Toward sustainable learning during school suspension: Socioeconomic, occupational aspirations, and learning behavior of vietnamese students during COVID-19

Abstract: The overspread of the novel coronavirus-SARS-CoV-2-over the globe has caused significant damage to manufacturing and service businesses, regardless of whether they are commercial, public, or not-for-profit sectors. While both the short-term and long-term impacts of most companies can be approximately measured or estimated, it is challenging to address the enduring effects of COVID-19 on teaching and learning activities. The target of this research is to investigate students' manners of studying at home during the school suspension time as a result of COVID-19. Through analyzing original survey data from 420 K6-12 students in Hanoi, Vietnam, this work demonstrates the different learning habits of students with different socioeconomic statuses and occupational aspirations during the disease's outbreak. In particular, we featured the differences in students' learning behaviors between private schools and public schools, as well as between students who plan to follow STEM-related careers and those who intend to engage in social science-related careers. The empirical evidence of this study can be used for the consideration of the local government to increase the sustainability of coming policies and regulations to boost students' self-efficacy, as it will affect 1.4 million students in Hanoi, as well as the larger population of nearly 10 million Vietnamese students. These results can also be the foundation for future investigations on how to elevate students' learning habits toward Sustainable Development Goal 4 (SDG4)-Quality Education-especially in fanciful situations in which the regular school operation has been disrupted, counting with limited observation and support from teachers and parents.


Career Confidential: Teacher wonders how to help students during coronavirus shutdown

Abstract: Phyllis Fagell provides workplace advice to educators in this Kappan column. This month, a teacher wants to know how she can provide emotional support to students when the school is closed for the COVID-19 pandemic. A teachers’ colleagues provide a lot of free after-school help to students, making her feel obligated to do the same, even when it interferes with her family time or when students have not been doing the work during class.


Modelling Singapore COVID-19 pandemic with a SEIR multiplex network model

Abstract: In this paper, we have implemented a large-scale agent-based model to study the outbreak of coronavirus infectious diseases (COVID-19) in Singapore, taking into account complex human interaction pattern. In particular, the concept of multiplex network is utilized to differentiate between social interactions that happen in households and workplaces. In addition, weak interactions among crowds, transient interactions within social gatherings, and dense human contact between foreign workers in dormitories are also taken into consideration. Such a categorization in terms of a multiplex of social network connections together with the Susceptible-Exposed-Infectious-Removed (SEIR) epidemic model have enabled a more precise study of the feasibility and efficacy of control measures such as social distancing, work from home, and lockdown, at different moments and stages of the pandemics.


WHO-INTEGRATE COVID framework Version 1.0: Criteria and considerations to guide evidence-informed decision-making on non-pharmacological interventions targeting COVID-19

Abstract: Background: Decision-making on matters of public health requires the balancing of numerous, often conflicting factors. One approach to ensure relevancy and comprehensiveness of the criteria underpinning the decision is a broad societal discourse and participatory decision-making process. However, this often was not feasible within the time constraints imposed on by the SARS-CoV-2 pandemic. While not able or intended to replace stakeholder participation, evidence-to-decision frameworks can serve as a tool to approach relevancy and comprehensiveness of the criteria considered, even if not all voices of affected stakeholders could be heard in the process. Objective: The objective of this research project was to develop a decision-making framework adapted to the challenges decision-makers face when deliberating on national and sub-national level on non-pharmacological interventions (NPIs) measures to address the global SARS-CoV-2 pandemic. Methods: We used the WHO-INTEGRATE framework Version 1.0 as a starting point. In phase I, we adapted the framework through brainstorming exercises and application to exemplary case studies. In phase II, we used the best-fit framework synthesis technique with the output of phase I serving as a priori framework. We conducted a content analysis of comprehensive strategy documents intended to guide the policy makers on the phasing out of the lockdown measures in Germany. Based on factors and criteria identified in this process, we adapted previous versions into the WHO-INTEGRATE COVID framework (WICID framework) Version 1.0. Results: Twelve comprehensive strategy documents were included in the content analysis. The revised WICID framework consists of eleven criteria, which are expanded on through 49 aspects contained within them, and the metacriterion quality of evidence. The criteria cover implications for the health of individuals and populations due to and beyond COVID-19, infringement on liberties and fundamental rights, acceptability considerations, societal, environmental, and economic implications, as well as resource and feasibility considerations. Discussion: In a third phase, the framework will be expanded through a comprehensive document analysis focusing on key-stakeholder groups across the society. The WICID framework V1.0 can be a tool to support comprehensive evidence-informed decision-making processes.


Lockdown measures in response to COVID-19 in Sub-Saharan Africa: A rapid study of nine countries

Abstract: Lockdown measures have been introduced worldwide to contain the transmission of COVID-19. This paper defines the term lockdown and describes the design, timing and implementation of lockdown in nine countries in Sub Saharan Africa: Ghana, Nigeria, South Africa, Sierra Leone, Sudan, Tanzania, Uganda, Zambia and Zimbabwe. It also discusses the manner in which lockdown is enforced, the need to mitigate the harms of lockdown, and the association between lockdown and the reported number of COVID-19 cases and deaths. While there are some commonalities in the implementation of lockdown, a more notable finding is the variation in the design, timing and implementation of lockdown measures across the nine countries. We found that the number of reported cases is heavily dependent on the number of tests done, and that testing rates ranged from 9 to 21,261 per million population. The reported number of COVID-19 deaths per million population also varies, but is generally low when compared to countries in Europe and North America. While lockdown measures may have helped inhibit some community transmission, the pattern and nature of the epidemic remains unclear. Of concern are signs of lockdown harming health by affecting the functioning of the health system and causing social and economic harms. This paper highlights the need for inter-sectoral and trans-disciplinary research capable of providing a rigorous and holistic assessment of the harms and benefits of lockdown.


Expected impact of reopening schools after lockdown on COVID-19 epidemic in Ile-de-France

Abstract: As several countries around the world are planning exit strategies to progressively lift the rigid social restrictions implemented with lockdown, different options are being chosen regarding the closure or reopening of schools. We evaluate the expected impact of reopening schools in lIe-de-France region after the withdrawal of lockdown currently scheduled for May 11, 2020. We explore several scenarios of partial, progressive, or full school reopening, coupled with moderate social distancing interventions and large-scale tracing, testing, and isolation. Accounting for current uncertainty on the role of children in COVID-19 epidemic, we test different hypotheses on children's transmissibility distinguishing between younger children (pre-school and primary school age) and adolescents (middle and high school age). Reopening schools after lifting lockdown will likely lead to an increase in the number of COVID-19 cases in the following 2 months, even with lower transmissibility of children, yet protocols exist that would allow maintaining the epidemic under control without saturating the healthcare system. With pre-schools and primary schools in session starting May 11, ICU occupation would reach at most 72% [55,83]% (95% probability ranges) of a 1,500-bed capacity (here foreseen as the routine capacity restored in the region post-first wave) if no other school level reopens before summer or if middle and high schools reopen one month later through a progressive protocol (increasing attendance week by week). Full attendance of adolescents at school starting in June would overwhelm the ICU system (138% [118,159]% occupation). Reopening all schools on May 11 would likely lead to a second wave similar to the one recently experienced, except if maximum attendance is limited to 50% for both younger children and adolescents. Based on the estimated situation on May 11, no substantial difference in the epidemic risk is predicted between progressive and prompt reopening of pre-schools and primary schools, thus allowing full attendance of younger children mostly in need of resuming learning and development. Reopening would require however large-scale trace and testing to promptly isolate cases, in addition to moderate social distancing interventions. Full attendance in middle and high schools is instead not recommended. Findings are consistent across different assumptions on the relative transmissibility of younger children and for small increase of the reproductive number possibly due to decreasing compliance to lockdown.


What can a Pandemic Teach Us about Competency Based Medical Education?

Abstract: Medical education is moving towards competency-based medical education (CBME) where learning and assessment are focused on predefined abilities and outcomes. While medical student and residency training have defined competencies and objectives that trainees need to achieve, training remains time -based. Students and residents graduate based on a preset length of training. The COVID -19 pandemic is disrupting educational and clinical environments and in some regions the workforce may not be adequate to respond to the needs of the community. This, therefore, presents an opportunity for the medical education community to reconsider time-based training and embrace a competency-based progression to accelerate entry into the workforce. This commentary discusses undergraduate and graduate medical education response to workforce pressures of COVID-19. On one hand, some medical schools are moving towards competency-based (early) graduation from medical school. On the other hand, residency programs have generally held to time -based completion of training. In the context of this clinical and educational disruption, there are two challenges to CBME progression of trainees. The first challenge is whether there is trust in competency-based assessment to permit time independent progression. The second involves a number of logistical issues to competency-based progression.


Prevent the resurgence of infectious disease with asymptomatic carriers

Abstract: As many countries reached the peak of the COVID-19 outbreak, there is debate on how to reopen the economy without causing a significant resurgence. Here we show, using a microsimulation model, that how to reopen safely depends on what percentage of COVID-19 cases can be detected by testing. The higher the detection rate, the less restrictive the reopen plan needs to be. If 70% of cases can be detected, schools and businesses can reopen if 2-layer quarantine is imposed on each confirmed case. Our results suggest that increasing the detection rate is essential to prevent the resurgence of COVID-19.


