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1.
Open Forum Infect Dis ; 9(7): ofac219, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1931882

ABSTRACT

Background: The Adaptive COVID Treatment Trial-2 (ACTT-2) found that baricitinib in combination with remdesivir therapy (BCT) sped recovery in hospitalized coronavirus disease 2019 (COVID-19) patients vs remdesivir monotherapy (RMT). We examined how BCT affected progression throughout hospitalization and utilization of intensive respiratory therapies. Methods: We characterized the clinical trajectories of 891 ACTT-2 participants requiring supplemental oxygen or higher levels of respiratory support at enrollment. We estimated the effect of BCT on cumulative incidence of clinical improvement and deterioration using competing risks models. We developed multistate models to estimate the effect of BCT on clinical improvement and deterioration and on utilization of respiratory therapies. Results: BCT resulted in more linear improvement and lower incidence of clinical deterioration compared with RMT (hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.95). The benefit was pronounced among participants enrolled on high-flow oxygen or noninvasive positive-pressure ventilation. In this group, BCT sped clinical improvement (HR, 1.21; 95% CI, 0.99 to 1.51) while slowing clinical deterioration (HR, 0.71; 95% CI, 0.48 to 1.02), which reduced the expected days in ordinal score (OS) 6 per 100 patients by 74 days (95% CI, -8 to 154 days) and the expected days in OS 7 per 100 patients by 161 days (95% CI, 46 to 291 days) compared with RMT. BCT did not benefit participants who were mechanically ventilated at enrollment. Conclusions: Compared with RMT, BCT reduces the clinical burden and utilization of intensive respiratory therapies for patients requiring low-flow oxygen or noninvasive positive-pressure ventilation compared with RMT and may thereby improve care for this patient population.

2.
Ann Intern Med ; 2022 Jul 05.
Article in English | MEDLINE | ID: covidwho-1924597

ABSTRACT

BACKGROUND: Immunoassays for determining past SARS-CoV-2 infection have not been systematically evaluated in vaccinated persons in comparison with unvaccinated persons. OBJECTIVE: To evaluate antinucleocapsid antibody (anti-N Ab) seropositivity in mRNA-1273 (Moderna) vaccinees with breakthrough SARS-CoV-2 infection. DESIGN: Nested substudy of a phase 3 randomized, double-blind, placebo-controlled vaccine efficacy trial. (ClinicalTrials.gov: NCT04470427). SETTING: 99 sites in the United States, July 2020 through March 2021. PARTICIPANTS: Participants were aged 18 years or older, had no known history of SARS-CoV-2 infection, and were at risk for SARS-CoV-2 infection or severe COVID-19. Substudy participants were diagnosed with SARS-CoV-2 infection during the trial's blinded phase. INTERVENTION: 2 mRNA-1273 or placebo injections 28 days apart. MEASUREMENTS: Nasopharyngeal swabs from days 1 and 29 (vaccination days) and from symptom-prompted illness visits were tested for SARS-CoV-2 via polymerase chain reaction (PCR). Serum samples from days 1, 29, and 57 and the participant decision visit (PDV, when participants were informed of treatment assignment; median day 149) were tested for anti-N Abs by the Elecsys immunoassay. RESULTS: Among 700 participants with PCR-confirmed COVID-19 illness during the blinded phase of the trial (through March 2021), seroconversion to anti-N Abs (median of 53 days after diagnosis) occurred in 21 of 52 mRNA-1273 vaccinees (40% [95% CI, 27% to 54%]) versus 605 of 648 placebo recipients (93% [CI, 92% to 95%]). Each 1-log increase in SARS-CoV-2 viral copies at diagnosis was associated with 90% higher odds of anti-N Ab seroconversion (odds ratio, 1.90 [CI, 1.59 to 2.28]). LIMITATION: The scope was restricted to mRNA-1273 vaccinees and the Elecsys assay, the sample size was small, data on Delta and Omicron infections were lacking, and the analysis did not address a prespecified objective of the trial. CONCLUSION: Vaccination status should be considered when interpreting seroprevalence and seropositivity data based solely on anti-N Ab testing. Primary Funding source: National Institute of Allergy and Infectious Diseases of the National Institutes of Health.

