Reliability and Validity of an Instrument of COVID-19 Patient-Reported Symptoms in Outpatients.

Importance: Patient-reported outcome instruments are key in assessing COVID-19-related symptoms and associated burden. However, a valid and reliable instrument to assess symptom severity and progression among outpatients with COVID-19 is not yet available. Objectives: To assess the extent to which the Symptoms Evolution of COVID-19 (SE-C19) instrument is valid, reliable, and able to detect symptom changes in outpatients with COVID-19, as well as to establish a definition of symptom resolution. Design, Setting, and Participants: In this diagnostic/prognostic study, psychometric properties of SE-C19 were assessed in participants recruited into an ongoing, adaptive, phase 1/2/3, randomized, double-blind, placebo-controlled clinical trial, during 2020 to 2022. Adult outpatients with symptomatic COVID-19 were randomized 1:1:1 to receive 2.4 g or 8.0 g intravenous casirivimab and imdevimab or placebo, in outpatient centers at 114 sites, from 2 countries (US and Mexico). Main Outcomes and Measures: Reliability, validity, and sensitivity to change of the SE-C19 were assessed. SE-C19 and Patient Global Impression of Severity (PGIS) were administered daily from predose at day 1 to day 29. Results: Analysis was conducted on 657 adult outpatients (342 female patients [52.1%], 562 White patients [85.5%]), and 337 non-Hispanic patients [51.3%]. At baseline, patients reported a mean (SD) of 6.6 (3.9) symptoms (ie, rated as at least mild) with a mean (SD) of 3.8 (3.3) of these symptoms being rated as moderate or severe. Stable patients according to PGIS showed scores with intraclass correlation values indicating moderate-to-good test-retest reliability (ie, 0.50-0.90). At baseline, 20 item scores (87%) varied significantly across PGIS-defined groups, supporting the validity of the SE-C19. A symptom-resolution end point was defined after excluding the item sneezing due to its low ability to discriminate severity levels, and excluding confusion, rash, and vomiting, due to their low prevalence in this population. Symptom resolution required complete absence of all remaining items, except cough, fatigue, and headache, which could be mild or moderate in severity. A total of 19 of 23 items from the SE-C19 instrument were identified as valid and reliable to measure disease-related symptoms in outpatients with COVID-19. Conclusions and Relevance: This study identified 19 items that are valid and reliable to measure disease-related symptoms in outpatients with COVID-19, and proposed a definition of symptom resolution for potential use in future clinical trials.

A drug-disease model for predicting survival in an Ebola outbreak.

REGN-EB3 (Inmazeb) is a cocktail of three human monoclonal antibodies approved for treatment of Ebola infection. This paper describes development of a mathematical model linking REGN-EB3's inhibition of Ebola virus to survival in a non-human primate (NHP) model, and translational scaling to predict survival in humans. Pharmacokinetic/pharmacodynamic data from single- and multiple-dose REGN-EB3 studies in infected rhesus macaques were incorporated. Using discrete indirect response models, the antiviral mechanism of action was used as a forcing function to drive the reversal of key Ebola disease hallmarks over time, for example, liver and kidney damage (elevated alanine [ALT] and aspartate aminotransferases [AST], blood urea nitrogen [BUN], and creatinine), and hemorrhage (decreased platelet count). A composite disease characteristic function was introduced to describe disease severity and integrated with the ordinary differential equations estimating the time course of clinical biomarkers. Model simulation results appropriately represented the concentration-dependence of the magnitude and time course of Ebola infection (viral and pathophysiological), including time course of viral load, ALT and AST elevations, platelet count, creatinine, and BUN. The model estimated the observed survival rate in rhesus macaques and the dose of REGN-EB3 required for saturation of the pharmacodynamic effects of viral inhibition, reversal of Ebola pathophysiology, and survival. The model also predicted survival in clinical trials with appropriate scaling to humans. This mathematical investigation demonstrates that drug-disease modeling can be an important translational tool to integrate preclinical data from an NHP model recapitulating disease progression to guide future translation of preclinical data to clinical study design.

