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1.
Thorax ; 2022 Jul 06.
Article in English | MEDLINE | ID: covidwho-1923310

ABSTRACT

OBJECTIVE: COVID-19 severity is correlated with granulocyte macrophage colony-stimulating factor (GM-CSF) and C reactive protein (CRP) levels. In the phase three LIVE-AIR trial, lenzilumab an anti-GM-CSF monoclonal antibody, improved the likelihood of survival without ventilation (SWOV) in COVID-19, with the greatest effect in participants having baseline CRP below a median of 79 mg/L. Herein, the utility of baseline CRP to guide lenzilumab treatment was assessed. DESIGN: A subanalysis of the randomised, blinded, controlled, LIVE-AIR trial in which lenzilumab or placebo was administered on day 0 and participants were followed through Day 28. PARTICIPANTS: Hospitalised COVID-19 participants (N=520) with SpO2 ≤94% on room air or requiring supplemental oxygen but not invasive mechanical ventilation. INTERVENTIONS: Lenzilumab (1800 mg; three divided doses, q8h, within 24 hours) or placebo infusion alongside corticosteroid and remdesivir treatments. MAIN OUTCOME MEASURES: The primary endpoint was the time-to-event analysis difference in SWOV through day 28 between lenzilumab and placebo treatments, stratified by baseline CRP. RESULTS: SWOV was achieved in 152 (90%; 95% CI 85 to 94) lenzilumab and 144 (79%; 72 to 84) placebo-treated participants with baseline CRP <150 mg/L (HR: 2.54; 95% CI 1.46 to 4.41; p=0.0009) but not with CRP ≥150 mg/L (HR: 1.04; 95% CI 0.51 to 2.14; p=0.9058). A statistically significant interaction between CRP and lenzilumab treatment was observed (p=0.044). Grade ≥3 adverse events with lenzilumab were comparable to placebo in both CRP strata. No treatment-emergent serious adverse events were attributed to lenzilumab. CONCLUSION: Hospitalised hypoxemic patients with COVID-19 with baseline CRP <150 mg/L derived the greatest clinical benefit from treatment with lenzilumab. TRIAL REGISTRATION NUMBER: NCT04351152; ClinicalTrials.gov.

2.
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.

3.
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)
2019-nCoV Vaccine mRNA-1273/immunology , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/prevention & control , SARS-CoV-2/immunology , Vaccine Efficacy , 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
4.
Open Forum Infectious Diseases ; 8(Supplement_1):S29-S29, 2021.
Article in English | PMC | ID: covidwho-1569742

ABSTRACT

BACKGROUND: Severe COVID19 pneumonia results from a hyperinflammatory immune response (cytokine storm, CS), characterized by GM CSF mediated activation and trafficking of myeloid cells, leading to elevation of downstream inflammatory chemokines (MCP1, IL8, IP10), cytokines (IL6, IL1), and other markers of systemic inflammation (CRP, D dimer, ferritin). CS leads to fever, hypotension, coagulopathy, respiratory failure, ARDS, and death. Lenzilumab is a novel Humaneered anti-human GM CSF monoclonal antibody that directly binds GM CSF and prevents signaling through its receptor. The LIVE AIR Phase 3 randomized, double blind, placebo controlled trial investigated the efficacy and safety of lenzilumab to assess the potential for lenzilumab to improve the likelihood of ventilator free survival (referred to herein as survival without ventilation, SWOV), beyond standard supportive care, in hospitalized subjects with severe COVID-19. METHODS: Subjects with COVID-19 (n=520), >18 years <94% oxygen saturation on room air and/or requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized to receive lenzilumab (600 mg, n=261) or placebo (n=259) via three intravenous infusions administered 8 hours apart. Subjects were followed through Day 28 following treatment. RESULTS: Baseline demographics were comparable between the two treatment groups: male, 64.7%;mean age, 60.5 years;mean BMI, 32.5 kg/m2;mean CRP, 98.36 mg/L;CRP was <150 mg/L in 77.9% of subjects. The most common comorbidities were obesity (55.1%), diabetes (53.4%), chronic kidney disease (14.0%), and coronary artery disease (13.6%). Subjects received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the likelihood of SWOV by 54% in the mITT population (HR: 1.54;95% CI: 1.02 to 2.31, p=0.041) and by 90% in the ITT population (HR: 1.90;1.02 to 3.52, nominal p=0.043) compared to placebo. SWOV also relatively improved by 92% in subjects who received both corticosteroids and remdesivir (1.92;1.20 to 3.07, nominal p=0.0067);by 2.96-fold in subjects with CRP<150 mg/L and age <85 years (2.96;1.63 to 5.37, nominal p=0.0003);and by 88% in subjects hospitalized <2 days prior to randomization (1.88;1.13 to 3.12, nominal p=0.015). Survival was improved by 2.17-fold in subjects with CRP<150 mg/L and age <85 years (2.17;1.04 to 4.54, nominal p=0.040). CONCLUSION: Lenzilumab significantly improved SWOV in hospitalized, hypoxic subjects with COVID-19 pneumonia over and above treatment with remdesivir and/or corticosteroids. Subjects with CRP<150 mg/L and age <85 years demonstrated an improvement in survival and had the greatest benefit from lenzilumab. NCT04351152

