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1.
J Infect ; 2022 Apr 08.
Article in English | MEDLINE | ID: covidwho-1778315

ABSTRACT

OBJECTIVES: To evaluate the persistence of immunogenicity three months after third dose boosters. METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. The analysis was conducted using all randomised participants who were SARS-CoV-2 naïve during the study. RESULTS: Among the 2883 participants randomised, there were 2422 SARS-CoV-2 naïve participants until D84 visit included in the analysis with median age of 70 (IQR: 30-94) years. In the participants who had two initial doses of ChAd, schedules using mRNA vaccines as third dose have the highest anti-spike IgG at D84 (e.g. geometric mean concentration of 8674 ELU/ml (95% CI: 7461-10085) following ChAd/ChAd/BNT). However, in people who had two initial doses of BNT there was no significant difference at D84 in people given ChAd versus BNT (geometric mean ratio (GMR) of 0.95 (95%CI: 0.78, 1.15). Also, people given Ad26.COV2.S (Janssen; hereafter referred to as Ad26) as a third dose had significantly higher anti-spike IgG at D84 than BNT (GMR of 1.20, 95%CI: 1.01,1.43). Responses at D84 between people who received BNT (15 µg) or BNT (30 µg) after ChAd/ChAd or BNT/BNT were similar, with anti-spike IgG GMRs of half-BNT (15 µg) versus BNT (30 µg) ranging between 0.74-0.86. The decay rate of cellular responses were similar between all the vaccine schedules and doses. CONCLUSIONS: 84 days after a third dose of COVID-19 vaccine the decay rates of humoral response were different between vaccines. Adenoviral vector vaccine anti-spike IgG concentration at D84 following BNT/BNT initial doses were higher than for a three dose (BNT/BNT/BNT) schedule. Half dose BNT immune responses were similar to full dose responses. While high antibody tires are desirable in situations of high transmission of new variants of concern, the maintenance of immune responses that confer long-lasting protection against severe disease or death is also of critical importance. Policymakers may also consider adenoviral vector, fractional dose of mRNA, or other non-mRNA vaccines as third doses.

2.
SSRN; 2022.
Preprint in English | SSRN | ID: ppcovidwho-332455

ABSTRACT

Background: Many high-income countries have deployed third “booster” doses of COVID-19 vaccines to populations and some countries have started offering fourth doses. Methods: The COV-BOOST trial is a multicentre, randomised, controlled, phase II trial of seven COVID-19 vaccines as third dose boosters. The current study invited participants who received BNT162b2 (BNT) as third dose in COV-BOOST to be randomised to receive a fourth dose of BNT or mRNA1273 (50 µg, half-m1273). The COV-BOOST trial is a multicentre, randomised, controlled, phase 2 trial of seven COVID-19 vaccines used as a third booster dose. Results: Between 11 and 25 January 2022, 166 participants in the original BNT arm were randomised and received a fourth dose vaccine. The median age was 70.1 (interquartile range: 51.6-77.5) years with 51.8 % (n=86) female participants. The median interval between third and fourth dose was 208.5 (interquartile range: 203.25-214.75) days.Pain and fatigue were the most common local and systemic solicited adverse events for BNT and half-m1273. None of three serious adverse events reported after a fourth dose were related to study vaccine.The fold rises in anti-spike IgG pre- and post-fourth dose were 12.19 (95%CI: 10.37-14.32) and 15.90 (95%CI: 12.92-19.58) in BNT and half-m1273 arms respectively, with fold changes compared to the post third dose-peak of 1.59 (95%CI: 1.41-1.78) and 2.19 (95%CI: 1.90-2.52). T cell responses also boosted. Conclusions: Fourth dose COVID-19 mRNA booster vaccines are well-tolerated and boost cellular and humoral immunity up to, and beyond peak levels achieved following third dose boosters (ISRCTN: 73765130).

