SARS-CoV-2 Antibodies Decline Over Time in COVID-19 Convalescent Plasma

Antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, appear to decline over time in donated convalescent plasma, according to a study published in Blood. These findings will have implications for the use of convalescent plasma to treat the disease.

“If it is shown that COVID-19 convalescent plasma has clinical efficacy and that antibodies to SARS-CoV-2 are important in mediating this effect, our results would mean that convalescent plasma should be collected as soon as possible after disease resolution to ensure that maximal levels of antibodies are present,” corresponding author Renée Bazin, PhD, of Héma-Québec in Canada, told ASH Clinical News.

Dr. Bazin said it has become increasingly recognized and accepted that SARS-CoV-2 antibody levels decline after a few months. “This doesn’t mean that SARS-CoV-2 antibodies can no longer be detected in many convalescent individuals, but it does mean that their level is significantly lower than the level measured in the weeks following the onset of the disease,” she explained.

With this study, Dr. Bazin and researchers assessed COVID-19 convalescent plasma from patients enrolled in the CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness, or CONCOR-1, trial, which sought to determine if plasma infusions reduced the risk of intubation or death in hospitalized adults with COVID-19. A total of 282 donors were recruited from Héma-Québec, the agency responsible for the blood supply in Québec, and plasma was collected at least 14 days after their COVID-19 symptoms resolved. A semi-quantitative ELISA was used to determine seropositivity in this population.

At time of donation, approximately 6.9% of the convalescent plasma donors tested seronegative. The proportion of donors who tested seronegative increased to 15% when the investigators considered only donors who waited more than 11 to 12 weeks following symptom onset before they donated. This observation prompted the researchers to perform a longitudinal analysis of the anti-receptor binding domain (RBD) antibody response in 15 people who donated convalescent plasma at least four times.

People had a median age of 56 years (range = 20-67) at the time of donation. The first donation occurred between 33 and 77 days after symptom onset, while the last donation occurred between 66 and 114 days after symptom onset. Donors had mild/moderate to severe COVID-19 symptoms, but none of the patients were hospitalized.

All donors had a decrease in anti-RBD antibody levels between the first and last donation. Some donors demonstrated an increase in anti-RBD antibodies after their first donation; however, this was invariably followed by a subsequent decline. There was no correlation between the decrease in anti-RBD levels with the number of donations (p=0.1221).

A significant correlation was observed between the decrease in anti-RBD levels as a function of time between symptom onset and the time of the last donation (p=0.0002). According to the investigators, this finding indicated a waning anti-RBD response over time of convalescence.

There was a significant decrease in the optical density (OD) value on ELISA from baseline through the last donation, indicating a drop in RBD antibody levels (p<0.0001). The investigators also found similar median and mean OD values from 33 to 53 days and from 54 to 69 days after symptom onset (p=0.0313), suggesting that anti-RBD response is stable during the first 10 weeks following COVID-19 onset.

In addition, the researchers noted a decrease in OD values after about 20 days, which they said was “reminiscent of the plasma immunoglobulin G half-life of 21 days,” suggesting that de novo synthesis of anti-RBD antibodies was halted between the third and fourth quartiles (70-84 and 85-114 days after symptom onset, respectively) in all COVID-19 convalescent plasma donors.

The investigators added that “this time frame is consistent with the first wave of a humoral immune response during which short-lived plasma cells actively secrete pathogen-specific antibodies until the antigen is eliminated.” This may be followed by the emergence of a cellular memory response that could be involved in long-term protection against reinfection.

The decline in antibody levels does not mean that previously infected people are no longer immune to the virus, noted Dr. Bazin. “There is another important component of the adaptive immune system, which is made up of memory cells that remain in our body after the resolution of infection and which ‘remember’ the pathogen and how to fight it effectively,” she commented. “These cells are likely to persist longer than antibodies and some of these cells will produce new antibodies when reactivated if re-exposed to the virus.” Dr. Bazin added that there is currently a lack of understanding as to whether memory cells will last for months, years, or even decades.

Limitations of this study included the measurement of only anti-RBD antibodies in convalescent plasma from a small number of donors.

Dr. Bazin noted that she and her colleagues are currently collecting samples from their COVID-19 convalescent plasma donors to continue the longitudinal evaluation of the humoral response, including at more than 200 days after disease onset in some donors.

Study authors report no relevant conflicts of interest.

Reference

Perreault J, Tremblay T, Fournier MJ, et al. Waning of SARS-CoV-2 RBD antibodies in longitudinal convalescent plasma samples within four months after symptom onset. Blood. 2020 October 1. [Epub ahead of print]

It will be interesting to see whether future studies indicate the antibody decline in plasma is a general phenomenon associated with decay or whether it is specific to any other antibody subtypes. I think the other thing we’re going to learn a lot about in the next months to a couple of years is that assay development, rather than diagnostics, is really going to be a big deal in convalescent plasma for COVID-19.”

Michael Joyner, MD
Mayo Clinic
Rochester, MN