Casirivimab and Imdevimab for the Treatment of Hospitalized Patients With COVID-19.

BACKGROUND: The open-label RECOVERY study reported improved survival in hospitalized, SARS-CoV-2 seronegative patients treated with casirivimab and imdevimab (CAS + IMD). METHODS: In this phase 1/2/3, double-blind, placebo-controlled trial conducted prior to widespread circulation of Delta and Omicron, hospitalized COVID-19 patients were randomized (1:1:1) to 2.4 g or 8.0 g CAS + IMD or placebo, and characterized at baseline for viral load and SARS-CoV-2 serostatus. RESULTS: In total, 1336 patients on low-flow or no supplemental (low-flow/no) oxygen were treated. The primary endpoint was met in seronegative patients, the least-squares mean difference (CAS + IMD versus placebo) for time-weighted average change from baseline in viral load through day 7 was -0.28 log10 copies/mL (95% confidence interval [CI], -.51 to -.05; P = .0172). The primary clinical analysis of death or mechanical ventilation from day 6 to 29 in patients with high viral load had a strong positive trend but did not reach significance. CAS + IMD numerically reduced all-cause mortality in seronegative patients through day 29 (relative risk reduction, 55.6%; 95% CI, 24.2%-74.0%). No safety concerns were noted. CONCLUSIONS: In hospitalized COVID-19 patients on low-flow/no oxygen, CAS + IMD reduced viral load and likely improves clinical outcomes in the overall population, with the benefit driven by seronegative patients, and no harm observed in seropositive patients. CLINICAL TRIALS REGISTRATION: NCT04426695.

Lay Summary . Monoclonal antibody therapies that block the virus that causes COVID-19 (SARS-CoV-2) can prevent patients from being hospitalized. We hypothesized that these antibodies may also benefit patients who are already hospitalized with COVID-19. Therefore, we performed a study to determine if the monoclonal antibody combination of casirivimab and imdevimab (CAS + IMD) can decrease the amount of virus in the nose of hospitalized patients and prevent the disease from becoming more severe. The study, conducted from June 2020 to April 2021, found that CAS + IMD treatment reduced the amount of virus in these patients, and may reduce their chance of dying or needing a ventilator (a machine that helps patients breathe). Patients were examined in 2 groups: those whose immune systems, at the start of the study, had not produced their own antibodies to fight SARS-CoV-2 (seronegative patients); or those that had already produced their own antibodies (seropositive patients) at the start of the study. Seronegative patients benefited the most from CAS + IMD. No safety concerns related to CAS + IMD were observed. These results demonstrate that monoclonal antibody therapy can help hospitalized patients with COVID-19 and may decrease their chances of needing assistance to breathe or dying.

Development and content validation of the Symptoms Evolution of COVID-19: a patient-reported electronic daily diary in clinical and real-world studies.

BACKGROUND: At the onset of the COVID-19 pandemic, there was limited understanding of symptom experience and disease progression. We developed and validated a fit-for-purpose disease-specific instrument to assess symptoms in patients with COVID-19 to inform endpoints in an interventional trial for non-hospitalized patients. METHODS: The initial drafting of the 23-item Symptoms Evolution of COVID-19 (SE-C19) Instrument was developed based on the Centers for Disease Control and Prevention symptom list and available published literature specific to patients with COVID-19 as of Spring 2020. The measurement principles outlined in the Food and Drug Administration (FDA) Patient-Reported Outcomes (PRO) guidance and the FDA's series of four methodological Patient-Focused Drug Development guidance documents were also considered. Following initial development, semi-structured qualitative interviews were conducted with a purposive sample of 30 non-hospitalized COVID-19 patients. Interviews involved two stages: (1) concept elicitation, to obtain information about the symptoms experienced as a result of COVID-19 in the patients' own words, and (2) cognitive debriefing, for patients to describe their understanding of the SE-C19 instructions, specific symptoms, response options, and recall period to ensure the content of the SE-C19 is relevant and comprehensive. Five clinicians treating COVID-19 outpatients were also interviewed to obtain their insights on symptoms experienced by patients and provide input on the SE-C19. RESULTS: Patients reported no issues regarding the relevance or appropriateness of the SE-C19 instructions, including the 24-h recall period. The comprehensiveness of the SE-C19 was confirmed against the conceptualization of the patient experience of symptoms developed in the qualitative research. Minor conceptual gaps were revealed to capture nuances in the experience of nasal and gustatory symptoms and systemic manifestations of sickness. Almost all items were endorsed by patients as being appropriate, well understood, and easy to respond to. The clinicians largely approved all items, response options, and recall period. CONCLUSIONS: The qualitative research provided supportive evidence of the content validity of the SE-C19 to assess the symptoms of outpatients with COVID-19, and its use in clinical trials to evaluate the benefit of treatment. Minor changes may be considered to improve conceptual clarity and ease of responding.

