The key is using the right dose on the right patient at the right time.
COVID-19 convalescent plasma (CCP) is human plasma collected from individuals who have recovered from COVID-19 within the past 6 months and whose plasma contains SARS-CoV-2 antibodies.1 In the US, CCP products with high titers of antibodies to SARS-CoV-2 are authorized as passive immunotherapy for the treatment of COVID-19 in patients with immunosuppressive disease or those who are receiving immunosuppressive treatment in either the outpatient or inpatient setting.1
One of 4 antiviral products authorized or approved for COVID-19 treatment in the US, CCP is the only one that is derived from people, not patented, capable of being generated anywhere there is modern blood banking capacity, and keeps up with new variants by continuously evolving in accordance with the pandemic’s dynamic nature. As a biological product, CCP works by blocking the interaction between the viral spike protein and cellular receptors on human epithelial tissues (direct antiviral activity), binding to other parts of the virus (direct antiviral activity), activating cellular mechanisms for viral killing, and modulating the immune response to infection.
As with other pharmaceutical products, passive immune therapy in the form of CCP must be given at the right dose to the right patient at the right time to be effective. Since the onset of the pandemic, a significant amount of in vitro and clinical data has been developed to understand those variables. A recent review found that in less than 3 years, CCP has been examined in an astounding 39 randomized clinical trials enrolling 21,529 participants and in 70 matched cohort studies enrolling 50,160 participants.2 From this body of work, the following principles of therapy have emerged: To be effective, CCP must contain sufficient levels of active antibodies against the circulating strains of SARS-CoV-2, be given to patients at highest risk for progression to severe infection, and administered at a time when antiviral therapy can make a difference.
THE RIGHT DOSE
The basis of passive immunotherapy for the treatment of infectious diseases relies on the transfer of preformed antibodies. In CCP, those antibodies were produced by individuals who had previously been infected with SARS-CoV-2 and subsequently developed a robust antibody response. As mentioned above, a major but not sole mechanism of action of CCP is by direct antiviral activity, known as viral neutralization. This activity can be measured in viral culture systems and is used to determine whether an antibody product, be it monoclonal or CCP, is expected to be effective against circulating strains of SARS-CoV-2. Tests measuring antibody titers in CCP can be used as a surrogate to approximate effectiveness. The FDA has authorized the use of multiple tests to detect antibody levels that qualify a product as high-titer CCP.1
The efficacy of CCP also depends on whether it is well suited to the circulating variants. As a polyclonal product, the barrier to resistance in CCP is much higher than for monoclonal antibodies. Nonetheless, time and distance matter. Convalescent plasma obtained close to the time and place of use is more likely to be effective than that obtained during previous waves and at a great distance from where it is utilized.3,4
The importance of using plasma with sufficiently high antibody titers has been demonstrated clinically. In the early days of the pandemic, an expanded access program (EAP) made CCP available to hospitalized patients across the US. The products were of varying antibody titers, and patients ranged from moderately to desperately ill. Retrospective analyses of outcomes in this EAP showed that among patients hospitalized with Covid-19 who were not receiving mechanical ventilation, transfusion of plasma with higher anti–SARS-CoV-2 IgG antibody levels was associated with a lower risk of death than transfusion of plasma with lower antibody levels.5 In a randomized, double-blind, placebo-controlled trial of CCP in older patients within 72 hours of onset of mild COVID-19 symptoms, higher titers were associated with reduction of progression to severe disease, while lower titers were not.6
Plasma obtained from people who have both been vaccinated and previously infected (termed VAXCCP or hybrid CCP) generally far exceeds the threshold antibody levels established by the FDA and effectively neutralizes SARS-CoV-2.4 As new variants emerge, the efficacy of CCP collected from people infected with previous variants can wane.
Although some studies have demonstrated that CCP from people who had either received a recent vaccine or contracted COVID-19 is effective in vitro against BQ and XBB variants, others have reported a significant decline in antiviral activity against these newest variants.7,8 To keep up with changing variants and deliver a sufficient dose of antibodies, we generally recommend treatment with 2 units (≈ 400 mL) of CCP obtained from individuals who have been vaccinated and have recovered from COVID-19 within the past 6 months.
