Mild cases of coronavirus disease 2019 (COVID-19) can trigger robust memory T cell responses, even in the absence of detectable virus-specific antibody responses, researchers report August 14 in the journal Cell. The authors say that memory T cell responses generated by natural exposure to or infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–the virus that causes COVID-19–may be a significant immune component to prevent recurrent episodes of severe disease.
“We are currently facing the biggest global health emergency in decades,” says senior author Marcus Buggert (@marcus_buggert) of the Karolinska Institutet. “In the absence of a protective vaccine, it is critical to determine if exposed or infected people, especially those with asymptomatic or very mild forms of the disease who likely act inadvertently as the major transmitters, develop robust adaptive immune responses against SARS-CoV-2.”
To date, there is limited evidence of reinfection in humans with previously documented COVID-19. Most studies of immune protection against SARS-CoV-2 in humans have focused on the induction of neutralizing antibodies. But antibody responses tend to wane and are not detectable in all patients, especially those with less severe forms of COVID-19. Research in mice has shown that vaccine-induced memory T cell responses, which can persist for many years, protect against the related virus SARS-CoV-1, even in the absence of detectable antibodies. Until now, it was not clear how SARS-CoV-2-specific T cell responses relate to antibody responses or to the clinical course of COVID-19 in humans.
To address this gap in knowledge, Buggert and his collaborators assessed SARS-CoV-2-specific T cell and antibody responses in more than 200 individuals from Sweden across the full spectrum of exposure, infection, and disease. During the acute phase of infection, the T cell responses were associated with various clinical markers of disease severity. After recovery from COVID-19, SARS-CoV-2-specific memory T cell responses were detectable. The strongest T cell responses were present in individuals who recovered from severe COVID-19. Meanwhile, progressively lower T cell responses were observed in individuals who recovered from very mild COVID-19, and family members exposed to the virus.
In line with expectations, all 23 individuals who recovered from severe COVID-19 developed both SARS-CoV-2-specific antibody and T cell responses. But surprisingly, SARS-CoV-2-specific memory T cell responses were detected months after infection in exposed family members and in most individuals with a history of very mild COVID-19, sometimes in the absence of SARS-CoV-2-specific antibodies. Among the 28 exposed family members, only 17 (a few more than half) had detectable antibody responses, whereas nearly all (26/28) showed T cell responses. Among the 31 individuals who recovered from mild COVID-19, almost all had detectable antibody responses (27/31) and developed T cell responses (30/31).
“Our findings suggest that the reliance on antibody responses may underestimate the extent of population-level immunity against SARS-CoV-2,” Buggert says. “The obvious next step is to determine whether robust memory T cell responses in the absence of detectable antibodies can protect against COVID-19 in the long-term.”
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The researchers were supported by the Swedish Research Council, the Karolinska Institutet, the Swedish Society for Medical Research, the Jeansson Stiftelser, the Åke Wibergs Stiftelse, the Swedish Society of Medicine, the Swedish Cancer Society, the Swedish Childhood Cancer Fund, the Magnus Bergvalls Stiftelse, the Hedlunds Stiftelse, the Lars Hiertas Stiftelse, the Swedish Physician against AIDS foundation, the Jonas Söderquist Stiftelse, the Clas Groschinskys Minnesfond, the Knut and Alice Wallenberg Foundation, and the Wellcome Trust.
Juul Labs (JUUL) says the FDA will begin reviewing its applications for its e-cigarette device and certain nicotine cartridges in a step forward for the company.
Juul filed the applications with the FDA late last month asking for permission to keep selling the products.
Another wildcard was added to the mix earlier this week when Stanford researchers said they found teens and young adults who use electronic cigarettes were at a much higher risk of contracting COVID-19.
The substantive review process by the FDA could reshape the U.S. market.
Waiting in the wings is Altria (NYSE:MO), which acquired a 35% stake in Juul in 2018
In an interview on Mad Money, eHealth (NASDAQ:EHTH) CEO Scott Flanders said he bought 50K shares in the health insurance marketplace operator because “It was a great value. I couldn’t resist it. Last time I bought shares they went up more than 10 times so I’m obviously optimistic.” The purchase boosted his stake to 703K shares or 8%.
Shares are down nearly 50% from Q1 highs when the stock briefly touched ~$150 on three occasions. The stock sold off in early June on a bearish Muddy Waters report and plunged in late July after it posted Q2 results that beat consensus with a 35% jump in revenues but operations consumed over $21M, 85% worse than a year ago.
