SARS-CoV-2 と COVID-19 に関する備忘録 Vol.1

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

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◆Body temperature as a predictor of mortality in COVID-19【nature：scientific reports　2023年8月23日】

Abstract

It remains uncertain if body temperature (BT) is a useful prognostic indicator in coronavirus disease 2019 (COVID-19). We investigated the relationship between BT and mortality in COVID-19 patients. We used a de-identified database that prospectively collected information from patients screened for COVID-19 at the Mount Sinai facilities from February 28, 2020 to July 28, 2021. All patients diagnosed with COVID-19 that had BT data were included. BT at initial presentation, maximum BT during hospitalization, comorbidity, and vaccination status data were extracted. Mortality rate was assessed as a primary outcome. Among 24,293 cases, patients with initial BT below 36 °C had higher mortality than those with BT of 36–37 °C (p < 0.001, odds ratio 2.82). Initial BT > 38 °C was associated with high mortality with an incremental trend at higher BT. In 10,503 in-patient cases, a positive association was observed between mortality and maximum BT except in patients with BT < 36 °C. Multiple logistic regression analyses including the comorbidities revealed that maximum BT was an independent predictor of mortality. While vaccination did not change the distribution of maximum BT, mortality was decreased in vaccinated patients. Our retrospective cohort study suggests that high maximum BT is an independent predictor of higher mortality in COVID-19 patients.

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, known as coronavirus disease 2019 (COVID-19), continues to be the most pressing public health concern worldwide. National guidelines for COVID-19 care were published in April 20201 and have been updated multiple times to reflect evolving evidence. Some studies have identified risk factors for severe or fatal cases allowing for prognostication and implementation of prophylactic measures2,3,4,5.

We previously reported that high maximum body temperature (BT) during COVID-19 infection was associated with poor prognosis6. However, the study was published in June 2020 and was limited in scope, because the original cohort was based on fewer patients and did not account for possible confounders. In addition, vaccination against COVID-19 was initiated in the United States in December 2020 after our first publication. Thus, we could not study how vaccination status might impact the relationship between BT and mortality.

Despite high incidence of fever in COVID-19, its impact on mortality remains unclear. Based on our preliminary study, we hypothesized that both high and low body temperatures are predictors of mortality in patients with COVID-19. Accordingly, we investigated the relationship between BT and mortality in COVID-19 patients using a larger database than in our previous study and also included a new analysis of a vaccinated population.

 


◆COVID-19 boosts risks of health problems 2 years later, giant study of veterans says【Science：Catherine Offord　2023年8月21日】

Three-and-a-half years since SARS-CoV-2 spread around the world, scientists are still documenting the virus’ myriad effects on human health. What’s clear already is that those effects can continue long beyond the original infection.

Now, researchers have attempted to quantify this long-term harm using a massive database of U.S. veterans’ health records. They found a dramatically increased risk of dozens of conditions including heart failure and fatigue, sometimes years postinfection. Overall, the team estimates, COVID-19’s public health impact is more than 50% greater than that of cancer or heart disease.

Other researchers say the conclusions broadly reflect what physicians have seen. However, several cite drawbacks in the study’s statistical analysis that could have led it to overestimate harm to the general population. “The authors have done a good job in doing the analysis, but there are some limitations and those limitations are not small,” says Maarten van Smeden, a medical statistician at the University Medical Center Utrecht. “You have to take this with a little grain of salt.”

To assess COVID-19’s impact, Ziyad Al-Aly, a clinical epidemiologist at Washington University in St. Louis and the VA Saint Louis Health Care System, and colleagues analyzed data from the U.S. Department of Veterans Affairs. In previous studies of this data set, the same researchers identified an elevated risk of heart attack and mental health disorders up to a year after infection.

This time, the team looked at 80 health problems—from fatigue and other symptoms commonly associated with Long Covid to neurodegenerative disease—and general risk of death or hospitalization up to 2 years postinfection. They included data from about 140,000 people who tested positive for SARS-CoV-2 in 2020 and 6 million people with no record of infection that year.

In the 3 months postinfection, people who’d had COVID-19 had higher rates of death and many health conditions including heart failure, diabetes, Alzheimer’s disease, and depression. The differences between groups declined over time. Yet even among people who weren’t hospitalized, the risks for about one-third of the health problems studied remained elevated 2 years later, the researchers report today in Nature Medicine. These people had about a 13% increased risk of diabetes compared with the no-infection group, for example.

The figures were starker for people hospitalized with COVID-19: Two years postinfection, this group had elevated risks for about two-thirds of the outcomes studied. Compared with controls, they were about 50% likelier to suffer heart failure and more than twice as likely to receive an Alzheimer’s diagnosis.

“This is a rigorous study that matches what we’ve been hearing from [clinicians and patients] for years,” says Francesca Beaudoin, a clinical epidemiologist at the Brown University School of Public Health who was not involved in the work. Although COVID-19 is directly causing some of these health problems, she adds, it could exacerbate others or accelerate their onset.

Al-Aly’s team also translated its results into disability-adjusted life years (DALYs), a measure of healthy lifetime lost because of disease or disability. (The metric, although controversial because of assumptions it makes about how disability affects quality of life, is used in policymaking to quantify public health impact.) The team calculated that SARS-CoV-2 infection led to over 80 DALYs per 1000 people who weren’t hospitalized, and more than 640 DALYs per 1000 people who were. Cancer and heart disease each have DALYs of about 50, says Al-Aly, who consults for Gilead Sciences. “Eighty is an astronomically high number.”

However, some scientists say it’s hard to extrapolate from the study’s patient pool to the general population. People who caught SARS-CoV-2 in 2020 were unvaccinated and would have had earlier variants of the virus, not the ones circulating now. What’s more, the veteran population was about 90% male, 70% white, and had an average age over 60.

“[Older] men are some of the people most afflicted by acute COVID,” says Shawn Murphy, a neurologist and bioinformatician at Harvard Medical School and Massachusetts General Hospital. Although the authors tried to correct for this statistically, still, “We need to be careful about doing these extrapolations.”

