Vaccine Information: EVUSHELD (Page 4 of 7)

12.4 Microbiology

Antiviral Activity

In a neutralization assay on Vero E6 cells, tixagevimab, cilgavimab, and their combination neutralized SARS-CoV-2 (USA-WA1/2020 isolate) with EC50 values of 60.7 pM (9 ng/mL), 211.5 pM (32 ng/mL), and 65.9 pM (10 ng/mL), respectively.

Tixagevimab, cilgavimab, and their combination showed reduced or no antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), or antibody-dependent natural killer cell activation (ADNKA) in cell culture studies. Tixagevimab, cilgavimab, and their combination did not mediate antibody-dependent complement deposition (ADCD) activity with guinea pig complement proteins.

Antibody Dependent Enhancement (ADE) of Infection

The potential of tixagevimab and cilgavimab to mediate antibody-dependent viral entry was assessed in FcγRII-expressing Raji cells co-incubated with recombinant virus-like particles (VLPs) pseudotyped with SARS-CoV-2 spike protein, with antibody concentrations at a range of 6.6 nM (1 µg/mL) to 824 pM (125 ng/mL). Tixagevimab, cilgavimab, and their combination did not mediate entry of VLPs into these cells under the tested conditions.

The potential for ADE was also evaluated in a non-human primate model of SARS-CoV-2 using EVUSHELD. Intravascular administration prior to virus inoculation resulted in a dose-dependent improvement in all measured outcomes (total viral RNA in the lungs or nasal mucosae, infectious virus levels in the lungs based on TCID50 measurements, or lung injury and pathology based on histology measurements). No evidence of enhancement of viral replication or disease was observed at any dose evaluated, including sub-neutralizing doses down to 0.04 mg/kg.

Antiviral Resistance

There is a potential risk of treatment failure due to the development of viral variants that are resistant to tixagevimab and cilgavimab. Prescribing healthcare providers should consider the prevalence of SARS-CoV-2 variants in their area, where data are available, when considering prophylactic treatment options.

Escape variants were identified following serial passage in cell culture of SARS-CoV-2 or replication competent recombinant vesicular stomatitis virus (VSV) expressing SARS-CoV-2 spike protein in the presence of tixagevimab or cilgavimab individually or in combination. Variants which showed reduced susceptibility to cilgavimab expressed spike protein amino acid substitutions R346I (>200-fold), K444E (>200-fold), and K444R (>200-fold). No escape variants to tixagevimab, or the tixagevimab and cilgavimab combination were selected.

In neutralization assays using recombinant VLPs pseudotyped with SARS-CoV-2 spike and harboring individual spike amino acid substitutions identified in circulating SARS-CoV-2, variants with reduced susceptibility to cilgavimab alone included those with R346I (>200-fold), K444E (>200-fold), K444Q (>200-fold), K444R (>200-fold), V445A (21- to 51-fold), G446V (4.2-fold), N450K (9.1-fold), or L452R (5.8-fold) substitutions. Variants with reduced susceptibility to tixagevimab alone included those with Q414R (4.6-fold), L455F (2.5- to 4.7-fold), G476S (3.3-fold), E484D (7.1-fold), E484K (6.2- to 12-fold), E484Q (3.0-fold), F486S (>600-fold), F486V (121- to 149-fold), Q493K (2.4- to 3.2-fold), Q493R (7.9-fold), E990A (6.1-fold), or T1009I (8.2-fold) substitutions. Variants harboring an E484K (2.4- to 5.4-fold), Q493R (3.4-fold), E990A (5.7-fold), or T1009I (4.5-fold) substitution exhibited low level reduced susceptibility to tixagevimab and cilgavimab in combination.

VLPs pseudotyped with the SARS-CoV-2 spike of variant strains with reduced susceptibility to cilgavimab included those with R346K:E484K:N501Y (Mu, 21-fold), and those with reduced susceptibility to tixagevimab included those harboring E484K (Alpha, 18.5-fold; Beta, 3.5- to 15-fold). Similar results were observed, where data was available, in neutralization assays using authentic SARS-CoV-2 variant strains.

