IDWeeK Infectious Disease Week 2022 – Coronavirus Frontier Express

EVUSHELD is a combination of two monoclonal antibodies (tixagevimab and cilgavimab), which are derived from B cells of patients convalescent from SARS-CoV-2 infection and bind to different epitopes of SARS-CoV-2 protein in a non-competitive manner to block SARS-CoV-2 virus entry into cells, thereby achieving preventive and therapeutic effects ⁶
。 It is the world's first new crown neutralizing antibody
approved for both prevention and treatment indications.
The PROVENT ^study6 evaluated the efficacy
of Evusheld in people at high risk of COVID infection 。 The results showed that Evusheld reduced the risk of symptomatic COVID by 83% within 6 months compared to placebo; In addition, pharmacokinetic data showed that Evusheld concentrations remained high in serum for 6 months after administration, indicating that a single dose of Evusheld could provide immune protection
against the new coronavirus for at least 6 months.
Another TACKLE ^study7 evaluated the safety and efficacy
of Evusheld in adult patients with mild to moderate COVID.
Results showed that administration within 7 days of symptom onset significantly reduced the risk of progression to severe disease or death by 50.
5% compared with placebo; When administered within 5 days of symptom onset, the risk was reduced by 66.
9%.

In exploratory analyses, administration within 3 days of symptom onset reduced risk by 88.
0%
compared to placebo.

➤ Variant-related studies: EVUSHELD The combination of two mAbs creates a genetic barrier of high drug resistance, suggesting support for the use of combinations of mAbs that combine different epitopes for the treatment of COVID-19; EVUSHELD maintained neutralizing activity against SARS-CoV-2 VOCs and VOIs, and its conservatism (≥99%) was high in most amino acid residues at the binding site of the novel coronavirus spike protein

One ^study8 evaluated the SARS-CoV-2 variant that emerged in TACKLE study participants after 15 days of treatment with Evusheld or placebo and determined the in vitro sensitivity
of the identified variant to Evusheld and a single monoclonal antibody component 。 The study collected samples from the TACKLE primary analysis (data as of August 2021) (nasal swabs collected at baseline and on days 3, 6, and 15) and performed next-generation sequencing
of the spike gene in nasal swabs positive for SARS-CoV-2 reverse transcription polymerase chain reaction.
SARS-CoV-2 lineage
is assigned using the spike nucleotide sequence.
Amino acid substitution, insertions, and deletions
were analyzed at AF (percentage of sequence reads represented by mutations) ≥ 25% and 3%~25%.
Assess fold changes
in susceptibility by pseudoviral neutralization assays.
Conclusions: After treatment with Evusheld, SARS-CoV-2 variants with tixagevimab/cilgavimab binding site mutations had a lower incidence and frequency comparable
to that of the placebo group.
Mutations in allele fraction (AF) ≥25% of test treatments did not show reduced
sensitivity to Evusheld.
These data suggest that the combination of two mAbs creates a high genetic barrier of resistance, supporting the use of combinations of mAbs that combine different epitopes to treat COVID-19
.

Another ^study9 evaluated the in vitro efficacy of EVUSHELD and its components against SARS-CoV-2 VOCs/VOIs and evaluated the effect of EVUSHELD binding site substitution on sensitivity to neutralizing variants and whether variants identified in PROVENT study participants exhibited reduced
sensitivity 。 The study evaluated N = 8,679,290 sequences from COVIDCG4 (Global Influenza Shared Database: December 1, 2019 to May 12, 2022) to identify prevalent spiny mutants and substitutions
within the tixagevimab/cilgavimab binding site 。 THE GLOBALLY CIRCULATING VARIANT (WBY CLASSIFICATION AS OF MAY 3, 2022) AND ITS CHARACTERISTIC RBD SURROGATE AND 7 SARS-COV-2 SPIKE-BASED LINEAGES WERE PHENOTYPICALLY ASSESSED
FOR DATA CUTOFF FOR EVUSHELD-NEUTRALIZATION BETWEEN DAY 1 TO 6 OF DISEASE PRESENTATION IN 20/42 PARTICIPANTS FROM PROVENT 。 Spike surrogates were included in SARS-CoV-2 Wuhan-Hu-1/2019 +D614G spike pseudolentivirus and sensitivity to EVUSHELD and its component mAbs was assessed by a microneutralization assay
.
The results showed that EVUSHELD maintained neutralizing activity against SARS-CoV-2 VOCs and VOIs and slightly decreased
activity against Omicron (BA.
1).
The conservatism of most amino acid residues at the binding sites of the new coronavirus spike protein to tixagevimab and cilgavimab is ≥99%.