There are other potential sources of bias, too. It’s unlikely everyone in the “uninfected” group—98% of people in the study—actually avoided infection all year, van Smeden says. Some probably had mild cases that didn’t require health care. If so, the “infected group” really means “people who had more severe infection,” which could magnify COVID-19’s lingering harms, he says.

The infected group may also have been on average less healthy than controls, says epidemiologist Justin Lessler of the University of North Carolina at Chapel Hill. He notes, for example, that hospitalized patients were five times likelier to be diagnosed with tobacco use disorders in the 3 months following infection. He doubts COVID-19 caused them to start smoking—some probably smoked before or would have started anyway. “What we may be seeing here is … people with poor health who are having severe COVID and continue to have poor health afterward.”

Duke University statistician Fan Li adds that greater use of health care—a typical consequence of getting COVID-19—increases a person’s chances of being diagnosed with other conditions. This also skews apparent differences between infected people and controls, and isn’t adequately addressed in the study, she says.

Al-Aly argues these issues don’t substantially affect the study’s findings, adding the team controlled for as many differences between infected and uninfected people as possible. He says the elevated disease risks are “very likely the result” of SARS-CoV-2 infection and that, if anything, the work underestimated COVID-19’s effects.

Researchers did agree on the seriousness of the virus’ long-term harms, and the importance of studying them. The new paper highlights multiple conditions—including diabetes, neurodegenerative disorders, and muscle diseases—that merit further investigation in connection with SARS-CoV-2 infection, Murphy says.

Post-COVID-19 illness “is going to be a lingering effect for many years,” he adds. “We need to put enough work into [not only] finding treatments for it, but being able to respect the disability claims that people are going to have. Those claims are well founded.”

 


◆m6A methylation: a potential key player in understanding and treating COVID-2019 infection【nature：cell death discovery　2023年8月18日】

Abstract

Since its discovery in 2019, coronavirus disease 2019 (COVID-2019) spans a wide clinical spectrum from the asymptomatic stage, mild infection, to severe pneumonia. In patients with COVID-2019, factors such as advanced age, diabetes, or hypertension are associated with a significantly increased risk of severe diseases and death. Of note, the mechanisms underlying differences in the risk and symptoms of COVID-2019 among different populations are still poorly characterized. Accordingly, it is imperative to elucidate potential pathophysiological mechanisms and develop targeted therapeutic approaches for COVID-2019 infection. N6-methyladenosine (m6A) is one of the most common modifications in mammalian RNA transcripts and is widely found in messenger RNAs and some non-coding RNAs. It has been reported that m6A methylation modifications are present in viral RNA transcripts, which are of great significance for the regulation of the viral life cycle. Furthermore, m6A methylation has recently been found to be strongly associated with COVID-2019 infection. Therefore, this article reviews recent advances in studies related to the role of m6A methylation in COVID-2019 infection.

Facts

  1. This article systematically reviews research on m6A and COVID-2019 infection;
  2. This article proposes potential future research directions on the relationship between m6A and COVID-2019 infection in the context of existing research.

Open Questions

  1. This article suggests a mathematical model based on m6A-related genes for the prediction of COVID-2019 infection;
  2. This article proposes a treatment strategy for COVID-2019 infection based on m6A-related pathways.

Introduction

The novel coronavirus is an RNA virus that belongs to the family Coronaviridae and is a close relative of the severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS), whose full name is Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This virus is the pathogen causing coronavirus disease 2019 (COVID-19). COVID-19 is a highly infectious and lethal disease that is majorly transmitted between individuals through respiratory droplets and contact routes and has caused hundreds of millions of infections and millions of deaths worldwide, for which there is no specific treatment. Some drugs, such as remdesivir, chloroquine, and hydroxychloroquine, have been used in the treatment of COVID-19, but their efficacy and safety still require further research. Currently, COVID-19 patients are mainly treated with supportive care, including oxygen therapy, fluid infusion, and organ support, which aims to enable patients to recover as well as possible. It has become a hot research topic to investigate the pathogenesis of COVID-19 at the molecular level and identify reliable therapeutic targets.

N6-methyladenosine (m6A) is a common RNA modification and widely exists in cells. m6A involves the addition of methyl groups to RNA molecules and plays an important role in biological processes such as transcription, translation, and splicing of RNA. Recently, mounting evidence has revealed that m6A methylation modifications are closely related to virus infection. As many studies demonstrated, m6A methylation can affect cellular function through various mechanisms during the occurrence of hepatitis virus, human immunodeficiency virus type 1, and SARS-CoV-2 infection to adapt to the life cycle demands of the virus. In turn, m6A methylation can also have an impact on viral infection, affecting the life cycle and pathogenicity of the virus. Therefore, elucidating the specific mechanism of m6A methylation in COVID-19 virus infection is important for the prevention and treatment of COVID-19.

 


◆A Systematic Review of Persistent Clinical Features After SARS-CoV-2 in the Pediatric Population【PEDIATRICS　2023年7月21日】

CONTEXT

Long-term health effects after coronavirus disease 2019 (COVID-19) have been increasingly reported but their prevalence and significance in the pediatric population remains uncertain.

OBJECTIVE

To present the prevalence and characteristics of the long-term clinical features of COVID-19 (long COVID) in the global pediatric population.

DATA SOURCES

PubMed, Embase, Web of Science, Cochrane Library, WHO COVID-19 database, google scholar, medRxiv, bioRxiv, and multiple national public health databases.

STUDY SELECTION

Published articles and preprints from December, 2019 to December, 2022 investigating the epidemiology and characteristics of persistent clinical features at least 3 months after COVID-19 in children and adolescents (0–19 years old) were included.

DATA EXTRACTION

Study characteristics and detailed description of long COVID were extracted into a predefined form.

RESULTS

Twenty seven cohorts and 4 cross-sectional studies met the inclusion criteria and involved over 15 000 pediatric participants. A total of more than 20 persistent symptoms and clinical features were reported among children and adolescents. 16.2% (95% confidence interval 8.5% to 28.6%) of the pediatric participants experienced 1 or more persistent symptom(s) at least 3 months post COVID-19. Female gender might be associated with developing certain long COVID symptoms.

LIMITATIONS

Included studies presented with great heterogeneity because of significant variations in the definition of “long COVID,” follow up duration, and method. There could be nonresponse and other potential bias.

