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.

Sincerely,

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

Mayo Clinic

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

Professor

Department of Medicine

Johns Hopkins School of Medicine

REFERENCES

1. NIH COVID-19 Treatment Guidelines: Therapeutic Management of Hospitalized Adults With COVID-19. August 8, 2022.
2. NIH COVID-19 Treatment Guidelines: Therapeutic Management of Non-hospitalized Adults With COVID-19. August 8, 2022.
3. NIH COVID-19 Treatment Guidelines: Special Considerations in People Who Are Immunocompromised.COVID-19. August 8, 2022.
4. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, Perez JL, Pérez Marc G, Moreira ED, Zerbini C, Bailey R, Swanson KA, Roychoudhury S, Koury K, Li P, Kalina WV, Cooper D, Frenck RW Jr, Hammitt LL, Türeci Ö, Nell H, Schaefer A, Ünal S, Tresnan DB, Mather S, Dormitzer PR, Şahin U, Jansen KU, Gruber WC; C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020 Dec 31;383(27):2603-2615. doi: 10.1056/NEJMoa2034577. Epub 2020 Dec 10. PMID: 33301246; PMCID: PMC7745181.
5. Baden LR, El Sahly HM, Essink B, Kotloff K, Frey S, Novak R, Diemert D, Spector SA, Rouphael N, Creech CB, McGettigan J, Khetan S, Segall N, Solis J, Brosz A, Fierro C, Schwartz H, Neuzil K, Corey L, Gilbert P, Janes H, Follmann D, Marovich M, Mascola J, Polakowski L, Ledgerwood J, Graham BS, Bennett H, Pajon R, Knightly C, Leav B, Deng W, Zhou H, Han S, Ivarsson M, Miller J, Zaks T; COVE Study Group. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. Engl J Med. 2021 Feb 4;384(5):403-416. doi: 10.1056/NEJMoa2035389. Epub 2020 Dec 30.PMID: 33378609; PMCID: PMC7787219.
6. 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
7. 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
8. 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.
9. 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.
10. 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
11. 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
12. 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
13. 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
14. 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
15. https://ccpp19.org/Letter%20to%20NIH%20asking%20for%20revisions%20to%20CCP%20recommendations%20May%209,%202022.pdf. May 9, 2022
16. 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.
17. 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