Quantifying the impact of US state non-pharmaceutical interventions on COVID-19 transmission

Abstract: COVID-19 is an ongoing public health emergency. Without a vaccine or effective antivirals, non-pharmaceutical interventions form the foundation of current response efforts. Quantifying the efficacy of these interventions is crucial. Using mortality data and a classification guide of state level responses, we relate the intensity of interventions to statistical estimates of transmission, finding that more stringent control measures are associated with larger reductions in disease proliferation. Additionally, we observe that transmission increases with population density, but not population size. These results may help inform future response efforts.


Predicting the second wave of COVID-19 in Washtenaw County, MI

Abstract: Marissa Renardy and Denise Kirschner University of Michigan Medical School The COVID-19 pandemic has highlighted the patchwork nature of disease epidemics, with infection spread dynamics varying wildly across countries and across states within the US. These heteroge- neous patterns are also observed within individual states, with patches of concentrated outbreaks. Data is being generated daily at all of these spatial scales, and answers to questions regarded re- opening strategies are desperately needed. Mathematical modeling is useful in exactly these cases, and using modeling at a county scale may be valuable to further predict disease dynamics for the purposes of public health interventions. To explore this issue, we study and predict the spread of COVID-19 in Washtenaw County, MI, the home to University of Michigan, Eastern Michigan University, and Google, as well as serving as a sister city to Detroit, MI where there has been a serious outbreak. Here, we apply a discrete and stochastic network-based modeling framework allowing us to track every individual in the county. In this framework, we construct contact net- works based on synthetic population datasets specific for Washtenaw County that are derived from US Census datasets. We assign individuals to households, workplaces, schools, and group quarters (such as prisons). In addition, we assign casual contacts to each individual at random. Using this framework, we explicitly simulate Michigan-specific government-mandated workplace and school closures as well as social distancing measures. We also perform sensitivity analyses to identify key model parameters and mechanisms contributing to the observed disease burden in the three months following the first observed cases on COVID-19 in Michigan. We then consider several scenarios for relaxing restrictions and reopening workplaces to predict what actions would be most prudent. In particular, we consider the effects of 1) different timings for reopening, and 2) different levels of workplace vs. casual contact re-engagement. Through simulations and sensitivity analyses, we explore mechanisms driving magnitude and timing of a second wave of infections upon re-opening. This model can be adapted to other US counties using synthetic population databases and data specific to those regions.


Effectiveness of stay-in-place-orders during COVID-19 pandemic: Evidence from US border counties.

Abstract: Recent studies on US counties, with varying effect sizes, show that stay-in-place-orders (SIPOs) are associated with a decline in new COVID-19 cases. Our estimation approach relies on county-pairs across state-borders where one state has SIPO whereas the other state does not, controls for matched county-pair fixed effects and day of observation fixed-effects. The county-pair sample from southern, mid-western, and mountain region states (from March 1, 2020 to April 25, 2020) shows that daily COVID-19 incidence case growth rate is 1.994 percentage points lower for counties in SIPO states relative to those bordering in non-SIPO states. Specifically, we find SIPO reduced daily growth rates by 1.97, 2.14, 2.03, and 2.27 percentage points after 1 to 5 days, 6 to 10 days, 11 to 15 days, and 16 to 20 days, respectively. Our effect sizes are much smaller than in the previous studies with the caveat that states in the northeast and on the west coast could not be included in the border county-pair specification. We find limited evidence of heterogeneous effects in counties with a higher population density, percentage of black or Hispanic residents, proportion of population over 65 years, and social association rates in a county. Nor do we find evidence of meaningful differences in effects of SIPO by county Gini index, unemployment, or GDP. The results of this study could further inform policymakers in making decisions on SIPO extensions or lifting of such orders.


SARS-CoV-2 antibody prevalence in blood in a large school community subject to a Covid-19 outbreak: a cross-sectional study

Abstract: BACKGROUND: A SARS-CoV-2 outbreak affecting 52 people from a large school community in Santiago, Chile was identified (March 12), nine days after the first country case. We assessed the magnitude of the outbreak and the role students and staff played using a self-administered antibody detection test and survey. METHODS: The school was closed on March 13, and the entire community was placed under quarantine. We implemented a home-delivery, self-administered, IgG/IgM antibody test and survey to a classroom stratified sample of students and all staff from May 4-19. We aimed to determine overall seroprevalence rates by age group, reported symptoms, contact exposure and to explore dynamics of transmission. RESULTS: Antibody positivity rates were 9.9% (95%CI: 8.2-11.8) for 1,009 students and 16.6% (95%CI: 12.1-21.9) for 235 staff. Among students, positivity was associated with younger age (P=0.01), lower grade level (P=0.05), prior RT-PCR positivity (P=0.03), and history of contact with a confirmed case (P<0.001). Among staff, positivity was higher in teachers (P=0.01) and in those previously RT-PCR positive (P<0.001). Excluding RT-PCR positive individuals, antibody positivity was associated with fever in adults and children (P=0.02; P=0.002), abdominal pain in children (P=0.001), and chest pain in adults (P=0.02). Within antibody positive individuals, 40% of students and 18% of staff reported no symptoms (P=0.01). CONCLUSIONS: Teachers were more affected during the outbreak and younger children were at higher infection risk, likely because index case(s) were teachers and/or parents from preschool. Self-administered antibody testing, supervised remotely, proved to be a suitable and rapid tool. Our study provides useful information for school re-openings.


Covid-19: US cases soar as Trump pushes for schools to open


Considering inequalities in the school closure response to COVID-19


Children and the COVID-19 pandemic

Abstract: As a result of the COVID-19 pandemic, many school districts have closed for the remainder of the academic year. These closures are unfortunate because, for many students, schools are their only source of trauma-informed care and supports. When schools reopen, they must develop a comprehensive plan to address the potential mental health needs of their students. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


La pandemia de la COVID-19 desde la SEAP./ [The Spanish Society of Pathologists on the COVID-19 pandemic]


[Interim Guidelines for Prevention and Control of COVID-19 for Students Back to School]


COVID-19 and the re-opening of schools: a policy maker's dilemma

Abstract: The epidemic of coronavirus disease 2019 (COVID-19) broke out in Wuhan, China, in December 2019 and rapidly spread across the world. In order to counter this epidemic, several countries put in place different restrictive measures, such as the school's closure and a total lockdown. However, as the knowledge on the disease progresses, clinical evidence showed that children mainly have asymptomatic or mild disease and it has been suggested that they are also less likely to spread the virus. Moreover, the lockdown and the school closure could have negative consequences on children, affecting their social life, their education and their mental health. As many countries have already entered or are planning a phase of gradual lifting of the containment measures of social distancing, it seems plausible that the re-opening of nursery schools and primary schools could be considered a policy to be implemented at an early stage of recovery efforts, putting in place measures to do it safely, such as the maintenance of social distance, the reorganisation of classes into smaller groups, the provision of adequate sanitization of spaces, furniture and toys, the prompt identification of cases in the school environment and their tracing. Therefore, policy makers have the task of balancing pros and cons of the school re-opening strategy, taking into account psychological, educational and social consequences for children and their families. Another issue to be considered is represented by socio-economic disparities and inequalities which could be amplified by school's closure.


How risk communication could have reduced controversy about school closures in Australia during the COVID-19 pandemic

Abstract: Although there has been consistent evidence indicating that school closures have only limited efficacy in reducing community transmission of coronavirus disease 2019 (COVID-19), the question of whether children should be kept home from school has attracted extensive and often divisive public debate in Australia. In this article we analyse the factors that drove high levels of concern among parents, teachers and the public and led to both demands for school closures in late March 2020, and to many parents' reluctance to return their children to school in May 2020. We discuss how the use of well-established principles of risk communication might have reduced much of this community concern. Then we set out a range of practical suggestions for communication practices that build trust and hence diminish concerns in relation to managing schools over the long term of the COVID-19 pandemic.


Covid-19: Delaying school reopening by two weeks would halve risks to children, says iSAGE


Un-Muting Medical Student Education: Utilizing Telemedicine During the COVID-19 Pandemic and Beyond

Abstract: UNSTRUCTURED: Due to the COVID-19 pandemic, medical schools have paused traditional clerkships, eliminating direct patient encounters from medical student education for the immediate future. Telemedicine offers opportunities in a variety of specialties that can augment student education during this time. The projected growth of telemedicine necessitates that students learn new skills to be effective providers. In this Viewpoint, we delineate specific telehealth opportunities that teach core competencies for patient care, while also teaching telemedicine specific skills. Schools can further augment student education through a variety of telemedicine initiatives across multiple medical fields. The explosion of telemedicine programs due to the pandemic can be a catalyst for schools to integrate telemedicine into their current curricula. The depth and variety of telemedicine opportunities allows schools to continue providing high quality medical education while maintaining social distancing policies.


