ABSTRACT
BackgroundThe monoclonal antibody combination casirivimab and imdevimab (REGEN-COV(R)) reduced viral load, hospitalisation, or death when administered 1:1 as an intravenous (IV) dose [≥]1200 mg in a phase 3 COVID-19 outpatient study. Availability of subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients. MethodsThis is a double-blind, placebo-controlled study of SARS-CoV-2-infected outpatients who were asymptomatic, or symptomatic but without risk factors for severe COVID-19. Patients were randomised to single IV dose (517 patients) of REGEN-COV 300, 600, 1200 or 2400 mg or placebo; or a single SC dose (286 patients) of REGEN-COV 600 or 1200 mg or placebo. The primary endpoint was time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative to SARS-CoV-2 at baseline. FindingsAll REGEN-COV treatments showed significant (p<0{middle dot}001 versus pooled placebo) virologic reduction through day 7. Least-squares mean differences in TWACB viral load for the treatments versus placebo ranged from -0{middle dot}56 to -0{middle dot}71 log10 copies/mL. Each REGEN-COV treatment showed significant (p<0{middle dot}001 versus pooled placebo) and similar virologic reduction through day 7. There were no safety concerns, dose-related safety findings, grade [≥]2 infusion related/hypersensitivity reactions, grade [≥]3 injection-site reactions, nor fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported. InterpretationIn asymptomatic and low-risk symptomatic SARS-CoV-2-infected outpatients seronegative for antibodies against SARS-CoV-2 at baseline, REGEN-COV significantly and comparably reduced viral load at all IV and SC doses. FundingRegeneron Pharmaceuticals, Inc. and Hoffman-La Roche RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSEarly phase 1/2 data in coronavirus disease 2019 (COVID-19) outpatients (NCT04425629) found that the REGEN-COV(R) antibody combination, casirivimab and imdevimab, administered 1:1 as a single intravenous (IV) dose of 2400 mg or 8000 mg significantly reduced viral load over the first week compared to placebo. Enhanced viral clearance was more pronounced in patients who were seronegative for antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or who had high viral load at baseline. The phase 3 portion of this outpatient treatment study subsequently evaluated 1200 mg IV and 2400 mg IV doses, demonstrating consistent virologic efficacy, further demonstrating that REGEN-COV treatment reduced risk of COVID-19-related hospitalisation or all-cause death, and shortened time to symptom resolution. Virologic clearance was similar among those treated with any of the three doses (8000 mg, 2400 mg, or 1200 mg); therefore, maximal virologic efficacy may have been achieved at the 1200 mg dose in this treatment setting. These results warranted investigation of lower dose regimens. Added value of this studyThe present dose-ranging study evaluated whether a lower dose regimen could demonstrate virologic efficacy similar to that observed with 1200 mg IV and 2400 mg IV doses in outpatient treatment study. Exploration of a wider dose range will provide further characterisation of the clinical effects of REGEN-COV. Moreover, identifying a lower efficacious dose could bolster the ability to provide an adequate therapeutic supply of REGEN-COV in the setting of a global pandemic. A 1200 mg subcutaneous (SC) dose of REGEN-COV also prevented COVID-19 in household contacts of SARS-CoV-2-infected individuals (NCT04452318). The availability of a SC regimen could improve access for patients who have confirmed SARS-CoV-2 infection but for who IV infusion is not feasible. Implications of all the available evidenceDespite the growing number of therapeutics with authorisation or approval for the treatment and/or prevention of COVID-19, there remains a significant global need for effective COVID-19 therapies. Additional therapeutics and dosing regimens will be required to meet demand and to meet the needs of specific patient populations. Lower IV doses of REGEN-COV, and the option of SC administration, should increase accessibility for patients. This increased availability needs to be weighed against several unanswered questions, including 1) whether the correlation between decreased viral load in the nasopharynx and improvement in clinical outcome holds at lower doses of REGEN-COV, and 2) whether the reduced drug exposure margins are sufficient to prevent viral escape and emergence of variants of concern.
