A second open letter to NIH for revisions to CCP recommendations
August 9, 2022
Dear NIH COVID – 19 Guidelines Committee,
We read with interest the recently updated (Aug 8, 2022) inpatient(1) outpatient (2) and immunocompromised(3) treatment guidelines for COVID-19 but were disappointed to see that the NIH committee declined to issue a recommendation on COVID-19 convalescent plasma (CCP) therapy in the immunocompromised population. We remain concerned that the committee is overlooking key data on CCP efficacy, and worse, applying a double standard in light of the criteria used to recommend bebtelovimab.
Current FDA-approved CCP resumed collection in 2022 after the widespread availability of SARS-CoV-2 vaccines and the emergence of Omicron. CCP from vaccinated and convalescent donors has extremely high titers and neutralizes multiple Omicron variants of concern (4,5,6). Unlike monoclonal antibody preparations, the polyclonal antibody response in recently collected CCP effectively adapts in real time to new variants and is readily sourced given the high community prevalence of SARS-CoV-2 infections (7). Notably, these current CCP units have markedly higher SARS-CoV-2 antibody titers than the CCP units used in many of the randomized clinical trials (RCT) and observational data published over the last two years. These kinds of data – in vitro binding and viral neutralization – were deemed sufficient for the committee’s recommendation of Bebtelovimab in the outpatient setting, even in the absence of RCT data on this product. In contrast, two well-conducted outpatient CCP RCTs (8,9) have demonstrated CCP efficacy. In view of this, it appears to us that different evidentiary standards were used to consider these two antibody-based therapies.
Data supporting CCP use in immunosuppressed - particularly B-cell depleted - patients, in inpatient and ambulatory settings, continues to emerge and have been recently summarized in a meta-analysis (10).We further note that three major societies, the IDSA, (11) the AABB, (12) and the European Conference on Infections in Leukemia (13) each recommend CCP use in immunosuppressed patients. The FDA EUA (14) explicitly endorses the use of CCP in immunosuppressed patients and patients on immunosuppressive therapy.
Relative to the threshold set for the committee’s bebtelovimab recommendation, we believe there is more than sufficient evidence for the NIH to support CCP use in immunocompromised patients and other high risk groups in accordance with the FDA authorization. In a letter from our group dated May 9. 2022 signed by dozens of prominent physicians (15) we asked the NIH to fully update and revise its CCP recommendations. Three months later, this has not happened.
Finally, beyond the rationale above, shrinking bebtelovimab supplies from the US Government (which may be exhausted by the end of August), rapid escape of mAbs by new variants, (16) non-durable responses to antivirals, and the smoldering cases (17) now seen in the immune suppressed, mean that CCP may become the only accessible antibody therapy in the near future. We ask again that the committee revisit the utility of CCP in multiple use cases and extend an offer to present the case for CCP to the committee via Zoom. The time to act is now.
The U.S. Convalescent Plasma Project leadership team (ccpp19.org)
Arturo Casadevall MD, PhD (CCPP19.org Chair)
Chair, Molecular Microbiology & Immunology
Alfred & Jill Sommer Professor and Chair
Bloomberg Distinguished Professor
Professor, Department of Molecular Microbiology and Medicine
Johns Hopkins School of Public Health and School of Medicine
Michael Joyner, MD
Caywood Professor of Anesthesiology
Vice Chair (Research) Department of Anesthesiology & Perioperative Medicine
Brenda J. Grossman, MD, MPH
Professor, Pathology & Immunology
Professor of Medicine
Medical Director, Transfusion Medicine Services
Washington University School of Medicine
Jeffrey P. Henderson, MD, PhD
Associate Professor of Medicine and Molecular Microbiology
Division of Infectious Diseases
Washington University School of Medicine
Nigel Paneth MD MPH
University Distinguished Professor, Emeritus
Departments of Epidemiology & Biostatistics and Pediatrics & Human Development
Michigan State University
Liise-anne Pirofski MD
Selma and Dr. Jacques Mitrani Chair in Biomedical Research
Professor, Medicine, Microbiology, and Immunology
Chief, Division of Infectious Diseases
Albert Einstein College of Medicine and Montefiore Medical Center
Shmuel Shoham MD
Department of Medicine
Johns Hopkins School of Medicine
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- Focosi D, Franchini M, Joyner M, Casadevall A, Sullivan D. Analysis of anti-Omicron neutralizing antibody titers in different convalescent plasma sources. medRxiv 2021.12.24.21268317; doi:https://doi.org/10.1101/2021.12.24.21268317
- Mayanka Awasthi, Hana Golding, Surender Khurana, SARS-CoV-2 hyperimmune intravenous human immunoglobulins neutralizes Omicron subvariants BA.1, BA.2, BA.2.12.1, BA.3 and BA.4/BA.5 for treatment of COVID-19, Clinical Infectious Diseases, 2022;, ciac642, https://doi.org/10.1093/cid/ciac642
- Libster R, Perez Marc G, Wappner D et al: Early High-Titer Plasma Therapy to Prevent Severe Covid-19 in Older Adults. N Engl J Med 2021 Feb 18;384(7):610-618.
- Sullivan DJ, Gebo KA, Shoham S et al: Early Outpatient Treatment for Covid-19 with Convalescent Plasma. N Engl J Med 2022 May 5;386(18):1700-1711.
- Senefeld JW, Franchini M, Mengoli C et al: COVID-19 convalescent plasma for the treatment of immunocompromised patients: a systematic review. https://doi.org/10.1101/2022.08.03.2227835
- The Infectious Disease Society of American: IDSA Guidelines on the Treatment and Management of Patients with COVID-19. Published by IDSA on 4/11/2020. Last updated, 6/29/2022
- Estcourt LJ, Cohn CS, Pagano MB: Clinical Practice Guidelines from the Association for the Advancement of Blood and Biotherapies (AABB): COVID-19 Convalescent Plasma.https://www.aabb.org/docs/default-source/default-document-library/regulatory/clinical-practice-guidelines-from-aabb-ccp.pdf?sfvrsn=e24ea825_0B
- Cesaro S, Ljungman P, Mikulska M et al: Recommendations for the management of COVID-19 in patients with haematological malignancies or haematopoietic cell transplantation, from the 2021 European Conference on Infections in Leukaemia (ECIL 9). Leukemia 2022; 36:1467–1480
- Letter from Jacqueline A. O'Shaughnessy, Acting Chief Scientist FDA to Dawn O’Connell, USDHHS. December 28, 2021. Chrome extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.fda.gov/media/141477/download
- https://ccpp19.org/Letter%20to%20NIH%20asking%20for%20revisions%20to%20CCP%20recommendations%20May%209,%202022.pdf. May 9, 2022
- Yamasoba D, Kosugi Y, Kimura I et al: Neutralisation sensitivity of SARS-CoV-2 omicron subvariants to therapeutic monoclonal antibodies. Lancet Infect Dis. 2022 Jul;22(7):942-943.
- Pommeret F, Colomba J, Bigenwald C et al: Bamlanivimab + etesevimab therapy induces SARS-CoV-2 immune escape mutations and secondary clinical deterioration in COVID-19 patients with B-cell malignancies. Ann Oncol 2021 Nov;32(11):1445-1447