Infectious Disease Updates
April 1, 2025
By Carol A. Kemper, MD, FIDSA
COVID Monoclonals Needed for PrEP
Source: Casadevall A, Focosi D, Pirofski LA, Shoham S. Single monoclonal antibodies should not be used for COVID-19 therapy: A call for antiviral stewardship. Clin Infect Dis. 2024;79(6):1404-1407.
During the COVID-19 pandemic, infectious disease physicians used antibody therapeutics for the first time, with the use of anti-spike monoclonal antibodies (mAbs), specifically for immunosuppressed (ICH) individuals and those at high risk for complications of SARS-CoV-2 infection. In the United States, a series of mAbs were temporarily approved for use by the United States Food and Drug Administration (FDA) Emergency Use Authorization (EUA). Unfortunately, the rapid emergence or divergence of spike protein mutations quickly rendered these agents ineffective, and the last of these agents was “deauthorized” more than two years ago.
While the emergence of SARS-CoV-2 variants was driven by multiple factors, these authors believe that the use of these agents in patients with active COVID-19 infection may have contributed to the emergence and transmission of resistance to mAbs. Simply put, when such agents are used for preexposure prophylaxis (PrEP), they are theoretically less likely to promote escape mutants in persons with exposure and initial infection (with a viral load of ~103 ribonucleic acid [RNA] copies) than in those with active infection (a diagnostic swab sample from an ICH person with active infection can have up to 1011 RNA copies).
However, there still is a need for PrEP in ICH persons who fail to mount an adequate immune response to COVID vaccine. Newer mAb agents are being developed: AstraZeneca has submitted a request to the European Medicines Agency for the use of sipavibart, a long-acting mAb, for PrEP in ICH. In a Phase III clinical trial, sipavibart was effective at preventing COVID-19 infection, at least for variants not containing the F456L spike mutation (which causes resistance). In 2024, in the United States, pemivibart (Pemgarda) was granted EUA for individuals 12 years of age or older with moderate to severe immune compromise due to a medical condition or receipt of immunosuppressive medications “who are unlikely to mount an adequate immune response to COVID-19 vaccination.”1 It is not approved for use in people with recent exposure to COVID-19 infection or those with active infection. Other spike-protein mAbs are in development.
These authors maintain that infectious disease physicians must refrain from the use of mAb agents for the treatment of active COVID-19 infection if their effectiveness is to be preserved for PrEP. Such agents should only be used in people who are SARS-CoV-2 seronegative (although it may not be possible to readily determine this) and who are at the greatest risk for more severe complications of infection. Viral genome sequencing data in a region may provide helpful information whether a specific mAb remains useful in that area. In addition, convalescent COVID-19 plasma (CCP) remains available by EUA and remains effective for rescue therapy in more severe COVID infection, despite the emergence of variants. In contrast to an mAb that targets a single epitope, CCP would be less likely to select for resistant variants.
Reference
1. Food and Drug Administration. Fact sheet for patients, parents, and caregivers: Emergency Use Authorization (EUA) of Pemgarda (pemivibart) for coronavirus disease 2019 (COVID-19). Revised August 2024. https://www.fda.gov/media/177069/download
Oral Camostat Ineffective in COVID-19
Source: Jilg N, Chew KW, Giganti MJ, et al. One week of oral camostat versus placebo in non-hospitalized adults with mild-to-moderate coronavirus disease 2019: A randomized controlled Phase 2 trial. Clin Infect Dis. 2023;77(7)941-949.
On occasion, patients still request off-label use of alternative agents and immunomodulatories for COVID infection, although with less frequency than two to four years ago. As part of a large-scale effort to assess a variety of potential therapeutics in COVID-19 infection, these authors at Brigham and Women’s Hospital examined oral camostat vs. placebo in the treatment of mild-to-moderate SARS-CoV-2 infection. Camostat is an oral serine protease inhibitor that is used for acid reflux and chronic pancreatitis (in Japan) and was found in vivo to block entry of virus into lung cells. Smaller clinical trials suggested it may have a beneficial effect on inflammatory markers and oxygenation in COVID-19 infection.
ACTIV-2/A5401 is a Phase II/III clinical trial of outpatient therapy of mild to moderate COVID-19 infection, examining the benefits of oral camostat 200 mg daily every six hours for seven days vs. a matching placebo. The study was conducted in 2021, and 224 participants were enrolled, of which 216 were included in the intent-to-treat analysis (109 camostat and 107 placebo). Of these, 92% completed treatment and were followed for 28 days. Baseline characteristics of the groups were similar. At day 7, 64% vs. 68% of patients demonstrated nasopharyngeal swabs with undetectable amounts of viral ribonucleic acid (RNA), and at day 14, 87% vs. 88% of patients had nasopharyngeal swabs with undetectable RNA.