The neutralizing activity of tixagevimab and cilgavimab in combination was tested against pseudotyped VLPs and/or authentic SARS-CoV-2 variant strains harboring all spike substitutions identified in Alpha (B.1.1.7, 0.5- to 5.2-fold), Beta (B.1.351, 1.0- to 3.8-fold), Gamma (P.1, 0.4- to 2.0-fold),Delta (B.1.617.2, 0.6- to 1.2-fold), and Delta [+K417N] (AY.1/ AY.2, 1.0-fold) variants of concern, and Eta (B.1.525, 3.1-fold), Iota (B.1.526, 0.3- to 3.4-fold), Kappa (B.1.617.1, 0.5- to 3.4-fold) Lambda (C.37, 0.7-fold), and Mu (B.1.621, 7.5-fold) variants of interest. Tixagevimab and cilgavimab in combination was also tested against Epsilon (B.1.427 / B.1.429, 0.8- to 3.5-fold), R.1 (3.5-fold), B.1.1.519 (1.4-fold), C.36.3 (2.3-fold), B.1.214.2 (0.8-fold), and B.1.619.1 (3.3-fold) variant alerts for further monitoring and B.1.616 (0.5-fold), A.23.1 (0.4-fold), A.27 (0.8-fold), and AV.1 (5.9-fold) variants de-escalated from further monitoring (Table 5).

Preliminary data for the neutralizing activities of tixagevimab, cilgavimab, and their combination against the Omicron (B.1.1.529) variant of concern are available. VLPs pseudotyped with the SARS-CoV-2 spike of Omicron showed reduced susceptibility to tixagevimab (>600- to >1,000-fold), cilgavimab (>700- to >1,000-fold), and to their combination (132- to 183-fold). Authentic Omicron viruses showed reduced susceptibility to tixagevimab (152- to 230-fold), cilgavimab (12- to 268-fold), and to their combination (12- to 30-fold).

Data collection is ongoing to better understand how the reductions in activity seen in pseudotyped VLP assays or authentic SARS-CoV-2 assays may correlate with clinical outcomes.

Table 5 Pseudotyped Virus-Like Particles and Authentic SARS-CoV-2 Neutralization Data for SARS-CoV-2 Variant Substitutions with EVUSHELD
Lineage with Spike Protein Substitution Country First Identified WHO Nomenclature Key Substitutions Tested Fold Reduction in
Susceptibility * (Pseudotyped VLPs )
Fold Reduction in
Susceptibility * (Authentic virus )
*
Range of reduced potency across multiple variants of each lineage using research-grade pseudotyped VLP neutralization assays; mean fold change in half maximal effective concentration (EC50 ) of mAb required for a 50% reduction in infection compared to wild type reference strain
Pseudotyped virus-like particles expressing the entire SARS-CoV-2 spike variant protein and individual characteristic spike substitutions except L452Q were tested including Alpha (+L455F, E484K, F490S, Q493R, and/or S494P), and Delta (+K417N) harboring additional indicated RBD substitutions that are no longer detected or detected at extremely low levels within these lineages
Authentic SARS-CoV-2 expressing the entire variant spike protein were tested including Alpha (+E484K or S494P) harboring additional indicated RBD substitutions that are no longer detected or detected at extremely low levels within these lineages
§
No change: <5-fold reduction in susceptibility
EC50 = 1.13 – 1.83 nM (171 — 277 ng/mL)

B.1.1.7

UK

Alpha

N501Y

0.5- to 5.2‑fold

No Change §

B.1.351

South Africa

Beta

K417N+E484K+N501Y

No Change §

No Change §

P.1
Brazil
Gamma

K417T+E484K+N501Y

No Change §

No Change §

B.1.617.2
India
Delta

L452R+T478K

No Change §

No Change §

AY.1/ AY.2
India
Delta [+K417N]

