ABSTRACT
Infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and vaccinations targeting the spike protein (S) offer protective immunity against coronavirus disease 2019 (COVID-19). This immunity may further be shaped by cross reactivity with common cold coronaviruses. Mutations arising in S that are associated with altered intrinsic virus properties and immune escape result in the continued circulation of SARS-CoV-2 variants. Potentially, vaccine updates will be required to protect against future variants of concern, as for influenza. To offer potent protection against future variants, these second-generation vaccines may need to redirect immunity to epitopes associated with immune escape and not merely boost immunity toward conserved domains in preimmune individuals. For influenza, efficacy of repeated vaccination is hampered by original antigenic sin, an attribute of immune memory that leads to greater induction of antibodies specific to the first-encountered variant of an immunogen compared with subsequent variants. In this Review, recent findings on original antigenic sin are discussed in the context of SARS-CoV-2 evolution. Unanswered questions and future directions are highlighted, with an emphasis on the impact on disease outcome and vaccine design.
ABSTRACT
Introduction: Anemia of inflammation is considered to be a main cause of anemia on the ICU. Inflammatory cytokines, most importantly IL-6, play a role in this pathogenesis. Given that both anemia and red blood cell (RBC) transfusions are associated with adverse outcomes, and iron is ineffective, novel treatments of anemia are wanted. The aim of this study is to investigate the effect of immunosuppressive agents on anemia development and RBC transfusions in critically ill COVID patients. Method(s): This retrospective cohort study included all ICU patients of two hospitals in the Netherlands between February 2020 and April 2022 with a PCR-positive COVID-19 ARDS. Actively bleeding patients were excluded. Evolving insights in the treatment protocol resulted in three treatment groups: no treatment, steroids or combination of steroids with tocilizumab. Daily lab results and number of RBC transfusion were retrieved and the decline in Hb level between ICU admission day 1 and 7 was calculated. A multiple linear regression analysis was used to compare outcomes. Result(s): In total, 719 patients were included, of which 168 in the no-treatment group, 337 in the steroid group and 212 in the steroids and tocilizumab group. Hb levels declined in all groups. The median decline in Hb level in the combination group was lowest, with -0.3 mmol/l [-0.9 to 0.2], -0.8 mmol/l [-1.3 to -0.1] in the group receiving steroids in the steroid group and [-1.6 to -0.5] in the no treatment group. The number of RBC transfusions was 1 [1-3] in the group receiving combination therapy, 3[1-6] in the group receiving steroids and 3[2-8] in the group receiving no treatment (p < 0.002). In a multivariate analysis, the receipt of combination therapy remained associated with inhibition of decline in Hb as well as with lowering the number of RBC transfusions. Conclusion(s): Treatment with either steroids or a combination of steroids and tocilizumab was associated with a slower decline in Hb levels during ICU stay and less RBC transfusions when compared to no treatment.
ABSTRACT
The emergence and rapid spread of SARS-CoV-2 variants may affect vaccine efficacy substantially. The Omicron variant termed BA.2, which differs substantially from BA.1 based on genetic sequence, is currently replacing BA.1 in several countries, but its antigenic characteristics have not yet been assessed. Here, we used antigenic cartography to quantify and visualize antigenic differences between early SARS-CoV-2 variants (614G, Alpha, Beta, Gamma, Zeta, Delta, and Mu) using hamster antisera obtained after primary infection. We first verified that the choice of the cell line for the neutralization assay did not affect the topology of the map substantially. Antigenic maps generated using pseudo-typed SARS-CoV-2 on the widely used VeroE6 cell line and the human airway cell line Calu-3 generated similar maps. Maps made using authentic SARS-CoV-2 on Calu-3 cells also closely resembled those generated with pseudo-typed viruses. The antigenic maps revealed a central cluster of SARS-CoV-2 variants, which grouped on the basis of mutual spike mutations. Whereas these early variants are antigenically similar, clustering relatively close to each other in antigenic space, Omicron BA.1 and BA.2 have evolved as two distinct antigenic outliers. Our data show that BA.1 and BA.2 both escape vaccine-induced antibody responses as a result of different antigenic characteristics. Thus, antigenic cartography could be used to assess antigenic properties of future SARS-CoV-2 variants of concern that emerge and to decide on the composition of novel spike-based (booster) vaccines.