3.
Cell Rep Med ; 3(7): 100679, 2022 07 19.
Article in English | MEDLINE | ID: covidwho-1895507

ABSTRACT

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibits reduced susceptibility to vaccine-induced neutralizing antibodies, requiring a boost to generate protective immunity. We assess the magnitude and short-term durability of neutralizing antibodies after homologous and heterologous boosting with mRNA and Ad26.COV2.S vaccines. All prime-boost combinations substantially increase the neutralization titers to Omicron, although the boosted titers decline rapidly within 2 months from the peak response compared with boosted titers against the prototypic D614G variant. Boosted Omicron neutralization titers are substantially higher for homologous mRNA vaccine boosting, and for heterologous mRNA and Ad26.COV2.S vaccine boosting, compared with homologous Ad26.COV2.S boosting. Homologous mRNA vaccine boosting generates nearly equivalent neutralizing activity against Omicron sublineages BA.1, BA.2, and BA.3 but modestly reduced neutralizing activity against BA.2.12.1 and BA.4/BA.5 compared with BA.1. These results have implications for boosting requirements to protect against Omicron and future variants of SARS-CoV-2. This trial was conducted under ClincalTrials.gov: NCT04889209.


Subject(s)
COVID-19 , Viral Vaccines , Ad26COVS1 , Antibodies, Neutralizing , Antibodies, Viral , COVID-19/prevention & control , Humans , RNA, Messenger , SARS-CoV-2/genetics , Vaccines, Synthetic , mRNA Vaccines
5.
J Infect Dis ; 2022 May 10.
Article in English | MEDLINE | ID: covidwho-1886452

ABSTRACT

BACKGROUND: mRNA-1273 vaccine demonstrated 93.2% efficacy against Coronavirus disease 2019 (COVID-19) in the Coronavirus efficacy (COVE) trial. The humoral immunogenicity results are now reported. METHODS: Participants received two mRNA-1273 (100 µg) or placebo injections, 28 days apart. Immune responses were evaluated in a pre-specified, randomly-selected per-protocol immunogenicity population (n = 272 placebo; n = 1,185 mRNA-1273). Serum binding (bAb) and neutralizing (nAb) antibodies to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-spike protein were assessed at days 1, 29, and 57 by baseline SARS-CoV-2-negative (n = 1,197) and -positive (n = 260) status, age and sex. RESULTS: SARS-CoV-2-negative vaccinees had bAb geometric mean (GM) AU/ml levels of 35,753 at day 29 that increased to 316,448 at day 57 and nAb ID50 titers of 55 at day 29 that rose to 1081 at day 57. In SARS-CoV-2-positive vacinees, the first mRNA-1273 injection elicited bAb and nAb levels that were 11-fold (410,049) and 27-fold (1,479) higher than in SARS-CoV-2-negative vaccinees, respectively, and were comparable to levels after two injections in uninfected participants. Findings were generally consistent by age and sex. CONCLUSION: mRNA-1273 elicited robust serologic immune responses across age, sex, and SARS-CoV-2-status, consistent with its high COVID-19 efficacy. Higher immune responses in those previously-infected support a booster-type effect.ClinicalTrials.gov: NCT04470427.

