2024 Clinical Practice Guideline Update by the Infectious Diseases Society of America on the Management of COVID-19: Anti-SARS-CoV-2 Neutralizing Antibody Pemivibart for Pre-exposure Prophylaxis Free

Abstract

This article was posted online at https://www.idsociety.org/practice-guideline/covid-19-guideline-treatment-and-management/ on 12 August 2024. Coronavirus disease 2019 (COVID-19) management guidelines may change rapidly with evolving virus variants and ongoing research, so please check the website for most updated version of this guideline.

As the pandemic evolves, new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants emerge with varying susceptibility to available anti–SARS-CoV-2 neutralizing antibodies. For current information, please refer to the Centers for Disease Control and Prevention (CDC) COVID-19 Data Tracker (Summary of Variant Surveillance) [1].

In moderately or severely immunocompromised persons aged 12 years or older, should pemivibart compared to no pemivibart be used for preexposure prophylaxis?

Recommendation: In moderately or severely immunocompromised individuals aged 12 years or older at risk for progression to severe COVID-19, the Infectious Diseases Society of America (IDSA) guideline panel suggests pre-exposure prophylaxis (PrEP) with pemivibart when predominant regional variants are susceptible to the agent (conditional recommendation, low certainty of evidence).

Remarks:

• The anticipated benefit is likely greatest in people who are the most immunocompromised because they have the highest risk of inadequate immune response and progression to severe disease. See Table 1 for examples of individuals with varying degrees of immunosuppression. See Figures 1 and 2 for information from the Food and Drug Administration (FDA) Emergency Use Authorization (EUA).

• The anticipated benefit may be lower in patients aged 12 to 17 years, who have less severe COVID-19 outcomes than adults, as reflected by lower rates of hospitalization.

• As the evidence is based on immunobridging and circulating variant susceptibility is evolving, additional clinical and laboratory data may impact this recommendation.

• Patients who place a higher value on potential harms, specifically, the observed 0.6% risk of anaphylaxis, and a lower value on the uncertain benefits of prevention of severe COVID-19 would reasonably decline pemivibart.

• Per the FDA EUA, pemivibart is authorized to be given at 4500 mg IV every 3 months.

• Per the FDA EUA, in individuals who have recently received a COVID-19 vaccine, pemivibart should be administered at least 2 weeks after vaccination.

Figure 1.

FDA emergency use authorization (EUA) criteria for the use of pemivibart for pre-exposure prophylaxis of COVID-19 in moderately or severely immunocompromised patients [2].

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Figure 2.

FDA EUA criteria for the use of pemivibart for pre-exposure prophylaxis of COVID-19 [2].

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BACKGROUND

Monoclonal antibodies (mAbs) directed at the receptor-binding domain of SARS-CoV-2 spike protein have been employed as prophylactic and therapeutic agents for COVID-19. Animal models, including those using the parent mAb for pemivibart, adintrevimab, have demonstrated the ability of these antibodies to inhibit viral replication in the lower respiratory tract, thereby reducing virus-induced pathology [5,6].

An advantage of an anti–SARS-CoV-2 mAb is its ability to provide protection for individuals who do not respond to vaccination. Additionally, this protection begins immediately after the infusion. The FDA previously issued an EUA for tixagevimab/cilgavimab (Evusheld) as pre-exposure prophylaxis for COVID-19 [7,8]. However, as the pandemic progressed, new SARS-CoV-2 variants emerged with reduced neutralizing susceptibility to various anti–SARS-CoV-2 mAbs in assays performed using infectious (also referred to as authentic) and pseudotyped viruses. There is evidence that the results of these in vitro neutralization assays can predict the efficacy of prophylactic or therapeutic anti–SARS-CoV-2 mAb activity [9, 10]. The FDA has employed these and other immunobridging studies to determine the withdrawal and authorization of anti–SARS CoV-2 mAbs [2, 11]. The FDA defines immunobridging as a method to infer vaccine (or by extension, monoclonal antibody) effectiveness by comparing immune responses, such as antibody levels, from a new vaccine (or antibody) to those of an approved vaccine or antibody under different conditions. This approach is useful when direct efficacy trials are impractical because of low disease incidence or ethical issues. Immunobridging allows for quicker and more cost-effective vaccine (and monoclonal) approvals, which is critical during public health emergencies like the COVID-19 pandemic. It has been used for evaluating COVID-19 vaccines across different age groups and for booster doses. In the case of pemivibart immunobridging, serum neutralization titer was used to compare pemivibart to previous mAbs [2, 12, 13].