ABSTRACT
Background: A central hallmark of ARDS is hypoxemic respiratory failure due to increased pulmonary capillary leakage. The kinase inhibitor imatinib was shown to reverse vascular leak. This study aimed to investigate the effect of intravenous imatinib on pulmonary edema in patients with COVID-19 ARDS. Method(s): This multicentre, randomised, double-blind, placebo-controlled clinical trial (ClinicalTrial.gov identifier NCT04794088) included adult patients admitted to the ICU with moderate or severe COVID-19 ARDS. Patients were randomised 1:1 to receive 200mg intravenous imatinib or placebo twice daily for seven days or until ICU discharge. The change in extravascular lung water index between day 1 and day 4, measured using a PiCCO catheter, was chosen as the primary endpoint. Secondary outcomes included the PaO2/FiO2 ratio, number of ventilator free days, length of ICU admission and 28-day mortality rate. Study drug safety was assessed by daily screening of the patient records for adverse and serious adverse event occurrence and by performing ECGs and targeted clinical laboratory tests to monitor renal, liver and cardiac function. Result(s): Between March 2021 and 2022, 67 predominantly male (58%) patients with a mean age of 63+/-10 years were randomized to receive imatinib or placebo. No adverse events were considered to be related to study drug administration. At the moment of the submission, data cleaning is still ongoing. Conclusion(s): Thus far, intravenous imatinib administration seems safe and feasible in patients with COVID-19 related ARDS.
ABSTRACT
OBJECTIVES: A systematic review was conducted with the aims of identifying sectors mentioned in the public health emergency preparedness and response (PHEPR) literature and mapping the involvement of those sectors in the seven PHEPR cycle domains. SETTING: A detailed search strategy was conducted in Embase and Scopus, covering the period between 1 January 2005 and 1 January 2020. METHODS: Published articles focusing on preparedness for and/or response to public health emergencies of multiple origins on the European continent were included. The frequency with which predetermined sectors were mentioned when describing collaboration during the preparedness and response cycle was determined. RESULTS: The results show that description of the involvement of sectors in PHEPR in general and collaboration during PHEPR is predominantly confined to a limited number of sectors, namely 'Governmental institutions', 'Human health industry', 'Experts' and 'Civil Society'. Description is also limited to only three domains of the PHEPR cycle, namely 'Risk and crisis management', 'Pre-event preparations and governance' and 'Surveillance'. CONCLUSIONS: Optimal preparedness and response require predefined collaboration with a broader scope of partners than currently seems to be the case based on this literature review. We recommend considering these outcomes when planning multisectoral collaboration during preparedness and response, as well as the need to further operationalise the term 'multisectoral collaboration' during PHEPRs. PROSPERO REGISTRATION NUMBER: PROSPERO with registration number 176 331.
Subject(s)
Civil Defense , Humans , Civil Defense/methods , Public Health/methodsABSTRACT
Almost two years after the introduction of SARS-CoV-2, it has become clear that the virus is unlikely to disappear any time soon. It is also clear that the virus mutates, resulting in specific variants of SARS-CoV-2. The exact implications of these variants are being investigated but it is likely that they have a selective advantage over previously circulating variants. It is possible that SARS-CoV-2 will mutate in the coming years to such an extent that existing vaccines do not offer sufficient protection against hospitalizations in the general population. At present, the protection of current vaccines against infection is observed to be reduced by the emergence of variants but remains high against hospitalizations and severe disease. Booster vaccinations are currently advised for specific risk groups where the regular vaccination schedule leads to an insufficient immune response, and are being considered for people in old age where the vaccine effectiveness is lower.
ABSTRACT
Background: Patients with cancer have an increased risk of complications from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Vaccination is recommended, but the impact of chemotherapy and immunotherapy on immunogenicity and safety is still unclear. Methods: This prospective multicenter non-inferiority trial comprises four cohorts: individuals without cancer (A) and patients with solid tumors who were treated with immunotherapy (B), chemotherapy (C) or chemo-immunotherapy (D). Participants received two mRNA-1273 vaccinations 28 days apart. The primary endpoint was SARS-CoV-2 Spike S1-specific IgG serum antibody response, defined as >10 binding antibody units (BAU)/ml 28 days after the second vaccination. We also assessed the virus neutralizing capacity of these antibodies, SARS-CoV-2 Spike-specific interferon-gamma T cell response, and adverse events. Results: Of the 791 participants enrolled, 743 were evaluable for the primary endpoint in cohort A (n=240), B (n=131), C (n=229) and D (n=143). A SARS-CoV-2-binding antibody response was found in 100%, 99.3%, 97.4%, and 100% of the participants in cohorts A, B, C, and D, respectively. To discriminate between suboptimal and adequate responders, we defined a cut-off level at 300 BAU/ml, based on neutralizing capacity. The antibody response was considered adequate after the first vaccination in 66.0%, 37.1%, 32.5%, and 33.3% of the participants in cohorts A, B, C, and D, respectively. This raised 28 days after the second vaccination to respectively 99.6%, 93.1%, 83.8%, and 88.8% in cohorts A, B, C, and D. Spike-specific T cell responses were detected in 46.7% of suboptimal and non-responders. No new safety signals were observed. Conclusions: mRNA-1273 vaccination is safe in the patient populations studied. For each cohort, the proportion of patients with a SARS-CoV-2-binding antibody response after two vaccinations is non-inferior compared to individuals without cancer. However, a significant minority lacks an adequate response. Most patients have an antibody concentration increase after the second vaccination. Therefore, an additional booster may turn inadequate into adequate responders. Clinical trial identification: NCT04715438. Legal entity responsible for the study: University Medical Center Groningen, the Netherlands. Funding: ZonMw, The Netherlands Organisation for Health Research and Development. Disclosure: All authors have declared no conflicts of interest.
