Efficacy, Safety, and Pharmacokinetics of AZD7442 (Tixagevimab/Cilgavimab) for Prevention of Symptomatic COVID-19: 15-Month Final Analysis of the PROVENT and STORM CHASER Trials.

INTRODUCTION: The phase 3 PROVENT and STORM CHASER studies evaluated AZD7442 (tixagevimab/cilgavimab) for pre-exposure and post-exposure prophylaxis of symptomatic coronavirus disease 2019 (COVID-19). We report the final 15-month results of both studies. METHODS: In PROVENT, participants were randomized 2:1 to receive 300 mg AZD7442 (n = 3460) or placebo (n = 1737). In STORM CHASER, participants were enrolled within 8 days of exposure to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individual and randomized 2:1 to receive 300 mg AZD7442 (n = 749) or placebo (n = 372). RESULTS: In PROVENT, the relative risk reduction (RRR) in symptomatic COVID-19 for AZD7442 versus placebo was 76.7% at primary analysis [95% confidence interval (CI) 46.1, 90.0; p < 0.001], 83.0% at day 183 (95% CI 67.3, 91.2; nominal p < 0.001), and 46.3% at day 366 (95% CI 23.1, 62.4; nominal p < 0.001). Severe/critical COVID-19 was reduced by 91.4% with AZD7442 versus placebo by day 366 (95% CI 61.3, 98.1; nominal p < 0.0001). Adverse events (AEs) occurred in 58.2% and 58.0% of participants administered AZD7442 or placebo, respectively; serious AEs (SAEs) occurred in 6.2% and 5.6%, respectively. In STORM CHASER, the RRR in symptomatic COVID-19 for AZD7442 versus placebo was 33.3% at primary analysis (95% CI - 25.9, 64.7; p = 0.212), 43.3% at day 183 (95% CI 1.4, 67.4; nominal p = 0.044) and 3.4% at day 366 (95% CI - 35.6, 31.2; nominal p = 0.842). Severe/critical COVID-19 did not occur in participants receiving AZD7442 versus 0.5% of participants receiving placebo by day 366. AEs occurred in 46.5% and 51.9% of participants administered AZD7442 or placebo, respectively; SAEs occurred in 2.7% and 4.3%, respectively. In both studies, serum concentration-time profiles over 457 days were similar for tixagevimab and cilgavimab and consistent with the extended half-life reported for AZD7442 (approximately 90 days). CONCLUSION: This analysis provides proof of concept supporting long-term safety of intramuscularly administered AZD7442 for prevention of symptomatic/severe COVID-19. A graphical abstract is available with this article. GOV IDENTIFIERS: PROVENT (NCT04625725) and STORM CHASER (NCT04625972).

Antibodies are proteins produced by the body's immune system to specifically target foreign substances, such as viruses. AZD7442 is made up of an antibody pair (tixagevimab and cilgavimab) that specifically bind and neutralize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing coronavirus disease 2019 (COVID-19). AZD7442 was designed to give several months of protection against the virus. These antibodies were tested in two clinical trials to see if they could either protect people from getting COVID-19 (PROVENT trial) or prevent people already exposed to SARS-CoV-2 from getting COVID-19 (STORM CHASER trial). In the two trials, approximately 6000 adults received AZD7442 or placebo (injections that look exactly like AZD7442 but contain no medicine). Protection against COVID-19 was monitored for up to 1 year, and safety for up to 15 months. The percentage of trial participants who reported side effects was similar in the AZD7442 and placebo groups, in both trials. The PROVENT trial showed that AZD7442 reduced the risk of getting COVID-19 up to 6 months and protected against severe COVID-19 for up to 1 year. In STORM CHASER, participants were treated after SARS-CoV-2 exposure but before a positive COVID-19 test. Some participants were already infected with SARS-CoV-2 at the start of the trial, others were not. STORM CHASER showed that AZD7442 protected people against COVID-19 for up to 6 months if they were not already infected at the start. The results of these trials provide proof of concept to support the long-term safety of AZD7442 for the prevention of COVID-19.

Accelerating therapeutics development during a pandemic: population pharmacokinetics of the long-acting antibody combination AZD7442 (tixagevimab/cilgavimab) in the prophylaxis and treatment of COVID-19.

AZD7442 is a combination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies, tixagevimab and cilgavimab, developed for pre-exposure prophylaxis (PrEP) and treatment of coronavirus disease 2019 (COVID-19). Using data from eight clinical trials, we describe a population pharmacokinetic (popPK) model of AZD7442 and show how modeling of "interim" data accelerated decision-making during the COVID-19 pandemic. The final model was a two-compartmental distribution model with first-order absorption and elimination, including standard allometric exponents for the effect of body weight on clearance and volume. Other covariates included were as follows: sex, age >65 years, body mass index ≥30 kg/m2, and diabetes on absorption rate; diabetes on clearance; Black race on central volume; and intramuscular (IM) injection site on bioavailability. Simulations indicated that IM injection site and body weight had > 20% effects on AZD7442 exposure, but no covariates were considered to have a clinically relevant impact requiring dose adjustment. The pharmacokinetics of AZD7442, cilgavimab, and tixagevimab were comparable and followed linear kinetics with extended half-lives (median 78.6 days for AZD7442), affording prolonged protection against susceptible SARS-CoV-2 variants. Comparison of popPK simulations based on "interim data" with a target concentration based on 80% viral inhibition and assuming 1.81% partitioning into the nasal lining fluid supported a decision to double the PrEP dosage from 300 mg to 600 mg to prolong protection against Omicron variants. Serum AZD7442 concentrations in adolescents weighing 40-95 kg were predicted to be only marginally different from those observed in adults, supporting authorization for use in adolescents before clinical data were available. In these cases, popPK modeling enabled accelerated clinical decision-making.

Safety, Efficacy and Pharmacokinetics of AZD7442 (Tixagevimab/Cilgavimab) for Treatment of Mild-to-Moderate COVID-19: 15-Month Final Analysis of the TACKLE Trial.

INTRODUCTION: In the phase 3 TACKLE study, outpatient treatment with AZD7442 (tixagevimab/cilgavimab) was well tolerated and significantly reduced progression to severe disease or death through day 29 in adults with mild-to-moderate coronavirus disease 2019 (COVID-19) at the primary analysis. Here, we report data from the final analysis of the TACKLE study, performed after approximately 15 months' follow-up. METHODS: Eligible participants were randomized 1:1 and dosed within 7 days of symptom onset with 600 mg intramuscular AZD7442 (n = 456; 300 mg tixagevimab/300 mg cilgavimab) or placebo (n = 454). RESULTS: Severe COVID-19 or death through day 29 occurred in 4.4% and 8.8% of participants who received AZD7442 or placebo, a relative risk reduction (RRR) of 50.4% [95% confidence interval (CI) 14.4, 71.3; p = 0.0096]; among participants dosed within 5 days of symptom onset, the RRR was 66.9% (95% CI 31.1, 84.1; p = 0.002). Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 occurred in 5.0% of participants receiving AZD7442 versus 9.7% receiving placebo, an RRR of 49.2% (95% CI 14.7, 69.8; p = 0.009). Adverse events occurred in 55.5% and 55.9% of participants who received AZD7442 or placebo, respectively, and were mostly mild or moderate in severity. Serious adverse events occurred in 10.2% and 14.4% of participants who received AZD7442 or placebo, respectively, and deaths occurred in 1.8% of participants in both groups. Serum concentration-time profiles recorded over 457 days were similar for AZD7442, tixagevimab, and cilgavimab, and were consistent with the extended half-life reported for AZD7442 (approx. 90 days). CONCLUSIONS: AZD7442 reduced the risk of progression to severe COVID-19, hospitalization, and death, was well tolerated through 15 months, and exhibited predictable pharmacokinetics in outpatients with mild-to-moderate COVID-19. These data support the long-term safety of using long-acting monoclonal antibodies to treat COVID-19. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04723394. ( https://clinicaltrials.gov/study/NCT04723394 .

The body's immune system produces proteins called antibodies that specifically target foreign substances such as viruses. AZD7442 is a combination of two antibodies (called tixagevimab and cilgavimab) that bind to the severe acute respiratory syndrome coronavirus 2 virus spike protein, preventing it from causing coronavirus disease 2019 (COVID-19). AZD7442 was designed to be "long-acting" and therefore provide prolonged protection against COVID-19 lasting several months from a single dose. It was tested in a clinical trial (TACKLE) to see if it could prevent people who had recently developed symptoms of COVID-19 from getting sicker, being hospitalized, or dying. Around 900 adults took part in this clinical trial. Half of this group were treated with a dose of AZD7442, given as two injections. The other half received a placebo (injections that look like the AZD7442 injections but contain no medicine). The effect of AZD7442 treatment against COVID-19 was monitored over 6 months, and safety was monitored over 15 months. Around the same percentage of participants in the trial reported side effects with AZD7442 and placebo, suggesting there were no safety issues with AZD7442. AZD7442 treatment reduced the risk of participants getting severe COVID-19 or dying from COVID-19 by approximately half, compared with the placebo group. Participants receiving AZD7442 also had fewer hospitalizations due to COVID-19 complications, compared with the placebo group. These results showed the long-term safety of using long-acting antibodies such as AZD7442 as a treatment for COVID-19.

In vivo delivery of engineered synthetic DNA-encoded SARS-CoV-2 monoclonal antibodies for pre-exposure prophylaxis in non-human primates.

COVID-19 remains a major public health concern. Monoclonal antibodies have received emergency use authorization (EUA) for pre-exposure prophylaxis against COVID-19 among high-risk groups for treatment of mild to moderate COVID-19. In addition to recombinant biologics, engineered synthetic DNA-encoded antibodies (DMAb) are an important strategy for direct in vivo delivery of protective mAb. A DMAb cocktail was synthetically engineered to encode the immunoglobulin heavy and light chains of two different two different Fc-engineered anti-SARS-CoV-2 antibodies. The DMAbs were designed to enhance in vivo expression and delivered intramuscularly to cynomolgus and rhesus macaques with a modified in vivo delivery regimen. Serum levels were detected in macaques, along with specific binding to SARS-CoV-2 spike receptor binding domain protein and neutralization of multiple SARS-CoV-2 variants of concern in pseudovirus and authentic live virus assays. Prophylactic administration was protective in rhesus macaques against signs of SARS-CoV-2 (USA-WA1/2020) associated disease in the lungs. Overall, the data support further study of DNA-encoded antibodies as an additional delivery mode for prevention of COVID-19 severe disease. These data have implications for human translation of gene-encoded mAbs for emerging infectious diseases and low dose mAb delivery against COVID-19.

Antibody targeting of conserved sites of vulnerability on the SARS-CoV-2 spike receptor-binding domain.

Given the continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs), immunotherapeutics that target conserved epitopes on the spike (S) glycoprotein have therapeutic advantages. Here, we report the crystal structure of the SARS-CoV-2 S receptor-binding domain (RBD) at 1.95 Å and describe flexibility and distinct conformations of the angiotensin-converting enzyme 2 (ACE2)-binding site. We identify a set of SARS-CoV-2-reactive monoclonal antibodies (mAbs) with broad RBD cross-reactivity including SARS-CoV-2 Omicron subvariants, SARS-CoV-1, and other sarbecoviruses and determine the crystal structures of mAb-RBD complexes with Ab246 and CR3022 mAbs targeting the class IV site, WRAIR-2134, which binds the recently designated class V epitope, and WRAIR-2123, the class I ACE2-binding site. The broad reactivity of class IV and V mAbs to conserved regions of SARS-CoV-2 VoCs and other sarbecovirus provides a framework for long-term immunotherapeutic development strategies.

Outpatient Treatment with AZD7442 (Tixagevimab/Cilgavimab) Prevented COVID-19 Hospitalizations over 6 Months and Reduced Symptom Progression in the TACKLE Randomized Trial.

INTRODUCTION: We assessed effects of AZD7442 (tixagevimab/cilgavimab) on deaths from any cause or hospitalizations due to coronavirus disease 2019 (COVID-19) and symptom severity and longer-term safety in the TACKLE adult outpatient treatment study. METHODS: Participants received 600 mg AZD7442 (n = 452) or placebo (n = 451) ≤ 7 days of COVID-19 symptom onset. RESULTS: Death from any cause or hospitalization for COVID-19 complications or sequelae through day 169 (key secondary endpoint) occurred in 20/399 (5.0%) participants receiving AZD7442 versus 40/407 (9.8%) receiving placebo [relative risk reduction (RRR) 49.1%; 95% confidence interval (CI) 14.5, 69.7; p = 0.009] or 50.7% (95% CI 17.5, 70.5; p = 0.006) after excluding participants unblinded before day 169 for consideration of vaccination). AZD7442 reduced progression of COVID-19 symptoms versus placebo through to day 29 (RRR 12.5%; 95% CI 0.5, 23.0) and improved most symptoms within 1-2 weeks. Over median safety follow-up of 170 days, adverse events occurred in 174 (38.5%) and 196 (43.5%) participants receiving AZD7442 or placebo, respectively. Cardiac serious adverse events occurred in two (0.4%) and three (0.7%) participants receiving AZD7442 or placebo, respectively. CONCLUSIONS: AZD7442 was well tolerated and reduced hospitalization and mortality through 6 months, and symptom burden through 29 days, in outpatients with mild-to-moderate COVID-19. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT04723394. ( https://beta. CLINICALTRIALS: gov/study/NCT04723394 ).

