Unlocking the Potential of HIV-Infected Deceased Donors for Organ Transplantation

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), has spurred a global health crisis. To date, there are no proven options for prophylaxis for those who have been exposed to SARS-CoV-2, nor proven therapy for those who develop COVID-19. Passive antibody (Ab) administration through transfusion of convalescent plasma may offer the best and only short- term strategy to confer immediate immunity to susceptible individuals. In the United States, convalescent plasma transfusions could potentially be used as a prophylaxis for those at high-risk or those showing early symptoms of SARS-CoV-2. The blood transfusion community has begun collecting convalescent plasma from individuals who have recovered from COVID-19. As part of this effort, the US Food and Drug Administration has set a target of a titer greater than 1:320 for the ideal convalescent plasma donor. However, in the US only 70% of recovered patients (at least 14 days symptom free) have had high viral titers meeting the FDA recommendation. It is unknown why some individuals have high titers and others do not. We propose that increased viral titers are associated with low Ab binding affinity and increased inflammation resulting from a `cytokine storm'. We hypothesize that individuals with low antibody titers have a strong neutralizing antibody response due to higher antibody binding avidity, past viral exposures, and a favorable inflammatory response making them suitable for effectively clearing SARS-CoV-2 viral infections. The proposed aims will utilize >120 recovered SARS-CoV-2 donors of plasma and peripheral blood mononuclear cells (PBMC). Our clinical team has already received FDA Investigational New Drug (IND) clearance (IND 19725) and IRB approval to begin collecting convalescent plasma from recovered donors. We have already screened >120 convalescent plasma donors and have access to demographic information. We propose the following aims: Aim 1: Evaluate total antibody repertoire and neutralizing antibody response in convalescent plasma donors. Aim 1b. Evaluate current or prior viral exposures effect on SARS- CoV-2 antibody titers. Aim 2: Characterize inflammatory environment of convalescent plasma donors comparing those with a high titer to those with low titer. Aim 3: Assess if SARS-CoV-2 infection and associated proinflammatory immune responses reactivate latent viral infections in convalescent plasma donors. Convalescent plasma, as well as future monoclonal Ab therapy, represent some of the few promising therapies for COVID-19, and it is critically important to fully understand how these protective antibodies develop and how the viral titer can be interpreted. These proposed studies will also aid in the development of assays to determine antibody avidity and affinity in convalescent patient plasma to be used for future transfusion treatments and future outbreaks.