Highlights
- SARS-CoV-2-specific CD8+ and CD4+ T cells were identified respectively in ∼70% and in 100% of COVID-19 convalescent patients
- SARS-CoV-2-reactive CD4+ T cells have been identified in individuals unexposed to the virus
- Adaptive immunity is weakened with aging
- Immunity for COVID-19 lasts over 6 months
- An integrated model for the immune response to SARS-CoV-2 was presented
La Jolla Institute for Immunology
La Jolla Institute for Immunology (LJI) was founded in 1988 as a nonprofit independent research organization. Scientists at LJI are dedicated to understanding the complexities of the immune system and apply their knowledge to disease prevention. LJI’s goal is life without disease.
LJI is home to three research centers working towards development of new vaccines and treatments to prevent and cure autoimmune conditions, cancer and infectious disease.
Coronavirus Taskforce
At the beginning of the COVID-19 pandemic, LJI launched a multi-lab Coronavirus Taskforce to respond to the current crisis with research into how immune cells respond to SARS-CoV-2. Three leading professors on this Taskforce, Shane Crotty, Bjoern Peters and Alessandro Sette were named “Highly Cited Researchers” by Clarivate. The designation recognizes researchers whose peer-reviewed studies have been cited most often by their scientific peers. Professors Crotty, Peters and Sette are among the top 1% of most cited for their field, between 2009 and 2019.
Immune response to SARS-CoV-2
Taskforce researchers were the first in the US to start studying blood samples from COVID-19 patients in order to understand the magnitude and composition of the human responses to SARS-CoV-2. The most important finding was that the immune system activates all three branches of “adaptive immunity” (which learns to recognize specific viruses) to try to fight the virus: CD4 “helper” T cells , CD8 “killer” T cells, and antibodies. Good immune responses to multiple different parts of SARS-CoV-2 were found, including the Spike protein, which is the main target of COVID-19 vaccines.
Published in Cell in May 2020, the article was lauded by NIAID Director Anthony Fauci during a Congressional hearing, as “work we really need to pursue.”
Anthony Fauci. Congress. August 2020
Excerpt from the article, highlight added:
SARS-CoV-2-specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers…
Importantly, we detected SARS-CoV-2-reactive CD4+ T cells in ∼40%–60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating “common cold” coronaviruses and SARS-CoV-2.
SARS-CoV-2-reactive CD4+ T Cells in Unexposed Individuals
Presence of the SARS-CoV-2-reactive CD4+ T cells in unexposed individuals was further addressed in an article published in Science in August, 2020. Quoted below, the article suggests that preexisting cross-reactive T cell memory is due to previous infections with “common cold” coronaviruses:
Using human blood samples derived before the SARS-CoV-2 virus was discovered in 2019, we mapped 142 T cell epitopes across the SARS-CoV-2 genome to facilitate precise interrogation of the SARS-CoV-2-specific CD4+ T cell repertoire. We demonstrate a range of preexisting memory CD4+ T cells that are cross-reactive with comparable affinity to SARS-CoV-2 and the common cold coronaviruses human coronavirus (HCoV)-OC43, HCoV-229E, HCoV-NL63, and HCoV-HKU1. Thus, variegated T cell memory to coronaviruses that cause the common cold may underlie at least some of the extensive heterogeneity observed in coronavirus disease 2019 (COVID-19) disease.
Latest LJI research offers a possible explanation for some people having notably milder COVID-19 cases. Though still a speculation, it would have to be evaluated through additional research and much additional data collection.
Adaptive Immunity and Disease Severity with Age
In September 2020 study published in Cell, LJI researchers examined adaptive immunity and COVID-19 disease severity. The adaptive immune system operates through three major lymphocyte types: B cells (antibody-producing cells), CD4+ T cells (helper T cells), and CD8+ T cells (cytotoxic, or killer, T cells). As all three components of adaptive immunity play an important role in protection against viral infections, the study presents a combined assessment of antigen-specific CD4+ T cells, CD8+ T cells, and neutralizing antibodies in acute cases of COVID-19. While coordinated SARS-CoV-2-specific adaptive immune response is associated with milder cases, uncoordinated response frequently fails to control the disease:
…coordination of SARS-CoV-2 antigen-specific responses was disrupted in individuals ≥ 65 years old. Scarcity of naive T cells was also associated with aging and poor disease outcomes. A parsimonious explanation is that coordinated CD4+ T cell, CD8+ T cell, and antibody responses are protective, but uncoordinated responses frequently fail to control disease, with a connection between aging and impaired adaptive immune responses to SARS-CoV-2.