Antibodies are proteins produced by the body's immune system to specifically combat foreign substances, such as viruses. Tixagevimab and cilgavimab are a pair of antibodies that bind to a specific part of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19). When they bind to the virus, they reduce its ability to cause disease. These antibodies were tested in a clinical trial to see if they could prevent people with COVID-19 from being hospitalized or dying. Around 900 adults took part in this clinical trial. These people all had COVID-19 but were not sick enough to be in hospital. Half of this group were treated with a dose of tixagevimab and cilgavimab, given as two injections. The other half received a placebo (injections that look exactly like the tixagevimab and cilgavimab injections but contain no medicine). The study found that, over 6 months, people with COVID-19 who received tixagevimab and cilgavimab were less likely to need to go to hospital than people who received the placebo. They were also less likely to die of COVID-19. Tixagevimab and cilgavimab also helped to improve COVID-19 symptoms. People who received the antibodies saw their symptoms improve faster than people who received the placebo. They were also less likely to have symptoms that got worse. Most people felt better within 1­2 weeks of getting treatment. No safety issues were found with tixagevimab and cilgavimab compared with placebo.

Safety and Efficacy of Combined Tixagevimab and Cilgavimab Administered Intramuscularly or Intravenously in Nonhospitalized Patients With COVID-19: 2 Randomized Clinical Trials.

Importance: Development of effective, scalable therapeutics for SARS-CoV-2 is a priority. Objective: To test the efficacy of combined tixagevimab and cilgavimab monoclonal antibodies for early COVID-19 treatment. Design, Setting, and Participants: Two phase 2 randomized blinded placebo-controlled clinical trials within the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV)-2/A5401 platform were performed at US ambulatory sites. Nonhospitalized adults 18 years or older within 10 days of positive SARS-CoV-2 test and symptom onset were eligible and were enrolled from February 1 to May 31, 2021. Interventions: Tixagevimab-cilgavimab, 300 mg (150 mg of each component) given intravenously (IV) or 600 mg (300 mg of each component) given intramuscularly (IM) in the lateral thigh, or pooled placebo. Main Outcomes and Measures: Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLOQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events through 28 days. Results: A total of 229 participants were randomized for the IM study and 119 were randomized for the IV study. The primary modified intention-to-treat population included 223 participants who initiated IM tixagevimab-cilgavimab (n = 106) or placebo treatment (n = 117) (median age, 39 [IQR, 30-48] years; 113 [50.7%] were men) and 114 who initiated IV tixagevimab-cilgavimab (n = 58) or placebo treatment (n = 56) (median age, 44 [IQR, 35-54] years; 67 [58.8%] were women). Enrollment in the IV study was stopped early based on a decision to focus on IM product development. Participants were enrolled at a median of 6 (IQR, 4-7) days from COVID-19 symptom onset. Significant differences in time to symptom improvement were not observed for IM tixagevimab-cilgavimab vs placebo or IV tixagevimab-cilgavimab vs placebo. A greater proportion in the IM tixagevimab-cilgavimab arm (69 of 86 [80.2%]) than placebo (62 of 96 [64.6%]) had nasopharyngeal SARS-CoV-2 RNA below LLOQ at day 7 (adjusted risk ratio, 1.33 [95% CI, 1.12-1.57]) but not days 3 and 14; the joint test across time points favored treatment (P = .003). Differences in the proportion below LLOQ were not observed for IV tixagevimab-cilgavimab vs placebo at any of the specified time points. There were no safety signals with either administration route. Conclusions: In these 2 phase 2 randomized clinical trials, IM or IV tixagevimab-cilgavimab was safe but did not change time to symptom improvement. Antiviral activity was more evident in the larger IM trial. Trial Registration: ClinicalTrials.gov Identifier: NCT04518410.

Durability of neutralizing RSV antibodies following nirsevimab administration and elicitation of the natural immune response to RSV infection in infants.