➤ Animal studies: EVUSHELD significantly reduced lung viral load and had a protective effect against SARS-CoV-2-induced lung inflammation and alveolar damage

An animal study ¹⁰ The in vivo
efficacy of AZD7442-TM (i.
e.
, EVUSHELD including TM modification but not YTE modification, YTE modification [M252Y/S254T/T256E] prolongs antibody half-life, and TM modification [L234F/L235E/P331S], which reduces binding of FC receptor and complement component C1q) for the prevention and treatment of SARS-CoV-2 was evaluated using the Syrian hamster model 。 Intranasal inhalation infection with the SARS-CoV-2 strain USA-WA1/2020 using Syrian hamsters on day 0 was studied for modelling in both the prophylactic and therapeutic groups
.
AZD7442-TM is administered
by intraperitoneal injection.
Serum and tissue are collected on days 3 and 7 post-infection; Record your weight
daily.
Tissue sections were stained with SARS-CoV-2 nucleocapsid protein-specific rabbit monoclonal antibodies and imaged and scored by veterinary pathologists in a blinded manner to determine the mean lung pathology score
on a scale of 0 (normal) to 25 (most severe).
The results showed that AZD7442-TM (without YTE modification) for prophylaxis or treatment significantly reduced lung viral load in a Syrian hamster model infected with SARS-CoV-2, and no antibody-dependent enhancement effect
of infection or disease was found.
And, lung pathology scores suggest that AZD7442-TM has a protective effect
against SARS-CoV-2-induced lung inflammation and alveolar damage.

➤ Clinical trial: EVUSHELD slowed symptom progression in patients with mild and moderate COVID-19; prevented all-cause death or hospitalization due to complications or sequelae of the disease in patients with mild to moderate COVID-19; When applied in immunocompromised patients, the rate of new crown infection, hospitalization and mortality is very low

A post-hoc analysis of the TACKLE ^study11 reported the benefit
of EVUSHELD in reducing self-reported COVID-19 symptom severity, symptom progression, and time to symptom relief to day 29 。 The proportion of participants who developed ≥1 COVID-19-related symptoms at day 29 progressed to worse status than recorded in the symptom diary prior to
the start of treatment was compared between the EVUSHELD and placebo groups using a protocol-defined scoring system on a daily basis (0: asymptomatic, 1: mild, 2: moderate, 3: severe, 4: emergency room or hospital visits).
Only people with a baseline severity score of <4 were included in the analysis
.
COVID-19 symptom severity assessment is based on a symptom severity score on day 29, including the day
of EVUSHELD or placebo.
Conclusions suggest that a single 600 mg intramuscular dose of EVUSHELD in patients with mild to moderate COVID-19 is associated with a slowing progression of COVID-19 symptom severity and may accelerate symptom improvement
by day 29.
This suggests that treatment with EVUSHELD may help outpatient patients with mild to moderate COVID-19 recover more quickly and return to normal activities with less likely disease
progression.

One ^study12 reported key secondary efficacy outcomes
using long-term safety data over 6 months from the TACKLE study 。 The TACKLE study is a Phase 3 study in adults with mild to moderate COVID-19, where subjects are randomly assigned in a 1:1 ratio and given a single dose of 600 mg EVUSHELD (300 mg per antibody) within 7 days of symptom onset; n=452) or placebo (n=451).