CONCLUSIONS

Persistent clinical features beyond 3 months among children and adolescents with proven COVID-19 are common and the symptom spectrum is wide. High-quality, prospective studies with proper controls are necessary in the future.

Given that more than 758 million coronavirus disease 2019 (COVID-19) cases have been confirmed worldwide with rates still escalating, increasing attention is being paid to the long-term effects of COVID-19 on population health. Several long-term clinical features post-COVID-19 have been observed, mainly in the adult population, involving multiple organs and systems. A clinical case definition for post-COVID-19 condition (long COVID) was developed by the World Health Organization (WHO) with multiple stakeholders in October 2021 that can be applied to all settings.

During the early stages of the COVID-19 pandemic, neonates, children, and adolescents aged less than 19 years occupied a small proportion (1% to 10%) of the total reported COVID-19 cases. They were also more likely to present with a milder clinical course and more favorable short-term outcomes compared with adults. However, with the subsequent surge of cases caused by the Δ and ο variants, and the fact that a large proportion of children under 12 years old still remain unvaccinated globally, the number of neonates, children, and adolescents infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been increasing significantly. With the increased epidemiologic burden of COVID-19, the long-term health effects of SARS-CoV-2 infection on this vulnerable group requires greater attention. It was thought at first that the pediatric population was relatively spared from the long-term effects of COVID-19 after infection, but this changed rapidly with increasing reports and studies of pediatric patients not fully recovering from acute COVID-19. Furthermore, since it was first reported in April 2020, multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19, also called pediatric inflammatory multisystem syndrome, has become increasingly recognized and widely studied worldwide. Not only can MIS-C lead to serious clinical acute presentation in the short term, it can also impact pediatric patients’ long-term health. For example, MIS-C can cause the formation of coronary artery aneurysm that can negatively impact cardiac function. However, long-term health data on neonates, children, and adolescents infected with SARS-CoV-2 (including MIS-C patients) are limited and of varying quality.

Our objective for this review was to synthesize and evaluate current evidence on the characteristics of the long-term clinical features of SARS-CoV-2 infection, defined as persistent or new onset clinical features and laboratory findings at least 3 months after the index infection, in the global pediatric population (0–19 years old) so as to inform clinical practice and public health policy making.

 


◆A Systematic Review of Persistent Clinical Features After SARS-CoV-2 in the Pediatric Population【NewYork Times：Dani Blum　2023年8月17日】

Doctors and scientists who study Covid-19 agree that for most people, getting infected for a second — or third or fourth — time is basically inevitable. The longer the virus sticks around, the more common repeat infections have and will become, especially in light of the summer uptick and a new dominant variant.

There is no risk-free Covid infection. But researchers are trying to untangle just how damaging repeated infections might be — whether symptoms tend to become more or less severe from one bout to the next, and whether one’s risk of developing long Covid increases after multiple illnesses.

There is a dearth of data on Covid outcomes, including what proportion of people with repeat infections go on to develop longer-term complications, said Dr. Marc Sala, co-director of the Northwestern Medicine Comprehensive COVID-19 Center. But here’s what we know so far.

The severity of repeat infections

For many people who get Covid multiple times, subsequent infections will be as mild as or milder than their first, emerging data shows, likely because of partial immunity from previous infections, vaccination and the fact that the latest circulating variants generally cause less severe symptoms. There are a few exceptions — notably, among some people who are immunocompromised, older or had particularly severe previous infections. People who had a severe first infection are more likely to end up hospitalized or to require medical attention for a reinfection, said Emily Hadley, a research data scientist at RTI International who studies long Covid.

Reinfection and long Covid

The chances you will get long Covid from a reinfection are fairly unpredictable — several experts interviewed for this story used the metaphor of Russian roulette. The milder your symptoms, the less likely you are to get long Covid, said Dr. Peter Chin-Hong, an infectious disease specialist at the University of California, San Francisco. But every time you get infected, no matter the severity, there is always a chance that you can develop longer-term symptoms.

A buzzy paper that was published in Nature Medicine last fall showed that people with two or more Covid infections were more than three times as likely to develop lung and heart issues, and over 1.5 times as likely to have a neurological disorder, including brain fog and strokes, than those who were only infected once. The study used data collected from U.S. Department of Veterans Affairs health care centers, which meant the participants tended to be older than the general population, and overwhelmingly male. But it showed, in pretty stark terms, that multiple infections are worse than one, said one of its authors, Dr. Ziyad Al-Aly, the chief of research and development at the V.A. St. Louis Healthcare System.

Dr. Sala said he frequently sees patients who were more or less fine after their first couple of infections wind up with long Covid in the wake of a third or fourth infection.

“Just because you were lucky enough previously to not have more persistent symptoms, that’s not a reassurance you won’t the next time around,” he said.

Still, it’s not a foregone conclusion that reinfection definitively raises the risk of long Covid, said Fikadu Tafesse, a virologist at Oregon Health & Science University. “Reinfection is very contentious,” he said. “Literally depending on which paper you are reading, there’s contradicting information regarding that. So I don’t know what to believe.”

Dr. Paul Sax, the clinical director of the division of infectious diseases at Brigham and Women’s Hospital, said that the overall risk of developing long Covid is still low, and it’s far lower now than it was at the start of the pandemic, when infections tended to be more severe.

Reinfection can worsen symptoms in people who already have long Covid, said Dr. Chin-Hong. Other people with long Covid may not see a change in their symptoms.

OK, so now what?

It’s easy to feel a sense of fatalism about reinfection, said Dr. Davey Smith, an infectious disease specialist at the University of California, San Diego. But he stressed that you can reduce your risk with common-sense measures like eating dinner outside while the weather’s warm and not hanging out with friends when they’re feeling sick.

Still, there’s a lot beyond our control. “You want to not get it if you can, but I’m not sure I would live in a bubble to try and not get it,” Dr. Chin-Hong said.

He also noted that there are ways to lower the risk of long-term complications from Covid: An updated vaccine, which can help buffer against reinfection, will be available this fall, and antivirals like Paxlovid may reduce the risk of developing long Covid.