5.
Open forum infectious diseases ; 8(Suppl 1):29-29, 2021.
Article in English | EuropePMC | ID: covidwho-1564907

ABSTRACT

Background Severe coronavirus disease 2019 (COVID-19) often results from the immune-mediated cytokine storm, triggered by granulocyte macrophage-colony stimulating factor (GM-CSF), potentially leading to respiratory failure and death. Lenzilumab, a novel anti-human GM-CSF monoclonal antibody, neutralizes GM-CSF and demonstrated potential to improve clinical outcomes in a matched case-cohort study of patients with severe COVID-19 pneumonia. This Phase 3 randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of lenzilumab to improve the likelihood of survival without invasive mechanical ventilation (SWOV), beyond available treatments. Methods Hypoxic patients, hospitalized with COVID-19 (n=520), requiring supplemental oxygen, but not invasive mechanical ventilation, were randomized on Day 0 to receive lenzilumab (1800mg, n=261) or placebo (n=259), and available treatments, including remdesivir and/or corticosteroids;and were followed through Day 28. Results Baseline demographics were comparable between groups: male, 64.7%;mean age, 60.5 years;median CRP, 79.0 mg/L. Patients across both groups received steroids (93.7%), remdesivir (72.4%), or both (69.1%). Lenzilumab improved the primary endpoint, likelihood of SWOV in the mITT population, by 1.54-fold (HR: 1.54;95%CI: 1.02-2.32, p=0.0403). Lenzilumab improved SWOV by 1.91-fold (nominal p=0.0073) and 1.92-fold (nominal p=0.0067) in patients receiving remdesivir or remdesivir and corticosteroids, respectively. A key secondary endpoint of incidence of IMV, ECMO or death was also improved in patients receiving remdesivir (p=0.020) or remdesivir and corticosteroids (p=0.0180). Treatment-emergent serious adverse events were similar across both groups. Conclusion Lenzilumab significantly improved SWOV in hypoxic COVID-19 patients upon hospitalization, with the greatest benefit observed in patients receiving treatment with remdesivir and corticosteroids. NCT04351152 Disclosures Zelalem Temesgem, MD, Humanigen, Inc (Grant/Research Support) Jason Baker, MD, Humanigen, Inc (Grant/Research Support) Christopher Polk, MD, Atea (Research Grant or Support)Gilead (Advisor or Review Panel member, Research Grant or Support)Humanigen (Research Grant or Support)Regeneron (Research Grant or Support) Claudia R. Libertin, MD, Gilead (Grant/Research Support) Colleen F. Kelley, MD, MPH, Gilead Sciences (Individual(s) Involved: Self): Grant/Research Support;Moderna (Individual(s) Involved: Self): Grant/Research Support;Novavax (Individual(s) Involved: Self): Grant/Research Support;Viiv (Individual(s) Involved: Self): Grant/Research Support Vincent Marconi, MD, Bayer (Consultant, Scientific Research Study Investigator)Eli Lilly (Consultant, Scientific Research Study Investigator)Gilead Sciences (Consultant, Scientific Research Study Investigator)ViiV (Consultant, Scientific Research Study Investigator) Victoria Catterson, PhD, Humanigen, Inc (Consultant) William Aronstein, MD, PhD, Humanigen, Inc (Consultant) Cameron Durrant, MD, Humanigen, Inc (Employee) Dale Chappell, MD, Humanigen, Inc (Employee) Omar Ahmed, PharmD, Humanigen, Inc (Employee) Gabrielle Chappell, MSc, Humanigen, Inc (Consultant) Andrew Badley, M.D., AbbVie (Consultant) for the LIVE-AIR Study Group, n/a, Humanigen, Inc (Grant/Research Support)