Less than half of patients (45%) had five or fewer days of symptoms at study entry, and 26% were at higher risk for more severe infection. Eleven patients required hospitalization (5.6% in the camostat arm vs. 4.7% in the placebo arm); one of the patients receiving camostat developed appendicitis, and there was one death in the camostat arm from progressive COVID-19 infection. The median time to improvement in symptoms was nine days for each of the study arms. In contrast, 14% vs. 16% of those receiving camostat vs. placebo did not meet the definition of symptom improvement at day 28 of follow-up. A subgroup analysis of those entering study with less than five days of symptoms demonstrated no apparent difference in outcomes.
No improved symptom response, nor reduction in hospitalization or death was observed with seven days of camostat in this placebo-controlled trial in patients with mild-to-moderate COVID-19 infection. The authors speculated that the lack of observed benefit could be multifactorial: Entry of virus into respiratory cells may differ depending on strain type; alternate routes of viral entry exist, so blocking the serine-dependent entry pathway may not be sufficient; the dosage of the drug may be insufficient for a respiratory pathogen (other studies suggest that higher dosages than those used here may be necessary); and every six hour dosing may have contributed to lower drug exposure; 19% of those in the camostat arm admitted to missing at least four doses of the drug during the seven days, and 11 patients initiating camostat withdrew or discontinued the drug before day 7.
Mpox: Lessons Learned from Rio
Source: Torres Silva MS, Coutinho C, Torres TS, et al. Exploring the resurgence of a neglected disease: Lessons from the 2023-2024 mpox outbreak in Rio de Janeiro, Brazil. Clin Infect Dis. 2024;79(3):656-659.
The worldwide outbreak of mpox surprised everyone in 2022-2023, but by May 2023 the World Health Organization declared the end of the mpox emergency. And yet, that was hardly the end for this infection, as mpox continues to occur with alarming frequency in 12 African countries, and a second wave of infection occurred in Brazil in late 2023. In all, 10,967 cases of mpox were confirmed in Brazil through December 2023.
These authors described their experience with mpox infection following the first outbreak of infection in Rio de Janeiro from June 2022 through May 2023, during which 983 cases of suspected mpox occurred (48% confirmed). Following this, there was a four-month hiatus in cases, where 64 individuals were tested for mpox, but none were positive, and authorities were confident the outbreak had been successfully quelled. However, in late September, a new case was detected, followed by a steady resurgence of cases through January 2024. During this second wave of infections, another 196 persons were diagnosed with mpox infection (60% confirmed).
Only 1/196 individuals diagnosed in the second outbreak had received the Jynneos vaccine (and that individual had received only one dose); none of the others were vaccinated. Compared with the first outbreak, a greater proportion of those in the second outbreak were men who have sex with men (MSM) (97%), self-identified as Black (69%), participated in anal sex (69%), and were younger than those diagnosed during the first outbreak. Nearly two-thirds of individuals in the second outbreak were human immunodeficiency virus (HIV)-infected (62%), and many were receiving HIV preexposure prophylaxis (PrEP) at the time of their mpox diagnosis. Participants took more time to present for evaluation during the second wave, perhaps because the outbreak supposedly had ended.
The resurgence of mpox cases in late 2023-2024 in Rio de Janeiro, Brazil, serves as a story board for the importance of sustained efforts at disease control. This second wave of infection confirms the continuous unrecognized transmission in persons at risk, even when authorities thought the epidemic had ended. These authors affirmed the need for ongoing surveillance in the community; maintaining a heightened awareness of disease in high-risk persons; the availability of rapid diagnostics; monitoring disease activity in wastewater; and the importance of vaccine strategies to target MSM and HIV-infected persons. Notably, many of the people affected by this second outbreak were receiving HIV treatment or PrEP, but none were sufficiently vaccinated for mpox. Even now, in the United States, Jynneos vaccine is in such short supply, people at risk must be referred to the public health department for vaccine risk stratification and immunization. Requiring extra steps for some of these high-risk patients, on the fringe of the socioeconomic divide and perhaps reluctant to divulge their activities, only diminishes immunization efforts.
Carol A. Kemper, MD, FIDSA, is Medical Director, Infection Prevention, El Camino Hospital, Palo Alto Medical Foundation.
COVID Monoclonals Needed for PrEP; Oral Camostat Ineffective in COVID-19; Mpox: Lessons Learned from Rio
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