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Distinct Immune Responses Develop in Hospitalized Patients with COVID-19

Key findings

  • This study profiled the antibody immune responses of 193 patients hospitalized for COVID-19 (82 with moderate disease, 76 with severe disease who required ICU admission but recovered, and 35 who died of severe COVID-19)
  • In the first week after symptom onset, similar IgM and IgA titers were observed in the three groups
  • Patients who survived severe COVID-19 class-switched to IgG antibodies with high-affinity binding to Fc receptors whereas nonsurvivors showed less robust switching, delayed evolution of Fc receptor binding and impairment of immune effector functions
  • The earliest functional antibody responses in survivors were to the S2-domain of the spike, which is super conserved across all coronaviruses; They may have effectively leveraged this pre-existing immune response to survive
  • This finding could be the foundation for making a better vaccine to an ultra-conserved site on the spike that could give broad coronavirus immunity

The development of vaccines against SARS-CoV-2 has focused on increasing antibody titers and promoting neutralization, in which antibodies bind to pathogens to inhibit their infectivity. However, once SARS-CoV-2 infection extends beyond the upper respiratory tract, more complex immune responses may be required to contain and eradicate it.

Galit Alter, PhD, principal investigator at the Ragon Institute of Massachusetts General Hospital, MIT and Harvard, and colleagues have found differences in the evolution of antibody titer and function in hospitalized patients with COVID-19. Specifically, as they report in Cell, recovery from severe infection requires early switching to IgG and the ability of antibodies to interact with Fc receptors, the "docking sites" on innate immune cells that target the virus's spike protein.

Study Cohort

The researchers studied 193 patients who were hospitalized for COVID-19:

  • 82 who did not require ICU admission (moderate COVID-19)
  • 76 with severe COVID-19 who required ICU admission but recovered
  • 35 who died of severe COVID-19

Early Responses

In the first week after symptom onset, similar IgM and IgA titers were observed in all three groups. This suggests the groups had similar early pathogen burden. However, IgG titers against the spike protein of SARS-CoV-2 were significantly higher in patients who survived severe disease than in the other two groups.

The Two Groups of Severely Ill Patients

After the first week, IgM and IgA responses increased in both survivors and nonsurvivors of severe illness, but the rise was more uniform and robust among survivors. Nonsurvivors also showed lower IgG response and lower binding of IgG to the Fc receptor.

By week three, killing of virus-infected cells and other immune effector functions were impaired in nonsurvivors compared with survivors.

The Two Groups of Survivors

Despite the delayed rise in IgG early in infection, individuals with moderate COVID-19 had IgM and IgA levels equivalent to those of survivors of severe illness by week three. IgG response, Fc receptor binding and immune effector functions evolved slowly, and they remained lower in individuals with moderate disease than in survivors of severe disease.

It's possible that antibody profiles among people with moderately severe COVID-19 don't require further functional evolution due to early and effective control of the virus.

Implications for COVID-19 Vaccines and Treatment

Understanding how antibody response develops during SARS-CoV-2 infection and contributes to recovery—beyond neutralization—may provide key insights for vaccine and therapeutic design. It may also be possible to identify which patients are on a deleterious clinical trajectory and need to be triaged to more intensive care.

The biggest takeaway: Just days after symptom onset, survivors of severe COVID-19 showed a vigorous response to an area of the S2-domain of the spike protein, which is super conserved across all coronaviruses. It's possible these S2-specific responses helped facilitate initial viral control.

This finding could be the foundation for making a better vaccine to an ultra-conserved site on the spike that could give broad coronavirus immunity.

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Related topics


On November 5, 2020, the Department of Medicine held a virtual Grand Rounds on COVID-19. Bruce Walker, MD, and Galit Alter, PhD, from the Ragon Institute, spoke with the local Boston medical community about the quest for a COVID-19 vaccine.


Five early immune response markers, considered together, correctly classified plasma samples as belonging to survivors or non-survivors of severe COVID-19.