SARS-CoV-2 と COVID-19 に関する備忘録 Vol.2――オミクロン株で周期は短周期化、変異株ピロラ（BA.2.86）は免疫回避力がこれまでで最も強い…etc.

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SARS-CoV-2 と COVID-19 に関するメモ・備忘録

まずは日本が誇る佐藤佳・東大教授が率いるチームによる最新の研究成果から


◆Transmissibility, infectivity, and immune resistance of the SARS-CoV-2 BA.2.86 variant【bioRxiv　2023年9月7日】

Abstract

In September 2023, the SARS-CoV-2 XBB descendants, such as XBB.1.5 and EG.5.1 (originally XBB.1.9.2.5.1), are predominantly circulating worldwide. Unexpectedly, however, a lineage distinct from XBB was identified and named BA.2.86 on August 14, 2023. Notably, BA.2.86 bears more than 30 mutations in the spike (S) protein when compared to XBB and the parental BA.2, and many of them are assumed to be associated with immune evasion. Although the number of reported cases is low (68 sequences have been reported as of 7 September 2023), BA.2.86 has been detected in several continents (Europe, North America and Africa), suggesting that this variant may be spreading silently worldwide. On 17 August 2023, the WHO designated BA.2.86 as a variant under monitoring. Here we show evidence suggesting that BA.2.86 potentially has greater fitness than current circulating XBB variants including EG.5.1. The pseudovirus assay showed that the infectivity of BA.2.86 was significantly lower than that of B.1.1 and EG.5.1, suggesting that the increased fitness of BA.2.86 is not due to the increased infectivity. We then performed a neutralization assay using XBB breakthrough infection sera to address whether BA.2.86 evades the antiviral effect of the humoral immunity induced by XBB subvariants. The 50% neutralization titer of XBB BTI sera against BA.2.86 was significantly (1.6-fold) lower than those against EG.5.1. The sera obtained from individuals vaccinated with 3rd-dose monovalent, 4th-dose monovalent, BA.1 bivalent, and BA.5 bivalent mRNA vaccines exhibited very little or no antiviral effects against BA.2.86. Moreover, the three monoclonal antibodies (Bebtelovimab, Sotrovimab and Cilgavimab), which worked against the parental BA.2, did not exhibit antiviral effects against BA.2.86. These results suggest that BA.2.86 is one of the most highly immune evasive variants ever.

 

オミクロン株の出現はウイルスが変異する周期が短く乃至早まることでもあるという、コロラド先生こと牧田寛さんの解説。
まったくもって、お説ごもっともなツイートです。
変異株の出現する周期が短くなり、その変異の特性が免疫回避の方向に傾くのであれば、ワクチンの開発が大きく後手に回ることは必然。
予防なり治療なり一から見直さざるを得ない状況なのですが、少なくともノーマスクはあり得ない。
短期間で何度も罹患しうる危険が生じていることまで考えが及ばないのでしょうか？

 


◆Acute blood biomarker profiles predict cognitive deficits 6 and 12 months after COVID-19 hospitalization【nature medicine　2023年8月31日】

Abstract

Post-COVID cognitive deficits, including ‘brain fog’, are clinically complex, with both objective and subjective components. They are common and debilitating, and can affect the ability to work, yet their biological underpinnings remain unknown. In this prospective cohort study of 1,837 adults hospitalized with COVID-19, we identified two distinct biomarker profiles measured during the acute admission, which predict cognitive outcomes 6 and 12 months after COVID-19. A first profile links elevated fibrinogen relative to C-reactive protein with both objective and subjective cognitive deficits. A second profile links elevated D-dimer relative to C-reactive protein with subjective cognitive deficits and occupational impact. This second profile was mediated by fatigue and shortness of breath. Neither profile was significantly mediated by depression or anxiety. Results were robust across secondary analyses. They were replicated, and their specificity to COVID-19 tested, in a large-scale electronic health records dataset. These findings provide insights into the heterogeneous biology of post-COVID cognitive deficits.

