STUDY: Immune Memory Persists After Mild Covid-19

If you had mild or asymptomatic Covid-19, will that help to protect your against contracting the virus again? A research study was published in January 2021 that concluded “mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks of antiviral immunity.” Read the research here…

Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID-19

Published Cell Volume 184, Issue 1, January 2021

Authors: Lauren Rodda, et al, University of Washington School of Medicine

Read the full study here: Cell Vol 184, Issue 1

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus is causing a global pandemic, and cases continue to rise. Most infected individuals experience mildly symptomatic coronavirus disease 2019 (COVID-19), but it is unknown whether this can induce persistent immune memory that could contribute to immunity. We performed a longitudinal assessment of individuals recovered from mild COVID-19 to determine whether they develop and sustain multifaceted SARS-CoV-2-specific immunological memory. Recovered individuals developed SARS-CoV-2-specific immunoglobulin (IgG) antibodies, neutralizing plasma, and memory B and memory T cells that persisted for at least 3 months. Our data further reveal that SARS-CoV-2-specific IgG memory B cells increased over time. Additionally, SARS-CoV-2-specific memory lymphocytes exhibited characteristics associated with potent antiviral function: memory T cells secreted cytokines and expanded upon antigen re-encounter, whereas memory B cells expressed receptors capable of neutralizing virus when expressed as monoclonal antibodies. Therefore, mild COVID-19 elicits memory lymphocytes that persist and display functional hallmarks of antiviral immunity.

Study Introduction and Discussion

It is critically important to understand if SARS-CoV-2-infected individuals who recover from mild disease develop functional immune memory cells capable of protection from subsequent SARS-CoV-2 infections, thereby reducing transmission and COVID-19 disease. Immunological memory is primarily mediated by cells of the adaptive immune system. In response to most acute viral infections, B and T cells that can bind viral proteins through their antigen receptors and become activated, expand, differentiate, and begin secreting effector molecules to help control the infection. Upon resolution of infection, approximately 90% of these virus-specific “effector cells” die, whereas 10% persist as long-lived “memory” cells (Ruterbusch et al., 2020). Immune memory cells can produce a continuous supply of effector molecules, as seen with long-lived antibody-secreting plasma cells (LLPCs). In most cases, however, quiescent memory lymphocytes are strategically positioned to rapidly reactivate in response to re-infection and execute effector programs imprinted upon them during the primary response. Upon re-infection, pathogen-specific memory B cells (MBCs) that express receptors associated with antigen experience and the transcription factor T-bet rapidly proliferate and differentiate into protective immunoglobulin (Ig)G+ antibody-secreting plasmablasts (PBs) (Kim et al., 2019Knox et al., 2019Nellore et al., 2019). Reactivated T-bet-expressing memory CD4+ T cells proliferate, “help” activate MBCs, and secrete cytokines (including interferon [IFN]-γ) to activate innate cells (Ruterbusch et al., 2020). Meanwhile, memory CD8+ T cells also secrete cytokines and kill virus-infected cells directly through the delivery of cytolytic molecules (Schmidt and Varga, 2018). These quantitatively and qualitatively enhanced virus-specific memory populations coordinate to quickly clear the virus, thereby preventing disease and reducing the chance of transmission. It is therefore critical to assess the full cadre of SARS-CoV-2-specific immune memory responses to determine whether mild infection induces a lasting, multilayered defense.

To infect cells and propagate, SARS-CoV-2 relies on the interaction between the receptor-binding domain (RBD) of its spike (S) protein and angiotensin converting enzyme 2 (ACE2) on host cells (Hoffmann et al., 2020). Multiple studies have shown that the majority of SARS-CoV-2-infected individuals produce S- and RBD-specific antibodies during the first 2 weeks of the primary response and that RBD-specific monoclonal antibodies can neutralize the virus in vitro and in vivo (Long et al., 2020Robbiani et al., 2020Shi et al., 2020). Therefore, RBD-specific antibodies would likely contribute to protection in response to reinfection if maintained in the plasma by LLPCs or rapidly expressed by MBCs.

We therefore assessed SARS-CoV-2-specific immune responses at 1 and 3 months post-symptom onset in individuals that had experienced mild COVID-19. We found that a multipotent SARS-CoV-2-specific immune memory response forms and is maintained in recovered individuals for the duration of our study. Furthermore, persistent memory lymphocytes display hallmarks of protective antiviral immunity, including a numerically increased population of virus-specific memory B cells capable of expressing SARS-CoV-2 neutralizing antibodies.

Different levels of severity of COVID-19 could be associated with different levels of immune memory and subsequent immune protection. We focused on the immune memory response to mild COVID-19, but whether similar memory populations form after severe COVID-19 is still unclear. In one largely histological study of post-mortem tissues from patients that succumbed to severe COVID-19, the lack of GC formation or the generation of CD4+ Tfh lymphocytes required for an optimal immune memory response suggested that forming immune memory could be difficult (Kaneko et al., 2020). However, as these patients died of acute disease, it is impossible to determine if germinal centers were transiently disrupted due to acute inflammation as has been seen in other highly inflammatory diseases like malaria (Keitany, 2016). Although additional studies are needed to determine how long memory to SARS-CoV-2 infection lasts, our work suggests that mild COVID-19 induces persistent, multifaceted immune memory. These functional antiviral memory lymphocytes are poised for a coordinated response to SARS-CoV-2 re-exposure that could contribute to immunity and help to curtail the pandemic.

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