6.
Lancet Respir Med ; 10(3): 237-246, 2022 03.
Article in English | MEDLINE | ID: covidwho-1550165

ABSTRACT

BACKGROUND: The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. METHODS: In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04351152, and is completed. FINDINGS: Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41-137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79-89) participants in the lenzilumab group and in 190 (78%; 72-83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02-2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. INTERPRETATION: Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. FUNDING: Humanigen.


Subject(s)
COVID-19 , Adult , Antibodies, Monoclonal, Humanized/adverse effects , COVID-19/drug therapy , Double-Blind Method , Humans , Male , Middle Aged , SARS-CoV-2 , Treatment Outcome
7.
FEBS Lett ; 595(17): 2257-2270, 2021 09.
Article in English | MEDLINE | ID: covidwho-1439663

ABSTRACT

HIV preferentially infects α4 ß7 + CD4 T cells, forming latent reservoirs that contribute to HIV persistence during antiretroviral therapy. However, the properties of α4 ß7 + CD4 T cells in blood and mucosal compartments remain understudied. Employing two distinct models of HIV infection, HIV-infected humans and simian-human immunodeficiency virus (SHIV)-infected rhesus macaques, we show that α4 ß7 + CD4 T cells in blood are enriched for genes regulating cell cycle progression and cellular metabolism. Unlike their circulating counterparts, rectal α4 ß7 + CD4 T cells exhibited a core tissue-residency gene expression program. These features were conserved across primate species, indicating that the environment influences memory T-cell transcriptional networks. Our findings provide an important molecular foundation for understanding the role of α4 ß7 in HIV infection.


Subject(s)
CD4-Positive T-Lymphocytes/metabolism , CD4-Positive T-Lymphocytes/virology , HIV Infections/blood , Integrins/metabolism , Adult , Animals , COVID-19/blood , COVID-19/virology , Cell Cycle , Cell Proliferation , Gastric Mucosa/cytology , Gastric Mucosa/virology , Gene Expression Regulation , Humans , Immunization , Macaca mulatta , Male , Simian Acquired Immunodeficiency Syndrome/blood , Simian Acquired Immunodeficiency Syndrome/virology
8.
AIDS ; 34(12): 1789-1794, 2020 10 01.
Article in English | MEDLINE | ID: covidwho-1301407

ABSTRACT

BACKGROUND: There are limited data describing the presenting characteristics and outcomes among US persons with HIV (PWH) requiring hospitalization for coronavirus disease 2019 (COVID-19). METHODS: We performed a case series of all PWH sequentially admitted with COVID-19 from 8 March 2020 to 23 April 2020 at three hospitals in Atlanta, Georgia. Sociodemographic, clinical and HIV-associated characteristics were collected. RESULTS: Of 530 confirmed COVID-19 cases hospitalized during this period, 20 occurred among PWH (3.8%). The median age was 57 (Q1-Q3, 48-62) years, 65% were men, and 85% were non-Hispanic Black. Presenting median symptom duration was 5 (Q1-Q3, 3-7) days; cough (90%), fever (65%), malaise (60%) and dyspnea (60%) were most common. On admission, 40% of patients required oxygenation support and 65% had an abnormal chest radiograph. Median length of hospitalization was 5 (Q1-Q3, 4-12) days, 30% required intensive care, 15% required intubation, and 15% died. Median CD4 cell count prior to admission was 425 (Q1-Q3, 262-815) cells/µl and 90% of patients had HIV-1 RNA less than 200 copies/ml. Half of the patients had at least five comorbidities; hypertension (70%), dyslipidemia (60%) and diabetes (45%) were most prevalent. All three patients who died had CD4 cell count more than 200, HIV suppression and each had a total of five comorbidities. CONCLUSION: The multisite series in the Southern United States provides characteristics and early outcomes of hospitalized PWH with COVID-19. Nearly all patients had controlled HIV and a high comorbidity burden. Additional study of COVID-19 among PWH is needed to determine the role of age, comorbidities and HIV control in mediating COVID-19 presentation and its sequelae.