Dr. Chin-Hong said that he walks around with a mask in his pocket, but wouldn’t pull out of a trip or avoid hugging a friend he ran into out of concerns about the virus. “I just do the best that I can,” he said. “But I’m not fearful.”

 


◆Epigenetic memory of coronavirus infection in innate immune cells and their progenitors【Cell　2023年8月18日】

Highlights

  • Severe COVID-19 programs durable epigenetic changes and hyper-activation in monocytes
  • Circulating HSPC capture post-COVID-19 changes in hematopoiesis and stem cell programs
  • Post-COVID-19 HSPC convey epigenetic and transcriptional memory to mature progeny cells
  • IL-6 contributes to epigenetic reprogramming of mouse and human HSPC and myeloid cells

Summary

Inflammation can trigger lasting phenotypes in immune and non-immune cells. Whether and how human infections and associated inflammation can form innate immune memory in hematopoietic stem and progenitor cells (HSPC) has remained unclear. We found that circulating HSPC, enriched from peripheral blood, captured the diversity of bone marrow HSPC, enabling investigation of their epigenomic reprogramming following coronavirus disease 2019 (COVID-19). Alterations in innate immune phenotypes and epigenetic programs of HSPC persisted for months to 1 year following severe COVID-19 and were associated with distinct transcription factor (TF) activities, altered regulation of inflammatory programs, and durable increases in myelopoiesis. HSPC epigenomic alterations were conveyed, through differentiation, to progeny innate immune cells. Early activity of IL-6 contributed to these persistent phenotypes in human COVID-19 and a mouse coronavirus infection model. Epigenetic reprogramming of HSPC may underlie altered immune function following infection and be broadly relevant, especially for millions of COVID-19 survivors.

Graphical abstract

Introduction

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is characterized by a range of symptoms and severity, and it frequently includes long-term complications. Innate immune cell activation together with delayed adaptive immune and interferon (IFN) responses feature prominently in acute severe COVID-19. Importantly, the long-term effects of COVID-19 on the immune system and the nature of persistent molecular and cellular changes are poorly understood. These durable changes in the immune system could influence subsequent immune responses to pathogens and vaccines and contribute to long-term clinical symptoms, e.g., post-acute sequelae of SARS-CoV-2 infection (PASC) and COVID-19-associated multisystem inflammatory syndrome in adults (MIS-A) and children (MIS-C). Although several biomarkers are associated with PASC, with examples including elevated antibody responses to Epstein-Barr virus, persistent SARS-CoV-2 virus, or low cortisol, the molecular and cellular changes following COVID-19 that alter immunity and contribute to ongoing pathology are poorly understood.

Recent studies have established that innate immune cells and their progenitors can maintain durable epigenetic memory of prior infection or inflammation, altering innate immune equilibrium and responses to subsequent challenges. Innate immune memory is primarily attributed to persistent chromatin alterations that modify cell responses, including in long-lived innate immune cells, epithelial stem cells, hematopoietic progenitors, and their mature progeny cells. Altered chromatin accessibility has been described in mature immune cells 1–3 months following COVID-19. Establishing the cellular source of such durable epigenetic memory has been a challenge, especially considering the short lifespan of many mature innate immune cells. Studies in mice indicate that hematopoietic stem and progenitor cells (HSPC) can be epigenetically reprogrammed upon exposure to inflammation, leading to long-lasting phenotypic changes in progeny cells. Underscoring the functional relevance of this epigenetic reprogramming, enhanced granulopoiesis in response to β-glucan drives improved anti-tumor responses, and IL-1 signaling-induced myelopoiesis contributes to an hematopoietic stem cell (HSC)-transplantable model of inflammatory disease.

Although innate immune memory is well-studied in mouse models, the breadth, relevance, and molecular features of such phenotypes in humans have been more elusive. Recent studies have revealed innate immune memory in humans after receiving Bacillus Calmette-Guérin (BCG), a tuberculosis vaccine. Importantly, certain bone marrow (BM) HSPC phenotypes, such as myeloid cell fate priming, persist for at least 3 months following BCG vaccination. Although controlled vaccine studies have established innate immune memory or trained immunity phenotypes in humans, the limited access to experimental studies on human HSPC has impeded our understanding of dynamic HSPC phenotypes in disease, especially in the context of natural infection.

In this study, we identified epigenetic innate immune memory that results from SARS-CoV-2 infection by characterizing the cellular and molecular features during the post-infection period of COVID-19. We focused on analyzing chromatin and transcription at the single-cell level in monocytes and their progenitors, HSPC. High-resolution transcriptomic and chromatin accessibility maps were generated for diverse HSPC subtypes and peripheral blood mononuclear cells (PBMC) following severe COVID-19. We discovered lasting epigenetic and transcription changes in HSPC and monocytes, indicating an altered innate immune response. These changes were associated with increased myelopoiesis in HSPC and led to inflammatory, migratory, and differentiating monocyte phenotypes. Although the blockade of IL-6 signaling modestly improved outcomes in critically ill patients, the impact of early activity of this pleiotropic cytokine on recovery remains unclear. We found that disruption of IL-6R signaling during acute infection resulted in a reduction in post-infection HSPC and monocyte inflammatory programs in human patients and mice. Our findings underscore the potential of inflammatory cytokine signaling, like IL-6, during acute viral infections to induce enduring epigenetic changes in HSPC and progeny innate immune cells, potentially influencing various post-infection phenomena in humans, including tissue repair, protection against other infections, chronic inflammation, and long-term sequelae.

 


◆COVID-19: examining the effectiveness of non-pharmaceutical interventions【The Royal Society　2023年8月24日】

What are non-pharmaceutical interventions (NPIs)?

Non-pharmaceutical interventions (NPIs), include any public health measure that is not a vaccine or drug. At the start of the COVID-19 pandemic, no drugs or vaccines were available to contain the spread of the causative virus, SARS-CoV-2. This meant countries were reliant on NPIs to protect populations and health systems until pharmaceutical interventions were developed.

A wide variety of NPIs were employed (typically as part of packages). The Royal Society report covered six broad categories used during the pandemic:

  • Masks and face coverings
  • Social distancing and ‘lockdowns’
  • Test, trace and isolate
  • Travel restrictions and controls across international borders
  • Environmental controls
  • Communications

For more in-depth discussion of each, please see the full evidence reviews published in a theme issue of Philosophical Transactions A.

