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Early Immune Responses Predict Outcome of Severe COVID-19

Key findings

  • In this study, researchers identified SARS-CoV-2 antibody signatures that evolved within 20 days after the onset of COVID-19 symptoms and correlated with death or recovery from severe disease
  • Specifically, 12 survivors of severe COVID-19 exhibited two immune response markers focused on the spike protein of SARS-CoV-2, whereas 10 non-survivors had three markers focused on the nucleocapsid
  • Similar results were observed in a validation cohort of 20 survivors and 20 non-survivors
  • Considered collectively, the five antibody features outperformed characteristics such as sex, age and viral load at distinguishing survivors from non-survivors; they appear capable of serving as biomarkers that predict the outcome of severe COVID-19

More alarming than the rapid spread of SARS-CoV-2 is the current inability to predict which infected individuals will have a mild or rapidly severe course of COVID-19. Now, researchers have identified SARS-CoV-2 antibody signatures in blood samples that evolve soon after infection and correlate with disease outcome.

Galit Alter, PhD, principal investigator at the Ragon Institute of Massachusetts General Hospital, MIT and Harvard, and Samana Cay MGH Research Scholar; graduate researchers Caroline Atyeo, Stephanie Fischinger and Tomer Zohar; and Helen Chu, MD, MPH, of the University of Washington; and colleagues published their findings in Immunity.

Initial Cohort

Plasma from 22 COVID-19 patients was collected at the time of their admission at the University of Washington in Seattle, one of the earliest U.S. epicenters of the disease. All samples were collected within 20 days after symptom onset. Twelve patients went on to recover and 10 died.

Antibody Profiles

The researchers performed a systems serology technique, developed at Mass General in the Alter Lab, to determine the biophysical and functional characteristics of antibodies against three SARS-CoV-2 proteins: the spike protein (S), the S-derived receptor-binding domain and the nucleocapsid (N). No single antibody feature discriminated between patients who recovered and those who died.

Antibody Profile Coordination

The researchers then examined whether multiple antibody features might work together to control SARS-CoV-2 infection. They found that survivors exhibited a more S-focused immune response, whereas non-survivors had a more N-focused response.

The minimum set of antibody features that differentiated the two groups were:

  • In survivors, S-specific IgM and IgA1 titers were enriched
  • In non-survivors, N-specific IgM and IgA2 titers were enriched along with N-specific antibody-dependent complement deposition

Individually, these five features possessed only modest power to differentiate survivors and non-survivors. Considered collectively, though, they outperformed characteristics such as sex, age, viral load and days since symptom onset.

Validation of the Immune Response

The same results were observed when the researchers studied 40 COVID-19 patients in Boston: 20 who recovered and 20 who died. As in Seattle, plasma samples were taken within 20 days after symptom onset. Survivors exhibited a bias toward elevated S-specific immunity compared with N-specific immunity.

New Biomarkers

These data suggest that antibody profiles evident early in severe COVID-19 are biomarkers that predict the outcome. Most importantly, these findings can be used to develop diagnostics to support clinical and also provide insights for the development of better drugs and vaccines.

This research involved patients with severe disease, but future studies may be able to define antibody profiles that classify individuals across the clinical spectrum of COVID-19, including asymptomatic disease.

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