 


◆Altered DNA methylation underlies monocyte dysregulation and innate exhaustion memory in sepsis【bioRxiv　2023年8月30日】

Abstract

Innate immune memory is the process by which pathogen exposure elicits cell-intrinsic states to alter the strength of future immune challenges. Such altered memory states drive monocyte dysregulation during sepsis, promoting pathogenic behavior characterized by pro-inflammatory, immunosuppressive gene expression in concert with emergency hematopoiesis. Epigenetic changes, notably in the form of histone modifications, have been shown to underlie innate immune memory, but the contribution of DNA methylation to this process remains poorly understood. Using an ex vivo sepsis model, we discovered broad changes in DNA methylation throughout the genome of exhausted monocytes, including at several genes previously implicated as major drivers of immune dysregulation during sepsis and Covid-19 infection (e.g. Plac8). Methylome alterations are driven in part by Wnt signaling inhibition in exhausted monocytes, and can be reversed through treatment with DNA methyltransferase inhibitors, Wnt agonists, or immune training molecules. Importantly, these changes are recapitulated in septic mice following cecal slurry injection, resulting in stable changes at critical immune genes that support the involvement of DNA methylation in acute and long-term monocyte dysregulation during sepsis.

 


◆Emerging SARS-CoV-2 variants of concern potentially expand host range to chickens: insights from AXL, NRP1 and ACE2 receptors【Virology Journal　2023年8月29日】

Abstract

Background

The possibilities of cross-species transmission of SARS-CoV-2 variants of concern (VOCs) between humans and poultry species are unknown. The analysis of the structure of receptor was used to investigate the potential of emerging SARS-CoV-2 VOCs to expand species tropism to chickens based on the interaction between Spike (S) protein and tyrosine kinase receptor UFO (AXL), angiotensin-converting enzyme 2 (ACE2), and neuropilin 1 (NRP1) with substantial public health importance.

Methods

The structural and genetic alignment and surface potential analysis of the amino acid (aa) in ACE2, AXL, and NRP1 in human, hamster, mouse, mink, ferret, rhesus monkey and chickens were performed by Swiss-Model and pymol software. The critical aa sites that determined the susceptibility of the SARS-CoV-2 to the host were screened by aligning the residues interfacing with the N-terminal domain (NTD) or receptor-binding domain (RBD) of Spike protein.

Results

The binding modes of chickens AXL and ACE2 to S protein are similar to that of the ferret. The spatial structure and electrostatic surface potential of NRP1 showed that SARS-CoV-2 VOCs could not invade chickens through NRP1 easily.

Conclusion

These results suggested that emerging SARS-CoV-2 VOCs potentially expand the host range to chickens mainly through ACE2 and AXL receptors, while NRP1 receptor may rarely participate in the future epidemic of coronavirus disease 2019 in chickens.

 


◆A unique cytotoxic CD4+ T cell-signature defines critical COVID-19【WILEY Online Library　2023年8月28日】

Abstract

Objectives

SARS-CoV-2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T-cell response to disease resolution or progression is still unclear. As newly emerging variants of concern have the capacity to partially escape NAb responses, defining the contribution of individual T-cell subsets to disease outcome is imperative to inform the development of next-generation COVID-19 vaccines.

Methods

Immunophenotyping of T-cell responses in unvaccinated individuals was performed, representing the full spectrum of COVID-19 clinical presentation. Computational and manual analyses were used to identify T-cell populations associated with distinct disease states.

Results

Critical SARS-CoV-2 infection was characterised by an increase in activated and cytotoxic CD4+ lymphocytes (CTL). These CD4+ CTLs were largely absent in asymptomatic to severe disease states. In contrast, non-critical COVID-19 was associated with high frequencies of naïve T cells and lack of activation marker expression.

Conclusion

Highly activated and cytotoxic CD4+ T-cell responses may contribute to cell-mediated host tissue damage and progression of COVID-19. Induction of these potentially detrimental T-cell responses should be considered when developing and implementing effective COVID-19 control strategies.