4.
J Med Virol ; 94(6): 2438-2452, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1669589

ABSTRACT

The ongoing COVID-19 pandemic severely impacts global public health and economies. To facilitate research on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virology and antiviral discovery, a noninfectious viral replicon system operating under biosafety level 2 containment is warranted. We report herein the construction and characterization of two SARS-CoV-2 minigenome replicon systems. First, we constructed the IVT-CoV2-Rep complementary DNA template to generate a replicon messenger RNA (mRNA) with nanoluciferase (NLuc) reporter via in vitro transcription (IVT). The replicon mRNA transfection assay demonstrated a rapid and transient replication of IVT-CoV2-Rep in a variety of cell lines, which could be completely abolished by known SARS-CoV-2 replication inhibitors. Our data also suggest that the transient phenotype of IVT-CoV2-Rep is not due to host innate antiviral responses. In addition, we have developed a DNA-launched replicon BAC-CoV2-Rep, which supports the in-cell transcription of a replicon mRNA as initial replication template. The BAC-CoV2-Rep transient transfection system exhibited a much stronger and longer replicon signal compared to the IVT-CoV2-Rep version. We also found that a portion of the NLuc reporter signal was derived from the spliced BAC-CoV2-Rep mRNA and was resistant to antiviral treatment, especially during the early phase after transfection. In summary, the established SARS-CoV-2 transient replicon systems are suitable for basic and antiviral research, and hold promise for stable replicon cell line development with further optimization.

5.
Lancet ; 398(10318): 2258-2276, 2021 12 18.
Article in English | MEDLINE | ID: covidwho-1550152

ABSTRACT

BACKGROUND: Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford-AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer-BioNtech, hearafter referred to as BNT). METHODS: COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY)control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130. FINDINGS: Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44-61) in the younger age group and 76 years (73-78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41-59) in the younger age group and 78 years (75-82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5-2·3) in the half VLA group to 32·3 (24·8-42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7-1·6) for ChAd to 3·6 (2·4-5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0-1·5) in the half VLA group to 11·5 (9·4-14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7-1·6) for half VLA to 4·7 (3·1-7·1) for m1273. The results were similar between those aged 30-69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30-69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273. INTERPRETATION: All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination. FUNDING: UK Vaccine Taskforce and National Institute for Health Research.


Subject(s)
/administration & dosage , COVID-19/prevention & control , Immunization, Secondary/methods , Immunogenicity, Vaccine , Adult , Aged , Aged, 80 and over , COVID-19/immunology , Female , Humans , Male , Middle Aged , Pandemics , Patient Safety , SARS-CoV-2 , United Kingdom
6.
J Med Virol ; 93(12): 6671-6685, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544318

ABSTRACT

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of syndromes involving multiple organ systems and is primarily mediated by viral spike (S) glycoprotein through the receptor-binding domain (RBD) and numerous cellular proteins including ACE2, transmembrane serine protease 2 (TMPRSS2), kidney injury molecule-1 (Kim-1), and neuropilin-1 (NRP-1). In this study, we examined the entry tropism of SARS-CoV-2 and SARS-CoV using S protein-based pseudoviruses to infect 22 cell lines and 3 types of primary cells isolated from respiratory, urinary, digestive, reproductive, and immune systems. At least one cell line or type of primary cell from each organ system was infected by both pseudoviruses. Infection by pseudoviruses is effectively blocked by S1, RBD, and ACE2 recombinant proteins, and more weakly by Kim-1 and NRP-1 recombinant proteins. Furthermore, cells with robust SARS-CoV-2 pseudovirus infection had strong expression of either ACE2 or Kim-1 and NRP-1 proteins. ACE2 glycosylation appeared to be critical for the infections of both viruses as there was a positive correlation between infectivity of either SARS-CoV-2 or SARS-CoV pseudovirus with the level of glycosylated ACE2 (gly-ACE2). These results reveal that SARS-CoV-2 cell entry could be mediated by either an ACE2-dependent or -independent mechanism, thus providing a likely molecular basis for its broad tropism for a wide variety of cell types.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Gastrointestinal Tract/virology , Genitalia/virology , Hepatitis A Virus Cellular Receptor 1/metabolism , Immune System/virology , Neuropilin-1/metabolism , Respiratory System/virology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Virus Internalization , Blotting, Western , COVID-19/metabolism , COVID-19/virology , Cell Line , Cells, Cultured , Fluorescent Antibody Technique , Gastrointestinal Tract/cytology , Genitalia/cytology , Humans , Immune System/cytology , Respiratory System/cytology
7.
J Stroke Cerebrovasc Dis ; 31(1): 106163, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1482759