Age Related Immunity and Disease Outcomes
Immunological Memory to SARS-CoV-2
In the study published in Science on Jan. 6, 2021, LJI scientists evaluated 188 recovered COVID-19 patients, for up to eight months post-infection. Subjects (80 male, 108 female) represent a range of asymptomatic, mild, moderate, and severe COVID-19 cases, with ages between 19 to 81 years old. Most subjects provided a single blood sample, between 6 days post symptom onset (PSO) and 240 days PSO. The study determined:
IgG to the Spike protein was relatively stable over 6+ months. Spike-specific memory B cells were more abundant at 6 months than at 1 month post symptom onset. SARS-CoV-2-specific CD4+ T cells and CD8+ T cells declined with a half-life of 3-5 months. By studying antibody, memory B cell, CD4+ T cell, and CD8+ T cell memory to SARS-CoV-2 in an integrated manner, we observed that each component of SARS-CoV-2 immune memory exhibited distinct kinetics.
Integrated Model of Immune Response
In the Jan. 12, 2021 preprint of their latest article in Cell, Alessandro Sette and Shane Crotty present their current understanding of the immunology of COVID-19, with a primary focus on adaptive immunity. The model of the immune response to SARS-CoV-2 is presented in Figure 2 below, though LJI researchers emphasize that while the investigation continues, alternative models might emerge.
Generic Infection (Fig 2A)
In an idealized example of a generic viral infection (Figure 2A), the innate immune system rapidly recognizes the infection and triggers early response such as type I interferons (IFNs). The innate immune response restricts viral replication within infected cells, creates antiviral state in the local tissue and primes the adaptive immune response. Adaptive immune response is slow, it takes 6-10 days after priming to generate sufficient B cells and T cells to control clear infected cells and circulating viruses.
Average Infection (Fig 2B)
It seems that SARS-CoV-2 is effectively evading or delaying triggering of early innate immune responses associated with type I and III interferons (IFNs). Without those responses, the virus initially replicates unabated and the adaptive immune responses are not primed until the innate immune alarms occur (Figure 2B). In an average case of COVID-19, a simple model is that temporal delay in innate immune responses is enough to result in asymptomatic infection or clinically mild disease (not requiring hospitalization) because the T cell and antibody responses occur relatively quickly and control the infection. The presence of T cells and antibodies is associated with successful resolution of average cases of COVID-19.
Severe Infection (Fig 2C)
Impaired and delayed type I and type III IFN responses are associated with the risk of severe COVID-19. If the innate immune response delay is too long, then the virus gets a large head start in replication in the upper respiratory tract (URT) and lungs, and failure to prime an adaptive immune response for a long time leads to severe enough lung disease for hospitalization (Figure 2C). These factors can be amplified by challenges of age, as elderly individuals have a smaller naive T cell pool and are therefore more likely to struggle to make a T cell and antibody response quickly so it can recognize this new virus.
If the adaptive immune response starts too late, and the viral burden is high, it is plausible that the innate immune system tries to fill the vacuum left by the absence of a T cell response and attempts to control the virus with an ever-expanding innate immune response. This massive innate response results in excessive lung immunopathology. It is consistent with many studies finding innate cytokine/chemokine signatures of immunopathology and particularly observation of elevated frequencies of neutrophils (the most common cell type of the innate immune system) in blood and massive numbers of neutrophils in lungs, associated with severe, end-stage COVID-19 disease. Consistent with the working model, early adaptive immune responses are very beneficial, and late adaptive immune responses are simply too late (Figure 2C).
Future Directions
Further, authors will apply proposed model to the topics in disease prevention, control and vaccine development by reviewing a large pool of published studies:
- Adaptive immunity to SARS-CoV-2 infection
- CD4+ T cells in acute COVID-19.
- CD4+ T cell functions in SARS-CoV-2 infection.
- CD8+ T cells
- Antibodies and B cells
- Protection and pathogenesis
- Immunological mechanisms of control of SARS-CoV-2 infection
- Immunopathogenesis
- Local immune responses
- Heterogeneity in adaptive immunity in different people
- Age
- Gender, racial, and ethnicity effects
- Heterogeneity in viral loads and tissue distribution.
- Long COVID
- Pre-existing immunity
- Immune memory and protection from reinfection
- Immune memory to SARS-CoV-2
- Protection from re-infection or 2o COVID-19
- SARS-CoV-2 variants
- Vaccine-elicited immunity
- Interim phase 3 vaccine trial results
Webinar on T cells
On Jan. 12, 2021, the same day when the article in Cell was published, The Scientist magazine conducted a webinar “T Cells: A New Hope for Lasting Protection against SARS-CoV-2” with Alessandro Sette and Shane Crotty. Below is one of the numerous infographics from the webinar.
Screenshot from the webinar recording, at 49:30:
