Belt and Suspenders: Vaccines and Tixagevimab/Cilgavimab for Prevention of COVID-19 in Immunocompromised Patients
Authors: Camille N. Kotton
Journal: Annals of Internal Medicine (2022)

Ideas and OpinionsJune 2022Belt and Suspenders: Vaccines and Tixagevimab/Cilgavimab for Prevention of COVID-19 in Immunocompromised PatientsFREECamille N. Kotton, MDCamille N. Kotton, MDInfectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusettes (C.N.K.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/M22-1026 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail 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 preexposure prophylaxis (prevention) of COVID-19 in those who are moderately 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 COVID-19 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).Table. Patient Prioritization for Preexposure Prophylaxis With Tixagevimab/CilgavimabThe 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 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.Moderately 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.References1. Fact sheet for healthcare providers: emergency use authorization for Evusheld™ (tixagevimab co-packaged with cilgavimab). Accessed at www.fda.gov/media/154701/download on 31 March 2022. Google Scholar2. Takashita E, Kinoshita N, Yamayoshi S, et al. Efficacy of antiviral agents against the SARS-CoV-2 omicron subvariant BA.2 [Letter]. N Engl J Med. 2022. [PMID: 35263535] doi:10.1056/NEJMc2201933 CrossrefMedlineGoogle Scholar3. Bruel T, Hadjadj J, Maes P, et al. Serum neutralization of SARS-CoV-2 Omicron sublineages BA.1 and BA.2 in patients receiving monoclonal antibodies. Nat Med. 2022. [PMID: 35322239] doi:10.1038/s41591-022-01792-5 CrossrefMedlineGoogle Scholar4. National Institutes of Health. Coronavirus disease 2019 (COVID-19) treatment guidelines. Accessed at www.covid19treatmentguidelines.nih.gov/ on 31 March 2022. Google Scholar5. HHS Office of the Assistant Secretary for Preparedness and Response. COVID-19 therapeutics locator. Accessed at https://covid-19-therapeutics-locator-dhhs.hub.arcgis.com/ on 31 March 2022. Google Scholar6. Find COVID-19 guidance for your community. Accessed at www.covid.gov/ on 31 March 2022. Google Scholar Comments0 CommentsSign In to Submit A Comment Barry Cooper, MDAbington Jefferson Health12 April 2022 Timing of Covid vaccines with Tixagevimab/Cilgavimab Although the guidelines indicate dosing of Tixagevimab/Cilgavimab should be delayed for 2 weeks after receiving a Covid vaccine, it is not clear to what extent Tixagevimab/Cilgavimab once given will interfere with the recommended timing of Covid vaccine. At AAAA website, https://www.aaaai.org/Allergist-Resources/Ask-the-Expert/Answers/2022/evusheld, it is stated " COVID-19 vaccination should be delayed 90 days from the administration of monoclonal antibodies." If this is evidenced based, it should be included in the guidelines from the CDC and the manufacturer. In addition, determining if the benefits of Tixagevimab/Cilgavimab outweigh the potential need to delay Covid vaccines becomes problematic. Camille N. Kotton, MDInfectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusettes (C.N.K.)19 April 2022 Author Response to Cooper Dear Dr. Cooper, Thank you for highlighting that information, which is dated February 1, 2022. Subsequently, the Centers for Disease Control and Prevention revised their recommendations to include this, "In people who previously received a COVID-19 vaccine, administration of tixagevimab/cilgavimab (EVUSHELD™) for pre-exposure prophylaxis should be deferred for at least two weeks after vaccination, per the product emergency use authorization." (from Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Approved or Authorized in the United States, available at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html#immunocompromised, accessed April 18, 2022). Thus, what is written on the website that you highlighted does not seem to be evidence-based or in alignment with current recommendations at this time; it does reflect prior guidance which is no longer in use. That author wrote "I will add that I am skeptical that the presence of monoclonal antibody or passive antibody will significantly modify the vaccine response" and current guidance agrees with that statement. Given that, it's not clear that the CDC needs to change their guidelines at this point. I would highlight that administering tixagevimab/cilgavimab is not intended to take the place of vaccines (except for those with severe reactions to vaccines), and we would not recommend any delays in vaccination in order to administer tixagevimab/cilgavimab. Lynne Strasfeld MD, YoungYoon Ham PharmD BCIDPDivision of Infectious Diseases, Oregon Health and Science University26 May 2022 In pursuit of equity – a "push not pull" model for Evusheld distribution We read this opinion piece with interest and strong agreement. In addition to ensuring patient and provider education regarding the potential benefits of Evusheld in select populations, we would like to further emphasize the importance of ensuring equity in distribution for products with major supply/demand mismatch. Like other COVID-19 therapeutics, Evusheld is allocated to state and territorial health departments by the Office of the Assistant Secretary for Preparedness and Response, based on the assumption that local jurisdictions are best able to determine optimal distribution to ensure efficient, fair and equitable delivery. Despite these goals, the lay press is rife with reports of Evusheld being allocated by means that rely on patient health literacy, economic advantage and/or provider advocacy. Herein, we summarize our approach to ensure efficient, fair and equitable delivery of Evusheld at our center, Oregon Health and Sciences University. Before Evusheld was allocated to our center, we compiled a list of all NIH Tier 1 risk group patients.1 Working from the University of Pittsburgh model, we used the Area Deprivation Index to give a higher weight (1.25) to patients historically disadvantaged by healthcare access.2 Similar weighting was applied to patient-facing employees who qualified for Evusheld. We implemented a "push not pull" model, reaching out to patients rather than having them or their providers initiate contact. Translation services facilitated communication with non-English speakers. To minimize financial barriers, we offered travel vouchers. Finally, our institution opted to not bill patients for uncovered facility or administrative fees, as an extension of the CDC COVID-19 Vaccination Program waiver, and assuming that patients might refuse care if there were potential costs. An audit of the first 425 patients who received Evusheld at our center revealed the demographics and payor status of this group largely mirrored Oregon census data. This was in contrast to earlier data we had gathered regarding antibody treatment for COVID-19 at our center, which had favored "historically advantaged" individuals, and as has also been reported in the literature.3 A "push not pull" paradigm required institutional motivation and participation from multiple stakeholders. Though the timeline for Evusheld may be limited, either as a consequence of a lapse in congressional funding or to emergence of resistance, our approach will provide a lasting legacy in our journey toward equity in care delivery. With many new COVID-19 therapeutics on the horizon, it is ever more important to work to mitigate disparities in healthcare access. REFERENCES 1 Prioritization of Anti-SARS-CoV-2 Therapies for the Treatment and Prevention of COVID-19 When There Are Logistical or Supply Constraints, <https://www.covid19treatmentguidelines.nih.gov/overview/prioritization-of-therapeutics/> (2022). 2 White, D. B. & Lo, B. Mitigating Inequities and Saving Lives with ICU Triage during the COVID-19 Pandemic. Am J Respir Crit Care Med 203, 287-295, doi:10.1164/rccm.202010-3809CP (2021). 3 Wu, E. L. et al. Disparities in COVID-19 Monoclonal Antibody Delivery: a Retrospective Cohort Study. J Gen Intern Med, doi:10.1007/s11606-022-07603-4 (2022). Author, Article, and Disclosure InformationAffiliations: Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusettes (C.N.K.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-1026.Corresponding Author: Camille N. Kotton, MD, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Cox 5, Boston, MA 02114; e-mail, [email protected]harvard.edu.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, or logistic support: C.N. Kotton.Collection and assembly of data: C.N. Kotton.This article was published at Annals.org on 12 April 2022. 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