Why do we need to understand the effectiveness of NPIs?

Scientists and policymakers knew very little about SARS-CoV-2 when the pandemic began. It was not clear what an optimal strategy for NPI implementation looked like, including how outcomes vary for people of different ages, ethnicities, health status and socioeconomic groups. The widespread roll out of NPIs was also economically costly and led to major social disruption with wider impacts on health and wellbeing.

Now is an opportune time learn from NPI implementation during the pandemic and highlight evidence gaps to ensure we are prepared for potential future outbreaks of infectious disease.

What are the main conclusions of the Royal Society’s report?

There is clear evidence from studies conducted during the pandemic that stringent implementation of packages of NPIs was effective in some countries in reducing transmission of SARS-CoV-2.

There is also evidence for the effectiveness of individual NPIs, but most NPIs were implemented in packages. Disentangling the effects of one NPI when other NPIs were implemented at the same time presents a significant challenge.

Evidence suggests that NPIs were, in general, more effective when case numbers and the associated transmission intensity of SARS-CoV-2 were lower. NPIs became less effective as more transmissible variants of the virus emerged (eg Delta, Omicron) which were better adapted to spreading between people and evading immune responses.

Stringency of application of individual NPIs and groups of NPIs influenced rates of transmission, eg respirator masks were more effective than surgical masks and two weeks of quarantine were more effective than shorter periods.

What lessons have been learnt to influence how we might approach future pandemics?

One of the most important lessons from this pandemic is that the effective application of NPIs ‘buys time’ to allow the development and manufacturing of drugs and vaccines. There is every reason to think that implementing packages of NPIs will be important in future pandemics.

Standardised protocols for data collection would improve the quality of observational studies when a novel pathogen emerges. National and international collaborations could be established to support this. It is of particular importance to design protocols that can disaggregate the effects of NPIs by different demographic factors.

Future assessments should also consider the costs as well as the benefits of NPIs, in terms of their impacts on amongst other things, livelihoods, economies, education, social cohesion and physical and mental wellbeing.

 


◆SARS-CoV-2–Specific Immune Responses in Patients With Postviral Syndrome After Suspected COVID-19【Neurology – Neuroimmunology & Neuroinflammation　2023年8月23日】

Introduction

The COVID-19 pandemic has led to over 103 million confirmed cases and more than 1.1 million deaths in the United States as of March 2023. Up to one-third of individuals who survive acute COVID-19 infection will develop symptoms persisting longer than 6 weeks, known as long COVID-19 or postacute sequelae of SARS-CoV-2 infection (PASC). Many individuals with PASC experience neurologic symptoms including cognitive impairment, fatigue, autonomic disturbances, myalgia, headache, and other pain syndromes, termed Neuro-PASC (NP).

Most patients with NP experience mild and transient respiratory symptoms of COVID-19 and do not require hospitalization during the acute infection. However, databases of confirmed infections underestimate the total number of COVID-19 cases due to limited access to testing early in the pandemic or because of testing outside the window of detectable nasopharyngeal viral shedding or seropositivity. This suggests that millions of Americans are experiencing the long-term consequences of COVID-19 without having an official diagnosis of acute disease. Because most post–COVID-19 clinics in the United States are only accepting patients with a prior positive SARS-CoV-2 test result, individuals experiencing postviral syndrome (PVS) identical to PASC are left without specialized care when exposure to SARS-CoV-2 is not confirmed. Furthermore, the same people are also excluded from participation to research studies on PASC. Therefore, we sought to investigate clinical and immunologic measures suggestive of SARS-CoV-2 exposure in patients with PVS seen at Northwestern Medicine’s Neuro COVID-19 clinic.

 


◆New variant drives up COVID-19 hospitalizations in New York【Spectrum News　2023年8月21日】

A new COVID-19 strain is throwing a monkey wrench into the end of the summer and start of school. The most recent variant, dubbed EG.5, has led to an uptick in COVID-19 cases across New York state, and health experts are investigating.

“Viruses mutate. That’s what they do,” said Stephen Thomas, director of the Institute for Global Health at SUNY Upstate Medical University.

According to estimates from the Center for Disease Control and Prevention, EG.5 was responsible for a little more than 20% of COVID-19 cases in the U.S. at the end of the third week of August, more than any other strain.

“This new variant, this new EG.5 variant, which is highly transmissable, is in Central New York. It’s in upstate New York. It’s the predominant variant around the country right now,” said Thomas.

According to Yale Medicine, the EG.5 variant has a new mutation in its spike protein that can potentially evade some immunity people have gotten from having COVID-19 or a vaccination. The World Health Organization has classified it as a “variant of interest,” meaning countries should monitor it more closely than others because of mutations that could make it more contagious or severe.

“The number of people being admitted to the hospital for COVID illness is increasing,” Thomas said. “Two, the number of staff that are out of work because of COVID illness is increasing.”

According to New York state’s COVID-19 hospitalization summary, there have been an increase of 282 COVID-related hospitalizations from the beginning of August to Aug. 18.

But is this strain more severe than others?

“We really do not have an answer, definitive answer, to that right now,” Thomas said.

A vaccine is coming later this year that can attack the variant.

“The new vaccine suggested by the CDC, which will be available some time at the end of September, that will be pretty close, or the closest vaccine possible, to what’s currently circulating,” said Richard Ellison, a professor of medicine at the University of Massachusetts Chan Medical School.

 

 


◆Distinctive serotypes of SARS-related coronaviruses defined by convalescent sera from unvaccinated individuals【ScienceDirect　2023年7月24日】

Highlights

  • Convalescent sera from severe acute respiratory syndrome (SARS) patients are unable to neutralize SARS coronavirus 2.
  • Neutralization escape by Omicron variants indicates significant antigenic change.
  • Distinctive serotypes of SARS-related coronaviruses (SARSr-CoVs) revealed using convalescent sera of primary infection.
  • Defining serotypes of SARSr-CoVs is important for future vaccine development.

