key: cord-0943192-v450yjpg
authors: Kotton, Camille N.
title: Belt and Suspenders: Vaccines and Tixagevimab/Cilgavimab for Prevention of COVID-19 in Immunocompromised Patients
date: 2022-04-12
journal: Ann Intern Med
DOI: 10.7326/m22-1026
sha: e4a304d8d4fbd3408ea9db778b4339fd04be7feb
doc_id: 943192
cord_uid: v450yjpg

On 8 December 2021, the U.S. Food and Drug Administration issued an emergency use authorization for AstraZeneca's Evusheld (tixagevimab copackaged with cilgavimab, administered as concomitant injections) for the prevention of COVID-19 in those who are moderately to severely compromised, are aged 12 years or older, and weigh more than 40 kg. This commentary discusses current appropriate use of this important preventive intervention.

Administration issued an emergency use authorization for AstraZeneca's Evusheld (tixagevimab copackaged with cilgavimab, administered as concomitant injections) for the preexposure prophylaxis (prevention) of COVID-19 in those who are moderate to severely compromised and who are aged 12 years or older and weigh more than 40 kg (1). Unlike other monoclonal antibodies, this is not approved for persons with active infection, nor is it for postexposure prophylaxis. It is intended to provide protection in those who are likely to have a reduced immune response to vaccination (examples are in the Table) or for those who have a history of severe adverse reactions to a COVID-19 vaccine for whom (re) vaccination is not recommended. Preexposure prophylaxis with tixagevimab/cilgavimab is not intended as a substitute for vaccination; persons should receive a full vaccine series, including booster doses in addition to receiving tixagevimab/ cilgavimab, unless full vaccination is not possible because of a history of severe allergic reaction to the COVID-19 vaccine. Tixagevimab/cilgavimab should not be given for at least 2 weeks after vaccine administration, per the product emergency use authorization (1).

The COVID-19 vaccines were a momentous inflection point during the pandemic. Given the diminished vaccine efficacy seen in many immunocompromised patients, preventative monoclonal antibodies can provide an additional level of protection. Efficacy estimates are largely based on in vitro data and prior work with monoclonal antibodies in immunocompromised patients. Developed before the advent of the Omicron variant, in vitro work predicts that tixagevimab/cilgavimab is less protective against the new variant. On 24 February 2022, the U.S. Food and Drug Administration approved a double dose of tixagevimab/ cilgavimab on the basis of data that this is more likely to be effective (1). Neutralization activity looks promising against the emerging and now widely circulating Omicron BA.2 subvariant (2). There have been numerous reports of breakthrough infections due to the Omicron variant in those who had received tixagevimab/cilgavimab (3) . Although estimated to provide 6 months of protection, the duration may be shorter with variant strains. Thus far, there is no recommendation for repeated interval dosing. Unlike vaccines, which allow for a polyclonal response, the specificity of monoclonal antibodies will remain problematic; already, use of numerous monoclonal antibodies has ceased given lack of efficacy against new strains (2) .

Defining the optimal target immunocompromised population has been a challenge. Other than using clinical risk factors for severe COVID-19 illness (Table) , we are not able to pinpoint who needs it most. Although it was believed that we should administer monoclonal antibodies on the basis of SARS-CoV-2 spike protein antibody titers-that is, the humoral response to vaccine-this does not address whether or not someone has had a cellular immune response. Furthermore, operationally, this becomes challenging if results of antibody testing are needed before administering tixagevimab/ cilgavimab, often resulting in several visits and some interval delays. For now, administration to those at highest risk for severe disease seems reasonable and pragmatic during a pandemic. When supply or administration capacity is limited, focusing on a subset of the highest-risk population, those least likely to mount an immune response to vaccination, is recommended (Table) (4).

Although rates of serious adverse events were generally similar between tixagevimab/cilgavimab and placebo, there has been some concern as a higher proportion of persons who received tixagevimab/cilgavimab (0.6%) versus placebo (0.2%) in the PROVENT (Phase III Double-blind, Placebo-controlled Study of AZD7442 for Pre-exposure Prophylaxis of COVID-19 in Adult) trial reported cardiac adverse effects, including myocardial infarctions, arrhythmias, and cardiac failures; all of these persons had cardiac risk factors and/or a history of cardiovascular disease at baseline (1). In the STORM CHASER (Phase III Double-blind, Placebo-controlled Study of AZD7442 for Post-Exposure Prophylaxis of COVID-19 in Adults) trial of postexposure prophylaxis with tixagevimab/cilgavimab, no cardiac events were noted, although the cohort was younger and had fewer cardiac risk factors. Overall, the benefit of additional protection for immunocompromised patients seems to outweigh the potential risk for cardiac events.

