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Neutralizing Antibodies Shortly
After COVID-19 Recovery: Scant But Strong
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Mark Mascolini
Most plasma collected in the month after recovery from COVID-19 does not contain high levels of neutralizing antibodies, according to results of a 149-person US study [1]. But all participants did have certain SARS-CoV-2 spike-specific antibodies with high neutralizing activity. That led researchers to suggest that "a vaccine designed to elicit such antibodies could be broadly effective."
SARS-CoV-2 depends on its spike-localized receptor binding domain (RBD) to enter target cells. Researchers from New York City's Rockefeller University and collaborators from other centers noted that antibodies against spike RBD will probably be essential to protect people who recover from COVID-19 from subsequent infection. Those antibodies form the rationale for treatment of COVID-19 with convalescent plasma, and a successful vaccine must elicit such antibodies. Because much remains unknown about antibody responses to SARS-CoV-2, they conducted this study.
People were eligible for the study if they had RT-PCR-confirmed SARS-CoV-2 infection (cases, 71%) or were close contacts of infected people (contacts, 29%). The 149 recruited cases and contacts were free of COVID-19 symptoms at least 14 days before sample collection. Almost all participants were non-Hispanic white, and most were men.
COVID-19 symptoms developed in all but 1 person infected with SARS-CoV-2 about 39 days (range 17 to 67) before researchers collected samples for this study. Symptoms lasted an average 12 days (range 0 to 35), and 11 people (7% of 149) got admitted to the hospital.
While 78% of plasma samples had anti-RBD antibody area under the curve (AUC) at least 2 standard deviations (SD) above control AUCs, 70% of samples had antispike IgG AUC above that level. Only 15% and 34% of plasma samples had anti-RBD and antispike IgM responses at least 2 SD above control AUC. Anti-RBD or antispike IgG or IgM levels did not correlate with symptom duration or plasma collection timing. Anti-RBD IgM levels correlated negatively with duration of symptoms and sample collection timing. Anti-RBD IgM levels correlated modestly with age and symptom severity.
The researchers measured neutralizing activity of plasma in convalescent participants by using HIV-1-based virions carrying a nanoluc luciferase reporter that were pseudotyped with the SARS-CoV-2 spike (SARS-CoV-2 pseudovirus). They included negative and positive controls in all experiments. Overall neutralizing activity in plasma of these people was low: 33% had had half-maximal pseudovirus neutralizing titers (NT50) below 1:50, while 79% were below 1:1000. Only 1% of samples had neutralizing titers above 1:5000. Geometric mean neutralizing titer stood at 121, and only 2 participants reached an NT50 above 5000. In the 2 top neutralizers and 4 high-to-intermediate neutralizers, antigen-specific B-cell frequency ranged from 0.07% to 0.005% of all circulating B cells in COVID-19 convalescents.
Still, the researchers found certain potent neutralizing antibodies in all participants regardless of their plasma NT50. Specifically, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50) as low as single-digit nanograms per milliliter. The researchers inferred that SARS-CoV-2 RBD bears multiple distinct neutralizing epitopes.
The finding that recurrent anti-SARS-CoV-2 RBD antibodies with strong neutralizing activity can be detected in COVID-19 convalescents with "unexceptional plasma neutralizing activity" suggests to the authors that "humans are intrinsically capable of generating anti-RBD antibodies that potently neutralize SARS-CoV-2." Vaccines inducing such antibodies may be "especially effective" in preventing COVID-19.
Reference
1. Robbiani DF, Gaebler C, Muecksch F, et al. Convergent antibody responses to SARS-CoV-2 in convalescent individuals. Nature 2020. https://doi.org/10.1038/s41586-020-2456-9
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