Skip to content

Efficient Early Immune Control of COVID-19 Predicts Favorable Long-term Adaptive Immunity

Key findings

  • To better understand immunity after COVID-19, this longitudinal study (up to 333 days) investigated the relationship between SARS-CoV-2–specific CD4+ memory T cells and persistent antibody responses
  • Blood samples were obtained from 61 convalescent patients who seroconverted during the first wave of the pandemic in Boston, before vaccines were available
  • SARS-CoV-2–specific CD4+ T cell populations differed across disease severities, in that individuals with mild symptoms had a greater proportion of T helper type 1 cells and circulating T follicular helper cells than those who had to be hospitalized
  • Individuals who exhibited sustained anti-spike antibody responses after symptom resolution also showed an increased proportion of circulating T follicular helper cells
  • COVID-19 vaccines should be designed to maximize response by these types of CD4+ T cells

As with other viral infections, the response of the adaptive immune system to SARS-CoV-2 relies on coordinated T and B cell responses. CD4+ T cells have a central role in long-term immunity because they differentiate into:

  • T helper type 1 (Th1) cells, which stimulate phagocytes and cytotoxic CD8+ T cells
  • T follicular helper (Tfh) cells, which promote high affinity and sustained antibody responses by B cells in germinal center reactions

To better understand immune memory to COVID-19, Ryan W. Nelson, MD, PhD, of the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital, Andrew D. Luster, MD, PhD, director of the Center and chief of the Division of Rheumatology, Allergy and Immunology at Mass General, and colleagues used an advanced method—peptide-major histocompatibility complex class II tetramers developed by James J. Moon, PhD, also of the Center—to directly identify CD4+ T cells that recognize SARS-CoV-2. Their report in Science Immunology adds to the growing body of evidence that the immune dysregulation associated with severe COVID-19 predicts less favorable long-term immunity.


The researchers conducted a longitudinal study of CD4+ T cell responses at the level of individual SARS-CoV-2 spike (S)- and nucleocapsid (N)-epitopes, along with paired antibody responses. Peripheral blood mononuclear cells (PBMC) and plasma were analyzed from convalescent patients who seroconverted during the first wave of the pandemic in Boston, before vaccines were available.

40 patients at Mass General had samples obtained between April 2020 and January 2021 (13–333 days after symptom onset). 21 patients at Brigham and Women's Hospital had samples obtained between August and November 2020 (150–242 days after symptom onset). Those cohorts included:

  • 52 patients with mild COVID-19 (no hospitalization)
  • Nine patients hospitalized with moderate to severe COVID-19, including six admitted to the ICU

Samples from the patients were compared with cryopreserved PBMC drawn from nine individuals before December 2019 as SARS-CoV-2 unexposed negative controls.

Principal Results

Compared with the pre-pandemic controls, most patients demonstrated expanded populations of circulating S- and N–specific CD4+ memory T cells. Those cells were evident throughout the follow-up period after symptom onset.

The makeup of the SARS-CoV-2–specific T cell populations varied, though, by COVID-19 severity:

  • No hospitalization required—Higher frequencies of Th1 or circulating Tfh cells
  • Hospitalization for moderate to severe symptoms—Lower frequencies of Th1 and circulating Tfh cells

The research team also analyzed a subset of individuals with mild symptoms and sustained antibody responses at or above the initial level throughout the study. They also showed an increased frequency of circulating Tfh cells.

Implications for Vaccine Development

Individuals with milder disease may be better equipped to re-engage germinal centers and generate new antibodies with higher affinity and breadth during subsequent exposures to SARS-CoV-2, including its variants.

The findings also support the existing immunological theory that optimal antibody responses require robust CD4+ T cell help. COVID-19 vaccines should be designed to maximize responses by that component of the adaptive immune system.

Visit the Center for Immunology & Inflammatory Diseases

Learn about the Division of Rheumatology, Allergy and Immunology

Related topics


Zachary S. Wallace, MD, MSc, Naomi J. Patel, MD, and colleagues determined retrospectively that the risk of death from COVID-19 is twice as high in patients who use anti-CD20 monoclonal antibodies for the treatment of immune-mediated diseases versus COVID-19 patients in the general population.


Yuqing Zhang, DSc, and colleagues in the Division of Rheumatology, Allergy and Immunology at Massachusetts General Hospital found the incidence of COVID-19 is higher among patients with rheumatoid arthritis than in the general population, regardless of medication use and multiple other potential confounders.