At this point, the main limitation seems to be knowledge on behalf of immunocompromised patients and clinicians because many are not aware that they could benefit from this, who is included in the target population, and how to obtain a dose. Although initially in short supply when it was approved, there has been a rapid increase in availability; as of 31 March, almost 217 000 doses were available in the United States (5) . Although tixagevimab/cilgavimab is included in recommendations from the National Institutes of Health, it is not included in Centers for Disease Control and Prevention recommendations for prevention, which largely focus on vaccines and nonpharmacologic methods of prevention. The recently developed government website for comprehensive COVID-19 community guidance contains information about masks, vaccines, treatment, and testing but does not include information about tixagevimab/cilgavimab (6) .

We need to have better methods to educate and engage with clinicians to ensure prompt and appropriate use. The rapidly evolving recommendations during the COVID-19 pandemic as well as limited clinical data and This article was published at Annals.org on 12 April 2022.

Annals of Internal Medicine © 2022 American College of Physicians 1

sometimes an absence of strong and clear recommendation from professional and government organizations can make it hard to stay current with state of the art guidance. For example, it took a while for many clinicians to become aware that the recommended tixagevimab/ cilgavimab dose had doubled, and many were unsure how to best obtain another dose for such patients. Developing websites and other educational platforms that are kept up to date with clear clinical recommendations has been imperative during this pandemic, yet further improvement is needed. Furthermore, we need to emphasize the benefits of such protection to patients and caretakers of patients. Immunocompromised patients have been strongly encouraged to stay home and isolate, and some are perplexed by the recommendation that they come to a health care facility for a preventative treatment; many need encouragement to understand the benefits versus risk. The evolving vaccine recommendations combined with a recommendation to also receive monoclonal antibodies has left many perplexed about what they truly need for best protection.

Unlike with COVID-19 vaccines, there has not been large-scale support for developing methods for tixagevimab/ cilgavimab distribution across many different communities and populations. We need to establish and ensure methods for more equitable distribution, with access for all regardless of health and social economic disparities. Variation in allocation across the different states has been dramatic. Furthermore, we need to provide guidance as to how to best establish a centralized and coordinated process for distribution and organize physical infrastructure for safe and efficient administration.

Moderate to severely immunocompromised patients are likely to remain more vulnerable to COVID-19 illness, even after multiple doses of vaccine. Monoclonal antibodies provide an alternative method for protection, and there will be an ongoing need for various monoclonal antibodies for preexposure prophylaxis. Moving forward, hopefully we can optimize the monoclonal antibodies being used based on the circulating variant strains, improve patient and clinician education, develop more effective and equitable methods of distribution, and enhance the safety and wellness of this vulnerable immunocompromised population. Solid organ transplant recipients with recent treatment for acute rejection with T-or B-cell depleting agents Patients with severe combined immunodeficiencies Patients with untreated HIV who have a CD4 T-lymphocyte cell count <0.05 Â 10 9 cells/L * The emergency use authorization includes persons with moderate to severe immune compromise that may result in an inadequate immune response to COVID-19 vaccination including (but not limited to) the medical conditions and treatments listed. Clinicians should consider the risks and benefits for an individual patient to guide decision making. † The National Institutes of Health Panel suggests prioritization including (but not limited to) these persons if logistical constraints or supply limitations prevent provision to all persons who are moderately to severely immunocompromised.

Tixagevimab/Cilgavimab to Prevent COVID-19 in Immunocompromised Patients

Efficacy of antiviral agents against the SARS-CoV-2 omicron subvariant BA

Patient Prioritization for Preexposure Prophylaxis With Tixagevimab/Cilgavimab Populations Included in the Emergency Use Authorization* Active treatment for solid tumor and hematologic malignancies Receipt of solid organ transplant and receiving immunosuppressive therapy Receipt of chimeric antigen receptor T-cell or hematopoietic stem cell transplant (within 2 y of transplant or receiving immunosuppression therapy) Moderate or severe primary immunodeficiency

Advanced or untreated HIV infection (persons with HIV and CD4 cell counts <0.20 Â 10 9 cells/L, history of an AIDS-defining illness without immune reconstitution, or clinical manifestations of symptomatic HIV)

≥20 mg of prednisone or equivalent per day when administered for ≥2 wk), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumor necrosis factor blockers, and other biologic agents that are immunosuppressive or immunomodulatory

Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies

HHS Office of the Assistant Secretary for Preparedness and Response. COVID-19 therapeutics locator

Find COVID-19 guidance for your community. Accessed at www. covid.gov/ on

Tixagevimab/Cilgavimab to Prevent COVID-19 in Immunocompromised Patients IDEAS AND OPINIONS Annals.org Annals of Internal Medicine Author Contributions: Conception and design: C.N. Kotton. Analysis and interpretation of the data: C.N. Kotton. Drafting of the article: C.N. Kotton. Critical revision of the article for important intellectual content: C.N. Kotton. Final approval of the article: C.N. Kotton. Administrative, technical