The Importance of Antibody Titer Determination to the Effective Use of Convalescent Plasma

Convalescent Plasma (CP) has been used prophylactically and therapeutically over the past century to address a variety of infectious threats. Two tenets of the use of CP were clear from prior experience in the setting of other infectious outbreaks: (1) best results are obtained when CP is given early in the course of the disease, and (2) plasma containing high-titer neutralizing capacity is necessary to achieve optimal results. The magnitude of the COVID-19 pandemic along with the initial lack of effective therapeutic alternatives, combined with the relative safety of the approach of administration of CP, led to the initiation of an expanded access program (EAP) that ultimately provided CP to tens of thousands of individuals. When the program was initiated, no high-throughput assay was available for the determination of antibody titers, so antibody positive units were administered without regard to titer. With foresight regarding the need to ultimately determine such titers, samples from the CP units administered were retained and titers were determined retrospectively. An automated live-virus neutralization assay was ultimately selected for this purpose based on an evaluation of its accuracy and precision. Ultimately, an analysis performed in 13,794 individuals from the EAP for which clinical outcomes were known following the administration of single units of COVID-19 CP between the period of April and August 2020 indicated that higher titer COVID-19 CP was associated with a modest reduction in absolute mortality. The benefit observed was confined to individuals who were not intubated, and there was a trend toward a greater reduction in mortality using the highest SARS-CoV-2 neutralizing antibody-containing CP units. This experience during the COVID-19 pandemic is instructive for the future. To facilitate the production of CP that is likely to be most effective, high-throughput assays to determine neutralizing antibody titers need to be developed and implemented early during an outbreak to facilitate the identification and early administration of high-titer units.