6.
Lancet Respir Med ; 2022 May 23.
Article in English | MEDLINE | ID: covidwho-1864689

ABSTRACT

BACKGROUND: Baricitinib and dexamethasone have randomised trials supporting their use for the treatment of patients with COVID-19. We assessed the combination of baricitinib plus remdesivir versus dexamethasone plus remdesivir in preventing progression to mechanical ventilation or death in hospitalised patients with COVID-19. METHODS: In this randomised, double-blind, double placebo-controlled trial, patients were enrolled at 67 trial sites in the USA (60 sites), South Korea (two sites), Mexico (two sites), Singapore (two sites), and Japan (one site). Hospitalised adults (≥18 years) with COVID-19 who required supplemental oxygen administered by low-flow (≤15 L/min), high-flow (>15 L/min), or non-invasive mechanical ventilation modalities who met the study eligibility criteria (male or non-pregnant female adults ≥18 years old with laboratory-confirmed SARS-CoV-2 infection) were enrolled in the study. Patients were randomly assigned (1:1) to receive either baricitinib, remdesivir, and placebo, or dexamethasone, remdesivir, and placebo using a permuted block design. Randomisation was stratified by study site and baseline ordinal score at enrolment. All patients received remdesivir (≤10 days) and either baricitinib (or matching oral placebo) for a maximum of 14 days or dexamethasone (or matching intravenous placebo) for a maximum of 10 days. The primary outcome was the difference in mechanical ventilation-free survival by day 29 between the two treatment groups in the modified intention-to-treat population. Safety analyses were done in the as-treated population, comprising all participants who received one dose of the study drug. The trial is registered with ClinicalTrials.gov, NCT04640168. FINDINGS: Between Dec 1, 2020, and April 13, 2021, 1047 patients were assessed for eligibility. 1010 patients were enrolled and randomly assigned, 516 (51%) to baricitinib plus remdesivir plus placebo and 494 (49%) to dexamethasone plus remdesivir plus placebo. The mean age of the patients was 58·3 years (SD 14·0) and 590 (58%) of 1010 patients were male. 588 (58%) of 1010 patients were White, 188 (19%) were Black, 70 (7%) were Asian, and 18 (2%) were American Indian or Alaska Native. 347 (34%) of 1010 patients were Hispanic or Latino. Mechanical ventilation-free survival by day 29 was similar between the study groups (Kaplan-Meier estimates of 87·0% [95% CI 83·7 to 89·6] in the baricitinib plus remdesivir plus placebo group and 87·6% [84·2 to 90·3] in the dexamethasone plus remdesivir plus placebo group; risk difference 0·6 [95% CI -3·6 to 4·8]; p=0·91). The odds ratio for improved status in the dexamethasone plus remdesivir plus placebo group compared with the baricitinib plus remdesivir plus placebo group was 1·01 (95% CI 0·80 to 1·27). At least one adverse event occurred in 149 (30%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 179 (37%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·5% [1·6 to 13·3]; p=0·014). 21 (4%) of 503 patients in the baricitinib plus remdesivir plus placebo group had at least one treatment-related adverse event versus 49 (10%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 6·0% [2·8 to 9·3]; p=0·00041). Severe or life-threatening grade 3 or 4 adverse events occurred in 143 (28%) of 503 patients in the baricitinib plus remdesivir plus placebo group and 174 (36%) of 482 patients in the dexamethasone plus remdesivir plus placebo group (risk difference 7·7% [1·8 to 13·4]; p=0·012). INTERPRETATION: In hospitalised patients with COVID-19 requiring supplemental oxygen by low-flow, high-flow, or non-invasive ventilation, baricitinib plus remdesivir and dexamethasone plus remdesivir resulted in similar mechanical ventilation-free survival by day 29, but dexamethasone was associated with significantly more adverse events, treatment-related adverse events, and severe or life-threatening adverse events. A more individually tailored choice of immunomodulation now appears possible, where side-effect profile, ease of administration, cost, and patient comorbidities can all be considered. FUNDING: National Institute of Allergy and Infectious Diseases.

7.
SSRN; 2022.
Preprint in English | SSRN | ID: ppcovidwho-333335

ABSTRACT

The Omicron variant of SARS-CoV-2 exhibits reduced susceptibility to vaccine-induced neutralizing antibodies, requiring a boost to generate protective immunity. Little is known about the durability of vaccine-boosted omicron neutralizing antibodies and the potential impact of boosting with heterologous vaccine modalities. We assessed the magnitude and short-term durability of neutralizing antibodies after homologous and heterologous boosting with mRNA and Ad26.COV2.S vaccines. Using pseudovirus and live virus neutralization assays, all prime-boost combinations substantially increased the neutralization titers to Omicron although the boosted titers declined rapidly within 2 months from the peak response compared to boosted titers against the prototypic D614G variant. Boosted Omicron neutralization titers were substantially higher for homologous mRNA vaccine boosting, and for heterologous mRNA and Ad26.COV2.S vaccine boosting, compared to homologous Ad26.COV2.S boosting. Homologous mRNA vaccine boosting generated nearly equivalent neutralizing activity against Omicron subvariants BA.1, BA.2 and BA.3. These results have implications for boosting requirements to protect against Omicron and future variants of SARS-CoV-2.

