Issue 10: Convalescent plasma (CP) (MAY 8, 2020)

CONVALESCENT PLASMA FOR TREATING COVID-19 PATIENTS

This refers to plasma collected from individuals following resolution of infection and development of neutralizing antibodies  that can block viral entry, fusion, or egress.1,2. Administration of antibodies through  transfusion of convalescent plasma (CP) is termed passive antibody therapy3. It may prevent clinical infection or minimize disease severity in individuals with recent pathogen exposure. CP can also be used to treat patients already manifesting symptoms of varying severity.

MECHANISM OF ACTION

The quality and quantity of the antibody response dictates functional outcomes. High-affinity antibodies can elicit recognize specific viral epitopes, effectively neutralizing the virus (Fig. 1)3-5. Antibody-mediated pathways such as complement activation, antibody-dependent cellular cytotoxicity, and/or phagocytosis may also bolster that therapeutic effect. In vitro models showed that although non-neutralizing antibodies bind to pathogens, they do not impact replication, but may contribute to prophylaxis and/or enhance recovery. CP offers the only short-term strategy to confer immediate immunity to susceptible individuals. The antibodies’ duration of efficacy is currently unknown but may last weeks to a few months. In addition, CP therapy may be most effective when administered prophylactically or used early after the onset of symptoms3. This is particularly relevant in the current COVID-19 pandemic1.

CP DONORS AND RECIPIENTS

Subjects with resolved COVID-19 produce who mount a significant response to the disease can be qualified donors6. Criteria for potential doors include a confirmed history of COVID-19 from a diagnostic test at time of illness or positive serological test after recovery; complete symptom resolution ≥ 14 days before donation; and SARS-CoV-2 titers if available. Neutralizing antibody titers should be optimally greater than 1:160. Individuals should also be virus-free at the time of blood collection, thereby minimizing potential risk of infection to staff and other donors.  Eligible recipients are defined as: Laboratory confirmed COVID-19  case with severe/immediately life-threatening COVID-19, with informed consent6.

CP USE IN COVID-19 patients

Since COVID-19 CP is not yet FDA-approved,  it is regulated as an investigational product6. As such, administration by a US health-care provider must occur as an investigational new drug application (IND), an expanded access IND, a single-patient emergency IND application (eIND), or via Clinical trials. No US studies have yet been reported.

  • In a Chinese pilot study (N=10), CP with COVID-19 neutralizing antibodies was collected and transfused into patients within 4 hrs7 . The neutralization activity of one 200-mL dose was >1:640. All 10 patients had symptom (1-3 days) and radiological improvement (7 days) after transfusion. Recovered patients (97.5%) displayed neutralizing antibody titers ≥160. No significant adverse events were reported.
  • A case series of five critically ill patients also reported improvement in clinical status following transfusion with CP (SARS-CoV-2 IgG titers >1000)8. They were  weaned off mechanical ventilation, showed reduction in viral loads, and had improved oxygenation and clinical stability.
  • Zhang et al. reported on four cases successfully treated with 200-400 mL of O- or B-compatible CP per dose given 1, 3, or 8 times; titers not reported9. Ye et al. reported successful treatment on six late-stage patients with 1-3 doses of ABO-compatible CP with IgG10. Two cases were also successfully treated in Korea with two doses of 250 mL each, where optical densities (ODs) for IgG were 0.586 and 0.532 (suggestive of good titers; OD cutoff: 0.22)11.

Early reports suggest good outcomes with CP; however,  studies were conducted in small patient numbers, with no control groups, and varied protocols. Thus, several questions arise12:

  • What is the optimal donor titer?
  • What is the optimal dose, and how long should CP be administered?
  • Should CP be administered earlier or later (<10 days vs.  >10 days  from symptom onset)?
  • Do other therapies impact results?

Hopefully, these and other CP-related questions will be answered by one of the many registered clinical trials.

REFERENCES:

  1. Bloch et al. J Clin Invest. 2020.
  2. Iwasaki and Yang. Nature Reviews Immunology (2020
  3. Casadevall et al. Trends Immunol. 2003;24(9):474-8.
  4. van Erp et al. Front Immunol. 2019;10:548.
  5. Gunn et al.  Cell Host Microbe. 2018;24(2):221-33.e5
  6. https://www.fda.gov/media/136798/download
  7. Duan et al. medRxiv. 2020:2020.03.16.20036145.
  8. Shen et al. Jama 2020. 323(16):1582-1589 .
  9. Zhang et al. Chest. 2020 Mar 31.
  10. Ye et al.  https://onlinelibrary.wiley.com/doi/epdf/10.1002/jmv.25882
  11. Ahn et al. J Korean Med Sci. 2020 Apr 13;35(14):e149
  12. Langhi Jr et al.  https://doi.org/10.1016/j.htct.2020.04.003