ABSTRACT
China is struggling with the outbreak of a new coronavirus that is not yet under control. What exactly is going on, what do we know and what not, and how should we proceed? This article lists the current state of affairs and discuss the international approach, as well as discussing past outbreaks, what they currently know about COVID-19, and public health preparation to control and prevent transmission of the virus in Netherlands.
ABSTRACT
Late in 2020, two genetically-distinct clusters of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with mutations of biological concern were reported, one in the United Kingdom and one in South Africa. Using a combination of data from routine surveillance, genomic sequencing and international travel we track the international dispersal of lineages B.1.1.7 and B.1.351 (variant 501Y-V2). We account for potential biases in genomic surveillance efforts by including passenger volumes from location of where the lineage was first reported, London and South Africa respectively. Using the software tool grinch (global report investigating novel coronavirus haplotypes), we track the international spread of lineages of concern with automated daily reports, Further, we have built a custom tracking website (cov-lineages.org/global_report.html) which hosts this daily report and will continue to include novel SARS-CoV-2 lineages of concern as they are detected.
ABSTRACT
Background: Convalescent plasma could be an inexpensive and widely available drug for COVID-19 patients. Reports on its effectiveness are inconclusive. We collected convalescent plasma with high titers of neutralizing anti-SARS-CoV-2 antibodies effectively blocking SARS-CoV-2 infection and assessed their clinical and viro-immunological responses in COVID-19 patients with severe disease. Methods: In a multicentre open-label randomized clinical trial in 14 secondary and academic hospitals in the Netherlands, included patients were admitted for COVID-19 with SARS-CoV-2 detected by PCR and not on mechanical ventilation for >96hours. Convalescent plasma donors were selected based on SARS-CoV-2 plaque reduction neutralization test (PRNT50) result of ≥1:80. Primary outcome was day 60 mortality. Secondary outcomes were disease severity, inflammatory and virological markers. Results: Included patients were 72% male, median 63 years (IQR 56-74) and with median 10 days of symptoms (IQR 6-15) at inclusion when they were randomized to convalescent plasma or standard of care. We found no significant difference in mortality at day 60 by using 300mL of convalescent plasma (median PRNT50 1:640) between the arms after adjustment (OR: 0.95, 95%CI: 0.20-4.67). Improvements in WHO COVID-19 disease severity scores at day 15 (OR: 1.30, 95%CI 0.52-3.32) and time to discharge (HR: 0.88, 95%CI: 0.49-1.60) were also comparable. The vast majority of patients already had potent neutralizing anti-SARS-CoV-2 antibodies at hospital admission and at comparable titers as the carefully selected plasma donors. No effect of convalescent plasma on viral clearance in the respiratory tract, anti- SARS-CoV-2 antibody development or changes in serum pro-inflammatory cytokine levels were observed. After the inclusion of 86 patients and per DSMB recommendation, we decided to interrupt the study for futility. Conclusion: Convalescent plasma treatment in this patient group did not improve survival or disease course, nor did it alter relevant virological and immunological parameters. Together, these data indicate that the variable effectivity observed in trials on convalescent plasma for COVID-19 may be explained by the timing of treatment and varying levels of preexisting anti-SARS-CoV-2 immunity in patients. It also substantiates that convalescent plasma should be studied as early as possible in the disease course or at least preceding the start of an autologous humoral response. (Clinicaltrials.gov: NCT04342182).
ABSTRACT
AIM: To investigate the sources of infection among healthcare workers (HCWs) and patients in a teaching hospital in the Netherlands during the early stages of the coronavirus disease 2019 (COVID-19) pandemic using epidemiological and whole-genome sequencing data. METHODS: From 3rd April to 11th May 2020, 88 HCWs and 215 patients were diagnosed with COVID-19. Whole-genome sequences were obtained for 30 HCWs and 20 patients. RESULTS: Seven and 11 sequence types were identified in HCWs and patients, respectively. Cluster A was the most common sequence type, detected in 23 (77%) HCWs; of these, 14 (61%) had direct patient contact and nine (39%) had indirect patient contact. In addition, seven patients who were not hospitalized in the COVID-19 cohort isolation ward who became positive during their admission were infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) cluster A. Following universal masking of all HCWs and emphasis on physical distancing during meals and breaks, no further evidence was found for patient-to-HCW or HCW-to-HCW transmission or vice versa. CONCLUSION: The finding that patients and HCWs were infected with SARS-CoV-2 cluster A suggests both HCW-to-HCW and HCW-to-patient transmission.