Nirsevimab is an extended half-life monoclonal antibody specific for the prefusion conformation of the respiratory syncytial virus (RSV) F protein, which has been studied in preterm and full-term infants in the phase 2b and phase 3 MELODY trials. We analyzed serum samples collected from 2,143 infants during these studies to characterize baseline levels of RSV-specific immunoglobulin G antibodies and neutralizing antibodies (NAbs), duration of RSV NAb levels following nirsevimab administration, the risk of RSV exposure during the first year of life and the infant's adaptive immune response to RSV following nirsevimab administration. Baseline RSV antibody levels varied widely; consistent with reports that maternal antibodies are transferred late in the third trimester, preterm infants had lower baseline RSV antibody levels than full-term infants. Nirsevimab recipients had RSV NAb levels >140-fold higher than baseline at day 31 and remained >50-fold higher at day 151 and >7-fold higher at day 361. Similar seroresponse rates to the postfusion form of RSV F protein in nirsevimab recipients (68-69%) compared with placebo recipients (63-70%; not statistically significant) suggest that while nirsevimab protects from RSV disease, it still allows an active immune response. In summary, nirsevimab provided sustained, high levels of NAb throughout an infant's first RSV season and prevented RSV disease while allowing the development of an immune response to RSV.

Nirsevimab binding-site conservation in respiratory syncytial virus fusion glycoprotein worldwide between 1956 and 2021: an analysis of observational study sequencing data.

BACKGROUND: Nirsevimab is an extended half-life monoclonal antibody to the respiratory syncytial virus (RSV) fusion protein that has been developed to protect infants for an entire RSV season. Previous studies have shown that the nirsevimab binding site is highly conserved. However, investigations of the geotemporal evolution of potential escape variants in recent (ie, 2015-2021) RSV seasons have been minimal. Here, we examine prospective RSV surveillance data to assess the geotemporal prevalence of RSV A and B, and functionally characterise the effect of the nirsevimab binding-site substitutions identified between 2015 and 2021. METHODS: We assessed the geotemporal prevalence of RSV A and B and nirsevimab binding-site conservation between 2015 and 2021 from three prospective RSV molecular surveillance studies (the US-based OUTSMART-RSV, the global INFORM-RSV, and a pilot study in South Africa). Nirsevimab binding-site substitutions were assessed in an RSV microneutralisation susceptibility assay. We contextualised our findings by assessing fusion-protein sequence diversity from 1956 to 2021 relative to other respiratory-virus envelope glycoproteins using RSV fusion protein sequences published in NCBI GenBank. FINDINGS: We identified 5675 RSV A and RSV B fusion protein sequences (2875 RSV A and 2800 RSV B) from the three surveillance studies (2015-2021). Nearly all (25 [100%] of 25 positions of RSV A fusion proteins and 22 [88%] of 25 positions of RSV B fusion proteins) amino acids within the nirsevimab binding site remained highly conserved between 2015 and 2021. A highly prevalent (ie, >40·0% of all sequences) nirsevimab binding-site Ile206Met:Gln209Arg RSV B polymorphism arose between 2016 and 2021. Nirsevimab neutralised a diverse set of recombinant RSV viruses, including new variants containing binding-site substitutions. RSV B variants with reduced susceptibility to nirsevimab neutralisation were detected at low frequencies (ie, prevalence <1·0%) between 2015 and 2021. We used 3626 RSV fusion-protein sequences published in NCBI GenBank between 1956 and 2021 (2024 RSV and 1602 RSV B) to show that the RSV fusion protein had lower genetic diversity than influenza haemagglutinin and SARS-CoV-2 spike proteins. INTERPRETATION: The nirsevimab binding site was highly conserved between 1956 and 2021. Nirsevimab escape variants were rare and have not increased over time. FUNDING: AstraZeneca and Sanofi.

Safety, Tolerability and Pharmacokinetics of Half-Life Extended Severe Acute Respiratory Syndrome Coronavirus 2 Neutralizing Monoclonal Antibodies AZD7442 (Tixagevimab-Cilgavimab) in Healthy Adults.

BACKGROUND: AZD7442 is a combination of extended half-life, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific neutralizing monoclonal antibodies (tixagevimab and cilgavimab). METHODS: This phase 1, first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study evaluated AZD7442 administered intramuscularly (300 mg) or intravenously (300, 1000, or 3000 mg) in healthy adults (aged 18-55 years). The primary end point was safety and tolerability. Secondary end points included pharmacokinetics and antidrug antibodies. RESULTS: Between 18 August and 16 October 2020, a total of 60 participants were enrolled; 50 received AZD7442, and 10 received placebo. Adverse events (all of mild or moderate intensity) occurred in 26 participants (52.0%) in the AZD7442 groups and 8 (80.0%) in the placebo group. No infusion or injection site or hypersensitivity reactions occurred. Tixagevimab and cilgavimab had mean half-lives of approximately 90 days (range, 87.0-95.3 days for tixagevimab and 79.8--91.1 days for cilgavimab) and similar pharmacokinetic profiles over the 361-day study period. SARS-CoV-2-specific neutralizing antibody titers provided by AZD7442 were maintained above those in plasma from convalescent patients with coronavirus disease 2019 (COVID-19). CONCLUSIONS: AZD7442 was well tolerated in healthy adults, showing a favorable safety profile across all doses. Depending on the SARS-CoV-2 variant, pharmacokinetic analyses suggest the AZD7442 could offer protection for ≥6 months against symptomatic COVID-19 after a single 300-mg intramuscular administration. CLINICAL TRIALS REGISTRATION: NCT04507256.

