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Convalescent plasma: Optimal timeframe and donor profile

The optimal timeframe for donating convalescent plasma for use in COVID-19 immunotherapy, which was given emergency-use authorisation by the US Food and Drug Administration in August 2020, is within 60 days of the onset of symptoms, according to a new Penn State University-led study. The research also reveals that the ideal convalescent plasma donor is a recovered COVID-19 patient who is older than 30 and whose illness had been severe.

“Millions of individuals worldwide have recovered from COVID-19 and may be eligible for participation in convalescent plasma donor programmes,” said Vivek Kapur, professor of microbiology and infectious diseases, Penn State. “Our findings enable identification of the most promising donors and suggest that these people should donate quickly before their antibodies begin to wane.”

To investigate the duration of the immune response to SARS-CoV-2, the team examined the titers of IgM, IgG and virus neutralising (VN) antibodies in a cohort of 175 convalescent plasma donors for 142 days after the patients’ symptoms began.

“IgMs are the first group of antibodies to appear upon infection,” explained Sreenidhi Srinivasan, postdoctoral scholar in the Huck Institutes of the Life Sciences, Penn State. “After about two weeks, the body switches to making IgG antibodies, which are more durable and long-lasting.”

VN antibodies are those IgM and IgG antibodies that bind directly to viruses and prevent them from infiltrating cells, added Abhinay Gontu, graduate student in pathobiology, Penn State. “The levels of these VN antibodies are, by far, the best possible metric for choosing potential donors for immunotherapy provides because they provide the most protective immunity,” he said.

Unfortunately, added Kapur, VN antibodies have been difficult to detect with current antibody tests. However, in a recent paper published in the Journal of Clinical Investigation, the team reported the results of its study showing that VN titers are correlated with certain types of IgG antibodies, and that ELISA assays, or enzyme-linked immunosorbent assays, can be used to determine the titers of these IgG antibodies faster and easier than currently used methods.

In their current study the researchers used ELISA assays to determine the longevity of IgM, IgG and VN antibodies in their study participants. They found that robust IgM and IgG antibodies persisted in their study participants for at least 140 days after the onset of COVID-19 symptoms; yet, VN antibodies declined rapidly after 60 days to below the FDA’s recommended level for convalescent plasma donation.

“Our finding that a strong immune response persists through 140 days after symptom onset in most COVID patients was unexpected and is contrary to the claims of short-lived immunity and potential re-infection of some COVID patients,” said Suresh Kuchipudi, clinical professor of veterinary and biomedical sciences, Penn State.

Kuchipudi noted that in their previous study, he and his colleagues found that nearly 40% of the donors they studied lacked the necessary VN antibodies to pass on immunity to others, likely because their window of opportunity for donation had passed.

“This is particularly important when you consider that, to date, more than 100,000 COVID-19-infected individuals in the United States have received convalescent plasma donations from recovered patients,” he said.

Kapur added, “Taken together, our findings suggest that care should be taken in identifying which recovered patients qualify to be donors and that, if they choose to donate, these donors should do so quickly before their valuable VN antibodies begin to wane.”

Other authors on the paper include Meera Surendran Nair, Ruth H Nissly, Denver Greenawalt, Ian M Bird, Catherine Herzog, Matthew J Ferrari, Indira Poojary, Robab Katani, Scott E Lindner, Allen M Minns and Randall Rossi, all at Penn State. Authors from the Houston Methodist Hospital include Eric Salazar, Paul A Christensen, Brian Castillo, Jian Chen, Todd N Eagar, Xin Yi, Randall J Olsen, Picheng Zhao, Christopher Leveque, David W Bernard, Jimmy Gollihar and James M Musser. Todd N Eagar, Xin Yi, Randall J Olsen, David W Bernard and James M Musser are also affiliated with the Weill Cornell Medical College. Jimmy Gollihar is also affiliated with the CCDC Army Research Laboratory-South.

The National Institute of Allergy and Infectious Diseases, Army Research Office and Huck Institutes of the Life Sciences at Penn State supported this research.