Mental health burden for Chinese middle school students affected by the COVID-19 pandemic


Covid-19: Government must plan for schools to reopen, say paediatricians


Somatic symptoms and concern regarding COVID-19 among Chinese college and primary school students: A cross-sectional survey

Abstract: The rapid, ongoing and worldwide coronavirus 2019 (COVID-19) pandemic represents a global public health emergency. Our objective was to explore the impact of the COVID-19 pandemic on somatic symptoms among Chinese college and primary school students, to provide reference data pertaining to the mental health of this population in the context of a public health emergency. In February and March 2020, we explored the somatic symptoms and concerns regarding COVID-19 of 399 college and primary school students in Sichuan Province using the Somatic Self-rating Scale (SSS) and a novel questionnaire, respectively. Logistic regression analysis and non-parametric tests were used to analyze the data. The incidence of somatic symptoms among college students was 34.85 (mild, 26.26%; moderate, 8.59%). The incidence of somatic symptoms in primary school students was 2.39% (all mild). Among the entire cohort, concern regarding COVID-19 was positively correlated with the occurrence of somatic symptoms. Somatic symptoms were more likely among college students expressing greater concern regarding the threat to life and health posed by COVID-19, and the efficacy of prevention and control measures. Among primary school students, only the concern for life and health was associated with a higher likelihood of somatic symptoms. Our data indicate that governments and other relevant agencies should implement different measures to prevent and control mental health disorders diseases in primary school and college students.


Novel coronavirus 2019 transmission risk in educational settings

Abstract: Transmission risk of SARS-CoV-2 in schools is unknown. Our investigations especially in pre-schools could not detect SARS-CoV-2 transmission despite screening of symptomatic and asymptomatic children. The data suggests that children are not the primary drivers of SARS-CoV-2 transmission in schools and could help inform exit strategies for lifting of lockdowns.


Mental health effects of school closures during COVID-19


COVID-19-We urgently need to start developing an exit strategy

Abstract: AIM: The purpose of this perspective is to review the options countries have to exit the draconian "lockdowns" in a carefully staged manner. METHODS: Experts from different countries experiencing Corona Virus Infectious Disease 2019 (COVID-19) reviewed evidence and country-specific approaches and the results of their interventions. RESULTS: Three factors are essential: 1. Reintroduction from countries with ongoing community transmission; 2. The need for extensive testing capacity and widespread community testing, and 3. An adequate supply of personal protective equipment, PPE, to protect health care workers. Discussed at length are lifting physical distancing, how to open manufacturing and construction, logistics, and the opening of higher educational institutions and schools. The use of electronic surveillance is considered. CONCLUSION: Each country should decide on the best path forward. However, we can learn from each other, and the approaches are, in reality, very similar.


Deployment of convalescent plasma for the prevention and treatment of COVID-19.

Abstract: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS-CoV-2, nor therapy for those who develop COVID-19. Immune (i.e. "convalescent") plasma refers to plasma that is collected from individuals, following resolution of infection and development of antibodies. Passive antibody administration through transfusion of convalescent plasma may offer the only short-term strategy to confer immediate immunity to susceptible individuals. There are numerous examples, where convalescent plasma has been used successfully as post-exposure prophylaxis and/or treatment of infectious diseases, including other outbreaks of coronaviruses (e.g., SARS-1, Middle East Respiratory Syndrome [MERS]). Convalescent plasma has also been used in the COVID-19 pandemic; limited data from China suggest clinical benefit, including radiological resolution, reduction in viral loads and improved survival. Globally, blood centers have robust infrastructure to undertake collections and construct inventories of convalescent plasma to meet the growing demand. Nonetheless, there are nuanced challenges, both regulatory and logistical, spanning donor eligibility, donor recruitment, collections and transfusion itself. Data from rigorously controlled clinical trials of convalescent plasma are also few, underscoring the need to evaluate its use objectively for a range of indications (e.g., prevention vs treatment) and patient populations (e.g., age, comorbid disease). We provide an overview of convalescent plasma, from evidence of benefit, regulatory considerations, logistical work flow and proposed clinical trials, as scale up is brought underway to mobilize this critical resource. .


Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.

Abstract: The clinical features and immune responses of asymptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been well described. We studied 37 asymptomatic individuals in the Wanzhou District who were diagnosed with RT-PCR-confirmed SARS-CoV-2 infections but without any relevant clinical symptoms in the preceding 14 d and during hospitalization. Asymptomatic individuals were admitted to the government-designated Wanzhou People's Hospital for centralized isolation in accordance with policy1. The median duration of viral shedding in the asymptomatic group was 19 d (interquartile range (IQR), 15-26 d). The asymptomatic group had a significantly longer duration of viral shedding than the symptomatic group (log-rank P = 0.028). The virus-specific IgG levels in the asymptomatic group (median S/CO, 3.4; IQR, 1.6-10.7) were significantly lower (P = 0.005) relative to the symptomatic group (median S/CO, 20.5; IQR, 5.8-38.2) in the acute phase. Of asymptomatic individuals, 93.3% (28/30) and 81.1% (30/37) had reduction in IgG and neutralizing antibody levels, respectively, during the early convalescent phase, as compared to 96.8% (30/31) and 62.2% (23/37) of symptomatic patients. Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.


Kinetics of viral load and antibody response in relation to COVID-19 severity.

Abstract: The SARS-CoV-2 is the causative agent for COVID-19 pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity and neutralization antibody response in COVID-19 patients. Two groups of RT-PCR confirmed COVID-19 patients were enrolled in this study, including 12 severe patients in ICUs who needed mechanical ventilation and 11 mild patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severe patients had viral shedding in a variety of tissues for 20~40 days post onset of disease (8/12, 66.7%); while the majority of mild patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA after 10 days post-onset (9/11, 81.8%). Mild patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both severe and mild groups at 9 days post onset and remained high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in COVID-19 patients but not in MERS patients. High-levels of neutralizing antibodies were induced after about 10 days post onset in both severe and mild patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from COVID-19 patients, but not convalescent SARS and MERS patients inhibited SARS-CoV-2 entry. Anti-SARS-CoV-2 S and N IgG level exhibited moderate correlation with neutralization titers in patients' plasma. This study improves our understanding of immune response in human after SARS-CoV-2 infection.


Spectrum of innate and adaptive immune response to SARS CoV 2 infection across asymptomatic, mild and severe cases; a longitudinal cohort study


Serum-IgG responses to SARS-CoV-2 after mild and severe COVID-19 infection and analysis of IgG non-responders

Abstract: Background: To accurately interpret COVID-19 seroprevalence surveys, knowledge of serum-IgG responses to SARS-CoV-2 with a better understanding of patients who do not seroconvert, is imperative. This study aimed to describe serum-IgG responses to SARS-CoV-2 in a cohort of patients with both severe and mild COVID-19, including extended studies of patients who remained seronegative more than 90 days post symptom onset. Results: Forty-seven patients (mean age 49 years, 38% female) were included. All (15/15) patients with severe symptoms and 29/32 (90.6%) patients with mild symptoms of COVID-19 developed SARS-CoV-2-specific IgG antibodies in serum. Time to seroconversion was significantly shorter (median 11 vs. 22 days, P=0.04) in patients with severe compared to mild symptoms. Of the three patients without detectable IgG-responses after >90 days, all had detectable virus-neutralizing antibodies and in two, spike-protein receptor binding domain-specific IgG was detected with an in-house assay. Antibody titers were preserved during follow-up and all patients who seroconverted, irrespective of the severity of symptoms, still had detectable IgG levels >75 days post symptom onset. Conclusions: Patients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS-CoV-2-specific IgG than patients with mild symptoms. Of those patients who not develop detectable IgG antibodies, all have detectable virus-neutralizing antibodies, suggesting immunity. Our results showing that not all COVID-19 patients develop detectable IgG using two validated commercial clinical methods, even over time, are vital for the interpretation of COVID-19 seroprevalence surveys and for estimating the true infection prevalence in populations.


Relative COVID-19 viral persistence and antibody kinetics

Abstract: Importance: The COVID-19 antibody response is a critical indicator for evaluating immunity and also serves as the knowledge base for vaccine development. The picture is still not clear because of many limitations including testing tools, time of sampling, and the unclear impact of varying clinical status. In addition to these problems, antibody levels may not be equivalent to protective capacity. Objective: To define the key factor for the different patterns of COVID-19 antibody response. Design: We elucidated the antibody response with time-series throat and serum samples for viral loads and antibody levels, then used a neutralization test to evaluate protectiveness. Setting: A medical center that typically cares for patients with moderate to severe diseases. Because of the low prevalence of COVID-19 in Taiwan and local government policy, however, we also admit COVID-19 patients with mild disease or even those without symptoms for inpatient care. Participants: RT-PCR-confirmed COVID-19 patients. Results: We found that only patients with relative persistence of virus at pharynx displayed strong antibody responses that were proportional to the pharyngeal viral load. They also had proportional neutralization titers per unit of serum. Although antibody levels decreased around 2 weeks after symptom onset, the neutralization efficacy per unit antibody remained steady and even continued to increase over time. The antibody response in patients with rapid virus clearance was weak, but the neutralization efficacy per unit antibody in these patients was comparable to those with persistent presence of virus. The deceased were with higher viral load, higher level of antibody, and higher neutralization titers in the serum, but the neutralization capacity per unit antibody is relatively low. Conclusions and Relevance: Strong antibody response depends on the relative persistence of the virus, instead of the absolute virus amount. The antibody response is still weak if large amount of virus is cleared quickly. The neutralization efficacy per unit antibody is comparable between high and low antibody patterns. Strong antibody response contains more inefficient and maybe even harmful antibodies. Low antibody response is also equipped with a capable B cell pool of efficient antibodies, which may expand with next virus encounter and confer protection.