K417N+L452R+T478K

No Change §

No Change §

B.1.1.529
Botswana
Omicron

G339D+S371L+S373P+ S375F+K417NN440K+G446S+S477N+ T478K+E484A +Q493R+ G496S+Q489R+N501Y+ Y505H

132- to 183-fold

12- to 30-fold

B.1.525
Multiple country origin
Eta

E484K

No Change §

ND

B.1.526
United States
Iota

E484K

No Change §

No Change §

B.1.617.1
India
Kappa

L452R+E484Q

No Change §

No Change §

C.37
Peru
Lambda

L452Q+F490S

No Change §

ND

B.1.621
Colombia
Mu

R346K+E484K+N501Y

7.5-fold

ND

B.1.427 / B.1.429
United States
Epsilon

L452R

No Change §

No Change §

R.1
Multiple country origin

E484K

No Change §

ND

B.1.1.519
Multiple country origin

T478K

No Change §

ND

B.1.616
France

V483A

No Change §

ND

A.23.1
UK

V367F

No Change §

ND

A.27
Multiple country origin

L452R+N501Y

No Change §

ND

AV.1
Multiple country origin

N439K+E484K

5.9-fold

ND

ND, not determined; RBD, receptor binding domain

It is not known how pseudotyped VLPs or authentic SARS-CoV-2 neutralization susceptibility data correlate with clinical outcome.

In PROVENT, illness visit sequencing data were available for 21 of 33 subjects with SARS-CoV-2 infection (6 of 13 who received tixagevimab and cilgavimab and 15 of 20 placebo). At an allele fraction ≥25%, 14 of 21 subjects were infected with variants of concern or variants of interest, including 8 subjects with Alpha (B.1.1.7) (8 who received placebo), 1 subject with Beta (B.1.351) (1 who received tixagevimab and cilgavimab), 3 subjects with Delta (B.1.617.2) (3 who received placebo), and 2 subjects with Epsilon (B.1.429) (2 who received tixagevimab and cilgavimab). Seven additional subjects were infected with B.1.375 (1 who received tixagevimab and cilgavimab) or the A_1 set of lineages containing a constellation of spike protein substitutions including D614G and P681H or Q677P (3 who received tixagevimab and cilgavimab and 3 placebo). Additional spike protein RBD substitutions detected at an allele fraction ≥3% included V503F in the tixagevimab and cilgavimab group.

In STORM CHASER, illness visit sequencing data was available for 19 subjects with SARS-CoV-2 infections (12 of 12 who received tixagevimab and cilgavimab and 7 of 7 placebo). At an allele fraction ≥25%, 12 of 19 subjects were infected with variants of concern or variants of interest, including 9 subjects with Alpha (B.1.1.7) (5 who received tixagevimab and cilgavimab and 4 placebo) and 3 subjects with Epsilon (B.1.427 / B.1.429) (2 who received tixagevimab and cilgavimab and 1 placebo). Seven additional subjects were infected with B.1.1.519 (1 who received tixagevimab and cilgavimab) or the A_1 set of lineages containing a constellation of spike protein substitutions including D614G and D138H, Q675H, Q677H, or V1176F (4 who received tixagevimab and cilgavimab and 2 placebo). Additional spike protein RBD substitutions detected at an allele fraction ≥3% included S325P, Del342, C361W, Del428, F429V, and F515C in the tixagevimab and cilgavimab group.

Evaluation of neutralization susceptibility of variants identified through global surveillance and in subjects who received tixagevimab and cilgavimab is ongoing.

It is possible that variants resistant to tixagevimab and cilgavimab could have cross-resistance to other monoclonal antibodies targeting the RBD of SARS-CoV-2. The combination of tixagevimab and cilgavimab retained activity against pseudotyped VLPs harboring individual SARS-CoV-2 spike substitutions (K417E/N, D420N, K444Q, V445A, Y453F, L455F, N460K/S/T, E484D/K/Q, F486V, F490S, Q493K/R, and S494P) identified in neutralization escape variants of other monoclonal antibodies targeting the RBD of SARS-CoV-2 spike protein.

VxLabels.com provides trustworthy package insert and label information about marketed drugs and vaccines as submitted by manufacturers to the U.S. Food and Drug Administration. Package information is not reviewed or updated separately by VxLabels.com. Every individual vaccine label and package insert entry contains a unique identifier which can be used to secure further details directly from the U.S. National Institutes of Health and/or the FDA.

Vaccine Sections

Vaccine Information by RSS

As the leading independent provider of trustworthy vaccine information, our database comes directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. VxLabels.com provides the full vaccine subset of the FDA's repository. Vaccine information provided here is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2022. All Rights Reserved.