25 June 2022 Episode 270: Clinical data from Evusheld and Sotrovimab mAbs

Episode 270: Clinical data from Evusheld and Sotrovimab mAbs

Dear colleagues,

First a correction/extension  of the conclusions of Ep 269:

• Post-acute or long COVID remains a rather poorly defined condition with many potential symptoms, but it is undeniable that a proportion of COVID patients has debilitating long-term consequences of the disease.
• Omicron may result in relatively less long COVID, but the high frequency of omicron infection may still result in many more long-COVID cases in absolute terms.
• Microclots and hyper)inflammation, associated with persistence of some viral material in tissues could explain the systemic and diffuse nature of long COVID
• Vaccination can partly protect against long COVID, while each reinfection increases the chances of a range of complications AFTER recovery, including premature death.  (Note: this is in contrast with protection against infection and acute severe disease, which is increased by vaccination and by previous infection cfr hybrid immunity).

In the present episode, I will address the controversial usefulness of mAb as prophylaxis against various omicron sublineages especially in immunocompromised subjects.

IN VITRO DATA

In previous episodes, a number of in vitro results showed that Sotrovimab (S-309) loses a lot of its activity against all omicron variants, while Evusheld or AZD7422 (= combination of Tixagevimab/COV2-2196/AZD8859 and Cilgavimab/COV2-2130/AZD1061) loses a lot of activity against BA.1, is still active against BA.2, but still les than against previous variants (e.g. Delta).   Evusheld’s activity against BA.2, however relies on Cilgavimab/2130/1061 only, hence monotherapy.

I give a limited overview of those early data (from previous Episodes)

Ep 270-1: Bruel Nat med May 2022

• Sotrovimab is still reasonably active against BA.1, but not BA.2
• Evusheld is more active against delta> BA.2>BA.1

These in vitro data are reflected in the neutralization titers of patients treated with these mAbs (note Ronaprene = combination of Casivirimab + Imdevimab):

• Sera from treated patients show strong ex vivo neut against delta, very weak if any activity against BA.1 and intermediate activity against BA.2.
• Combined Ronaprene/Evusheld offers no advantage.  

Not surprisingly, 4 breakthrough infections were observed in 29 immunocompromised patients prophylactically treated with Evusheld.  Note: in view of the time period, presumably all BA.1

Ep 270-2: Xiaoliang Xie in Res Square shows that Evusheld (in fact Cilgavimab/COV2-2130)  and Sotrovimab retain some activity against BA-2 sublineages B1.2-12-1 and BA.4/5 (but 10 X less active than against D614G);

  ↑    ↑                ↑                                                                                  ↑

Ep 270-3:  Wang 26 May 2022 shows very similar data for Evusheld (COV2-2196 + COV2-2130)

Ep 270-4:  Similar data provided by Astra-Zeneca (Evusheld = AZD7442; Sotrovimab = S309)

INTERPRETATION: Limitations

• In vitro data largely generated with “pseudoviruses”; while real viruses are (about 10 X) less easily neutralized.
• IC50 concentrations are by definition not enough for full neutralization: in vivo you need to block the virus 100 % to prevent facilitation of resistance by mutations.
• Pharmacoknietic studies suggest that standard intravenous doses in the clinic might result in concentrations in vivo, which could  be suboptimal for these already partly resistant variants.  

EVUSHELD clinical efficacy

Ep 270-5: Benotmane medRxiv March 2022: Pre-exposure prophylaxis with Evusheld™ elicits limited ex vivo neutralizing activity against the omicron BA.1 variant in kidney transplant patients:

Less than 10% of patients who received Evusheld™ were able to neutralize omicron BA.1 at 29 post-injection days, while convalescent sera (after infection) had a much higher neutralizing capacity.   

Ep 270-6: Al Jurdi medRxiv 17 May 2022: Evusheld prophylaxis associated lower breakthrough infections (BTI) during Omicron (mainly BA.1) in solid organ transplantation recipients (SOTR).

Rather large (> 200 cases and controls) retrospective study in Boston

(A) Types of SOTR subjects in the study (B) the number of vaccines that subjects  received.

(C) Number of Evusheld doses given stratified by date of administration.

(D) Wastewater SARS-CoV-RNA levels in Massachusetts (MA) by date.

(E) Survival curve of cumulative incidence of breakthrough COVID-19 in SOTRs who received Evusheld (n=222) and age-matched vaccinated SOTRs (n=222).

(F-J) No difference in kidney or liver function tests between cases and controls.

Ep 270-7: Karaba medRxiv 28 May 2022 Omicron BA.1 and BA.2 ex vivo Neutralizing Activity Following Pre-Exposure Prophylaxis with Evusheld in Vaccinated Solid Organ Transplant Recipients

The proportion demonstrating neutralizing inhibition by patient serum after Evusheld injection:

• Against vaccine strain increased from 46% to 100% (p<0.001).
• BA.1 neutralization was low and did not increase (8% to 16%)
• In contrast, BA.2 neutralization increased from 7% to 72% of participants

Notes: - Neutralization test used =  inhibition of binding Spike of various VOC to ACE receptor.

- Standard and double doses of Evusheld (Tixagevimab +Cilgavimab) were compared

→ Clearly: omicron BA.1 is not neutralized even after double dosing, while BA.2 is partly and dose dependently neutralized.

Conclusion: Evusheld presumably more useful for prevention of BTI with BA.2 than with BA.1.