Systems-level immunomonitoring from acute to recovery phase of severe COVID-19

Abstract: The immune response to SARS-CoV2 is under intense investigation, but not fully understood att this moment. Severe disease is characterized by vigorous inflammatory responses in the lung, often with a sudden onset after 5-7 days of stable disease. Efforts to modulate this hyperinflammation and the associated acute respiratory distress syndrome, rely on the unraveling of the immune cell interactions and cytokines that drive such responses. Systems-level analyses are required to simultaneously capture all immune cell populations and the many protein mediators by which cells communicate. Since every patient analyzed will be captured at different stages of his or her infection, longitudinal monitoring of the immune response is critical. Here we report on a systems-level blood immunomonitoring study of 39 adult patients, hospitalized with severe COVID-19 and followed with up to 14 blood samples from acute to recovery phases of the disease. We describe an IFNg-Eosinophil axis activated prior to lung hyperinflammation and changes in cell-cell coregulation during different stages of the disease. We also map an immune trajectory during recovery that is shared among patients with severe COVID-19.


Reappearance of Effector T Cells Predicts Successful Recovery from COVID-19

Abstract: Background: Elucidating the role of T cell responses in COVID-19 is of utmost importance to understand the clearance of SARS-CoV-2 infection. Methods: 90 individuals were enrolled in this study, 30 hospitalized COVID-19 patients and 60 age- and gender-matched healthy controls (HC). Using two comprehensive 11-color flow cytometric panels conforming to Good Laboratory Practice (GLP) and approved for clinical diagnostics, we longitudinally examined cell count differences in lymphocyte populations and T cell activation in COVID-19 patients. Findings: Absolute numbers of lymphocyte subsets were differentially decreased in COVID-19 patients according to clinical severity. In severe disease (SD) patients, all lymphocyte subsets were reduced, whilst in mild disease (MD) NK, NKT and {gamma}{delta} T cells were at the level of HC. Additionally, we provide evidence of T cell activation in MD but not SD, when compared to HC. Interestingly, follow up samples revealed a marked increase in effector T cells and memory subsets in convalescing but not in non-convalescing patients. Interpretation: Our data suggest that activation and expansion of innate and adaptive lymphocytes play a major role in COVID-19. Additionally, recovery is associated with formation of T cell memory as suggested by the missing formation of effector and central memory T cells in SD but not in MD. Our data imply that the presence of SARS-CoV-2 responsive T cells contributes to convalescence in MD. Thus, understanding the T cell-response in the context of clinical severity might serve as foundation to overcome the lack of effective anti-viral immune response in severely affected COVID-19 patients and can offer prognostic value as biomarker for disease outcome and control.


IgA dominates the early neutralizing antibody response to SARS-CoV-2

Abstract: A major dogma in immunology has it that the IgM antibody response precedes secondary memory responses built on the production of IgG, IgA and, occasionaly, IgE. Here, we measured acute humoral responses to SARS-CoV-2, including the frequency of antibody-secreting cells and the presence of specific, neutralizing, antibodies in serum and broncho-alveolar fluid of 145 patients with COVID-19. Surprisingly, early SARS-CoV-2-specific humoral responses were found to be typically dominated by antibodies of the IgA isotype. Peripheral expansion of IgA-plasmablasts with mucosal-homing potential was detected shortly after the onset of symptoms and peaked during the third week of the disease. While the specific antibody response included IgG, IgM and IgA, the latter contributed to a much larger extent to virus neutralization, as compared to IgG. However, specific IgA serum levels notably decrease after one month of evolution. These results represent a challenging observation given the present uncertainty as to which kind of humoral response would optimally protect against re-infection, and whether vaccine regimens should consider boosting a potent, although, at least in blood, fading IgA response.


IL-33 expression in response to SARS-CoV-2 correlates with seropositivity in COVID-19 convalescent individuals

Abstract: Our understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is still developing. We investigated seroprevalence and immune responses in subjects professionally exposed to SARS-CoV-2 and their family members (155 individuals; ages 5-79 years). Seropositivity for SARS-CoV-2 spike glycoprotein aligned with PCR results that confirmed previous infection. Anti-spike IgG titers remained high 60 days post-infection and did not associate with symptoms, but spike-specific IgM did associate with malaise and fever. We found limited household transmission, with children of infected individuals seldomly seropositive, highlighting professional exposure as the dominant route of infection in our cohort. We analyzed PBMCs from a subset of seropositive and seronegative adults. TLR7 agonist- activation revealed an increased population of IL-6+TNF-IL-1{beta}+ monocytes, while SARS-CoV-2 peptide stimulation elicited IL-33, IL-6, IFNa2, and IL-23 expression in seropositive individuals. IL-33 correlated with CD4+ T cell activation in PBMCs from convalescent subjects, and was likely due to T cell-mediated effects on IL-33- producing cells. IL-33 is associated with pulmonary infection and chronic diseases like asthma and COPD, but its role in COVID-19 is unknown. Analysis of published scRNAseq data of bronchoalveolar lavage fluid (BALF) from patients with mild to severe COVID-19 revealed a population of IL-33-producing cells that increases with disease. Together these findings show that IL-33 production is linked to SARS-CoV- 2 infection and warrant further investigation of IL-33 in COVID-19 pathogenesis and immunity.


Human B cell clonal expansion and convergent antibody responses to SARS-CoV-2

Abstract: During virus infection B cells are critical for the production of antibodies and protective immunity. Here we show that the human B cell compartment in patients with diagnostically confirmed SARS-CoV-2 and clinical COVID-19 is rapidly altered with the early recruitment of B cells expressing a limited subset of IGHV genes, progressing to a highly polyclonal response of B cells with broader IGHV gene usage and extensive class switching to IgG and IgA subclasses with limited somatic hypermutation in the initial weeks of infection. We identify extensive convergence of antibody sequences across SARS-CoV-2 patients, highlighting stereotyped naïve responses to this virus. Notably, sequence-based detection in COVID-19 patients of convergent B cell clonotypes previously reported in SARS-CoV infection predicts the presence of SARS-CoV/SARS-CoV-2 cross-reactive antibody titers specific for the receptor-binding domain. These findings offer molecular insights into shared features of human B cell responses to SARS-CoV-2 and other zoonotic spillover coronaviruses.


Neutralizing Antibodies Responses to SARS-CoV-2 in COVID-19 Inpatients and Convalescent Patients

Abstract: Background. COVID-19 is a pandemic with no specific antiviral treatments or vaccines. The urgent needs for exploring the neutralizing antibodies from patients with different clinical characteristics are emerging. Methods. A total of 117 blood samples were collected from 70 COVID-19 inpatients and convalescent patients. The presence of neutralizing antibody was determined with a modified cytopathogenic assay based on live SARS-CoV-2. The dynamics of neutralizing antibody levels at different with different clinical characteristics were analyzed. Results. The seropositivity rate reached up to 100.0% within 20 days since onset, and remained 100.0% till day 41-53. The total GMT was 1:163.7 (95% CI, 128.5 to 208.6), and the antibody level was highest during day 31-40 since onset, and then decreased slightly. Individual differences in changes of antibody levels were observed among 8 representative convalescent patients. In multivariate GEE analysis, patients at age of 31-60 and 61-84 had a higher antibody level than those at age of 16-30 (β=1.0518, P=0.0152; β=1.3718, P=0.0020). Patients with a worse clinical classification had a higher antibody titer (β=0.4639, P=0.0227). Conclusions. The neutralizing antibodies were detected even at the early stage of disease, and a significant response showed in convalescent patients. Moreover, changes on antibody levels ware individual specific.