RIGHT PATIENT, RIGHT TIME
The vast majority of people with COVID-19 recover from acute infection whether or not they receive antiviral therapy. This is especially likely in highly immunized populations. Passive immunotherapy with CCP will make a measurable difference in people who do not have robust SARS-CoV-2 immunity and are at higher risk for progression to severe or persistent infection. According to the benefit index developed to identify whether an individual is likely to benefit from CCP,9 patients with preexisting conditions (diabetes, cardiovascular and pulmonary diseases) and blood type A or AB who are at an early COVID-19 stage (low baseline WHO scores) are expected to benefit, whereas those without preexisting conditions and at more advanced stages could be harmed.
In the US, CCP is authorized only for use in the treatment of COVID-19 in patients with immunosuppressive disease or those receiving immunosuppressive treatment.1 Immunocompromised patients, even those who have been vaccinated, may fail to develop an appropriate antiviral response to infection in a timely fashion and are at higher risk for progressive infection and even death. Patients with lung cancer or hematologic malignancy and those receiving chemotherapy are at particularly high risk. Several retrospective studies have shown CCP to be effective in patients with hematologic malignancy.10,11 In contrast, a retrospective study at centers across Italy failed to show an impact on efficacy in such patients, although concerns have been raised about the quality of the CCP used in that study.12 In a randomized clinical trial involving patients with severe COVID- 19, the subgroup of cancer patients who received CCP had a shortened median time to improvement (HR, 2.50; P = .003) and superior survival compared to the control group (HR, 0.28; P = .042).13 In another randomized trial, patients hospitalized with COVID-19 at less than 9 days since symptoms onset were assigned to receive 4 units of plasma over 2 days (≈ 840 mL) or usual care alone. In the subgroup of immunocompromised patients, mortality was lower among those who received CCP (HR, 0.37; 95% CI, 0.14-0.97).14 In a systematic review and meta-analysis, including 3 randomized clinical trials, 5 matched cohort studies, 13 uncontrolled large case series, and 125 case report series, transfusion of CCP was associated with a mortality benefit in immunocompromised patients with COVID-19.2
As with all antiviral therapy, treatment with CCP is most effective when the disease process is driven by active viral replication rather than by an overexuberant immune response. For most people, that is during the first few days of infection, but that period can be much longer in immune-compromised patients. Data from clinical trials indicates that CCP can be effective at preventing progression of disease when given early in the course of infection.6,15,16 Treatment at a much later period in the course of illness is generally ineffective,17,18 except in the immunocompromised, who often fail to develop effective antibody responses.
Because such patients may not have an effective antiviral immune response to infection but have persistently high levels of the virus that is driving the disease process, passive immunotherapy in the form of CCP can be effective at a later date. They include patients with B-cell malignancies and primary or acquired immunoglobulin deficiencies and recipients of CAR T-cell therapy, hematopoietic stem cell or solid organ transplant, and anti-CD19/20 therapy and other lymphocyte-targeted therapy. These patients may have persistent and relapsing fever, shortness of breath, hypoxemia, chest radiographic abnormalities, and prolonged periods of high respiratory tract viral levels as measured by low cycle threshold values on nucleic acid amplification testing.19 CCP has been effectively used alone and in combination with other antiviral agents to control infections in such individuals,19-21 who often need repeated doses of CCP as guided by clinical and virologic responses. Hence, timing is critical for the success of CCP or any antibody therapy in non-immunocompromised patients, whereas for the immunocompromised, even late use can be effective.
In the fourth year of the pandemic, most people have some immune experience with SARS-CoV-2 as a result of infection or vaccination, and mortality in this group is very low. However, the immunosuppressed lack this protection because their underlying conditions often preclude effective immune response. Today CCP has an important role in the management of COVID-19 in this vulnerable population, but to be effective, it must be given at the right dose, to the right patient, and at the right time. An approach to determining whether CCP could be used in a specific patient is outlined in the FIGURE.