Patient experience of symptoms and impacts of COVID-19: a qualitative investigation with symptomatic outpatients.

OBJECTIVES: There is little in-depth qualitative evidence of how symptoms manifest themselves in outpatients with COVID-19 and how these in turn impact outpatients' daily lives. The objective of the study was therefore to explore the experience of outpatients with COVID-19 qualitatively, concerning the symptomatic experience and its subsequent impact on daily life. SETTING: Qualitative research study comprising virtual in-depth, open-ended interviews with outpatients and clinicians. PARTICIPANTS: Thirty US adult patients with COVID-19 were interviewed within 21 days of diagnosis. Patients were 60% female and 87% white, who had to self-report one of the following: fever, cough, shortness of breath/difficulty breathing, change/loss of taste/smell, vomiting/diarrhoea or body/muscle aches. Five independent clinicians were also interviewed about their experience treating outpatients. PRIMARY AND SECONDARY OUTCOME MEASURES: Transcripts were analysed thematically to organise symptoms and impacts of daily life into higher-order overarching categories, and subsequently propose a conceptual model. The adequacy of the sample size was assessed by conceptual saturation analysis. RESULTS: Patient-reported concepts were organised into six symptom themes (upper respiratory, lower respiratory, systemic, gastrointestinal, smell and taste, and other) and seven impact themes (activities of daily living, broad daily activities, leisure/social activities, and physical, emotional, professional and quarantine-specific impacts). Symptom type, severity, duration and time of onset varied by patient. Clinicians endorsed all patient-reported symptoms. CONCLUSIONS: The manifestation of symptoms in outpatients is heterogeneous and affects all aspects of daily life. Outpatients offered new detailed insights into their symptomatic experiences, including heterogeneous experiences of smell and taste, and the impacts that symptoms had on their daily lives. Findings of this research may be used to supplement existing knowledge of the outpatient experience of mild-to-moderate COVID-19, to further inform treatment guidelines and to provide an evidence base for evaluating potential treatment benefits.

Efficacy and Safety of Sarilumab in Hospitalized Patients With Coronavirus Disease 2019: A Randomized Clinical Trial.