Clinical Characteristics of Recurrent-positive Coronavirus Disease 2019 after Curative Discharge: a retrospective analysis of 15 cases in Wuhan China

Abstract: In China, the patients with previously negative RT-PCR results again test positive during the post-discharge isolation period. We aimed to determine the clinical characteristics of these recurrent-positive patients. We retrospectively reviewed the data of 15 recurrent-positive patients and 107 control patients with non-recurrent, moderate COVID-19 treated in Wuhan, China. Clinical data and laboratory results were comparatively analyzed. We found that recurrent-positive patients had moderate disease. The rate of recurrent-positive disease in our hospital was 1.87%. Recurrent-positive patients were significantly younger (43(35-54) years) than control patients (60(43-69) years) (P=0.011). The early LOS (length of stay in hospital before recurrence) was significantly longer in recurrent-positive patients (36(34-45) days) than in control patients (15(7-30) days) (P =0.001). The time required for the first conversion of RT-PCR results from positive to negative was significantly longer in recurrent-positive patients (14(10-17) days) than in control patients (6(3-9) days) (P =0.011). Serum COVID-19 antibody levels were significantly lower in recurrent-positive patients than in control patients (IgM: 13.69 {+/-} 4.38 vs. 68.10 {+/-} 20.85 AU/mL, P = 0.015; IgG: 78.53 {+/-} 9.30 vs. 147.85 {+/-} 13.33 AU/mL, P < 0.0001). Recurrent-positive patients were younger than control patients. The early LOS (length of stay in hospital before recurrence) was significantly longer in recurrent-positive group than that in control group. COVID-19 IgM/IgG antibody levels were significantly lower in recurrent-positive group than those in control group, which might explain why the virus RNA RT-PCR was positive after the initial clinical cure(with three times of virus RNA RT-PCR negative). The virus might not be fully eliminated because of the lower IgG level and their later replicating might result in recurrent-positive virus RNA RT-PCR.


Broad phenotypic alterations and potential dysfunctions of lymphocytes in COVID-19 recovered individuals

Abstract: Background Lymphopenia is a typical symptom in the COVID-19 patients. While millions of patients are clinical recovered, little is known about the immune status of lymphocytes in these individuals. Methods A clinical recovered cohort (CR) of 55 COVID-19 individuals (discharged from hospital 4 to 11 weeks), and 55 age and sex matched healthy donors cohort (HD) were recruited. Detailed analysis on phenotype of the lymphocytes in peripheral blood mononuclear cells (PBMCs) was performed by flow cytometry. Findings Compared with cohort HD, the CD8+ T cells in cohort CR had higher Teff and Tem, but lower Tc1 (IFN-{gamma}+), Tc2 (IL-4+) and Tc17 (IL-17A+) frequencies. The CD4+ T cells of CR had decreased frequency, especially on the Tcm subset. Moreover, CD4+ T cells of CR expressed lower PD-1 and had lower frequencies of Th1 (IFN-{gamma}+), Th2 (IL-4+), Th17 (IL-17A+) as well as circulating Tfh (CXCR5+PD-1+). Accordingly, isotype-switched memory B cell (IgM-CD20hi) in CR had significantly lower proportion in B cells, though level of activation marker CD71 elevated. For CD3-HLA-DRlo lymphocytes of CR, besides levels of IFN-{gamma}, Granzyme B and T-bet were lower, the correlation between T-bet and IFN-{gamma} became irrelevant. In addition, taken into account of discharged days, all the lowered function associated phenotypes showed no recovery tendency within whole observation period. Interpretation The CR COVID-19 individuals still showed remarkable phenotypic alterations in lymphocytes after clinical recovery 4 to 11 weeks. This suggests SARS-CoV-2 infection imprints profoundly on lymphocytes and results in long-lasting potential dysfunctions.


Clinical characteristics of rehospitalized patients with COVID-19 in China

Abstract: This study aims to observe the clinical characteristics of recovered patients from Coronavirus Disease 2019 (COVID-19) with positive in reverse transcription-polymerase chain reaction (RT-PCR) or serum antibody. The profile, clinical symptoms, laboratory outcomes, and radiologic assessments were extracted on 11 patients, who tested positive for COVID-19 with RT-PCR or serum antibody after discharged and was admitted to Hubei No. 3 People's Hospital of Jianghan University for a second treatment in March 2020. The average interval time between the first discharge and the second admission measured 16.00 ± 7.14 days, ranging from 6 to 27 days. In the second hospitalization, one patient was positive for RT-PCR and serum antibody immunoglobulin M (IgM)-immunoglobulin G (IgG), five patients were positive for both IgM and IgG but negative for RT-PCR. Three patients were positive for both RT-PCR and IgG but negative for IgM. The main symptoms were cough (54.55%), fever (27.27%), and feeble (27.27%) in the second hospitalization. Compared with the first hospitalization, there were significant decreases in gastrointestinal symptoms (5 vs 0, P = .035), elevated levels of both white blood cell count (P = .036) and lymphocyte count (P = .002), remarkedly decreases in C-reactive protein and serum amyloid A (P < .05) in the second hospitalization. Additionally, six patients' chest computed tomography (CT) exhibited notable improvements in acute exudative lesions. There could be positive results for RT-PCR analysis or serum IgM-IgG in discharged patients, even with mild clinical symptoms, however, their laboratory outcomes and chest CT images would not indicate the on-going development in those patients.


Seven discharged patients turning positive again for SARS-CoV-2 on quantitative RT-PCR


SARS-CoV-2 positivity in a discharged COVID-19 patient: a case report


Reappearance of effector T cells is associated with recovery from COVID-19

Abstract: BACKGROUND: Elucidating the role of T cell responses in COVID-19 is of utmost importance to understand the clearance of SARS-CoV-2 infection. METHODS: 30 hospitalized COVID-19 patients and 60 age- and gender-matched healthy controls (HC) participated in this study. We used two comprehensive 11-colour flow cytometric panels conforming to Good Laboratory Practice and approved for clinical diagnostics. FINDINGS: Absolute numbers of lymphocyte subsets were differentially decreased in COVID-19 patients according to clinical severity. In severe disease (SD) patients, all lymphocyte subsets were reduced, whilst in mild disease (MD) NK, NKT and Î³Î´ T cells were at the level of HC. Additionally, we provide evidence of T cell activation in MD but not SD, when compared to HC. Follow up samples revealed a marked increase in effector T cells and memory subsets in convalescing but not in non-convalescing patients. INTERPRETATION: Our data suggest that activation and expansion of innate and adaptive lymphocytes play a major role in COVID-19. Additionally, recovery is associated with formation of T cell memory as suggested by the missing formation of effector and central memory T cells in SD but not in MD. Understanding T cell-responses in the context of clinical severity might serve as foundation to overcome the lack of effective anti-viral immune response in severely affected COVID-19 patients and can offer prognostic value as biomarker for disease outcome and control. FUNDING: Funded by State of Lower Saxony grant 14-76,103-184CORONA-11/20 and German Research Foundation, Excellence Strategy - EXC2155"RESIST"-Project ID39087428, and DFG-SFB900/3-Project ID158989968, grants SFB900-B3, SFB900-B8.


COVID-19 and Postinfection Immunity: Limited Evidence, Many Remaining Questions


Probable causes and risk factors for positive SARS-CoV-2 test in recovered patients: Evidence from Brunei Darussalam

Abstract: Case reports of COVID-19 patients who have been discharged and subsequently report positive RT-PCR again (hereafter referred as 're-positive') do not fully describe the magnitude and significance of this issue. In order to determine the re-positive rate (proportion) and review probable causes and outcomes, we conduct a retrospective study of all 119 discharged patients in Brunei Darussalam up till April 23. Patients who were discharged are required to self-isolate at home for 14 days and undergo NP specimen collection post-discharge. Discharged patients found to be re-positive were readmitted. We reviewed the clinical and epidemiological records of all discharged patients and apply log-binomial models to obtain risk ratios for re-positive status. One in five recovered patients subsequently test positive again for SARS-CoV-2 - this risk is more than six times higher in persons aged 60 years and above. The average Ct value of re-positive patients was lower pre-discharge compared to their readmission Ct value. Out of 111 close contacts tested, none were found to be positive as a result of exposure to a re-positive patient. Our findings support prolonged but intermittent viral shedding as the probable cause for this phenomenon. We did not observe infectivity potential in these patients. This article is protected by copyright. All rights reserved.


Rehospitalization of a Recovered Coronavirus Disease 19 (COVID-19) Child With Positive Nucleic Acid Detection

Abstract: Since December 2019, novel coronavirus-infected pneumonia (coronavirus disease 19) occurred in Wuhan and rapidly spread throughout China and beyond. During this period, increasing of reports found that several recovered patients from different hospitals showed positive results of nucleic acid test again soon after discharge. However, little attention has been paid to recovered children. Herein, we reported a case of 8-year-old recovered child, who was rehospitalized again because of unexplained fever.


Retest positive for SARS-CoV-2 RNA of "recovered" patients with COVID-19: Persistence, sampling issues, or re-infection?

Abstract: "Retest Positive" for severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) from "recovered" coronavirus disease-19 (COVID-19) has been reported and raised several important questions for this novel coronavirus and COVID-19 disease. In this commentary, we discussed several questions: (a) Can SARS-CoV-2 re-infect the individuals who recovered from COVID-19? This question is also associated with other questions: whether or not SARS-CoV-2 infection induces protective reaction or neutralized antibody? Will SARS-CoV-2 vaccines work? (b) Why could some recovered patients with COVID-19 be re-tested positive for SARS-CoV-2 RNA? (c) Are some recovered pwith atients COVID-19 with re-testing positive for SARS-CoV-2 RNA infectious? and (d) How should the COVID-19 patients with retest positive for SARS-CoV-2 be managed?