ABSTRACT

The SARS-CoV-2 virus, which causes Coronavirus disease 2019 (COVID-19), has resulted in millions of worldwide deaths. When the SARS-CoV-2 virus emerged from Wuhan, China in December 2019, reports of patients with COVID-19 revealed that hospitalized patients had acute changes in mental status, cognition, and encephalopathy. Neurologic complications can be a consequence from overall severity of the systemic infection, direct viral invasion of the SARS-CoV-2 virus in the central nervous system, and possible immune mediated mechanisms. We will examine the landscape regarding this topic in this review in addition to current understandings of COVID-19 and hemostasis, treatment, and prevention, as well as vaccination.


Subject(s)
COVID-19 , Central Nervous System/virology , Nervous System Diseases , Thrombophilia/prevention & control , Anticoagulants , Hemostasis , Humans , Nervous System Diseases/diagnosis , Nervous System Diseases/etiology , SARS-CoV-2 , Thrombophilia/diagnosis
8.
Blood ; 136(Supplement 1):58-59, 2020.
Article in English | PMC | ID: covidwho-1338952

ABSTRACT

Introduction: Initial studies from Wuhan, China reported patients infected with SARS-CoV-2 have uncontrolled coagulopathy and an increased risk for thrombotic complications, including pulmonary embolism (PE), deep vein thrombosis (DVT), and arterial thrombosis.1 The incidence of thrombosis attributed to coronavirus disease 2019 (COVID-19) ranged from 9.5% in all hospital-admitted patients to 31% in the critically ill.2,3COVID-19 has had a major impact on the Chicago metropolitan area with over 121,000 confirmed cases as of August 2020, Cook county being the 4th highest affected county after Maricopa, Miami-Dade and Los Angeles counties.4 The primary goal of this study is to describe the rate of thrombotic events in the Chicago metropolitan area, highlighting an ethnically diverse population, and identify new risk factors for thrombosis between three university health systems.Methods: We conducted a retrospective analysis between three university health systems in the Chicago metropolitan area: Loyola University Health System (LUHS): comprised of one tertiary and two community hospitals, Rush University System for Health (RUSH): comprised of one tertiary and two community hospitals, and University of Illinois-Chicago (UIC): a tertiary hospital. All patients had positive SARS-CoV-2 testing and were hospitalized for COVID-19. PE, DVT or arterial thrombosis were confirmed by supportive imaging modalities. Wilcoxon rank sum test were used to test the associations of continuous variables;Chi-square test or Fisher's exact test were used to test the associations of categorical variables. All analyses were performed with SAS 9.4 and two-sided p-value <.05 were deemed statistically significant.Results: Between March and May 2020, 2,180 patients from LUHS, RUSH and UIC were hospitalized for COVID-19 and were included in our analysis. Baseline patient demographics are described in Table 1. Race/ethnicity demographics are as follows: Hispanics (H)/ African Americans (AA) represented 47%/17% of LUHS patients, 32%/42% of RUSH patients, and 36%/51% of UIC patients, respectively (Figure 1). Intensive care admissions were needed in 33% of all patients. Documented total thrombotic events are as follows: LUHS = 5.4% (41 VTE/PE, 10 arterial and 5 with both venous and arterial);RUSH = 9.7% (70 VTE/PE, 7 arterial and 4 with both venous/arterial);UIC = 6% (14 VTE/PE, 4 arterial and 0 with both venous/arterial). Patients that developed a thrombotic event were similar by age, sex, and BMI to those without a thrombotic event. Anticoagulation prophylaxis was given to 82% of pts at LUHS and UIC at time of admission. Collectively, those with thrombotic events (N=156) had higher incidence of intensive care admission, elevated white blood cell (WBC) count and a d-dimer >5X upper limit normal (ULN) at presentation. Furthermore, a higher proportion of pts that had a thrombotic event were diabetic at LUHS and RUSH (Table 2). Mortality in COVID-19 patients was 13-16% and patients that had a thrombotic event had a higher risk of death in the RUSH and UIC cohorts.Conclusions: In a racially diverse, multi-institutional cohort of patients, we demonstrate that 7.2% of COVID-19 patients had a thrombotic event. Consistent risk factors for thrombosis across the different centers included an initial d-dimer levels >5X ULN, elevated initial WBC count, diabetes, and being critically ill. Mortality differences and anticoagulation practices between the institutions as well as race/ethnicity differences regarding thrombosis will be explored in future combined multivariate analyses. Finally, based off these risk factors, identification of patients at most risk for thrombosis is needed to reduce the morbidity and mortality when diagnosed with COVID-19.References-Tang et. al. J Thromb Haemost. 2020;18:844-847.-Klock et. Al. Thrombosis Research 2020;191:145-147.-Al-Samkari H, Laef RS, Dzik WH et. Al. COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136(4):489-500.-https://www.cdc.gov/coronavirus/2019-nc v/cases-updates/county-map.html;accessed 8/7/20.