 

Study details 1
Convalescent plasma anti–SARS-CoV-2 spike protein ectodomain and receptor-binding domain IgG correlate with virus neutralization

Eric Salazar, Suresh V. Kuchipudi, Paul A Christensen, Todd Eagar, Xin Yi, Picheng Zhao, Zhicheng Jin, S Wesley Long, Randall J Olsen, Jian Chen, Brian Castillo, Christopher Leveque, Dalton Towers, Jason Lavinder, Jimmy Gollihar, Jose Cardona, Gregory Ippolito, Ruth Nissly, Ian Bird, Denver Greenawalt, Randall M Rossi, Abhinay Gontu, Sreenidhi Srinivasan, Indira Poojary, Isabella M Cattadori, Peter J Hudson, Nicole M Josleyn, Laura Prugar, Kathleen Huie, Andrew Herbert, David W Bernard, John M Dye, Vivek Kapur, James M. Musser

Published in The Journal of Clinical Investigation on 10 September 2020

Abstract
The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) highlights the urgent need for assays that detect protective levels of neutralizing antibodies. We studied the relationship among anti-spike ectodomain (anti-ECD), anti– receptor-binding domain (anti-RBD) IgG titers, and SARS-CoV-2 virus neutralization (VN) titers generated by 2 in vitro assays using convalescent plasma samples from 68 patients with COVID-19. We report a strong positive correlation between both plasma anti-RBD and anti-ECD IgG titers and in vitro VN titers. The probability of a VN titer of ≥160, the FDA-recommended level for convalescent plasma used for COVID-19 treatment, was ≥80% when anti-RBD or anti-ECD titers were ≥1:1350. Of all donors, 37% lacked VN titers of ≥160. Dyspnea, hospitalization, and disease severity were significantly associated with higher VN titer. Frequent donation of convalescent plasma did not significantly decrease VN or IgG titers. Analysis of 2814 asymptomatic adults found 73 individuals with anti-ECD IgG titers of ≥1:50 and strong positive correlation with anti-RBD and VN titers. Fourteen of these individuals had VN titers of ≥1:160, and all of them had anti-RBD titers of ≥1:1350. We conclude that anti-RBD or anti-ECD IgG titers can serve as a surrogate for VN titers to identify suitable plasma donors. Plasma anti-RBD or anti-ECD titers of ≥1:1350 may provide critical information about protection against COVID-19 disease.

 

Study details 2
Limited window for donation of convalescent plasma with high live-virus neutralizing antibody titers for COVID-19 immunotherapy

Abhinay Gontu, Sreenidhi Srinivasan, Eric Salazar, Meera Surendran Nair, Ruth H. Nissly, Denver Greenawalt, Ian M. Bird, Catherine M. Herzog, Matthew J. Ferrari, Indira Poojary, Robab Katani, Scott E. Lindner, Allen M. Minns, Randall Rossi, Paul A. Christensen, Brian Castillo, Jian Chen, Todd N. Eagar, Xin Yi, Picheng Zhao, Christopher Leveque, Randall J. Olsen, David W. Bernard, Jimmy Gollihar, Suresh V. Kuchipudi, James M. Musser, Vivek Kapur

Published in Communications Biology on 24 February 2021

Abstract
Millions of individuals who have recovered from SARS-CoV-2 infection may be eligible to participate in convalescent plasma donor programs, yet the optimal window for donating high neutralizing titer convalescent plasma for COVID-19 immunotherapy remains unknown. Here we studied the response trajectories of antibodies directed to the SARS-CoV-2 surface spike glycoprotein and in vitro SARS-CoV-2 live virus neutralizing titers (VN) in 175 convalescent donors longitudinally sampled for up to 142 days post onset of symptoms (DPO). We observed robust IgM, IgG, and viral neutralization responses to SARS-CoV-2 that persist, in the aggregate, for at least 100 DPO. However, there is a notable decline in VN titers ≥160 for convalescent plasma therapy, starting 60 DPO. The results also show that individuals 30 years of age or younger have significantly lower VN, IgG and IgM antibody titers than those in the older age groups; and individuals with greater disease severity also have significantly higher IgM and IgG antibody titers. Taken together, these findings define the optimal window for donating convalescent plasma useful for immunotherapy of COVID-19 patients and reveal important predictors of an ideal plasma donor.

[link url="https://www.jci.org/articles/view/141206/pdf"]The Journal of Clinical Investigation study (Open access)[/link]

 

[link url="https://www.nature.com/articles/s42003-021-01813-y"]Communications Biology study (Open access)[/link]

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