Immune response in children with COVID-19 is characterized by lower levels of T cell activation than infected adults

Abstract: XX XXX This article is protected by copyright. All rights reserved.


Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections

Abstract: The clinical features and immune responses of asymptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been well described. We studied 37 asymptomatic individuals in the Wanzhou District who were diagnosed with RT-PCR-confirmed SARS-CoV-2 infections but without any relevant clinical symptoms in the preceding 14 d and during hospitalization. Asymptomatic individuals were admitted to the government-designated Wanzhou People's Hospital for centralized isolation in accordance with policy1. The median duration of viral shedding in the asymptomatic group was 19 d (interquartile range (IQR), 15-26 d). The asymptomatic group had a significantly longer duration of viral shedding than the symptomatic group (log-rank P = 0.028). The virus-specific IgG levels in the asymptomatic group (median S/CO, 3.4; IQR, 1.6-10.7) were significantly lower (P = 0.005) relative to the symptomatic group (median S/CO, 20.5; IQR, 5.8-38.2) in the acute phase. Of asymptomatic individuals, 93.3% (28/30) and 81.1% (30/37) had reduction in IgG and neutralizing antibody levels, respectively, during the early convalescent phase, as compared to 96.8% (30/31) and 62.2% (23/37) of symptomatic patients. Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.


Kinetics of viral load and antibody response in relation to COVID-19 severity

Abstract: The SARS-CoV-2 is the causative agent for COVID-19 pneumonia. Little is known about the kinetics, tissue distribution, cross-reactivity and neutralization antibody response in COVID-19 patients. Two groups of RT-PCR confirmed COVID-19 patients were enrolled in this study, including 12 severe patients in ICUs who needed mechanical ventilation and 11 mild patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severe patients had viral shedding in a variety of tissues for 20~40 days post onset of disease (8/12, 66.7%); while the majority of mild patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA after 10 days post-onset (9/11, 81.8%). Mild patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both severe and mild groups at 9 days post onset and remained high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in COVID-19 patients but not in MERS patients. High-levels of neutralizing antibodies were induced after about 10 days post onset in both severe and mild patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from COVID-19 patients, but not convalescent SARS and MERS patients inhibited SARS-CoV-2 entry. Anti-SARS-CoV-2 S and N IgG level exhibited moderate correlation with neutralization titers in patients' plasma. This study improves our understanding of immune response in human after SARS-CoV-2 infection.


Discharged COVID-19 Patients Testing Positive Again for SARS-CoV-2 RNA: A Minireview of Published Studies from China

Abstract: In the ongoing COVID-19 pandemic, one potential cause of concern is that some discharged COVID-19 patients are testing positive again for SARS-CoV-2 RNA. To better understand what is happening and to provide public health policy planners and clinicians timely information, we have searched and reviewed published studies about discharged patients testing positive again for the SARS-CoV-2 RNA. Our search found 12 reports, all of which described patients in China. Our review of these reports indicates the presence of discharged patients who remain asymptomatic but test positive. However, it is unclear whether they are contagious because a positive RT-PCR test does not necessarily indicate the presence of replicating and transmissible virus. Our review suggests the need for timely, parallel testing of different samples, including for example, fecal specimens, from COVID-19 patients before and after they are discharged from hospitals. This article is protected by copyright. All rights reserved.


The treatment and follow-up of "recurrence" with discharged COVID-19 patients: Data from Guizhou, China

Abstract: We reported 20 cases of discharged COVID-19 patients whose RT-PCR test results showed "re-positive". After finding "re-positive ", these patients were admitted to hospital for the second time and were followed up until the end of May 2020. Methods: Record detailed treatment and follow-up process, and collect relevant data. The possible causes and potential clinical significance of this phenomenon are discussed. This article is protected by copyright. All rights reserved.


The clinical characteristic of eight patients of COVID-19 with positive RT-PCR test after discharge

Abstract: Corona virus disease 2019 (COVID-19) was caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The phenomenon of positive real time reverse transcription polymerase chain reaction (RT-PCR) result of SARS-CoV-2 in recovered patients had occurred and the research about these patients was rare. In our study, we did a retrospective review of medical records from COVID-19 patients admitted to one ward of Tongji Hospital of Hua Zhong University of Science and Technology from 10 February to 13 April 2020. From 10 February to 13 April 2020, there were 108 patients of COVID-19 admitted in the one ward of Tongji Hospital. Among them, eight cases were readmission patients because the RT-PCR result of SARS-CoV-2 was positive again after discharge. On the second admission, they had no symptoms and their chest computed tomography was almost normal. Data from laboratory tests of the readmission patients showed that all eight patients had normal white blood cell count, lymphocyte count. The inflammatory factors like procalcitonin and interleukin 6 were normal. After treatment, two patients met the standard and were discharged. The other six patients were still in the hospital because their RT-PCR of SARS-CoV-2 did not get three consecutive negative results and the course of two patients had persisted more than 90 days. We still needed to be alert that these patients could infect other people as a source of infection, and we also needed to be alert that these patients become chronic virus carriers. It also aroused our concern about the discharge standard of COVID-19.


Serum antibody response in critically ill patients with COVID-19


Probable causes and risk factors for positive SARS‐CoV‐2 test in recovered patients: Evidence from Brunei Darussalam

Abstract: Case reports of COVID‐19 patients who have been discharged and subsequently report positive RT‐PCR again (hereafter referred as ‘re‐positive’) do not fully describe the magnitude and significance of this issue. In order to determine the re‐positive rate (proportion) and review probable causes and outcomes, we conduct a retrospective study of all 119 discharged patients in Brunei Darussalam up till April 23. Patients who were discharged are required to self‐isolate at home for 14 days and undergo NP specimen collection post‐discharge. Discharged patients found to be re‐positive were readmitted. We reviewed the clinical and epidemiological records of all discharged patients and apply log‐binomial models to obtain risk ratios for re‐positive status. One in five recovered patients subsequently test positive again for SARS‐CoV‐2 – this risk is more than six times higher in persons aged 60 years and above. The average Ct value of re‐positive patients was lower pre‐discharge compared to their readmission Ct value. Out of 111 close contacts tested, none were found to be positive as a result of exposure to a re‐positive patient. Our findings support prolonged but intermittent viral shedding as the probable cause for this phenomenon. We did not observe infectivity potential in these patients. This article is protected by copyright. All rights reserved.


The clinical characteristic of eight patients of COVID‐19 with positive RT‐PCR test after discharge

Abstract: Corona virus disease 2019 (COVID‐19) was caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). The phenomenon of positive real time reverse transcription polymerase chain reaction (RT‐PCR) result of SARS‐CoV‐2 in recovered patients had occurred and the research about these patients was rare. In our study, we did a retrospective review of medical records from COVID‐19 patients admitted to one ward of Tongji Hospital of Hua Zhong University of Science and Technology from 10 February to 13 April 2020. From 10 February to 13 April 2020, there were 108 patients of COVID‐19 admitted in the one ward of Tongji Hospital. Among them, eight cases were readmission patients because the RT‐PCR result of SARS‐CoV‐2 was positive again after discharge. On the second admission, they had no symptoms and their chest computed tomography was almost normal. Data from laboratory tests of the readmission patients showed that all eight patients had normal white blood cell count, lymphocyte count. The inflammatory factors like procalcitonin and interleukin 6 were normal. After treatment, two patients met the standard and were discharged. The other six patients were still in the hospital because their RT‐PCR of SARS‐CoV‐2 did not get three consecutive negative results and the course of two patients had persisted more than 90 days. We still needed to be alert that these patients could infect other people as a source of infection, and we also needed to be alert that these patients become chronic virus carriers. It also aroused our concern about the discharge standard of COVID‐19.


Assessment of patients who tested positive for COVID-19 after recovery


The issue of recurrently positive patients who recovered from COVID-19 according to the current discharge criteria: investigation of patients from multiple medical institutions in Wuhan, China

Abstract: The current discharge criteria for COVID-19 require that patients have two consecutive negative results for RT-PCR detection. Here, we observed that recurrently positive RT-PCR test results in patients with three consecutive negative results (3xNegRPos, 5.4%) were significantly decreased compared with those in patients with two consecutive negative results (2xNegRPos, 20.6%); such patients reported positive RT-PCR test results within 1 to 12 days after meeting the discharge criteria. These results confirmed that many recovered patients could show a positive RT-PCR test result, and most of these patients could be identified by an additional RT-PCR test prior to discharge.