Subject(s)
Coronavirus Infections/epidemiology , HIV Infections/epidemiology , Pneumonia, Viral/epidemiology , African Americans/statistics & numerical data , CD4 Lymphocyte Count , COVID-19 , Comorbidity , Coronavirus Infections/ethnology , Coronavirus Infections/therapy , Female , Georgia/epidemiology , HIV Infections/ethnology , HIV Infections/therapy , Hospitalization/statistics & numerical data , Humans , Male , Middle Aged , Pandemics , Pneumonia, Viral/ethnology , Pneumonia, Viral/therapy , Retrospective Studies
9.
Obstet Gynecol ; 137(3): 408-414, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-1066433

ABSTRACT

Coronavirus disease 2019 (COVID-19) vaccines have begun to be distributed across the United States and to be offered initially to priority groups including health care personnel and persons living in long-term care facilities. Guidance regarding whether pregnant persons should receive a COVID-19 vaccine is needed. Because pregnant persons were excluded from the initial phase 3 clinical trials of COVID-19 vaccines, limited data are available on their efficacy and safety during pregnancy. After developmental and reproductive toxicology studies are completed, some companies are expected to conduct clinical trials in pregnant persons. Until then, pregnant persons and their obstetricians will need to use available data to weigh the benefits and risks of COVID-19 vaccines. Issues to be considered when counseling pregnant persons include data from animal studies and inadvertently exposed pregnancies during vaccine clinical trials when available, potential risks to pregnancy of vaccine reactogenicity, timing of vaccination during pregnancy, evidence for safety of other vaccines during pregnancy, risk of COVID-19 complications due to pregnancy and the pregnant person's underlying conditions, and risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential for risk mitigation. The Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine have each issued guidance supportive of offering COVID-19 vaccine to pregnant persons. As additional information from clinical trials and from data collected on vaccinated pregnant persons becomes available, it will be critical for obstetricians to keep up to date with this information.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Health Knowledge, Attitudes, Practice , Pregnancy Complications, Infectious/prevention & control , COVID-19/transmission , Centers for Disease Control and Prevention, U.S. , Clinical Trials as Topic , Female , Humans , Infectious Disease Transmission, Vertical , Practice Guidelines as Topic , Pregnancy , SARS-CoV-2 , Societies, Medical , United States , Vaccination
10.
Obstet Gynecol ; 137(3): 408-414, 2021 03 01.
Article in English | MEDLINE | ID: covidwho-998491

ABSTRACT

Coronavirus disease 2019 (COVID-19) vaccines have begun to be distributed across the United States and to be offered initially to priority groups including health care personnel and persons living in long-term care facilities. Guidance regarding whether pregnant persons should receive a COVID-19 vaccine is needed. Because pregnant persons were excluded from the initial phase 3 clinical trials of COVID-19 vaccines, limited data are available on their efficacy and safety during pregnancy. After developmental and reproductive toxicology studies are completed, some companies are expected to conduct clinical trials in pregnant persons. Until then, pregnant persons and their obstetricians will need to use available data to weigh the benefits and risks of COVID-19 vaccines. Issues to be considered when counseling pregnant persons include data from animal studies and inadvertently exposed pregnancies during vaccine clinical trials when available, potential risks to pregnancy of vaccine reactogenicity, timing of vaccination during pregnancy, evidence for safety of other vaccines during pregnancy, risk of COVID-19 complications due to pregnancy and the pregnant person's underlying conditions, and risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential for risk mitigation. The Centers for Disease Control and Prevention, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine have each issued guidance supportive of offering COVID-19 vaccine to pregnant persons. As additional information from clinical trials and from data collected on vaccinated pregnant persons becomes available, it will be critical for obstetricians to keep up to date with this information.


