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Evusheld: Government is urged to expedite covid antibody treatment for vulnerable patients

BMJ 2022; 379 doi: (Published 10 October 2022) Cite this as: BMJ 2022;379:o2431

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Protect the immunocompromised against new variants with Evusheld- don't throw the baby out with the bathwater without checking.

Dear Editor,

The coronavirus pandemic continues to spread with ongoing infection waves. Ongoing hospitalisation and deaths are principally in the unvaccinated, elderly and immunocompromised patients who have not responded to the coronavirus vaccine. Furthermore, new variants continue to be identified which may render our coronavirus treatments or vaccines ineffectual.

As a case in point, for immunocompromised patients who haven’t responded to coronavirus vaccines, their only option for coronavirus protection is the prophylactic antibody therapies, Tixagevimab/Cilgavimab (Evusheld). Lab scientists using neutralisation assays have proposed that variants like BQ1 and BQ1.1 could completely evade protection by drugs like Evusheld. [1] We have also heard concerns of evasion for variants such as BA.1, BA.2, BA4 and BA5 based on similar neutralisation assays. [2] This has partly led to the UK not purchasing this drug for immunocompromised patients, in contrast to 32 other countries where it is being delivered.

We would suggest that for coronavirus protection with antibody therapies, laboratory evidence is counter-balanced with the following points.

i) Mixed variant winter. There are several SARS-CoV-2 variants in circulation and it seems unlikely that a single dominant strain will emerge this Winter. Whilst any given antibody treatment might exhibit some resistance to one or two variants, there will be other variants for which antibody treatments remain highly effective. This means that the treatment will be very unlikely to be rendered completely ineffectual.

ii) Variant forecasting and chasing. The scientific community to date has not been able to forecast the next likely variant nor its capacity for immune escape. Ultimately, the benefit of prophylactic antibody treatments must be based on published and peer reviewed evidence from human studies and not crystal ball gazing on what might come next.

iii) Antibody function. Laboratory studies might lead the reader to accept that antibodies do little more than neutralise. However, antibodies have a diversity of other functions not measured by neutralisation assays.

iv) Assays. There are a multitude of different neutralising assays which work well against different variants. These assays are poorly standardised and it is easy to call "non-neutralisation“ when an assay was not performed to the requisite standard due to technical difficulties. There is also poor correlation between neutralisation assays and animal studies. [3] This makes it even more important for there to be validation of laboratory studies and establish how these relate to real world data before human efficacy concerns are raised.

v) Post marketing surveillance studies. There have not been any studies that have shown that a neutralisation result is correlated in any fashion to human correlates of protection. Until this link is established, we should rely on post marketing clinical surveillance studies to examine efficacy of antibody treatments. To date these have shown ongoing protective immunity in terms of reduction in hospitalisation and death despite some reduction in neutralization data for some omicron variants.

Finally, we have recently published as a preprint the largest global systematic review of Evusheld. Across 17 studies, the majority from the omicron variant era, clinical effectiveness was 40.5%, 69.2%, 87.9 and 86.4% against breakthrough infection, hospitalisation, ITU admission and COVID-19 mortality which is very reassuring. [4]

Clearly, the overall picture for immunocompromised patients has improved, however, they still remain at a significantly higher risk than the general population. Antibody treatments are not a magic wand but may provide significant protection for the most vulnerable in our community. Pre-exposure prophylaxis for the immunocompromised patients is the best option.

1. Cao, Y. et al. Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. 2022.09.15.507787 Preprint at (2022).
2. Takashita, E. et al. Efficacy of Antibodies and Antiviral Drugs against Omicron BA.2.12.1, BA.4, and BA.5 Subvariants. N. Engl. J. Med. 2022 Aug 4; 387(5):468-470
3. Case, J. B. et al. Resilience of S309 and AZD7442 monoclonal antibody treatments against infection by SARS-CoV-2 Omicron lineage strains. Nat. Commun. 13, 3824 (2022).
4. Suribhatla, R. et al. Systematic review of the clinical effectiveness of Tixagevimab/Cilgavimab for prophylaxis of COVID-19 in immunocompromised patients. 2022.11.07.22281786 Preprint at (2022).

Competing interests: No competing interests

17 November 2022
Lennard YW Lee
Academic Medical Oncologist
Sanskriti Swarup, Mark Tuthill, Michelle Willicombe, Antonio Pagliuca, Alex Richter
Department of Oncology, University of Oxford Old Road Campus Research Building, Roosevelt Drive, Oxford, OX3 7DQ