While vaccination remains the first-line approach for the prevention of COVID-19, there are some immunosuppressed individuals who may not mount an adequate protective response to COVID-19 vaccines. Certain immunocompromised patients (examples listed in Table 1) are at particularly high risk for complications of COVID-19. Immunosuppressed individuals may benefit from PrEP. Anti–SARS-CoV-2 mAbs have track records of efficacy for both treatment and prevention of COVID-19. In March 2024, the FDA conferred emergency use authorization for pemivibart for the PrEP of COVID-19 in adults and adolescents (12 years of age and older weighing at least 40 kg) based on immunobridging data from the CANOPY study, which suggests pemivibart should have similar efficacy against the newer Omicron subvariants as was previously seen with adintrevimab (the parent mAb of pemivibart) in the setting of circulating Delta variants and other anti–SARS-CoV-2 mAbs [2]. FDA authorization was based on immunobridging; the serum neutralization titer was used to compare pemivibart to other anti–SARS-CoV-2 mAbs that showed clinical efficacy.

In this focused update to the 2023 guideline [14], a recommendation and remarks are provided for pemivibart as PrEP. The primary audience for this recommendation is clinicians managing moderately or severely immunocompromised persons aged 12 years or older.

METHODS

The panel's recommendation is based on evidence derived from a systematic review and adheres to a standardized methodology for rating the certainty of evidence and strength of recommendation according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach (Supplementary Figure 1) [15]. The recommendation has been endorsed by the Pediatric Infectious Diseases Society, the Society of Infectious Diseases Pharmacists, the Society for Healthcare Epidemiology of America, and the Society of Critical Care Medicine.

Strong recommendations are made when the recommended course of action would apply to most people with few exceptions. Conditional recommendations are made when the suggested course of action would apply to the majority of people with many exceptions and shared decision making is important.

A literature search was conducted in May 2024 as part of a systematic review. Key eligibility criteria at both the topic and clinical question levels guided the selection of studies for inclusion. For this clinical question, immunocompromised persons aged 12 years or older were included. The primary comparator of interest was pemivibart versus no pemivibart; however, other mAbs were also considered.

A critical appraisal of the evidence according to the GRADE approach, along with an assessment of the benefits and harms of care options informed the recommendation(s) [15, 16]. Details of the systematic review and guideline development processes are available in the Supplementary material.

SUMMARY OF EVIDENCE

One ongoing randomized controlled trial (RCT) was identified studying PrEP with a single dose of 4500 mg IV pemivibart administration in adults aged ≥18 years at increased risk of SARS-CoV-2 infection or inadequate response to COVID-19 vaccination [17] (Supplementary Table 1). Results of the effect of pemivibart in preventing symptomatic COVID-19 infections are expected later in 2024. In the interim, to inform anticipated clinical benefits of pemivibart, the panel relied on indirect evidence from an RCT of adintrevimab (see Table 2), the ancestral neutralizing antibody from which pemivibart was derived, previous studies evaluating other anti–SARS-CoV-2 mAbs, and immunobridging evidence [2, 10].

Benefits

In the EVADE RCT conducted in unvaccinated individuals, symptomatic COVID-19 infections occurred in 40/728 (5.5%) patients receiving placebo compared to 12/752 (1.6%) patients receiving adintrevimab (relative risk, 0.29; 95% confidence interval [CI], 0.15–0.55) [18]. Additionally, prior studies found that in vitro neutralizing titers of anti–SARS-CoV-2 mAbs, including adintrevimab and other anti–SARS-CoV-2 mAbs, were associated with clinical benefit [2, 10]. In vitro neutralizing activity of pemivibart appears retained with currently circulating variants as of June 2024 [19].

Harms

In the CANOPY trial, serious adverse events included anaphylaxis, which was observed in 4/623 (0.6%) participants receiving pemivibart, 2 of which were described as life-threatening (absolute risk increase of 6 more anaphylactic reactions in 1000; 95% CI, from 0 more to 12 more) [2].

Other Considerations

The panel's suggestion for the use of pemivibart is based on the following lines of evidence: the track record of success of anti–SARS-CoV-2 mAbs for both treatment and prevention; the phase 2/3 randomized controlled trial of the parent mAb adintrevimab demonstrating a 71% protection from symptomatic COVID-19; and immunobridging data.