Mr. Flanders may be one of the few bargain hunters taking action. Many investors appear to be on the sidelines over concerns with churn in Medicare Advantage customers which spiked to 42% in Q2 despite substantial investments in marketing/advertising and customer care and enrollment, together representing 68% of revenue.
After the close today, the company disclosed that COO David Francis will resign effective on August 31.
Shao’s employment with the company “terminated in its entirety, effectively immediately” yesterday, according to today’s filing.
Today the company has named Najjam Asghar as its new CFO; he’ll take over the duties of principal financial officer and principal accounting officer. (He’s been chief accounting officer since June 2019).
That firm quotes a senior official at Columbia (from which Sorrento bought its test for just $5M and royalties) saying “It’s a complete joke. Columbia wasn’t under the assumption they were getting involved in a stock pump-and-dump.”
Galapagos NV (NASDAQ:GLPG) reports that collaboration partner and licensee Gilead Sciences (NASDAQ:GILD) received a Complete Response Letter (CRL) from the FDA regarding its marketing application seeking approval of filgotinib for the treatment of moderate-to-severe rheumatoid arthritis (RA).
The CRL cited the need for data from the MANTA and MANTA-RAy trials, designed to assess filgotinib’s effect on sperm parameters, before completing its review. Topline results from both studies should be available in H1 2021.
The review team also expressed concerns with the benefit/risk profile of the 200 mg dose.
Gilead CMO Merdad Parsey, M.D., Ph.D., says, “We are disappointed in this outcome and will evaluate the points raised in the CRL for discussion with the FDA. We continue to believe in the benefit/risk profile of filgotinib in RA, which has been demonstrated in the FINCH Phase 3 clinical program.”
Galapagos has revised its 2020 cash consumption guidance to €520M from €490M as a result.
Version:1.0 StartHTML:000000227 EndHTML:000065940 StartFragment:000029561 EndFragment:000065831 StartSelection:000029561 EndSelection:000065815 SourceURL:https://www.ajconline.org/article/S0002-9149(20)30823-7/fulltext Meta-analysis of Effectiveness of Statins in Patients with Severe COVID-19 – American Journal of Cardiology With the occurrence of novel coronavirus disease 2019 (COVID-19) pandemic, there have been many discussions on the repurposing of existing drugs for the treatment of COVID-19, one of which is the statins. However, there are two opposing views on the effects of statins on the clinical course of COVID-19. Dysregulation of the myeloid differentiation primary response protein (MYD) 88 pathway which results in overwhelming inflammation has been observed and associated with poor prognosis in other coronavirus infections; this could be the case for COVID-19 but has not been conclusively proven1
Yuan S
Statins May Decrease the Fatality Rate of Middle East Respiratory Syndrome Infection.mBio.2015; 6: e01120
. Statins are known inhibitors of MYD88 and could stabilize MYD88 levels in the presence of external stressors, which thus suggest their roles in protecting COVID-19 patients from the development of overwhelming inflammatory responses3
Totura AL
Whitmore A
Agnihothram S
Toll-Like Receptor 3 Signaling via TRIF Contributes to a Protective Innate Immune Response to Severe Acute Respiratory Syndrome Coronavirus Infection.mBio.2015; 6 (e00638-15)
. Besides, statins are known to experimentally up-regulate ACE2 expression, and therefore might be protective towards lung injury induced by coronavirus4
Li YH
Wang QX
Zhou JW
Effects of rosuvastatin on expression of angiotensin-converting enzyme 2 after vascular balloon injury in rats.J Geriatr Cardiol.2013; 10: 151-158
. On the other hand, statins cause deficiency of endogenous cholesterol content in the cells, leading to upregulation of low-density lipoprotein receptors, which in turn results in constant incorporation of exogenous cholesterol onto the cell membrane and the subsequent formation of multiple lipid rafts, thus enhancing accessibility for coronaviruses5
Shresta S
Statin drug therapy may increase COVID-19 infection.Nepal Med J.2020; 5
have also argued that statins might promote the development of a more severe course of COVID-19 due to activation of the inflammasome pathway in acute respiratory distress syndrome, leading to increased pro-inflammatory interleukin-18 (IL-18) levels and subsequent cytokine storm7
Goldstein MR
Poland GA
Graeber CW
Are certain drugs associated with enhanced mortality in COVID-19?.QJM.2020; ([published online ahead of print, 2020 Mar 27]): hcaa103
Association of elevated plasma interleukin-18 level with increased mortality in a clinical trial of statin treatment for acute respiratory distress syndrome.Crit Care Med.2019; 47: 1089-1096
Role of Drugs Affecting the Renin-Angiotensin-Aldosterone System on Susceptibility and Severity of COVID-19: A Large Case-Control Study from Zheijang Province, China. Preprint.medRxiv.2020; (2020.04.24.20077875)