BACKGROUND: Open-label platform trials and a prospective meta-analysis suggest efficacy of anti-interleukin (IL)-6R therapies in hospitalized patients with coronavirus disease 2019 (COVID-19) receiving corticosteroids. This study evaluated the efficacy and safety of sarilumab, an anti-IL-6R monoclonal antibody, in the treatment of hospitalized patients with COVID-19. METHODS: In this adaptive, phase 2/3, randomized, double-blind, placebo-controlled trial, adults hospitalized with COVID-19 received intravenous sarilumab 400 mg or placebo. The phase 3 primary analysis population included patients with critical COVID-19 receiving mechanical ventilation (MV). The primary outcome was proportion of patients with ≥1-point improvement in clinical status from baseline to day 22. RESULTS: There were 457 and 1365 patients randomized and treated in phases 2 and 3, respectively. In phase 3, patients with critical COVID-19 receiving MV (n = 298; 28.2% on corticosteroids), the proportion with ≥1-point improvement in clinical status (alive, not receiving MV) at day 22 was 43.2% for sarilumab and 35.5% for placebo (risk difference, +7.5%; 95% confidence interval [CI], -7.4 to 21.3; P =.3261), a relative risk improvement of 21.7%. In post hoc analyses pooling phase 2 and 3 critical patients receiving MV, the hazard ratio for death for sarilumab vs placebo was 0.76 (95% CI, .51 to 1.13) overall and 0.49 (95% CI, .25 to .94) in patients receiving corticosteroids at baseline. CONCLUSIONS: This study did not establish the efficacy of sarilumab in hospitalized patients with severe/critical COVID-19. Post hoc analyses were consistent with other studies that found a benefit of sarilumab in patients receiving corticosteroids. CLINICAL TRIALS REGISTRATION: NCT04315298.

Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus.

BACKGROUND: REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. METHODS: Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. RESULTS: Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. CONCLUSIONS: REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.

Baseline Severe Acute Respiratory Syndrome Viral Load Is Associated With Coronavirus Disease 2019 Severity and Clinical Outcomes: Post Hoc Analyses of a Phase 2/3 Trial.

BACKGROUND: Elucidating the relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and clinical outcomes is critical for understanding coronavirus disease 2019 (COVID-19). METHODS: The SARS-CoV-2 levels were analyzed by quantitative real-time polymerase chain reaction (RT-qPCR) of nasopharyngeal or oropharyngeal swab specimens collected at baseline, and clinical outcomes were recorded over 60 days from 1362 COVID-19 hospitalized patients enrolled in a multicenter, randomized, placebo-controlled phase 2/3 trial of sarilumab for COVID-19 (ClinicalTrials.gov NCT04315298). RESULTS: In post hoc analyses, higher baseline viral load, measured by both RT-qPCR cycle threshold and log10 copies/mL, was associated with greater supplemental oxygenation requirements and disease severity at study entry. Higher baseline viral load was associated with higher mortality, lower likelihood of improvement in clinical status and supplemental oxygenation requirements, and lower rates of hospital discharge. Viral load was not impacted by sarilumab treatment over time versus placebo. CONCLUSIONS: These data support viral load as an important determinant of clinical outcomes in hospitalized patients with COVID-19 requiring supplemental oxygen or assisted ventilation.

REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19.

BACKGROUND: In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern. METHODS: In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated. RESULTS: Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log10 copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log10 copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups. CONCLUSIONS: REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).

The monoclonal antibody combination REGEN-COV protects against SARS-CoV-2 mutational escape in preclinical and human studies.

Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting.

A Retrospective Study of COVID-19-Related Urgent Medical Visits and Hospitalizations After Outpatient COVID-19 Diagnosis in the US.

INTRODUCTION: Identifying risk factors for progression to severe COVID-19 requiring urgent medical visits and hospitalizations (UMVs) among patients initially diagnosed in the outpatient setting may help inform patient management. The objective of this study was to estimate the incidence of and risk factors for COVID-19-related UMVs after outpatient COVID-19 diagnosis or positive SARS-CoV-2 test. METHODS: Data for this retrospective cohort study were from the Optum® de-identified COVID-19 Electronic Health Record database from June 1 to December 9, 2020. Adults with first COVID-19 diagnosis or positive SARS-CoV-2 test in outpatient settings were identified. Cumulative incidence function analysis stratified by risk factors was used to estimate the 30-day incidence of COVID-19-related UMVs. Competing risk regression models were used to derive adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for factors associated with UMVs. RESULTS: Among 206,741 patients [58.8% female, 77.5% non-Hispanic Caucasian, mean (SD) age: 46.7 (17.8) years], the 30-day incidence was 9.4% (95% CI 9.3-9.6) for COVID-19-related emergency room (ER)/urgent care (UC)/hospitalizations and 3.8% (95% CI 3.7-3.9) for COVID-19-related hospitalizations. Likelihood of hospitalization increased with age and body mass index, with age the strongest risk factor (aHR 5.61; 95% CI 4.90-6.32 for patients ≥ 85 years). Increased likelihood of hospitalization was observed for first presentation in the ER/UC vs. non-ER/UC outpatient settings (aHR 2.35; 95% CI 2.22-2.47) and prior all-cause hospitalization (aHR 1.90; 95% CI 1.79-2.00). Clinical risk factors of hospitalizations included pregnancy, uncontrolled diabetes, chronic obstructive pulmonary disease, chronic kidney disease, and autoimmune disease. A study limitation is that data on COVID-19 severity and symptoms were not captured. CONCLUSION: Predictors of COVID-19-related UMVs include older age, obesity, and several comorbidities. These findings may inform patient management and resource allocation following outpatient COVID-19 diagnosis.