The panel agreed the overall certainty of evidence for this recommendation was low (Table 2) because of concerns about: indirectness of evidence, given that efficacy of pemivibart is derived from immunobridging studies compared to adintrevimab and other anti–SARS-CoV-2 mAbs; uncertainty that pemivibart is active against the currently circulating variants; uncertain risks of pemivibart, including anaphylaxis; uncertainty regarding likelihood of symptomatic infections leading to hospitalizations and severe COVID-19 because of a lower risk of progression in 2024 than earlier in the pandemic when the adintrevimab study was conducted; lack of peer review for the immunobridging study; study risk of bias (Supplementary Table 2) in the CANOPY results reported; and imprecision because of the low number of symptomatic infections in the indirect data from adintrevimab. An additional source of uncertainty in adolescents is indirectness related to the inclusion of just 9 participants aged <18 years in the PrEP cohort of the EVADE trial and no participants <18 years of age in the CANOPY trial, necessitating extrapolation from adult data.

In the CANOPY study, 4/623 (0.6%) of participants were diagnosed with anaphylaxis, including 2 who were considered to have a severe reaction requiring emergency department visit and/or hospitalization. Because of the small number of participants who have received pemivibart in this trial, the true frequency of severe anaphylaxis remains unclear.

EQUITY CONSIDERATIONS

Efforts should be made to provide equitable access to this therapy for patients who may benefit, including those from marginalized communities, underserved populations, and diverse socioeconomic backgrounds. These include addressing barriers such as geographical disparities, financial constraints, language accessibility, and cultural considerations to ensure that all individuals have fair and inclusive opportunities to receive this treatment.

CONCLUSIONS AND RESEARCH NEEDS

The guideline panel issued a conditional recommendation for PrEP with pemivibart in moderately or severely immunocompromised individuals. Because of the limited clinical evidence, the resulting net benefit remains unknown for adults and may be clarified when final randomized trial evidence is available; it will remain unknown for patients aged 12–17 years because they were not included in the trial. Detailed data on the efficacy of PrEP specifically in immunocompromised individuals who have received COVID-19 vaccines are needed. Additionally, data regarding safety, serum neutralizing against emerging variants, clinical efficacy, and pharmacoeconomic analyses are needed.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The expert panel acknowledge the work of former panelists for their work on the primary guideline, as well as Drs. Scott Dryden-Peterson, Emmy Rubin, Alyssa Letourneau, and Ann Woolley for creating an early version of the risk stratification table. The panel also acknowledges the following organizations and selected reviewers for their review of the draft manuscript: Pediatric Infectious Diseases Society, Society of Infectious Diseases Pharmacists, Society for Healthcare Epidemiology of America, Society of Critical Care Medicine, and Drs. Roy Gulick and Annie Luetkemeyer.

Drs. Adarsh Bhimraj and Rajesh T. Gandhi are chair and vice chair of the panel, respectively. The Immunocompromised subgroup, under the leadership of Dr. Arthur Kim, led the development of the recommendation and associated remarks. Remaining panelists assisted with interpretation of data, as well as drafting, revising, and approving the recommendation and manuscript. Dr. Yngve Falck-Ytter, lead methodologist, and Dr. Rebecca Morgan, methodologist, were responsible for designing and performing the data analyses and leading the panel according to the GRADE process. Jennifer Loveless, methodologist, was responsible for project planning and management, including revisions to and final approval of the recommendation and manuscript.

Disclaimer. It is important to recognize that guidelines cannot always account for individual variation among patients. They are assessments of current scientific and clinical information provided as an educational service; are not continually updated and may not reflect the most recent evidence (new evidence may emerge between the time information is drafted and when it is published or read); should not be considered inclusive of all proper methods of care, or as a statement of the standard of care; do not mandate any course of medical care; and are not intended to supplant clinician judgment with respect to particular patients or situations. Whether to follow guidelines and to what extent is voluntary, with the ultimate determination regarding their application to be made by the clinician in the light of each patient's individual circumstances. While IDSA makes every effort to present accurate, complete, and reliable information, these guidelines are presented “as is” without any warranty, either express or implied. IDSA (and its officers, directors, members, employees, and agents) assume no responsibility for any loss, damage, or claim with respect to any liabilities, including direct, special, indirect, or consequential damages, incurred in connection with these guidelines or reliance on the information presented.

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Financial support. This work was supported by the Infectious Diseases Society of America. This work was funded in part by a cooperative agreement with the Centers for Disease Control and Prevention (CDC; grant number 6 NU50CK000477-04-01). The CDC is an agency within the Department of Health and Human Services (HHS). The contents of this guideline do not necessarily represent the policy of CDC or HHS and should not be considered an endorsement by the Federal Government.

References

Author notes