In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19.Cell Metab.2020; ([published online ahead of print, 2020 Jun 24]) (S1550-4131(20)30316-30318)https://doi.org/10.1016/j.cmet.2020.06.015
Risk Factors Associated With Mortality Among Patients With COVID-19 in Intensive Care Units in Lombardy, Italy.JAMA Intern Med.2020; ([published online ahead of print, 2020 Jul 15])e203539
have since reported on this area and we carried out a meta-analysis to summarise the existing evidence on the effect of statins on the clinical outcomes of COVID-19 from adjusted analyses.We searched PubMed, Google Scholar, and medRxiv (preprint repository) databases, up to 27 July 2020, for studies evaluating the risk of severe illness and/or mortality in COVID-19 among statin users compared to non-statin users, with the following keywords and their MeSH terms: “COVID-19”, “statin”, and “HMG-CoA reductase” without language restrictions. The reference lists of reviews and retrieved articles were also screened for additional pertinent papers. Studies were included if they are of cohort or case-control design, included patients with confirmed COVID-19, and with data available to compare the risk of severe illness and/or mortality among statin users compared to non-statin users in adjusted analyses. Each included article was independently evaluated by two authors (CSK and SSH) who extracted the study characteristics and measures of effect. In case of discrepancies in data extraction, the consensus was achieved through discussion. The quality of observational studies was evaluated using the Newcastle-Ottawa Scale13
Wells G, Shea B, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. 2013. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp(accessed July 27, 2020)
. Adjusted hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) from each study were pooled using a random-effects model using Meta XL, version 5.3 (EpiGear International, Queensland, Australia). The I2 statistic was performed to estimate the heterogeneity. A p-value <0.05 was considered significant.Our Pubmed search yielded 274 potential studies. After deduplication and application of the eligibility criteria, four studies with a total of 8,990 COVID-19 patients were included for meta-analysis. Except for Yan et al. which is of moderate quality (5/9), other studies are of good quality (at least 7/9). Study characteristics are provided in Table 1. The pooled analysis revealed a significantly reduced hazard for fatal or severe disease with the use of statins (Figure 1; pooled HR=0.70; 95% CI 0.53-0.94) compared to non-use of statins in COVID-19 patients. Since our meta-analysis included a fairly large total number of COVID-19 patients from four studies in which 3 are large-scale studies that adjusted extensively for multiple potential confounding factors, the findings can be considered reliable. Current preliminary findings suggested a reduction in fatal or severe disease by 30% and discredited the suggestion of harms with the use of statins in COVID-19 patients. Much left to be determined on the regimen of statin for the treatment of COVID-19 though available evidence suggests that statin therapy of moderate-to-high intensity could be effective. Nevertheless, we await more data from prospective studies to substantiate our findings. Future well-designed randomized controlled trials are also needed to confirm the benefits of statins in COVID-19 patients.Table 1
Study
Country
Design
Total number of patients
Age
Statin regimen
Mortality
Severe diseaseaa The definition of severe disease in the study by Yan et al. is based on the definition given in Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia by Chinese National Health Commission while in the study by Zhang et al. is based on the admission into intensive care unit.
indicators of disease severity and organ injuries, low-density-lipoprotein-cholesterol increase, total cholesterol increase
8/9
Rodriguez-Nava et al.
USA
Retrospective, single center
87
68 (58-75)
Atorvastatin 40 mg
N/A
N/A
HR=0.38
(0.18-0.77)
–
–
–
Age, hypertension, cardiovascular disease, invasive mechanical ventilation, severity according to the National Institutes of Health criteria, number of comorbidities, and adjuvant therapies
7/9
Grasselli et al
Italy
Retrospective, multicenter
3,988
63 (56-69)
N/A
N/A
N/A
HR=0.98
(0.81-1.20)
–
–
–
Age, gender, type of respiratory support, comorbidities, angiotensin-converting enzyme inhibitor therapy, angiotensin receptor blocker, diuretic, positive end-expiratory pressure at admission, fraction of inspired oxygen at admission, arterial partial pressure of oxygen/fraction of inspired oxygen at admission
7/9
HR=hazard ratio; NOS=Newcastle-Ottawa Scale.a The definition of severe disease in the study by Yan et al. is based on the definition given in Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia by Chinese National Health Commission while in the study by Zhang et al. is based on the admission into intensive care unit.
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