8.
Nat Med ; 28(4): 823-830, 2022 04.
Article in English | MEDLINE | ID: covidwho-1684093

ABSTRACT

The mRNA-1273 vaccine for coronavirus disease 2019 (COVID-19) demonstrated 93.2% efficacy in reduction of symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the blinded portion of the Phase 3 Coronavirus Efficacy (COVE) trial. While mRNA-1273 demonstrated high efficacy in prevention of COVID-19, including severe disease, its effect on the viral dynamics of SARS-CoV-2 infections is not understood. Here, in exploratory analyses, we assessed the impact of mRNA-1273 vaccination in the ongoing COVE trial (number NCT04470427) on SARS-CoV-2 copy number and shedding, burden of disease and infection, and viral variants. Viral variants were sequenced in all COVID-19 and adjudicated COVID-19 cases (n = 832), from July 2020 in the blinded part A of the study to May 2021 of the open-label part B of the study, in which participants in the placebo arm started to receive the mRNA-1273 vaccine after US Food and Drug Administration emergency use authorization of mRNA-1273 in December 2020. mRNA-1273 vaccination significantly reduced SARS-CoV-2 viral copy number (95% confidence interval) by 100-fold on the day of diagnosis compared with placebo (4.1 (3.4-4.8) versus 6.2 (6.0-6.4) log10 copies per ml). Median times to undetectable viral copies were 4 days for mRNA-1273 and 7 days for placebo. Vaccination also substantially reduced the burden of disease and infection scores. Vaccine efficacies (95% confidence interval) against SARS-CoV-2 variants circulating in the United States during the trial assessed in this post hoc analysis were 82.4% (40.4-94.8%) for variants Epsilon and Gamma and 81.2% (36.1-94.5%) for Epsilon. The detection of other, non-SARS-CoV-2, respiratory viruses during the trial was similar between groups. While additional study is needed, these data show that in SARS-CoV-2-infected individuals, vaccination reduced both the viral copy number and duration of detectable viral RNA, which may be markers for the risk of virus transmission.


Subject(s)
COVID-19 , SARS-CoV-2 , 2019-nCoV Vaccine mRNA-1273 , COVID-19/epidemiology , COVID-19/prevention & control , Humans , SARS-CoV-2/genetics , United States
9.
N Engl J Med ; 386(11): 1046-1057, 2022 03 17.
Article in English | MEDLINE | ID: covidwho-1655751

ABSTRACT

BACKGROUND: Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. METHODS: In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 µg, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5×1010 virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 µg. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. RESULTS: Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. CONCLUSIONS: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier. (Funded by the National Institute of Allergy and Infectious Diseases; DMID 21-0012 ClinicalTrials.gov number, NCT04889209.).


Subject(s)
/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Vaccines/immunology , Immunogenicity, Vaccine , Adult , Aged , Aged, 80 and over , COVID-19 Vaccines/adverse effects , Female , Humans , Immunization, Secondary/adverse effects , Injections, Intramuscular/adverse effects , Male , Middle Aged , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , T-Lymphocytes/immunology
10.
Science ; 375(6576): 43-50, 2022 Jan 07.
Article in English | MEDLINE | ID: covidwho-1649486

ABSTRACT

In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipients with postvaccination 50% neutralization titers 10, 100, and 1000 had estimated vaccine efficacies of 78% (95% confidence interval, 54 to 89%), 91% (87 to 94%), and 96% (94 to 98%), respectively. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines.


Subject(s)
/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Clinical Trials, Phase III as Topic , Female , Humans , Immunogenicity, Vaccine , Male , Middle Aged , Randomized Controlled Trials as Topic , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/immunology , Young Adult
11.
Transl Res ; 242: 1-19, 2022 04.
Article in English | MEDLINE | ID: covidwho-1586297

ABSTRACT

The mRNA therapeutics have been studied since the 1970s and the currently available mRNA vaccines against COVID-19 are the culmination of decades of scientific research. The mRNA vaccines BNT162b2 and mRNA-1273 have played a key role in our global response to the COVID-19 pandemic as they have demonstrated significant advantages over conventional vaccines and have proven to be highly effective against COVID-19 associated hospitalization and severe illness in large clinical trials and studies using real-world data.


Subject(s)
COVID-19 , Vaccines , COVID-19/prevention & control , COVID-19 Vaccines , Humans , Pandemics/prevention & control , RNA, Messenger , SARS-CoV-2
13.
N Engl J Med ; 385(19): 1774-1785, 2021 Nov 04.
Article in English | MEDLINE | ID: covidwho-1434206

ABSTRACT

BACKGROUND: At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported. METHODS: We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021. RESULTS: The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified. CONCLUSIONS: The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunogenicity, Vaccine , Adolescent , Adult , Aged , COVID-19/epidemiology , COVID-19 Vaccines/adverse effects , Follow-Up Studies , Humans , Immunization, Secondary , Incidence , Intention to Treat Analysis , Male , Middle Aged , Patient Acuity , Single-Blind Method , Treatment Outcome , Young Adult
14.
Ann Intern Med ; 174(8): 1118-1125, 2021 08.
Article in English | MEDLINE | ID: covidwho-1181776