ABSTRACT
Projections of the stage of the Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pandemic and local, regional and national public health policies designed to limit the spread of the epidemic as well as "reopen" cities and states, are best informed by serum neutralizing antibody titers measured by reproducible, high throughput, and statically credible antibody (Ab) assays. To date, a myriad of Ab tests, both available and authorized for emergency use by the FDA, has led to confusion rather than insight per se. The present study reports the results of a rapid, point-in-time 1,000-person cohort study using serial blood donors in the New York City metropolitan area (NYC) using multiple serological tests, including enzyme-linked immunosorbent assays (ELISAs) and high throughput serological assays (HTSAs). These were then tested and associated with assays for neutralizing Ab (NAb). Of the 1,000 NYC blood donor samples in late June and early July 2020, 12.1% and 10.9% were seropositive using the Ortho Total Ig and the Abbott IgG HTSA assays, respectively. These serological assays correlated with neutralization activity specific to SARS-CoV-2. The data reported herein suggest that seroconversion in this population occurred in approximately 1 in 8 blood donors from the beginning of the pandemic in NYC (considered March 1, 2020). These findings deviate with an earlier seroprevalence study in NYC showing 13.7% positivity. Collectively however, these data demonstrate that a low number of individuals have serologic evidence of infection during this "first wave" and suggest that the notion of "herd immunity" at rates of [~]60% or higher are not near. Furthermore, the data presented herein show that the nature of the Ab-based immunity is not invariably associated with the development of NAb. While the blood donor population may not mimic precisely the NYC population as a whole, rapid assessment of seroprevalence in this cohort and serial reassessment could aid public health decision making.
ABSTRACT
The SARS-CoV-2 spike (S) protein variant D614G supplanted the ancestral virus worldwide in a matter of months. Here we show that D614G was more infectious than the ancestral form on human lung cells, colon cells, and cells rendered permissive by ectopic expression of various mammalian ACE2 orthologs. Nonetheless, D614G affinity for ACE2 was reduced due to a faster dissociation rate. Assessment of the S protein trimer by cryo-electron microscopy showed that D614G disrupts a critical interprotomer contact and that this dramatically shifts the S protein trimer conformation toward an ACE2-binding and fusion-competent state. Consistent with the more open conformation, neutralization potency of antibodies targeting the S protein receptor-binding domain was not attenuated. These results indicate that D614G adopts conformations that make virion membrane fusion with the target cell membrane more probable but that D614G retains susceptibility to therapies that disrupt interaction of the SARS-CoV-2 S protein with the ACE2 receptor.
ABSTRACT
There are no known cures or vaccines for COVID-19, the defining pandemic of this era. Animal models are essential to fast track new interventions and nonhuman primate (NHP) models of other infectious diseases have proven extremely valuable. Here we compare SARS-CoV-2 infection in three species of experimentally infected NHPs (rhesus macaques, baboons, and marmosets). During the first 3 days, macaques developed clinical signatures of viral infection and systemic inflammation, coupled with early evidence of viral replication and mild-to-moderate interstitial and alveolar pneumonitis, as well as extra-pulmonary pathologies. Cone-beam CT scans showed evidence of moderate pneumonia, which progressed over 3 days. Longitudinal studies showed that while both young and old macaques developed early signs of COVID-19, both groups recovered within a two-week period. Recovery was characterized by low-levels of viral persistence in the lung, suggesting mechanisms by which individuals with compromised immune systems may be susceptible to prolonged and progressive COVID-19. The lung compartment contained a complex early inflammatory milieu with an influx of innate and adaptive immune cells, particularly interstitial macrophages, neutrophils and plasmacytoid dendritic cells, and a prominent Type I-interferon response. While macaques developed moderate disease, baboons exhibited prolonged shedding of virus and extensive pathology following infection; and marmosets demonstrated a milder form of infection. These results showcase in critical detail, the robust early cellular immune responses to SARS-CoV-2 infection, which are not sterilizing and likely impact development of antibody responses. Thus, various NHP genera recapitulate heterogeneous progression of COVID-19. Rhesus macaques and baboons develop different, quantifiable disease attributes making them immediately available essential models to test new vaccines and therapies.