9.
J Med Virol ; 93(12): 6671-6685, 2021 12.
Article in English | MEDLINE | ID: covidwho-1330343

ABSTRACT

Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a wide spectrum of syndromes involving multiple organ systems and is primarily mediated by viral spike (S) glycoprotein through the receptor-binding domain (RBD) and numerous cellular proteins including ACE2, transmembrane serine protease 2 (TMPRSS2), kidney injury molecule-1 (Kim-1), and neuropilin-1 (NRP-1). In this study, we examined the entry tropism of SARS-CoV-2 and SARS-CoV using S protein-based pseudoviruses to infect 22 cell lines and 3 types of primary cells isolated from respiratory, urinary, digestive, reproductive, and immune systems. At least one cell line or type of primary cell from each organ system was infected by both pseudoviruses. Infection by pseudoviruses is effectively blocked by S1, RBD, and ACE2 recombinant proteins, and more weakly by Kim-1 and NRP-1 recombinant proteins. Furthermore, cells with robust SARS-CoV-2 pseudovirus infection had strong expression of either ACE2 or Kim-1 and NRP-1 proteins. ACE2 glycosylation appeared to be critical for the infections of both viruses as there was a positive correlation between infectivity of either SARS-CoV-2 or SARS-CoV pseudovirus with the level of glycosylated ACE2 (gly-ACE2). These results reveal that SARS-CoV-2 cell entry could be mediated by either an ACE2-dependent or -independent mechanism, thus providing a likely molecular basis for its broad tropism for a wide variety of cell types.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Gastrointestinal Tract/virology , Genitalia/virology , Hepatitis A Virus Cellular Receptor 1/metabolism , Immune System/virology , Neuropilin-1/metabolism , Respiratory System/virology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Virus Internalization , Blotting, Western , COVID-19/metabolism , COVID-19/virology , Cell Line , Cells, Cultured , Fluorescent Antibody Technique , Gastrointestinal Tract/cytology , Genitalia/cytology , Humans , Immune System/cytology , Respiratory System/cytology
10.
N Engl J Med ; 385(13): 1172-1183, 2021 09 23.
Article in English | MEDLINE | ID: covidwho-1287849

ABSTRACT

BACKGROUND: Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population. METHODS: In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-µg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline. RESULTS: A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups. CONCLUSIONS: A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Immunogenicity, Vaccine , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/epidemiology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Humans , Injections, Intramuscular/adverse effects , Middle Aged , SARS-CoV-2 , Single-Blind Method , Vaccines, Synthetic/immunology , Young Adult
11.
bioRxiv ; 2020 Oct 19.
Article in English | MEDLINE | ID: covidwho-900763

ABSTRACT

The human airway epithelium is the initial site of SARS-CoV-2 infection. We used flow cytometry and single cell RNA-sequencing to understand how the heterogeneity of this diverse cell population contributes to elements of viral tropism and pathogenesis, antiviral immunity, and treatment response to remdesivir. We found that, while a variety of epithelial cell types are susceptible to infection, ciliated cells are the predominant cell target of SARS-CoV-2. The host protease TMPRSS2 was required for infection of these cells. Importantly, remdesivir treatment effectively inhibited viral replication across cell types, and blunted hyperinflammatory responses. Induction of interferon responses within infected cells was rare and there was significant heterogeneity in the antiviral gene signatures, varying with the burden of infection in each cell. We also found that heavily infected secretory cells expressed abundant IL-6, a potential mediator of COVID-19 pathogenesis.

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