Antibodies are proteins produced by the body in response to infections caused by microbes, including viruses. AZD7442 is a combination of 2 human antibodies, with an extended duration of effect, sourced from people who had recovered from coronavirus disease 2019 (COVID-19). These antibodies recognize a specific part (spike protein) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, and prevent the virus from infecting cells in the body. The current study evaluated the safety of AZD7442 in healthy volunteers. Sixty adults were given AZD7442 or placebo (salt solution) as injections into the muscle (300-mg dose) or infusions into a vein (300­3000-mg doses). The study did not find any safety issues with AZD7442, including at the highest dose. AZD7442 was measured in the blood 12 months after dosing, suggesting a long duration of protection. Following this study, AZD7442 was tested in larger clinical trials to investigate its potential in preventing and treating COVID-19. AZD7442 is currently authorized as treatment for outpatients with COVID-19 and as a preventive drug in people who may not respond well to COVID-19 vaccines and need additional protection (eg, those taking medications that dampen the immune system).

AZD7442 (Tixagevimab/Cilgavimab) for Post-Exposure Prophylaxis of Symptomatic Coronavirus Disease 2019.

BACKGROUND: This phase 3 trial assessed AZD7442 (tixagevimab/cilgavimab) for post-exposure prophylaxis against symptomatic coronavirus disease 2019 (COVID-19). METHODS: Adults without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or COVID-19 vaccination were enrolled within 8 days of exposure to a SARS-CoV-2-infected individual and randomized 2:1 to a single 300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and cilgavimab) or placebo. Primary end points were safety and first post-dose SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR)-positive symptomatic COVID-19 event before day 183. RESULTS: A total of 1121 participants were randomized and dosed (AZD7442, n = 749; placebo, n = 372). Median (range) follow-up was 49 (5-115) and 48 (20-113) days for AZD7442 and placebo, respectively. Adverse events occurred in 162 of 749 (21.6%) and 111 of 372 (29.8%) participants with AZD7442 and placebo, respectively, mostly mild/moderate. RT-PCR-positive symptomatic COVID-19 occurred in 23 of 749 (3.1%) and 17 of 372 (4.6%) AZD7442- and placebo-treated participants, respectively (relative risk reduction, 33.3%; 95% confidence interval [CI], -25.9 to 64.7; P = .21). In predefined subgroup analyses of 1073 (96%) participants who were SARS-CoV-2 RT-PCR-negative (n = 974, 87%) or missing an RT-PCR result (n = 99, 9%) at baseline, AZD7442 reduced RT-PCR-positive symptomatic COVID-19 by 73.2% (95% CI, 27.1 to 90.1) vs placebo. CONCLUSIONS: This study did not meet the primary efficacy end point of post-exposure prevention of symptomatic COVID-19. However, analysis of participants who were SARS-CoV-2 RT-PCR-negative or missing an RT-PCR result at baseline support a role for AZD7442 in preventing symptomatic COVID-19. Clinical Trials Registration. NCT04625972.

Developability profiling of a panel of Fc engineered SARS-CoV-2 neutralizing antibodies.