Abstract

Multiple Omicron sub-lineages have emerged, with Omicron XBB and XBB.1.5 subvariants becoming the dominant variants globally at the time of this study. The key feature of new variants is their ability to escape humoral immunity despite the fact that there are limited genetic changes from their preceding variants. This raises the question of whether Omicron should be regarded as a separate serotype from viruses serologically clustered with the ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Here, we present cross-neutralization data based on a pseudovirus neutralization test using convalescent sera from naïve individuals who had recovered from primary infection by SARS-CoV-1 and SARS-CoV-2 strains/variants including the ancestral virus and variants Beta, Delta, Omicron BA.1, Omicron BA.2 and Omicron BA.5. The results revealed no significant cross-neutralization in any of the three-way testing for SARS-CoV-1, ancestral SARS-CoV-2 and SARS-CoV-2 Omicron subvariants. The data argue for the assignment of three distinct serotypes for the currently known human-infecting SARS-related coronaviruses.

Graphical abstract

 


◆Retrospective study of COVID-19 experiences in elite multinational aquatic athletes【nature：scientific reports　2023年8月26日】

Abstract

This study assessed the experiences of elite aquatic athletes with coronavirus disease 2019 (COVID-19) during the first World Championship conducted without social distancing and an isolation “bubble”. An online questionnaire was completed by 812 athletes (22.7 ± 5.9 years, 467 females) to provide data on demographics, sports activity, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates, symptoms, reinfection, vaccination status, and psychological aspects. The answers revealed that 49.4% of athletes had experienced SARS-CoV-2 infection. The infection rates varied significantly across different aquatic sports, with open water swimmers having the lowest (28%) and water polo players (67%) and artistic swimmers (61%) having the highest infection rates (p < 0.0001). The majority reported mild (51%) or moderate (27%) symptoms, while 16% remained asymptomatic. Reinfection occurred in 13%, and 10% of initial infections led to long COVID, with fatigue (65%) and shortness of breath (48%) being the most common long-term symptoms. Significantly, 92% of athletes received at least two vaccine doses and reported a positive vaccination experience (median score of 8 out of 10 for each shot). Mood changes and subjective performance drops significantly correlated with the overall experience scores (rho: 0.617, p < 0.0001, and rho: 0.466, p < 0.0001, respectively). In conclusion, most athletes experienced a benign disease course despite a relatively high infection rate. This study provides valuable insights into the COVID-19 experiences of elite aquatic athletes. The findings emphasize the importance of vaccination initiatives, monitoring psychological well-being and the need to fortify athletes’ resilience in the face of future health challenges.

Introduction

The recurring Coronavirus Disease 2019 (COVID-19) waves have changed the world of sports in terms of specific regulations and concerns for athlete health. Evaluating the global impact of the COVID-19 pandemic on athletes is challenging, given the international variability in incidence and disease intensity.

The first wave of the COVID-19 pandemic carried the risk of unforeseen health issues, which raised the question of the optimal return to play and potential cardiac and respiratory complications.

However, the most significant questions regarding possible cardiac involvement have been answered.

In addition, athletic performance may be influenced by the long COVID syndrome, which may lead to a delayed return to play. In contrast with the initial extensive post-COVID screening practice, current recommendations do not require comprehensive return-to-play examinations for all athletes, as nowadays, the course of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection is predominantly mild, without complications.

Athletes participating in water sports have been particularly affected by the consequences of SARS-CoV-2 infection and long COVID syndrome. This has involved the postponement or cancellation of numerous international events, including the 2020 Tokyo Olympics. However, the experience gained from the postponed Tokyo Olympics informed the organization of other significant sports events, including the 2022 FIFA World Cup.

In addition, training opportunities were significantly limited due to the temporary closure of training sites, including swimming pools17. These factors altered periodised training programmes, affecting athletes’ physical performance and mental health.

Fortunately, the development of vaccines has significantly reduced the number of severe cases. Some concerns have arisen regarding vaccination-related myocarditis, and vigilant monitoring seemed rational, considering myocarditis’ implication in athletes. Nevertheless, one must also consider optimal timing for vaccination to mitigate potential side effects and the impact on athletic performance.

Currently, there is a dearth of data regarding aquatic athlete experiences during the pandemic. Athlete infection and reinfection rates and disease course relative to the general population are unknown, as are their vaccination status and ability to cope with added psychological hardship. In addition, most surveys and studies focus on local trends, with little application to global experiences and disease patterns.

This study aimed to assess the COVID-19 experience of a unique multinational cohort of elite aquatic athletes competing in the first global sports event without the imposition of an isolation “bubble”. We used a digital questionnaire to collect data on the infection rate, disease course, symptoms of SARS-CoV-2 infection, vaccination experiences and psychological well-being.

 

 


◆Retrospective study of COVID-19 experiences in elite multinational aquatic athletes【University of Minnesota – CIDRAP：Mary Van Beusekom　2023年8月30日】

Patients diagnosed as having long COVID and myalgic encephalitis/chronic fatigue syndrome (ME/CFS) reported that most symptoms remained severe up to 20 months after SARS-CoV-2 infection, while those with long COVID alone reported improvement, according to a recent observational study in eClinicalMedicine.

Researchers at Charite Universitatsmedizin Berlin evaluated symptom severity and biomarkers in 106 patients with long COVID (post-COVID syndrome [PCS]) who had moderate to severe fatigue and exertion intolerance. They assessed them at 9 to 16 and/or 17 to 20 months after infection from July 2020 to February 2022. The team based its findings on physician-supervised patient questionnaires and clinical, functional, and lab results.

The authors noted that some long-COVID patients with severe fatigue and exertion intolerance also meet the criteria for ME/CFS, a neuro-immunologic disease characterized by these symptoms and post-exertional aggravation of symptoms that can lead to physical disability. Patients with long COVID alone have similar symptoms but in general have milder post-exertion symptoms that resolve sooner.

Patients still fatigued at 16 months

Fifty-five patients met the Canadian Consensus Criteria (CCC) for ME/CFS and were classified as having PCS-ME/CFS, and the other 51 were classified as having PCS alone. Only 7 of the 55 patients (13%) in the former group saw improvement in their physical impairments over time.

At baseline, patients with long COVID alone had, on average, a lower Chalder Fatigue Score (CFQ) than patients with PCS-ME/CFS, with 33% of long-COVID and 55% of PCS-ME/CFS patients reporting severe fatigue (at least 28 CFQ points).

