and spleens of vaccinated mice. In contrast, the plasmid homologous vaccine strategy led to the induction of local mono and polyfunctional T-cells secreting IFN-γ. Outcomes of this study support the potential of QAC-nano vaccines to elicit significant mucosal immune responses against respiratory coronaviruses.

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          Most cited references 55

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          Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

          Summary Background Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. Methods In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. Findings 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03–1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61–12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64–128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0–24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. Interpretation The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Funding Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.
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            Virological assessment of hospitalized patients with COVID-2019

            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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              SARS and MERS: recent insights into emerging coronaviruses

              Key Points Severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are zoonotic pathogens that can cause severe respiratory disease in humans. Although disease progression is fairly similar for SARS and MERS, the case fatality rate of MERS is much higher than that of SARS. Comorbidities have an important role in SARS and MERS. Several risk factors are associated with progression to acute respiratory distress syndrome (ARDS) in SARS and MERS cases, especially advanced age and male sex. For MERS, additional risk factors that are associated with severe disease include chronic conditions such as diabetes mellitus, hypertension, cancer, renal and lung disease, and co-infections. Although the ancestors of SARS-CoV and MERS-CoV probably circulate in bats, zoonotic transmission of SARS-CoV required an incidental amplifying host. Dromedary camels are the MERS-CoV reservoir from which zoonotic transmission occurs; serological evidence indicates that MERS-CoV-like viruses have been circulating in dromedary camels for at least three decades. Human-to-human transmission of SARS-CoV and MERS-CoV occurs mainly in health care settings. Patients do not shed large amounts of virus until well after the onset of symptoms, when patients are most probably already seeking medical care. Analysis of hospital surfaces after the treatment of patients with MERS showed the ubiquitous presence of infectious virus. Our understanding of the pathogenesis of SARS-CoV and MERS-CoV is still incomplete, but the combination of viral replication in the lower respiratory tract and an aberrant immune response is thought to have a crucial role in the severity of both syndromes. The severity of the diseases that are caused by emerging coronaviruses highlights the need to develop effective therapeutic measures against these viruses. Although several treatments for SARS and MERS (based on inhibition of viral replication with drugs or neutralizing antibodies, or on dampening the host response) have been identified in animal models and in vitro studies, efficacy data from human clinical trials are urgently required. Supplementary information The online version of this article (doi:10.1038/nrmicro.2016.81) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Vaccines (Basel)
                Vaccines (Basel)
                vaccines
                Vaccines
                MDPI
                2076-393X
                06 February 2021
                February 2021
                : 9
                : 2
                Affiliations
                [1 ]Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI 53706, USA; schandrasek5@ 123456wisc.edu (S.S.C.); rhildebrand@ 123456wisc.edu (R.E.H.); hanafy@ 123456wisc.edu (M.H.); chiaweiwu@ 123456wisc.edu (C.-W.W.); chungyi.hansen@ 123456wisc.edu (C.H.H.); jorge.osorio@ 123456wisc.edu (J.E.O.); suresh.marulasiddappa@ 123456wisc.edu (M.S.)
                [2 ]Pan Genome Systems, Madison, WI 53719, USA; phanse@ 123456pangenosys.com
                [3 ]Department of Microbiology and Immunology, Faculty of Veterinary Medicine, Cairo University, Giza 12211, Egypt
                [4 ]Colombia Wisconsin One Health Consortium, Universidad Nacional Medellín, Calle 75#79a 5, Colombia
                Author notes
                [* ]Correspondence: adel.talaat@ 123456wisc.edu ; Tel.: +1-608-262-2861
                Article
                vaccines-09-00132
                10.3390/vaccines9020132
                7914464
                33562141
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

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