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has been ongoing since March of 2020. As of February 2023, over 754 million cases of SARS-CoV-2 infection and 6.83 million fatalities from coronavirus disease 2019 (COVID-19) have been reported. While several vaccines are now available for use, SARS-CoV-2 remains a leading cause of infectious disease death globally. One of the major challenges with SARS-CoV-2 infection is the spectrum of COVID-19 clinical presentation, ranging from asymptomatic to fatal. It is thought that more severe disease results from a dysregulated immune response to infection; however, variability in this immune dysfunction between individuals has limited understanding of the correlates of disease severity. Developing a more comprehensive understanding of the immune response across the spectrum of COVID-19 clinical presentation will help to differentiate protective from pathogenic immune responses. This is essential to inform the development of next-generation therapies and vaccines against SARS-CoV-2, with improved longevity and efficacy against newly emerging variants of concern (VOC).

The key correlate of protective immunity against infection and severe disease in COVID-19 is neutralising antibody responses (NAb). As such, the factors that contribute to breakthrough infection following vaccination centre around humoral immune responses, such as waning NAb titres, and antibody escape mutations in the dominant VOC. The T-cell response appears to have greater longevity than detectable NAbs, with sustained response to antigen stimulation demonstrated > 1-year post-infection. Additionally, the dominant T-cell epitopes do not overlap with areas of high mutation on variant viruses, and as a result the T-cell response is preserved against antibody-escape VOC. Considering the limitations of current vaccines, it has been suggested that the long-lived T-cell response against SARS-CoV-2 variants may contribute to protective immunity in the absence of a robust humoral immune response. While NAb responses have been shown to tightly correlate with protection against disease, no such correlation has been shown with the T-cell response to SARS-CoV-2. There is evidence that polyfunctional and cross-reactive T-cell responses to seasonal coronaviruses are associated with milder disease and faster viral clearance. However, several studies have also described an expansion of highly activated T cells in severe COVID-19 that could potentially contribute to excessive inflammatory immune responses and host-tissue damage. As such, whether T cells play a protective or pathogenic role in COVID-19 is still unresolved.

To better define the role of T-cell subsets, we performed an explorative investigation into T-cell phenotypes across the clinical spectrum of COVID-19 presentation, utilising an unbiased analysis approach with a T-cell-centric high-dimensional cytometry panel. We report that critical COVID-19 infection is characterised by a shift from naïve T-cell phenotypes to an expansion of cytotoxic CD4+ T lymphocyte subsets.

 


◆Clinical and immunological characteristics of prolonged SARS-CoV-2 Omicron infection in hematologic disease【nature：Blood Cancer journal　2023年9月5日】

Prolonged viral shedding (PVS) results from a failure of viral eradication. Before the emergence of SARS-CoV-2 Omicron variant, PVS was reported mainly in patients with hematologic disease (HD), posing significant concerns regarding patient outcomes and public health. Lee et al. showed that 13.9% (51/368) of patients infected with SARS-CoV-2 developed PVS, and among the evaluable cases with persistent infection, 26.3% (5/19) died. Moreover, they showed that the combined depletion of B and CD4 + T-cells played a dominant role in viral persistence. Nevertheless, although several studies have reported the incidence of PVS, knowledge integrating the clinical and immunological characteristics of PVS in the Omicron era is limited. This study aimed to identify the risk factors for Omicron PVS and to profile the associated immune deficits in a cohort with HD.

We conducted a retrospective analysis of patients with HD who developed laboratory-confirmed breakthrough COVID-19 infection from January 2022 to 2023, when Omicron was the predominant variant in Japan. Using reverse transcription-PCR, PVS was defined as cycle threshold value (Ct) < 30 for 21 days or more after the onset of COVID-19 according to previous studies. In subgroups with available samples, Omicron-specific neutralizing effects were evaluated using competitive enzyme-linked immunosorbent assay, and T-cell phenotype was analyzed to classify activated (CD38high /HLA-DRhigh) and exhausted T-cells (PD-1high). Detailed methods regarding study design are described in Supplementary method.