To combat the COVID-19 pandemic, potential therapies have been developed and moved into clinical trials at an unprecedented pace. Some of the most promising therapies are neutralizing antibodies against SARS-CoV-2. In order to maximize the therapeutic effectiveness of such neutralizing antibodies, Fc engineering to modulate effector functions and to extend half-life is desirable. However, it is critical that Fc engineering does not negatively impact the developability properties of the antibodies, as these properties play a key role in ensuring rapid development, successful manufacturing, and improved overall chances of clinical success. In this study, we describe the biophysical characterization of a panel of Fc engineered ("TM-YTE") SARS-CoV-2 neutralizing antibodies, the same Fc modifications as those found in AstraZeneca's Evusheld (AZD7442; tixagevimab and cilgavimab), in which the TM modification (L234F/L235E/P331S) reduce binding to FcγR and C1q and the YTE modification (M252Y/S254T/T256E) extends serum half-life. We have previously shown that combining both the TM and YTE Fc modifications can reduce the thermal stability of the CH2 domain and possibly lead to developability challenges. Here we show, using a diverse panel of TM-YTE SARS-CoV-2 neutralizing antibodies, that despite lowering the thermal stability of the Fc CH2 domain, the TM-YTE platform does not have any inherent developability liabilities and shows an in vivo pharmacokinetic profile in human FcRn transgenic mice similar to the well-characterized YTE platform. The TM-YTE is therefore a developable, effector function reduced, half-life extended antibody platform.

Safety and Efficacy of MEDI0457 plus Durvalumab in Patients with Human Papillomavirus-Associated Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma.

PURPOSE: Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18-associated HNSCC. PATIENTS AND METHODS: In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS). RESULTS: Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7-47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. <25%). DCR-16 was 44.8% (95% CI, 26.5-64.3). Median PFS was 3.5 months (95% CI, 1.9-9.0); median OS was 29.2 months (15.2-not calculable). Twenty-eight (80.0%) patients had treatment-related adverse events [grade 3: 5 (14.3%); no grade 4/5], resulting in discontinuation in 2 (5.7%) patients. HPV-16/18-specific T cells increased on treatment; 4 of 8 evaluable patients had a >2-fold increase in tumor-infiltrating CD8+ T cells. CONCLUSIONS: MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.

A prefusion-stabilized RSV F subunit vaccine elicits B cell responses with greater breadth and potency than a postfusion F vaccine.

There is currently no licensed vaccine for respiratory syncytial virus (RSV). Here, we assess the effect of RSV fusion protein (F) conformation on B cell responses in a post hoc comparison of samples from the DS-Cav1 [prefusion (pre-F)] and MEDI7510 [postfusion (post-F)] vaccine clinical trials. We compared the magnitude and quality of the serological and B cell responses across time points and vaccines. We measured RSV A and B neutralization, F-binding immunoglobulin G titers, and competition assays at week 0 (before vaccination) and week 4 (after vaccination) to evaluate antibody specificity and potency. To compare B cell specificity and activation, we used pre-F and post-F probes in tandem with a 17-color immunophenotyping flow cytometry panel at week 0 (before vaccination) and week 1 (after vaccination). Our data demonstrate that both DS-Cav1 and MEDI7510 vaccination robustly elicit F-specific antibodies and B cells, but DS-Cav1 elicited antibodies that more potently neutralized both RSV A and B. The superior potency was mediated by antibodies that bind antigenic sites on the apex of pre-F that are not present on post-F. In the memory (CD27+) B cell compartment, vaccination with DS-Cav1 or MEDI7510 elicited B cells with different epitope specificities. B cells preferentially binding the pre-F probe were activated in DS-Cav1-vaccinated participants but not in MEDI7510-vaccinated participants. Our findings emphasize the importance of using pre-F as an immunogen in humans because of its deterministic role in eliciting highly potent neutralizing antibodies and memory B cells.

Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial.

BACKGROUND: Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) in preventing PA nosocomial pneumonia was assessed in PA-colonised mechanically ventilated subjects. METHODS: EVADE (NCT02696902) was a phase 2, randomised, parallel-group, double-blind, placebo-controlled study in Europe, Turkey, Israel, and the USA. Subjects ≥ 18 years old, mechanically ventilated, tracheally colonised with PA, and without new-onset pneumonia, were randomised (1:1:1) to MEDI3902 500, 1500 mg (single intravenous dose), or placebo. The primary efficacy endpoint was the incidence of nosocomial PA pneumonia through 21 days post-dose in MEDI3902 1500 mg versus placebo, determined by an independent adjudication committee. RESULTS: Even if the initial sample size was not reached because of low recruitment, 188 subjects were randomised (MEDI3902 500/1500 mg: n = 16/87; placebo: n = 85) between 13 April 2016 and 17 October 2019. Out of these, 184 were dosed (MEDI3902 500/1500 mg: n = 16/85; placebo: n = 83), comprising the modified intent-to-treat set. Enrolment in the 500 mg arm was discontinued due to pharmacokinetic data demonstrating low MEDI3902 serum concentrations. Subsequently, enrolled subjects were randomised (1:1) to MEDI3902 1500 mg or placebo. PA pneumonia was confirmed in 22.4% (n = 19/85) of MEDI3902 1500 mg recipients and in 18.1% (n = 15/83) of placebo recipients (relative risk reduction [RRR]: - 23.7%; 80% confidence interval [CI] - 83.8%, 16.8%; p = 0.49). At 21 days post-1500 mg dose, the mean (standard deviation) serum MEDI3902 concentration was 9.46 (7.91) µg/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 µg/mL, a level associated with improved outcome in animal models. Treatment-emergent adverse event incidence was similar between groups. CONCLUSIONS: The bivalent, bispecific monoclonal antibody MEDI3902 (gremubamab) did not reduce PA nosocomial pneumonia incidence in PA-colonised mechanically ventilated subjects. Trial registration Registered on Clinicaltrials.gov ( NCT02696902 ) on 11th February 2016 and on EudraCT ( 2015-001706-34 ) on 7th March 2016.