While CFQ scores remained high in the PCS-ME/CFS group over time, they declined significantly in patients with PCS alone. At 9 to 16 months, only 3% of long-COVID patients but 46% of those with PCS-ME/CFS still reported CFQ scores of 28 points or higher.

The duration, severity, and frequency of post-exertional malaise (PEM) were significantly higher in PCS-ME/CFS patients than in those with PCS alone at baseline and remained higher up to 9 to 16 months.

While neither group reported a reduction in PEM duration, PEM frequency and severity improved over time. PEM duration fell below 10 hours in seven (17%) of the PCS-ME/CFS group at 9 to 16 months, no longer fulfilling CCC. Five of the seven reported similar improvement in PEM severity and frequency.

In addition to ramping up our efforts to find effective therapies, this means we also need to quickly establish healthcare facilities where patients can receive multidisciplinary care based on current scientific findings and clinical experience.

Both PCS-alone and PCS-ME/CFS had a low median Bell disability score (40) at baseline, with only 4 of 55 PCS-ME/CFS and 1 of 51 PCS-alone patients reporting that they were too debilitated to leave their homes. A lower Bell score indicates greater disability.

But 53 of 55 PCS-ME/CFS and 43 of 51 PCS patients said that they couldn’t work even part-time (Bell scale, fewer than 70 of 100). By 9 to 16 months, PCS-ME/CFS patients still had a Bell scale of 40, but PCS patients’ Bell scales rose to 60, with only 12% of PCS-ME/CFS but 43% of PCS patients having a Bell score of 70 or higher.

Nineteen participants dropped out of the study; 63% of them were initially diagnosed as having PCS, and the remainder were diagnosed as having PCS-ME/CFS. Of the 70% of the dropouts who chose not to continue in the study because their symptoms had improved, two diagnosed as having PCS-ME/CFS disenrolled because of severe symptoms, and the remainder cited non–disease-related reasons.

Hand grip strength may be prognostic factor

Hand grip strength (HGS), an objective indication, was diminished in PCS-ME/CFS patients and was tied to disease severity at baseline and to symptom burden at follow-up. A low HGS average and maximum force at baseline correlated with increased fatigue, PEM, functional disability, pain, sleep disturbances, and emotional problems at 3 to 8 months.

A high HGS fatigue ratio—indicating faster fatigability—at baseline correlated with more fatigue and functional disability at 3 to 8 months and low baseline HGS recovery ratios correlated with increased fatigue and disability at 9 to 16 months. There were fewer and weaker correlations of HGS parameters at baseline with symptom outcomes at follow-up in PCS patients.

“Grip strength was not only a parameter for how severe the disease was to start with, but also a predictor of how ME/CFS would progress,” co-principal investigator Carmen Scheibenbogen, MD, said in a Charite Universitatsmedizin Berlin press release. “Before we can use grip strength as a prognostic factor, though, we need further studies to confirm how meaningful it is.”

Scheibenbogen said that the number of Europeans with ME/CFS has doubled since the pandemic began. “Our study shows that most people with ME/CFS remain severely ill,” she said. “In addition to ramping up our efforts to find effective therapies, this means we also need to quickly establish healthcare facilities where patients can receive multidisciplinary care based on current scientific findings and clinical experience.”

 


◆Accelerated evolution of SARS-CoV-2 in free-ranging white-tailed deer【nature：nature communications　2023年8月28日】

Abstract

The zoonotic origin of the COVID-19 pandemic virus highlights the need to fill the vast gaps in our knowledge of SARS-CoV-2 ecology and evolution in non-human hosts. Here, we detected that SARS-CoV-2 was introduced from humans into white-tailed deer more than 30 times in Ohio, USA during November 2021-March 2022. Subsequently, deer-to-deer transmission persisted for 2–8 months, disseminating across hundreds of kilometers. Newly developed Bayesian phylogenetic methods quantified how SARS-CoV-2 evolution is not only three-times faster in white-tailed deer compared to the rate observed in humans but also driven by different mutational biases and selection pressures. The long-term effect of this accelerated evolutionary rate remains to be seen as no critical phenotypic changes were observed in our animal models using white-tailed deer origin viruses. Still, SARS-CoV-2 has transmitted in white-tailed deer populations for a relatively short duration, and the risk of future changes may have serious consequences for humans and livestock.

Introduction

As of December 2022, over 645 million human cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were reported globally, resulting in over 6.6 million deaths. Evolution of this virus involves rapid mutation, recombination, and host-switching. The emergence of new divergent variants that more efficiently transmit and/or evade host immune response has repeatedly altered the trajectory of the pandemic, delaying economic and societal recovery. Variants with unpredictable characteristics continue to evolve and the role of animal hosts in the future evolution of SARS-CoV-2 remains unclear. SARS-CoV-2 is capable of infecting a broad range of mammals. The largest number of non-human SARS-CoV-2 infections have been detected in mink, felines, canines, and cervids. Spillback of mutated variants from animals back to humans has been confirmed in hamsters in Hong Kong and mink in the Netherlands and Denmark, which led to mass culling. However, mass culling is not feasible in free-ranging animals, such as white-tailed deer (WTD), and wildlife reservoirs present a more intractable problem.

White-tailed deer were identified as wildlife host for SARS-CoV-2 in July 2021, when antibodies against SARS-CoV-2 were detected in 40% of the tested free-ranging WTD from four US states. One month later, we reported the first confirmed cases of active SARS-CoV-2 infection in free-ranging deer. During January–March 2021, one-third of nasal swabs collected from WTD in northeast Ohio were positive for SARS-CoV-2 by rRT-PCR. Phylogenetic analysis indicated that at least six human-to-deer transmissions occurred, and one deer-to-deer transmission cluster persisted for at least several weeks. Since then, the virus has been repeatedly and frequently detected in white-tailed deer in multiple North American locations. Retrospective testing of samples collected in Iowa identified active SARS-CoV-2 infections in WTD as early as September 2020. High seroprevalence (94.4%) was reported in a captive WTD facility in Texas. The omicron variant was detected in WTD in Staten Island, New York in January 2022, following the omicron wave in humans. Intriguingly, an Ontario WTD clade of SARS-CoV-2 that is related to the B.1.641 lineage was identified with likely deer-to-human spillback. As of January 17, 2023, The US Department of Agriculture confirmed SARS-CoV-2 by PCR in wild WTD in 27 states.