Key secondary endpoints were analysed using the Cochran-Mantel-Haenszel test, which was stratified
by time to symptom onset (≤ 5 versus 5 days >) and risk of progression to severe COVID-19 (high vs low).
THE RESULTS SHOWED 20 (6.
8%) AND 40 (13.
7%) ENDPOINT EVENTS IN THE EVUSHELD AND PLACEBO GROUPS, RESPECTIVELY.
RRR was 50.
7% (95% CI 17.
5–70.
5; P = 0.
006)
compared with placebo.
Suggests that a single intramuscular injection of 600 mg of EVUSHELD within 7 days of onset of symptoms in outpatients with mild to moderate COVID-19 prevents all-cause death or hospitalization
for complications or sequelae of COVID-19 within 6 months.
EVUSHELD tolerated well at 6 months with no new safety concerns
compared to initial analysis.
These data further support the use of EVUSHELD in outpatient care to reduce the COVID-19-related inpatient and hospital burden
.

One ^study1-3 evaluated EVUSHELD use in patients in Minnesota, including the incidence of possible breakthrough infections and vaccination of those receiving EVUSHELD
.
The Minnesota Department of Health (MDH) established a voluntary patient registry through a secure REDCap form in December 2021, and the study investigation ended
on June 30.
Matched with state COVID 19 case data on July 27 to check for the occurrence of SARS-CoV-2 infection (defined by a positive PCR or antigen test) and hospitalizations or deaths
following EVUSHELD use 。 The study included a total of 296 patients who met FDA criteria for EVUSHELD, most of whom were eligible for treatment due to immunosuppressants or underlying hematologic malignancies, resulting in a total of 17 patients with breakthrough infections (5.
7%), hospitalization rates (1.
4%), and Covid-19 related deaths (0%)
。 Conclusions: In samples of immunocompromised patients who received EVUSHELD injection, the infection rate (SARS-CoV-2 test positivity rate), hospitalization rate, and mortality rate were low, supporting its use
in this population.

In summary, the IDWeek Conference 2022 brings us the latest research progress in high-risk groups of new crown pneumonia and new crown neutralizing antibodies, which will bring more thinking and insights to clinical experts, and provide more scientific ideas and directions
for better protection of high-risk groups and treatment of new crown pneumonia.

References

IDWeek official website: https://idweek.
org/

1.
   style="font-size: 12px;color: rgb(127, 127, 127);font-family: Helvetica, Arial, sans-serif;" _msthash="272756" _msttexthash="11178596">2.
 288 - Prognostic Factors for In-hospital Mortality of Patients with Severe COVID-19 Hospitalized in the University Medical Center, Lithuania.

3.
 1086 - COVID-19 in a comprehensive Cancer Center: 2020-2022.

4.
 1089 - Evaluation of breakthrough infections in solid organ transplant recipients: the prospective CONTRAST cohort.

5.
 1939 - COVID-19 vaccine immunogenicity among CD19 receptor T-cell (CAR-T) therapy.

6.
Levin MJ,et al.
N Engl J Med.
2022 Jun 9; 386(23):2188-2200.

7.
Montgomery H, et al.
Lancet Respir Med.
2022 Jun 7; S2213-2600(22)00180-1

8.
 1160 - Treatment-Emergent Viral Variants in the Phase 3 TACKLE Trial Investigating Efficacy and Safety of AZD7442 (Tixagevimab/Cilgavimab) for the Treatment of Mild to Moderate COVID-19 in Adults1066 - Precision phenotyping of “long COVID” through machine learning.

9.
 1110 - AZD7442 (Tixagevimab/Cilgavimab) Demonstrates Potent In Vitro Activity Against SARS-CoV-2 Spike Variants Identified in Circulation and in Prophylaxis Clinical Studies

10.
 1143 - Prophylactic and Therapeutic Activity of AZD7442 (Tixagevimab/Cilgavimab) in SARS-CoV-2 Hamster Challenge Models

11.
 1918 - Impact of the SARS-CoV-2–Neutralizing Antibody Combination AZD7442 (Tixagevimab/Cilgavimab) on the Severity and Progression of COVID-19 Symptoms in the Phase 3 TACKLE Trial

12.
 1924 - Outpatient Treatment With the SARS-CoV-2–Neutralizing Antibody Combination AZD7442 (Tixagevimab/Cilgavimab) for Preventing COVID-19 Hospitalizations in the Phase 3 TACKLE Trial

13.
 1925 - Prevalence of SARS-CoV-2 Infection in Immunocompromised Patients Following Receipt of Tixagevimab/Cilgavimab