Ep 270-8:  Young-Xu medRxiv 29 May Effect of Evusheld in large Veterans’ administration cohort during omicron (Jan-April 2022: BA.1 and BA.2) in older vaccinated individuals, many of whom with immune compromise:

Using national real-world data from predominantly vaccinated, immunocompromised

Veterans, administration of Evusheld was associated with lower rates of SARS-CoV-2 infection, COVID-19 hospitalization, and all-cause mortality during the Omicron surge.(Hazard ratio≈ 0.3)

SOTROVIMAB clinical efficacy

Ep 270-9: Aggarwal JID May 2022:  Real-World Evidence of Sotrovimab for Preventing Hospitalization and  Mortality in COVID-19 Outpatients during DELTA wave (Oct-Dec 2021)

Over 2000 patients with SARS-COV2 infection of whom 522 receiving sotrovimab matched to 1563 not receiving mAbs. (In each group 50 % had coi-morbidity and 25 % was immunocompromised)

Sotrovimab treatment was associated with a 63% decrease in hospitalization and an 89%

decrease all-cause 28-day mortality

Ep 270-10: Aggarwal medRxiv 18 June 2022: Low Effectiveness of Sotrovimab for Preventing Hospitalization and Mortality in COVID-19 Outpatients During the Omicron BA.1 (Dec 21-March 22)

The same set-up on > 1000 treated and > 3000 untreated SARS-CoV-2 infected subjects showed NO significant reduction during BA.1 wave.

Ep 270-11: Bang Zeng medRxiv 23 May 2022:  Comparative effectiveness of sotrovimab and molnupiravir for prevention of severe COVID-19 outcomes in UK general practice (Dec 21-Feb 22)

Retrospective cohort of 3288 Sotrovimab and 2663 Molnupiravir treated SARS-CoV-2 breakthrough infected subjects with high risk and 90 % having received 3 doses of vaccine

→ resulted in only 84 “events” (hospitalization or death within 28 days).

Sotrovimab had a significantly better outcome.

The significance of this observation is limited as there was no untreated control group and the number of events was low.

INDUCTION OF RESISTANCE

I could not find evidence for Evusheld, but 3 papers on Sotrovimab

Ep 270-12: Rebecca Rockett medRxiv 21 Dec 2021 RESISTANCE CONFERRING MUTATIONS IN SARS-CoV-2 DELTA FOLLOWING SOTROVIMAB INFUSION

Of the 100 delta-infected patients that received sotrovimab because of risk factors, 23 had persistent SARS-CoV-2 RNA detected by RT-PCR for > 10 days.  Eight of these were studied and 4 showed resistance associated mutations

Mutations conferring high level resistance to sotrovimab and dynamics of SARS-CoV-2 viral load.

A) Depicts the co-ordinates of mutations that are acquired after sotrovimab treatment in the receptor binding domain (RBD) of the spike (S) protein: S:E340K/A/V and S:P337L/T which have been reported to reduce the susceptibility to sotrovimab by 297, 100, 200, 192 to 10-fold, respectively.

B) Subsampled global phylogeny of SARS-CoV-2 VOC Delta, the geographical region of each sequence is indicated in the outer metabar. SARS-CoV-2 genomes sequenced in this study are highlighted in orange in the outer metabar, red nodes indicate genomes that developed resistance-conferring mutations.

C) The dynamics of four cases of SARS-CoV-2 infection treated with sotrovimab are outlined on separate graphs; the x-axis indicates the days sampled pre- and post-sotrovimab infusion. The bar graph depicts the acquisition and read frequency (left y-axis) of mutations conferring high levels of resistance to sotrovimab (green S:340E>K, blue S:E340A, purple S:E340V and pink S:P337L) for each case. The overlayed red line graph shows the SARS-CoV-2 viral load at each sampling point (right-hand y-axis scale.

Ep 270-13: Huygens medRxiv April 2022:  High incidence of sotrovimab resistance and viral persistence in immunocompromised patients infected with the SARS-CoV-2 Omicron BA.1 or BA.2

Spike mutations associated with reduced in vitro susceptibility were detected in 6 of 47 (13%) patients with solid organ transplantation, some with B-cell depleting therapy

• 4 patients infected with BA.1 showed mutations in S337 or 340 + others (e.g. D796Y)
• 2 patients with BA.2, both with D796Y

Clearance of virus was prolonged, especially in the BA.1 patients with mutations.  

Ep 270-14: Destras medRxiv April 2022:  Sotrovimab drives SARS-CoV-2 Omicron variant evolution in

immunocompromised patients

Amongst > 22,900 sequences between Dec 21 and March 22, only 25 with S:337 and S:340 substitutions.   Of these 9 in 6 patients with immunocompromise

HOW TO PREVENT HOSPITALIZATION?

Ep 270-15: Sullivan medRxiv 37 May 22: historical review of many trials, confirming that most monoclonals, but also convalescent plasma (CCP) suffer from the omicron sublineage, while Nirmatrelvir, Molnupiravir and Remdesivir remain active.?  

GENERAL CONCLUSIONS

1. Evusheld is much more active against BA.2 than BA.1 (in vitro and ex vivo). Nevertheless, there is clinical evidence that Evusheld can prevent a part of breakthrough infections with either BA.1 or BA.2 at a regular dosage of 150mg of both Ab.
2. Sotrovimab, which was very active against delta in vivo, has very limited, if any, activity against omicron with the present dosing of 500 mg.  

Clearly, the difference in clinical effect is not surprising, since the in vitro EC50 of Sotrovimab is at least 50 X higher than Evusheld, while the in vivo dosing differs only by a factor 4 (taking into account that only Cilgavimab is effective against omicron)

3. Crucial mutations for Sotrovimab resistance are in Spike 337 and 340 (+ 796) and have been observed in Sotrovimab-exposed immunocompromised patients, chronically infected with either delta, BA.1 and BA.2.

I hope this was useful.

Best wishes,

Guido