ABSTRACT

Multiple candidate vaccines to prevent COVID-19 have entered large-scale phase 3 placebo-controlled randomized clinical trials, and several have demonstrated substantial short-term efficacy. At some point after demonstration of substantial efficacy, placebo recipients should be offered the efficacious vaccine from their trial, which will occur before longer-term efficacy and safety are known. The absence of a placebo group could compromise assessment of longer-term vaccine effects. However, by continuing follow-up after vaccination of the placebo group, this study shows that placebo-controlled vaccine efficacy can be mathematically derived by assuming that the benefit of vaccination over time has the same profile for the original vaccine recipients and the original placebo recipients after their vaccination. Although this derivation provides less precise estimates than would be obtained by a standard trial where the placebo group remains unvaccinated, this proposed approach allows estimation of longer-term effect, including durability of vaccine efficacy and whether the vaccine eventually becomes harmful for some. Deferred vaccination, if done open-label, may lead to riskier behavior in the unblinded original vaccine group, confounding estimates of long-term vaccine efficacy. Hence, deferred vaccination via blinded crossover, where the vaccine group receives placebo and vice versa, would be the preferred way to assess vaccine durability and potential delayed harm. Deferred vaccination allows placebo recipients timely access to the vaccine when it would no longer be proper to maintain them on placebo, yet still allows important insights about immunologic and clinical effectiveness over time.


Subject(s)
COVID-19 Vaccines/administration & dosage , COVID-19/prevention & control , Clinical Trials, Phase III as Topic/standards , Randomized Controlled Trials as Topic/standards , Clinical Trials, Phase III as Topic/methods , Cross-Over Studies , Double-Blind Method , Drug Administration Schedule , Follow-Up Studies , Humans , Randomized Controlled Trials as Topic/methods , Research Design/standards , SARS-CoV-2 , Treatment Outcome
15.
Open Forum Infect Dis ; 7(12): ofaa509, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1010601

ABSTRACT

As the coronavirus disease 2019 (COVID-19) pandemic has progressed, a large volume of literature has developed delineating the clinical manifestations of acute infection. Recent reports have also started to describe persistent symptoms extending beyond the period of initial illness or hospitalization. Anecdotes of different signs and symptoms occurring after acute infection have also arisen in the lay press. Here we describe the current existing medical literature on the emerging concept of postacute COVID-19 and suggest an approach to classifying different manifestations of the syndrome. We also review long-term clinical manifestations observed in patients who recovered from infection due to other epidemic coronaviruses and briefly discuss potential mechanisms driving the phenomenon of postacute COVID-19.

16.
N Engl J Med ; 384(5): 403-416, 2021 02 04.
Article in English | MEDLINE | ID: covidwho-998039

ABSTRACT

BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 µg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. RESULTS: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. CONCLUSIONS: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , SARS-CoV-2 , Adolescent , Adult , Aged , COVID-19/diagnosis , COVID-19/immunology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , Female , Humans , Incidence , Male , Middle Aged , Patient Acuity , Single-Blind Method , Spike Glycoprotein, Coronavirus , Treatment Outcome , Young Adult
17.
N Engl J Med ; 384(9): 795-807, 2021 03 04.
Article in English | MEDLINE | ID: covidwho-972740

ABSTRACT

BACKGROUND: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. METHODS: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. RESULTS: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). CONCLUSIONS: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Azetidines/therapeutic use , COVID-19/drug therapy , Purines/therapeutic use , Pyrazoles/therapeutic use , Sulfonamides/therapeutic use , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/therapeutic use , Adult , Aged , Alanine/adverse effects , Alanine/therapeutic use , Antiviral Agents/adverse effects , Azetidines/adverse effects , COVID-19/mortality , COVID-19/therapy , Double-Blind Method , Drug Therapy, Combination , Female , Hospital Mortality , Hospitalization , Humans , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/therapeutic use , Male , Middle Aged , Oxygen Inhalation Therapy , Purines/adverse effects , Pyrazoles/adverse effects , Respiration, Artificial , Sulfonamides/adverse effects , Treatment Outcome
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