Re-evaluation of retested nucleic acid-positive cases in recovered COVID-19 patients: Report from a designated transfer hospital in Chongqing, China

Abstract: Since the outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, Hubei Province, China [1], a large number of confirmed cases met the discharge criteria (one of which is two consecutive negative nucleic acid tests with an interval of at least 24 h) [2]. Previous studies have paid more attention to the epidemic situation of COVID-19 and patient diagnosis and treatment. Close attention also should be paid to the discharged patients. Surprisingly, a previous follow-up reported that some patients’ nucleic acid retest results were positive again after discharge [3]. Factors impacting these follow-up test results should be further investigated. Since the first confirmed case was diagnosed in our hospital (Chongqing Emergency Medical Center, the designated transfer hospital) on February 4th, we confirmed a total of 17 cases. All patients infected with the novel coronavirus were transferred to a designated hospital in Southwest China’s Chongqing by ambulance with an inbuilt negative-pressure chamber [4]. In the follow-up examination of these patients, RT-PCR tests were conducted again 3 days after discharged from the designated hospital. Four patients showed recurrence of positive results after a few days of discharge. Thus, we examined these cases herein, aiming to provide information for policy formulation and modification of discharge plans.


Elevated nucleoprotein-induced interferon-γ release in COVID-19 patients detected in a SARS-CoV-2 enzyme-linked immunosorbent spot assay


Recurrent pneumonia in a patient with new coronavirus infection after discharge from hospital for insufficient antibody production: a case report

Abstract: BACKGROUND: The rapid spread of coronavirus disease 2019 (COVID-19) was declared as an emerging public health threat by the World Health Organization. As various measures have been taken successfully to combat the epidemic caused by SARS-CoV-2, a growing number of fully recovered patients have been discharged from hospitals. However, some of them have relapsed. Little is known about the causes that triggered the relapse. CASE PRESENTATION: We report a case of a 40 years old man who suffered from recurrent pulmonary infection with progression of lesions on chest computed tomography (CT), elevated levels of ferritin and IL2R, reduced lymphocyte count and positive oropharyngeal swab test for SARS-CoV-2 again after 5 days discharge from hospital. The anti-SARS-CoV-2 antibody level of this patient was very low at the time of relapse, suggesting a weak humoral immune response to the virus. Total exon sequencing revealed mutations in TRNT1 gene, which may be responsible for B cell immunodeficiency. Therefore, uncleared SARS-CoV-2 at his first discharge was likely to lead to his recurrence. However, viral superinfection and non-infectious organizing pneumonia could not be completely excluded. CONCLUSION: COVID-19 relapse may occur in a part of discharged patients with low titers of anti-SARS-CoV-2 antibodies. These patients should be maintained in isolation for longer time even after discharge. A more sensitive method to detect SARS-CoV-2 needs to be established and serological testing for specific antibodies may be used as a reference to determine the duration of isolation.


Longitudinal anti-SARS-CoV-2 antibody profile and neutralization activity of a COVID-19 patient

Abstract: We followed–up a mild COVID-19 patient for 91 days and serially monitored his serum antibodies to four SARS-CoV-2 related antigens (NP, RBD, S1 and ECD) and neutralization activities. Our data revealed a profile of serial antibody responses during the progress and a quick decline of neutralization activities after discharge.


Discharged COVID‐19 Patients Testing Positive Again for SARS‐CoV‐2 RNA: A Minireview of Published Studies from China

Abstract: In the ongoing COVID‐19 pandemic, one potential cause of concern is that some discharged COVID‐19 patients are testing positive again for SARS‐CoV‐2 RNA. To better understand what is happening and to provide public health policy planners and clinicians timely information, we have searched and reviewed published studies about discharged patients testing positive again for the SARS‐CoV‐2 RNA. Our search found 12 reports, all of which described patients in China. Our review of these reports indicates the presence of discharged patients who remain asymptomatic but test positive. However, it is unclear whether they are contagious because a positive RT‐PCR test does not necessarily indicate the presence of replicating and transmissible virus. Our review suggests the need for timely, parallel testing of different samples, including for example, fecal specimens, from COVID‐19 patients before and after they are discharged from hospitals. This article is protected by copyright. All rights reserved.


Antibody responses against SARS‐CoV‐2 in COVID‐19 patients

Abstract: The emerging coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has become a global pandemic, and brings formidable challenges to public health, society and the economy worldwide. Currently, the antibody responses against SARS‐CoV‐2 remains largely unknown. We herein estimated the longevity of specific antibodies against SARS‐CoV‐2, and reported that antibodies waned over substantially in COVID‐19 patients after recovery. This article is protected by copyright. All rights reserved.


Neutralizing antibody response in mild COVID-19


Do you become immune once you have been infected?


The treatment and follow‐up of “recurrence” with discharged COVID‐19 patients: Data from Guizhou, China

Abstract: We reported 20 cases of discharged COVID‐19 patients whose RT‐PCR test results showed “re‐positive”. After finding “re‐positive ”, these patients were admitted to hospital for the second time and were followed up until the end of May 2020. Methods: Record detailed treatment and follow‐up process, and collect relevant data. The possible causes and potential clinical significance of this phenomenon are discussed. This article is protected by copyright. All rights reserved.


Functional exhaustion of antiviral lymphocytes in COVID-19 patients


Clinical recurrences of COVID-19 symptoms after recovery: viral relapse, reinfection or inflammatory rebound?

Abstract: For the first 3 months of COVID-19 pandemic, COVID-19 was expected to be an immunizing non-relapsing disease. We report a national case series of 11 virologically-confirmed COVID-19 patients having experienced a second clinically- and virologically-confirmed acute COVID-19 episode. According to the clinical history, we discuss either re-infection or reactivation hypothesis. Larger studies including further virological, immunological and epidemiologic data are needed to understand the mechanisms of these recurrences.


Current Status of Multiple Drug Molecules, and Vaccines: An Update in SARS-CoV-2 Therapeutics

Abstract: The coronavirus disease of 2019 (COVID-19) is a pandemic disease that has taken the lives of many around the world. It is caused by severe acute respiratory syndrome-corona virus-2 (SARS-CoV-2). To date, the USA, Italy, Spain, France, Russia, and the UK have been hit the hardest by the virus. However, death counts are still rising. Some nations have managed to “flatten” the death rate via protective measures such physical distancing, quarantine measures, and therapeutic management. The structure of the SARS-CoV-2 virus comprises of S proteins, M proteins, E proteins, hemagglutinin esterases, nucleocapsid proteins, and a 30-kb RNA genome. Viral proteases cleave these polyproteins and RNA-dependent polymerases replicate the genome. Currently, there are no effective therapies against this new disease. Numerous investigators are developing novel protease inhibitors, some of which have made it into clinical trials. Researchers are also attempting to develop a vaccine. In this review paper, we discuss the latest therapeutic developments against COVID-19. [Figure: see text]


Vaccines and Therapies in Development for SARS-CoV-2 Infections.

Abstract: The current COVID-19 pandemic is caused by the novel coronavirus SARS-CoV-2. The virus causes severe respiratory symptoms which manifest disproportionately in the elderly. Currently, there are over 6.5 million cases and 380,000 deaths reported. Given the current severity of the outbreak, there is a great need for antiviral therapies and vaccines to treat and prevent COVID-19. In this review, we provide an overview of SARS-CoV-2 and discuss the emerging therapies and vaccines that show promise in combating COVID-19. We also highlight potential viral targets that could be exploited by researchers and drug manufacturers.


Structural and functional conservation of the programmed -1 ribosomal frameshift signal of SARS coronavirus 2 (SARS-CoV-2).

Abstract: About 17 years after the severe acute respiratory syndrome coronavirus (SARS-CoV) epidemic, the world is currently facing the COVID-19 pandemic caused by SARS coronavirus 2 (SARS-CoV-2). According to the most optimistic projections, it will take more than a year to develop a vaccine, so the best short-term strategy may lie in identifying virus-specific targets for small molecule-based interventions. All coronaviruses utilize a molecular mechanism called programmed -1 ribosomal frameshift (-1 PRF) to control the relative expression of their proteins. Previous analyses of SARS-CoV have revealed that it employs a structurally unique three-stemmed mRNA pseudoknot that stimulates high -1 PRF rates and that it also harbors a -1 PRF attenuation element. Altering -1 PRF activity impairs virus replication, suggesting that this activity may be therapeutically targeted. Here, we comparatively analyzed the SARS-CoV and SARS-CoV-2 frameshift signals. Structural and functional analyses revealed that both elements promote similar -1 PRF rates and that silent coding mutations in the slippery sites and in all three stems of the pseudoknot strongly ablate -1 PRF activity. We noted that the upstream attenuator hairpin activity is also functionally retained in both viruses, despite differences in the primary sequence in this region. Small-angle X-ray scattering analyses indicated that the pseudoknots in SARS-CoV and SARS-CoV-2 have the same conformation. Finally, a small molecule previously shown to bind the SARS-CoV pseudoknot and inhibit -1 PRF was similarly effective against -1 PRF in SARS-CoV-2, suggesting that such frameshift inhibitors may be promising lead compounds to combat the current COVID-19 pandemic.