Suptavumab for the Prevention of Medically Attended Respiratory Syncytial Virus Infection in Preterm Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of childhood medically attended respiratory infection (MARI). METHODS: We conducted a randomized, double-blind, placebo-controlled phase 3 trial in 1154 preterm infants of 1 or 2 doses of suptavumab, a human monoclonal antibody that can bind and block a conserved epitope on RSV A and B subtypes, for the prevention of RSV MARI. The primary endpoint was proportion of subjects with RSV-confirmed hospitalizations or outpatient lower respiratory tract infection (LRTI). RESULTS: There were no significant differences between primary endpoint rates (8.1%, placebo; 7.7%, 1-dose; 9.3%, 2-dose). Suptavumab prevented RSV A infections (relative risks, .38; 95% confidence interval [CI], .14-1.05 in the 1-dose group and .39 [95% CI, .14-1.07] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .0499), while increasing the rate of RSV B infections (relative risk 1.36 [95% CI, .73-2.56] in the 1-dose group and 1.69 [95% CI, .92-3.08] in the 2-dose group; nominal significance of combined suptavumab group vs placebo; P = .12). Sequenced RSV isolates demonstrated no suptavumab epitope changes in RSV A isolates, while all RSV B isolates had 2-amino acid substitution in the suptavumab epitope that led to loss of neutralization activity. Treatment emergent adverse events were balanced across treatment groups. CONCLUSIONS: Suptavumab did not reduce overall RSV hospitalizations or outpatient LRTI because of a newly circulating mutant strain of RSV B. Genetic variation in circulating RSV strains will continue to challenge prevention efforts. CLINICAL TRIALS REGISTRATION: NCT02325791.

REGN-COV2, a Neutralizing Antibody Cocktail, in Outpatients with Covid-19.

BACKGROUND: Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. METHODS: In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients. RESULTS: Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log10 copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log10 copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group. CONCLUSIONS: In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).

Complement levels in patients with bloodstream infection due to Staphylococcus aureus or Gram-negative bacteria.

The complement system is a vital component of the innate immune system, though its role in bacteremia is poorly understood. We present complement levels in Staphylococcus aureus bacteremia (SAB) and Gram-negative bacteremia (GNB) and describe observed associations of complement levels with clinical outcomes. Complement and cytokine levels were measured in serum samples from 20 hospitalized patients with SAB, 20 hospitalized patients with GNB, 10 non-infected hospitalized patients, and 10 community controls. C5a levels were significantly higher in patients with SAB as compared to patients with GNB. Low C4 and C3 levels were associated with septic shock and 30-day mortality in patients with GNB, and elevated C3 was associated with a desirable outcome defined as absence of (1) septic shock, (2) acute renal failure, and (3) death within 30 days of bacteremia. Low levels of C9 were associated with septic shock in patients with GNB but not SAB. Elevated IL-10 was associated with increased 30-day mortality in patients with SAB. Complement profiles differ in patients with SAB and those with GNB. Measurement of IL-10 in patients with SAB and of C4, C3, and C9 in patients with GNB may help to identify those at higher risk for poor outcomes.

Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail.

Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola-one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure. On the basis of these criteria, we selected pairs of highly potent individual antibodies that simultaneously bind the receptor binding domain of the spike protein, thereby providing ideal partners for a therapeutic antibody cocktail that aims to decrease the potential for virus escape mutants that might arise in response to selective pressure from a single-antibody treatment.

A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Safety, pharmacokinetics, and immunogenicity of a co-formulated cocktail of three human monoclonal antibodies targeting Ebola virus glycoprotein in healthy adults: a randomised, first-in-human phase 1 study.

BACKGROUND: REGN3470-3471-3479 is a co-formulated cocktail of three human monoclonal antibodies targeting three non-overlapping epitopes on Ebola virus. We investigated safety, tolerability, pharmacokinetics, and anti-drug antibodies in healthy adults. METHODS: This randomised, double-blind, placebo-controlled, dose-escalation study was done at a phase 1 unit in the USA. Healthy adults, aged 18-60 years, with a body-mass index of 18·0-30·0 kg/m2 were randomly assigned (3:1) to receive a single intravenous dose of REGN3470-3471-3479 or placebo on day 1 (baseline) in one of the four sequential ascending intravenous dose cohorts (3 mg/kg, 15 mg/kg, 60 mg/kg, and 150 mg/kg). Site investigators and participants were masked to the treatment assignment, whereas designated personnel at the site who prepared and generated the study medication were aware of the randomisation treatment assignments. The primary outcome was safety and the secondary outcomes were the pharmacokinetic profiles and immunogenicity. Study assessments were done the day before study drug administration, on the day of drug administration, on day 2 (before discharge), on days 3, 4, 8, 15, 29, 57, 85, 113, and 141, and at the end of study on day 169. The safety analysis included all randomised participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT002777151. FINDINGS: Between May 18, 2016, and October 27, 2016, 70 adults were screened and 24 participants were enrolled in the study. 18 participants were assigned to and received REGN3470-3471-3479, and six participants were assigned to and received placebo as a single intravenous infusion. 19 treatment-emergent adverse events occurred in the combined REGN3470-3471-3479 treatment groups, and four treatment-emergent adverse events occurred in combined placebo groups. Adverse events were transient and mild-to-moderate in severity. The most common treatment-emergent adverse event was headache (six [33%] of 18 participants in the combined REGN3470-3471-3479 group vs none of six participants in the placebo group. Headaches were mild-to-moderate in severity, with onset between 2 h and 27 days after start of study drug infusion. There were no deaths, serious adverse events, or adverse events that led to study discontinuation. The pharmacokinetics of each antibody was linear, with mean half-lives of 27·3 days for REGN3471, 21·7 days for REGN3470, and 23·3 days for REGN3479. No participants tested positive for anti-REGN3470, anti-REGN3471, or anti-REGN3479 antibodies. INTERPRETATION: REGN3470-3471-3479 was well tolerated, displayed linear pharmacokinetics, and did not lead to detectable immunogenicity. These data support further clinical development of REGN3470-3471-3479 as a single-dose therapeutic drug for acute Ebola virus infection. FUNDING: The Department of Health and Human Services, the Office of the Assistant Secretary for Preparedness and Response, and the Biomedical Advanced Research and Development Authority.

Integrating Household Water Treatment, Hand Washing, and Insecticide-Treated Bed Nets Into Pediatric HIV Care in Mombasa, Kenya: Impact on Diarrhea and Malaria Risk.