1.FDA. Clinical Memorandum: COVID-19 Convalescent Plasma. December 27, 2021. https://www.fda.gov/media/155159/downloadAccessed January 19, 2023
2.Senefeld, JW, Gorman EK.Johnson, PW, et al. Mortality rates among hospitalized patients with COVID-19 treated with convalescent plasma: a systematic review and meta-analysis. medRxiv. Preprint posted online January 12, 2023. doi: doi:10.1101/2023.01.11.23284347
3.Kunze KL, Johnson PW, van Helmond N, et al. Mortality in individuals treated with COVID-19 convalescent plasma varies with the geographic provenance of donors. Nat Commun. 2021;12(1):4864. doi:10.1038/s41467-021-25113-5
4.Sullivan DJ, Franchini M, Joyner MJ, Casadevall A, Focosi D. Analysis of anti-SARS-CoV-2 Omicron-neutralizing antibody titers in different vaccinated and unvaccinated convalescent plasma sources. Nat Commun. 2022;13(1):6478. doi:10.1038/s41467-022-33864-y
5.Joyner MJ, Carter RE, Senefeld JW, et al. Convalescent Plasma antibody levels and the risk of death from Covid-19. N Engl J Med. 2021;384(11):1015-1027. doi:10.1056/NEJMoa2031893
6.Libster R, Pérez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe Covid-19 in older adults. N Engl J Med. 2021;384(7):610-618. doi:10.1056/NEJMoa2033700
7.Sullivan DJ, Franchini M, Senefeld JW, Joyner MJ, Casadevall A, Focosi D. Plasma after both SARS-CoV-2 boosted vaccination and COVID-19 potently neutralizes BQ.1.1 and XBB.1. bioRxiv. Preprint posted online December 16 2022. doi:10.1101/2022.11.25.517977
8.Wang Q, Iketani S, Li Z, et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell. 2023;186(2):279-286.e8. doi:10.1016/j.cell.2022.12.018
9.Park H, Tarpey T, Liu M, et al. Development and validation of a treatment benefit index to identify hospitalized patients with COVID-19 who may benefit from convalescent plasma. JAMA Netw Open. 2022;5(1):e2147375. doi:10.1001/jamanetworkopen.2021.47375
10.Thompson MA, Henderson JP, Shah PK, et al. Association of convalescent plasma therapy with survival in patients with hematologic cancers and COVID-19. JAMA Oncol. 2021;7(8):1167-1175. doi:10.1001/jamaoncol.2021.1799
11.Hueso T, Godron AS, Lanoy E, et al. Convalescent plasma improves overall survival in patients with B-cell lymphoid malignancy and COVID-19: a longitudinal cohort and propensity score analysis. Leukemia. 2022;36(4):1025-1034. doi:10.1038/s41375-022-01511-6
12.Lanza F, Monaco F, Ciceri F, et al. Lack of efficacy of convalescent plasma in COVID-19 patients with concomitant hematological malignancies: an Italian retrospective study. Hematol Oncol. 2022;40(5):857-863. doi:10.1002/hon.3060
13.Denkinger CM, Janssen M, Schäkel U, et al. Anti-SARS-CoV-2 antibody-containing plasma improves outcome in patients with hematologic or solid cancer and severe COVID-19: a randomized clinical trial. Nat Cancer. 2023;4(1):96-107. doi:10.1038/s43018-022-00503-w
14.LacombeK, Hueso T, Porcher R, et al. COVID-19 convalescent plasma to treat hospitalised COVID-19 patients with or without underlying immunodeficiency. medRxiv. Preprint posted online October 27, 2022. doi:10.1101/2022.08.09.22278329
15.Sullivan DJ, Gebo KA, Shoham S, et al. Early outpatient treatment for Covid-19 with convalescent plasma. N Engl J Med. 2022;386(18):1700-1711. doi:10.1056/NEJMoa2119657
16.Bar KJ, Shaw PA, Choi GH, et al. A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia. J Clin Invest. 2021;131(24): e155114. doi:10.1172/JCI155114
17.RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial. Lancet. 2021;397(10289):2049-2059. doi:10.1016/S0140-6736(21)00897-7
18.Estcourt LJ, Turgeon AF, McQuilten ZK, et al; Writing Committee for the REMAP-CAP Investigators. Effect of convalescent plasma on organ support-free days in critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2021;326(17):1690-1702. doi:10.1001/jama.2021.18178
19.Dioverti V, Salto-Alejandre S, Haidar G. Immunocompromised patients with protracted covid-19: a review of “long persisters”. Curr Transplant Rep. 2022;9(4):209-218. doi:10.1007/s40472-022-00385-y
20.Senefeld JW, Klassen SA, Ford SK, et al. Use of convalescent plasma in COVID-19 patients with immunosuppression. Transfusion. 2021;61(8):2503-2511. doi:10.1111/trf.16525
21.Hueso T, Pouderoux C, Péré H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood. 2020;136(20):2290-2295. doi:10.1182/blood.2020008423