Ohio is one of the most populous states in the United States (ranked 7th in population) and has the 8th highest recorded number of human COVID-19 cases (2.9 million as of July 25, 2022). To further investigate the status of SARS-CoV-2 in WTD in Ohio, we conducted statewide surveillance from November 2021 to March 2022, collecting 1522 nasal swabs from WTD in 83 of Ohio’s 88 counties. This study is a large-scale effort to characterize the infection rate, persistence, spatial spread, and evolution of SARS-CoV-2 in WTD within a geographic area of approximately 115 thousand square kilometers.

 

 

 


◆A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection【nature　2023年7月19日】

Abstract

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01–peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

 


◆Persistent symptoms after COVID-19 are not associated with differential SARS-CoV-2 antibody or T cell immunity【nature：nature communications　2023年8月23日】

Abstract

Among the unknowns in decoding the pathogenesis of SARS-CoV-2 persistent symptoms in Long Covid is whether there is a contributory role of abnormal immunity during acute infection. It has been proposed that Long Covid is a consequence of either an excessive or inadequate initial immune response. Here, we analyze SARS-CoV-2 humoral and cellular immunity in 86 healthcare workers with laboratory confirmed mild or asymptomatic SARS-CoV-2 infection during the first wave. Symptom questionnaires allow stratification into those with persistent symptoms and those without for comparison. During the period up to 18-weeks post-infection, we observe no difference in antibody responses to spike RBD or nucleoprotein, virus neutralization, or T cell responses. Also, there is no difference in the profile of antibody waning. Analysis at 1-year, after two vaccine doses, comparing those with persistent symptoms to those without, again shows similar SARS-CoV-2 immunity. Thus, quantitative differences in these measured parameters of SARS-CoV-2 adaptive immunity following mild or asymptomatic acute infection are unlikely to have contributed to Long Covid causality. ClinicalTrials.gov (NCT04318314).

Introduction

There is a substantial ongoing problem posed by the accumulating global disease burden of those suffering from persistent symptoms after SARS-CoV-2 acute infection. Long Covid describes the persistence of symptoms more than 4-weeks after acute infection with around one-fifth of cases comprising those now symptomatic beyond 2-years. A number of recent studies have sought to clarify the range of symptoms, the combinations in which they occur and their progression through what is often a relapsing and remitting timecourse. Studies identify over 200 associated symptoms, though with a core, diagnostic set encompassing fatigue/exhaustion, pain, post-exertional malaise, cardiovascular, respiratory, neurological and cognitive function.

Even documenting the Long Covid disease burden can be difficult considering that many sufferers did not access testing to confirm the initiating SARS-CoV-2 acute infection, and that there are no agreed diagnostic tests or clinical criteria to define the persistent condition. Most now estimate that Long Covid ensues from around 10% of all infections, though the incidence may be somewhat lower in a period of largely breakthrough infections by Omicron subvariants in vaccinated populations. The UK, which collects relatively granular population data through the Office for National Statistics (ONS), estimates over 2-million with Long Covid in the UK alone, with US Census Bureau data estimating over 16-million cases there. There are numerous hypotheses as to the immunopathogenesis of Long Covid. Within a medical research agenda which has been strongly driven by the initiatives of the patients themselves, one area of focus has been the hypothesis that disease may have been triggered by anomalies in the immune response to SARS-CoV-2 during acute infection. It has been variously proposed either that Long Covid sufferers are unusual in having especially low adaptive immunity to the virus, or alternatively, that the persistent symptoms may be related to an excessively high and uncontrolled anti-viral response. The ‘high anti-viral response’ hypothesis is potentially compatible with a related hypothesis of Long Covid aetiology, namely that there is a chronic reservoir of persistent SARS-CoV-2 antigen, for example in the gut. Several studies have looked at T cell subset phenotypes and at T cell immunity to SARS-CoV-2 comparing individuals with or without Long Covid finding a number of potential differences though, as yet, no consensus. Some find evidence of enhanced SARS-CoV-2 adaptive immunity in those progressing to Long Covid: for example, among ongoing pulmonary Long Covid cases, substantially increased CD4 and CD8 responses were found, while another study showed a more sustained T cell and Ab response, albeit in a more severe cohort, many of whom had been hospitalised. Increased convalescent antibody titers have been reported by some as a marker of Long Covid. Other cohort studies either found no difference between groups in SARS-CoV-2 immunity, or that reduced or rapidly declining responses were found in Long Covid.

Throughout the pandemic we have reported longitudinal immune parameters in the BARTS COVIDsortium London Healthcare worker (HCW) cohort, analysed since March 2020, and including proteomic analysis of Long Covid biomarkers. That is, 731 HCW were recruited into the bioresource, including a cross-sectional case controlled sub-study of 136 HCW, 76 of whom had mild/asymptomatic SARS-CoV-2 infection during the first wave, captured by serial sampling, with SARS-CoV-2 infection determined by baseline and weekly nasal RNA swabs, Roche Cobas® SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) test and baseline and weekly S1 and N antibody (Ab) testing (see Methods). All HCW, irrespective of infection status, also reported data on a symptom questionnaire. While some Long Covid studies have been criticised in that they recruit ‘self-reported’ cases and also sometimes lack control populations, our study offers a number of advantages: HCW gave longitudinal blood samples allowing us to compare immune parameters in HCW with mild or asymptomatic laboratory confirmed SARS-CoV-2 infection during the first wave. Furthermore, the symptom diary questionnaires were initiated at a time when there was no knowledge of Long Covid and it’s symptom profile, making this a study relevant to symptom persistence in Long Covid, collected in real-time at a period of the pandemic when HCW had no knowledge of the condition.

Here, we show that parameters of the longitudinal Ab and T cell response to SARS-CoV-2 antigens following mild or asymptomatic infection during the first wave are indistinguishable between HCW who did or did not go on to develop persistent symptoms.