[…to be continued]

 


◆SARS-CoV-2 reservoir in post-acute sequelae of COVID-19 (PASC)【nature：nature immunology　2023年9月4日】

Abstract

Millions of people are suffering from Long COVID or post-acute sequelae of COVID-19 (PASC). Several biological factors have emerged as potential drivers of PASC pathology. Some individuals with PASC may not fully clear the coronavirus SARS-CoV-2 after acute infection. Instead, replicating virus and/or viral RNA—potentially capable of being translated to produce viral proteins—persist in tissue as a ‘reservoir’. This reservoir could modulate host immune responses or release viral proteins into the circulation. Here we review studies that have identified SARS-CoV-2 RNA/protein or immune responses indicative of a SARS-CoV-2 reservoir in PASC samples. Mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology, including coagulation, microbiome and neuroimmune abnormalities, are delineated. We identify research priorities to guide the further study of a SARS-CoV-2 reservoir in PASC, with the goal that clinical trials of antivirals or other therapeutics with potential to clear a SARS-CoV-2 reservoir are accelerated.

Main

A subset of individuals infected with the coronavirus SARS-CoV-2 develop new symptoms or sequelae that do not resolve for months or years. This condition is known as Long COVID or post-acute sequelae of COVID-19 (PASC). Based on the Census Bureau Household Pulse Survey, the US Centers for Disease Control and Prevention estimates that ~6% of US adults suffer from new symptoms lasting three or more months after contracting COVID-19. Of those, 80.7% state that their new symptoms limit their ability to carry out day-to-day activities; 26.2% say that their activity is limited ‘a lot’. Estimates place the total US economic cost of PASC at approximately $743 billion per year, including reduced quality of life, lost earnings and increased medical spending.

Common PASC symptoms include fatigue, flu-like symptoms, autonomic dysfunction, trouble with memory or concentration and post-exertional malaise. However, more than 200 PASC symptoms have been documented and symptom presentation can differ from person to person. In addition, many individuals with PASC report symptoms of fluctuating severity or a relapsing/remitting nature. PASC can occur in children, with an incidence of up to 25% of cases in earlier COVID-19 waves, and more recent reports suggesting that roughly 6% of children infected with SARS-CoV-2 meet PASC criteria. The most severe post-COVID-19 sequelae in children is multisystem inflammatory syndrome (MIS-C): a sometimes fatal SARS-CoV-2-related inflammatory disorder that has been defined as part of the PASC spectrum. More than 9,300 children have developed MIS-C in the USA alone. Overall, the tremendous disability and economic burden of PASC on both adult and pediatric populations requires that core biological drivers of the disease process be rapidly delineated.

Several biological trends are emerging as primary potential drivers of PASC pathology. One is that some individuals with PASC may not fully clear SARS-CoV-2 after initial infection. Instead, replicating virus and/or viral RNA—potentially capable of being translated to produce viral proteins—may persist in patients’ tissues in a ‘reservoir’. SARS-CoV-2 is a positive-sense single-stranded RNA virus from the Coronaviridae family. There is precedence for the persistence of other single-stranded RNA viruses after acute illness. RNA from Ebola virus, Zika virus, enteroviruses and measles virus has been identified in tissue obtained months or years after initial infection. In multiple instances, these viral reservoirs have been shown to be capable of driving chronic disease. In the case of Ebola virus disease, new outbreaks have been sparked by individuals carrying persistent Ebola virus years after acute illness, and there are multiple reports of sexual transmission of Zika virus many months after recovery from acute disease.

In this Review, we explore evidence for SARS-CoV-2 reservoir in PASC and provide context on interpretation of the findings. We delineate mechanisms by which a SARS-CoV-2 reservoir may contribute to PASC pathology and identify central research priorities and methods to guide the continued study of SARS-CoV-2 persistence in PASC. If used synergistically, these approaches should reveal biomarkers and therapeutic candidates for PASC clinical trials including immunomodulators and direct-acting and host-directed antivirals.