INTRODUCTION: In developing countries, HIV-infected children are at higher risk of morbidity and mortality from opportunistic infections than HIV-uninfected children. To address this problem, the Healthy Living Initiative (HLI) in Mombasa, Kenya distributed basic care packages (BCPs) containing improved water storage vessels, water treatment solution, soap, and insecticide-treated bed nets to prevent diarrhea and malaria in children, and had community health workers (CHWs) make bimonthly home visits to encourage adherence to HLI interventions and antiretroviral (ARV) medicine use. METHODS: To evaluate HLI, we enrolled 500 HIV-infected children from Bomu Hospital. In the implementation phase, from February to August 2011, we conducted surveys of caregivers, then provided free BCPs. In the evaluation phase, from September 2011 to August 2012, CHWs recorded observations of BCP use during home visits. We abstracted hospital data to compare diarrhea and malaria episodes, and pharmacy data on ARVs dispensed, between the 12-month preimplementation baseline phase (February 2010-January 2011) and the evaluation phase. RESULTS: The retention rate of children in HLI was 78.4%. In a multivariable logistic regression model adjusting for demographic characteristics, number of CHW home visits, distance to clinic, orphan status, and number of ARVs dispensed, children in HLI had 71% lower risk of diarrhea (relative risk 0.29, P < 0.001) and 87% lower risk of malaria (relative risk 0.13, P = 0.001) during the evaluation phase than the baseline phase; there was no independent association between ARV use and illness. CONCLUSIONS: HIV-infected children in HLI were less likely to experience diarrhea and malaria during the evaluation phase than the baseline phase.

An effective intervention to reduce intravaginal practices among HIV-1 uninfected Kenyan women.

Intravaginal practices (IVP) are common among African women and are associated with HIV acquisition. A behavioral intervention to reduce IVP is a potential new HIV risk-reduction strategy. Fifty-eight HIV-1-uninfected Kenyan women reporting IVP and 42 women who denied IVP were followed for 3 months. Women using IVP attended a skill-building, theory-based group intervention occurring weekly for 3 weeks to encourage IVP cessation. Vaginal swabs at each visit were used to detect yeast, to detect bacterial vaginosis, and to characterize the vaginal microbiota. Intravaginal insertion of soapy water (59%) and lemon juice (45%) was most common among 58 IVP women. The group-counseling intervention led to a decrease in IVP from 95% (54/58) at baseline to 0% (0/39) at month 3 (p=0.001). After 3 months of cessation, there was a reduction in yeast on vaginal wet preparation (22% to 7%, p=0.011). Women in the IVP group were more likely to have a Lactobacillus iners-dominated vaginal microbiota at baseline compared to controls [odds ratio (OR), 6.4, p=0.006] without significant change in the microbiota after IVP cessation. The group counseling intervention was effective in reducing IVP for 3 months. Reducing IVP may be important in itself, as well as to support effective use of vaginal microbicides, to prevent HIV acquisition.

Recurrence of Helicobacter pylori infection in Bolivian children and adults after a population-based "screen and treat" strategy.

BACKGROUND: Strategies to prevent gastric cancer by decreasing Helicobacter pylori infections in high-prevalence, low-income countries could include a population-based "screen and treat" eradication program. METHODS: We tested residents of two rural villages for H. pylori infection using urea breath test (UBT), treated infected persons using directly observed therapy (DOT), retested for cure, and retested after 1 year later for H. pylori infection. FINDINGS: We tested 1,065 (92%) of 1153 residents from two villages in rural Bolivia. Baseline H. pylori prevalence was 80% (95% confidence interval [CI]: 78-84). Age-specific cure rates were similar (≥92%) after DOT. Among those cured, 12% (95% CI: 8-15) had recurrent infection. Age-specific annual H. pylori recurrence rates for combined villages were 20% (95% CI: 10-29) in persons <5 years, 20% (95% CI: 10-29) in 5-9 years, 8% (95% CI: 1-15) in 10-14 years, and 8% (95% CI: 4-12) in persons ≥15 years. Compared with the referent population, those ≥15 years, recurrent infections were significantly more likely in children <5 years (odds ratios [OR] 2.7, 95% CI: 1.2-5.8) and 5-9 years (OR 2.7, 95% CI: 1.4-5.1). INTERPRETATION: Children <10 years had high H. pylori recurrence rates following a population-based screen and treat program; this H. pylori eradication strategy may not be feasible in high-prevalence, low-income settings.