Subject(s)
COVID-19 Vaccines , COVID-19/prevention & control , Health Knowledge, Attitudes, Practice , Pregnancy Complications, Infectious/prevention & control , COVID-19/transmission , Centers for Disease Control and Prevention, U.S. , Clinical Trials as Topic , Female , Humans , Infectious Disease Transmission, Vertical , Practice Guidelines as Topic , Pregnancy , SARS-CoV-2 , Societies, Medical , United States , Vaccination
12.
Ann Epidemiol ; 49: 50-60, 2020 09.
Article in English | MEDLINE | ID: covidwho-703961

ABSTRACT

PURPOSE: The U.S. response to the SARS-CoV-2 epidemic has been hampered by early and ongoing delays in testing for infection; without data on where infections were occurring and the magnitude of the epidemic, early public health responses were not data-driven. Understanding the prevalence of SARS-CoV-2 infections and immune response is critical to developing and implementing effective public health responses. Most serological surveys have been limited to localities that opted to conduct them and/or were based on convenience samples. Moreover, results of antibody testing might be subject to high false positive rates in the setting of low prevalence of immune response and imperfect test specificity. METHODS: We will conduct a national serosurvey for SARS-CoV-2 PCR positivity and immune experience. A probability sample of U.S. addresses will be mailed invitations and kits for the self-collection of anterior nares swab and finger prick dried blood spot specimens. Within each sampled household, one adult 18 years or older will be randomly selected and asked to complete a questionnaire and to collect and return biological specimens to a central laboratory. Nasal swab specimens will be tested for SARS-CoV-2 RNA by RNA PCR; dried blood spot specimens will be tested for antibodies to SARS-CoV-2 (i.e., immune experience) by enzyme-linked immunoassays. Positive screening tests for antibodies will be confirmed by a second antibody test with different antigenic basis to improve predictive value of positive (PPV) antibody test results. All persons returning specimens in the baseline phase will be enrolled into a follow-up cohort and mailed additional specimen collection kits 3 months after baseline. A subset of 10% of selected households will be invited to participate in full household testing, with tests offered for all household members aged ≥3 years. The main study outcomes will be period prevalence of infection with SARS-CoV-2 and immune experience, and incidence of SARS-CoV-2 infection and antibody responses. RESULTS: Power calculations indicate that a national sample of 4000 households will facilitate estimation of national SARS-CoV-2 infection and antibody prevalence with acceptably narrow 95% confidence intervals across several possible scenarios of prevalence levels. Oversampling in up to seven populous states will allow for prevalence estimation among subpopulations. Our 2-stage algorithm for antibody testing produces acceptable PPV at prevalence levels ≥1.0%. Including oversamples in states, we expect to receive data from as many as 9156 participants in 7495 U.S. households. CONCLUSIONS: In addition to providing robust estimates of prevalence of SARS-CoV-2 infection and immune experience, we anticipate this study will establish a replicable methodology for home-based SARS-CoV-2 testing surveys, address concerns about selection bias, and improve positive predictive value of serology results. Prevalence estimates of SARS-CoV-2 infection and immune experience produced by this study will greatly improve our understanding of the spectrum of COVID-19 disease, its current penetration in various demographic, geographic, and occupational groups, and inform the range of symptoms associated with infection. These data will inform resource needs for control of the ongoing epidemic and facilitate data-driven decisions for epidemic mitigation strategies.


Subject(s)
Clinical Laboratory Techniques/methods , Coronavirus Infections/diagnosis , Coronavirus/genetics , Pneumonia, Viral/diagnosis , RNA, Viral/isolation & purification , Betacoronavirus , COVID-19 , COVID-19 Testing , Clinical Trial Protocols as Topic , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Disease Outbreaks , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , SARS-CoV-2
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