DNA-delivered antibody cocktail exhibits improved pharmacokinetics and confers prophylactic protection against SARS-CoV-2.

Monoclonal antibody therapy has played an important role against SARS-CoV-2. Strategies to deliver functional, antibody-based therapeutics with improved in vivo durability are needed to supplement current efforts and reach underserved populations. Here, we compare recombinant mAbs COV2-2196 and COV2-2130, which compromise clinical cocktail Tixagevimab/Cilgavimab, with optimized nucleic acid-launched forms. Functional profiling of in vivo-expressed, DNA-encoded monoclonal antibodies (DMAbs) demonstrated similar specificity, broad antiviral potency and equivalent protective efficacy in multiple animal challenge models of SARS-CoV-2 prophylaxis compared to protein delivery. In PK studies, DNA-delivery drove significant serum antibody titers that were better maintained compared to protein administration. Furthermore, cryo-EM studies performed on serum-derived DMAbs provide the first high-resolution visualization of in vivo-launched antibodies, revealing new interactions that may promote cooperative binding to trimeric antigen and broad activity against VoC including Omicron lineages. These data support the further study of DMAb technology in the development and delivery of valuable biologics.

A bivalent SARS-CoV-2 monoclonal antibody combination does not affect the immunogenicity of a vector-based COVID-19 vaccine in macaques.

Human monoclonal antibodies (mAbs) that target the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) offer a promising approach for the prevention and treatment of coronavirus disease 2019 (COVID-19). Given suboptimal global vaccination rates, waning immunity in vaccinated individuals, and the emergence of SARS-CoV-2 variants of concern, the use of mAbs for COVID-19 prevention may increase and may need to be administered together with vaccines in certain settings. However, it is unknown whether administration of mAbs will affect the immunogenicity of SARS-CoV-2 vaccines. Using an adenovirus vector-based SARS-CoV-2 vaccine, we show that simultaneous administration of the vaccine with SARS-CoV-2 mAbs does not diminish vaccine-induced humoral or cellular immunity in cynomolgus macaques. These results suggest that SARS-CoV-2 mAbs and viral vector-based SARS-CoV-2 vaccines can be administered together without loss of potency of either product. Additional studies will be required to evaluate coadministration of mAbs with other vaccine platforms.

Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains.

Omicron variant strains encode large numbers of changes in the spike protein compared to historical SARS-CoV-2 isolates. Although in vitro studies have suggested that several monoclonal antibody therapies lose neutralizing activity against Omicron variants, the effects in vivo remain largely unknown. Here, we report on the protective efficacy against three SARS-CoV-2 Omicron lineage strains (BA.1, BA.1.1, and BA.2) of two monoclonal antibody therapeutics (S309 [Vir Biotechnology] monotherapy and AZD7442 [AstraZeneca] combination), which correspond to ones used to treat or prevent SARS-CoV-2 infections in humans. Despite losses in neutralization potency in cell culture, S309 or AZD7442 treatments reduced BA.1, BA.1.1, and BA.2 lung infection in susceptible mice that express human ACE2 (K18-hACE2) in prophylactic and therapeutic settings. Correlation analyses between in vitro neutralizing activity and reductions in viral burden in K18-hACE2 or human FcγR transgenic mice suggest that S309 and AZD7442 have different mechanisms of protection against Omicron variants, with S309 utilizing Fc effector function interactions and AZD7442 acting principally by direct neutralization. Our data in mice demonstrate the resilience of S309 and AZD7442 mAbs against emerging SARS-CoV-2 variant strains and provide insight into the relationship between loss of antibody neutralization potency and retained protection in vivo.