Quantitative measurement of activity of JAK-STAT signaling pathways in blood samples and immune cells to predict innate and adaptive cellular immune response to viral infection and accelerate vaccine development

Abstract: The host immune response determines the clinical course of a viral infection, for example in case of COVID-19 infection. The effectiveness of vaccination also depends on the induced immune response. Currently there is no method to measure the cellular immune response in blood samples. The functional activity of cells of innate and adaptive immune system is determined by coordinated activity of signaling pathways, especially the JAK-STAT pathways. Using a previously described approach we developed mRNA-based tests to measure activity of these signaling pathways, and show that they can be used to measure in a quantitative manner the cellular innate and adaptive immune response to a viral infection or vaccine in whole blood, PBMC, and specific immune cell type samples. Pathway activity level and range in healthy individuals was established, enabling interpretation of a pathway activity score on a patient sample without the need for a reference sample. Evidence is presented that the pathway activity analysis may also be useful for in vitro vaccine development and assessment of vaccine immunogenicity. Other envisioned applications lie in development of immunomodulatory drugs and drug response prediction and monitoring. Tests are expected to be of value in the COVID-19 crisis. In addition to the described Affymetrix microarray-based pathway tests for measuring host immune response, qPCR-based versions are in development; the latter can in principle be performed within three hours in routine hospital labs.


mRNA Vaccines: Possible Tools to Combat SARS-CoV-2


LinearDesign: Efficient Algorithms for Optimized mRNA Sequence Design

Abstract: A messenger RNA (mRNA) vaccine has emerged as a promising direction to combat the current COVID-19 pandemic. This requires an mRNA sequence that is stable and highly productive in protein expression, features which have been shown to benefit from greater mRNA secondary structure folding stability and optimal codon usage. However, sequence design remains a hard problem due to the exponentially many synonymous mRNA sequences that encode the same protein. We show that this design problem can be reduced to a classical problem in formal language theory and computational linguistics that can be solved in O(n^3) time, where n is the mRNA sequence length. This algorithm could still be too slow for large n (e.g., n = 3, 822 nucleotides for the spike protein of SARS-CoV-2), so we further developed a linear-time approximate version, LinearDesign, inspired by our recent work, LinearFold. This algorithm, LinearDesign, can compute the approximate minimum free energy mRNA sequence for this spike protein in just 11 minutes using beam size b = 1, 000, with only 0.6% loss in free energy change compared to exact search (i.e., b = +infinity, which costs 1 hour). We also develop two algorithms for incorporating the codon optimality into the design, one based on k-best parsing to find alternative sequences and one directly incorporating codon optimality into the dynamic programming. Our work provides efficient computational tools to speed up and improve mRNA vaccine development.


Vaccines and Therapies in Development for SARS-CoV-2 Infections


Deconvoluting Lipid Nanoparticle Structure for Messenger RNA Delivery

Abstract: Lipid nanoparticle (LNP) packaged mRNA vaccines have been deployed against infectious diseases such as COVID-19, yet their structural features remain unclear. Cholesterol, a major constituent within LNPs, contributes to their morphology that influences gene delivery. Herein, we examine the structure of LNPs containing cholesterol derivatives using electron microscopy, differential scanning calorimetry, and membrane fluidity assays. LNPs formulated with C24 alkyl derivatives of cholesterol show a polymorphic shape and various degrees of multilamellarity and lipid partitioning, likely due to phase separation. The addition of methyl and ethyl groups to the C24 alkyl tail of the cholesterol backbone induces multilamellarity (>50% increase compared to cholesterol), while the addition of a double bond induces lipid partitioning (>90% increase compared to cholesterol). LNPs with multilamellar and faceted structures, as well as a lamellar lipid phase, showed higher gene transfection. Unraveling the structure of mRNA-LNPs can enable their rational design toward enhanced gene delivery.


RNA to the rescue: RNA is one of the most promising targets for drug development given its wide variety of uses

Abstract: The race for a vaccine against SARS‐CoV‐2 has accelerated research on RNA‐based therapeutics. Beyond vaccines, RNA also shows great potential for cancer therapies.[Image: see text]


Identification of a Noncanonical Signal for Transcription of a Novel Subgenomic mRNA of Mouse Hepatitis Virus: Implication for the Mechanism of Coronavirus RNA Transcription

Abstract: Abstract Subgenomic RNA transcription of coronaviruses involves the interaction between the leader (or antileader) and the intergenic (IG) sequences. However, it is not clear how these two sequences interact with each other. In this report, a previously unrecognized minor species of subgenomic mRNA, termed mRNA5–1, was identified in cells infected with mouse hepatitis virus (MHV) strains JHM2c, JHM(2), JHM(3), A59, and MHV-1. Sequence analysis revealed that the leader-body fusion site of the mRNA is located at approximately 150 nucleotides (nt) downstream of the consensus IG sequence for mRNA 5 and did not have sequence homology with any known IG consensus sequences. To determine whether this sequence functions independently as a promoter, we cloned a 140-nt sequence (from ≈70 nt upstream to ≈70 nt downstream of the fusion site) from viral genomic RNA and placed it in front of a reporter gene in the defective-interfering (DI) RNA-chloramphenicol acetyltransferase (CAT) reporter vector. Transfection of the reporter RNA into MHV-infected cells resulted in synthesis of a CAT-specific subgenomic mRNA detected by reverse transcription-polymerase chain reaction (RT-PCR). The strength of this promoter was similar to that of the IG7 (for mRNA 7) as measured by the CAT activity. Deletion analysis showed that the sequence as few as 13 nt was sufficient to initiate mRNA transcription, while mutations within the 13-nt abolished mRNA transcription. In vitro translation study confirmed that the envelope (E) protein was translated from mRNA5–1, which encodes the open reading frame (ORF) 5b at its 5′-end, indicating that mRNA5–1 is a functional message. Furthermore, when the ORF5b was replaced with the CAT gene and placed in the DI in the context of viral mini-genome, CAT was expressed not only from the first ORF of mRNA5–1 but also from the second and third ORF of mRNA5 and genomic DI RNA, respectively, suggesting that more than one mechanism is involved in regulation of ORF5b expression. Our findings thus support the notion that base-pairing between the leader (or antileader) and the IG is not the sole mechanism in subgenomic RNA transcription.


Antiviral RNAi therapy: emerging approaches for hitting a moving target

Abstract: The field of directed RNA interference (RNAi) has rapidly developed into a highly promising approach for specifically downregulating genes to alleviate disease pathology. This technology is especially well-suited to treating viral infections, and numerous examples now illustrate that a wide range of viruses can be inhibited with RNAi, both in vitro and in vivo. One principle that has arisen from this work is that antiviral RNAi therapies must be tailored to the unique life cycle of each pathogen, including the choice of delivery vehicle, route of administration, gene(s) targeted and regulation and duration of RNAi induction. Although effective strategies will be customized to each virus, all such therapies must overcome similar challenges. Importantly, treatment strategies must compensate for the inevitable fact that viral genome sequences evolve extremely rapidly, and computational and bioinformatics approaches may aid in the development of therapies that resist viral escape. Furthermore, all RNAi strategies involve the delivery of nucleic acids to target cells, and all will therefore benefit from the development of enhanced gene design and delivery technologies. Here, we review the substantial progress that has been made towards identifying effective antiviral RNAi targets and discuss strategies for translating these findings into effective clinical therapies.


The crystal structure of nsp10-nsp16 heterodimer from SARS-CoV-2 in complex with S-adenosylmethionine

Abstract: SARS-CoV-2 is a member of the coronaviridae family and is the etiological agent of the respiratory Coronavirus Disease 2019. The virus has spread rapidly around the world resulting in over two million cases and nearly 150,000 deaths as of April 17, 2020. Since no treatments or vaccines are available to treat COVID-19 and SARS-CoV-2, respiratory complications derived from the infections have overwhelmed healthcare systems around the world. This virus is related to SARS-CoV-1, the virus that caused the 2002-2004 outbreak of Severe Acute Respiratory Syndrome. In January 2020, the Center for Structural Genomics of Infectious Diseases implemented a structural genomics pipeline to solve the structures of proteins essential for coronavirus replication-transcription. Here we show the first structure of the SARS-CoV-2 nsp10-nsp16 2’-O-methyltransferase complex with S-adenosylmethionine at a resolution of 1.80 Å. This heterodimer complex is essential for capping viral mRNA transcripts for efficient translation and to evade immune surveillance.


COVID-19 vaccine development pipeline gears up


Preclinical data from SARS-CoV-2 mRNA vaccine


Emerging Technologies for Use in the Study, Diagnosis, and Treatment of Patients with COVID-19

Abstract: INTRODUCTION: The COVID-19 pandemic has caused an unprecedented health and economic worldwide crisis. Innovative solutions are imperative given limited resources and immediate need for medical supplies, healthcare support and treatments. AIM: The purpose of this review is to summarize emerging technologies being implemented in the study, diagnosis, and treatment of COVID-19. RESULTS: Key focus areas include the applications of artificial intelligence, the use of Big Data and Internet of Things, the importance of mathematical modeling for predictions, utilization of technology for community screening, the use of nanotechnology for treatment and vaccine development, the utility of telemedicine, the implementation of 3D-printing to manage new demands and the potential of robotics. CONCLUSION: The review concludes by highlighting the need for collaboration in the scientific community with open sharing of knowledge, tools, and expertise.


Preparing for Pandemics: RNA Vaccines at the Forefront