Why do most SARS-CoV-2 infected people not get COVID?

Performing in-depth 'immunopathology' diagnostic analyses on people with severe COVID does little to help the understanding of why the majority of people only get minor symptoms following an infection by the SARS-CoV-2 virus. With most of the research conducted to date on the severely ill, it is probably not too surprising that there is so little information on natural immune functions explaining how most people are relatively unaffected.

However, due to their access to people testing positive to SARS-CoV-2, but either then asymptomatic - or with mild symptoms, The Luxembourg Institute of Health (LIH) have been able to conduct detailed analysis of samples from these patients in order to see what it is about their immune systems that keeps us healthy.

What the researchers found was that a rapid switching on of multiple immune functions in parallel, and "in a highly coordinated fashion", was critical to mounting an effective immune response.

When multiple immune functions are not coordinated

This would seem to make sense as when multiple immune functions are not rapidly switched on in a coordinated fashion, problems are likely to occur. This fundamental observation may be one of the underlying causes for the rapidly declining vaccine performance - as reported by UKHSA. In addition, immune processes such as antibody-dependent cellular cytotoxicity (ADCC) when causing the death of healthy cells might be such an example. ADCC is an immune function involving Natural Killer cells, which as the name implies hunt and destroy other cells expressing viral infection markers (such as spike proteins), however, they naturally need to be targeted at only those cells that are infected. The concept of original antigenic sin (OAS) is also a text book example of how interferences can impact on the quality of normal, natural immune responses.

The point is that the new study helps to shed some light on what is going on.

Natural immunity involves pathways more complex than just raising antibodies

The findings from all-Luxembourg study point out that it is equally, if not more important to understand the protective immune factors in our body. Using state-of-the-art deep immune profiling and systems immunology-driven data analysis, the translational biomedical research team, which was led by the Department of Infection and Immunity of the Luxembourg Institute of Health, revealed that it is the unique combination of various early-stage immune responses that can differentiate between mild patients, hospitalized COVID-19 patients and their non- infected household controls.

The insurgence of COVID-19 has had dramatic effects worldwide, leading to an unprecedented diversification and intensification in research efforts to counteract its spread. However, while immunopathology has been widely studied in severe COVID-19 patients, immune responses in non- hospitalized patients have remained largely elusive. Furthermore, research to date has lacked a comprehensive multi-faceted approach to the full immune response following infection. It was therefore unknown, up to now, whether the immune alterations present in hospitalized individuals were also present in mild COVID-19 PCR-positive patients. To this end, Feng Hefeng and Markus Ollert from the Department of Infection and Immunity of the Luxembourg Institute of Health (LIH) led a study to reveal the early-stage immune features of patients who had recently contracted the virus but displayed mild COVID-19 symptoms only.

Testing SARS-CoV-2-infected people with only mild or no symptoms

The all-Luxembourg study took full advantage of the translational medicine research structure established across the nation. The translational study was based on the cohort Predicting the severity of COVID-19 infection1 (Predi-COVID), which was initiated in April 2020 to identify important risk factors and biomarkers associated with COVID-19 severity in Luxembourg. “Our work was only possible thanks to the unique opportunity to conduct a population-wide PCR screening in Luxembourg from May 2020 on that allowed us to recruit many SARS-CoV-2-infected people with only mild or no symptoms,” acknowledged Guy Fagherazzi, Director of the LIH Department of Precision Health and one of the two Principle Investigators (PI) of the Predi-COVID project. Indeed, since its launch in April 2020, the study has collected data from COVID-19 positive adults in Luxembourg, and followed their health evolution during the first three weeks after their diagnosis and beyond.

turning on multiple immune functions in parallel and very early in a highly coordinated fashion appears to be a major contributor to the beneficial clinical outcome

Coordinated immune responses only in patients with mild symptoms

To obtain a comprehensive picture of the early-stage immune responses in COVID-19 infection, patients were categorised according to their symptoms’ severity (asymptomatic, mild, and hospitalized). By comparing immune responses between the different groups in more than 100 patients and household controls, the team found that, within three days following the positive PCR test, there was an early-stage increase in coordinated immune responses only in patients with mild symptoms. \

Key immune mediators such as:

  • interferon beta and
  • interferon gamma-induced protein 10 (IP- 10)

temporarily increased early-on according to the amount of virus present in the body of mild patients.

After three weeks, these immune markers remained high in hospitalized patients, but decreased to normal values in mild patients. The early increase of crucial biomarkers in mild patients was accompanied by a rise in immune cells reacting specifically to the SARS-CoV-2 virus like CD4 T cells, which are part of the adaptive arm of the immune system, and of early-reacting innate immune cells, such as antigen-presenting cells and monocytes.

Anticipating antiviral antibodies

Very importantly, these early immune reactions anticipated the presence of specific antiviral antibodies three weeks later in mild patients, a feature that was absent in hospitalized patients. While hospitalized COVID-19 patients mounted an equally strong T cell response as mild patients, the frequency of innate immune cells and the expression of key functional molecules on these cells were strikingly impaired already very early on during infection in hospitalized patients. According to Christophe M. Capelle, a Luxembourgish LIH Ph.D. graduate and first author of the study, turning on multiple immune functions in parallel and very early in a highly coordinated fashion appears to be a major contributor to the beneficial clinical outcome of patients with mild symptoms.

“These pioneering findings are the perfect example of the tremendous translational potential of our research infrastructure in Luxembourg,” commented Dr Hefeng. “The longitudinal Predi-COVID study gave us unique access to PCR-positive mild non-hospitalized COVID-19 patients, which empowered us to gain a comprehensive picture of distinct early-stage protective immune signatures in mild COVID- 19 patients versus hospitalized patients, asymptomatic individuals and household controls during the first waves of the pandemic.”

Studying the essential facets of immune responses

“Our work provides a rich data and clinical sample resource based on the unique opportunity to fully explore and understand all essential facets of the early-stage and dynamic immunological changes following recent SARS-CoV-2 infection in mild COVID-19 patients, using an unbiased, combinatorial and prospective approach,” added Markus Ollert, Director of the Department of Infection and Immunity of the LIH, who is the other PI of the Predi-COVID project. “Our current study does not only provide information on the number and frequency of a wide spectrum of immune cells helping to defend against viruses like SARS-CoV-2 in our blood, but also on the functional status and characteristics of individual immune cell types.”

These first research results of the Predi-COVID study were recently published in the leading biomedical journal Cell Reports Medicine by Cell Press under the full title: ‘Combinatorial analysis reveals highly coordinated early-stage immune reactions that predict later antiviral immunity in mild COVID-19 patients’. Predi-COVID will continue from 2022 onwards under the umbrella of CoVaLux (COVID-19, Vaccination & long-term health consequences of COVID-19 in Luxembourg), a national research effort coordinated by Research Luxembourg to address key unanswered questions related to COVID-19, with a particular focus on vaccination efficacy and the longer-term health impact of COVID-19.

1Fagherazzi G, Fischer A, Betsou F, et al. Protocol for a prospective, longitudinal cohort of people with COVID-19 and their household members to study factors associated with disease severity: the Predi-COVID study. BMJ Open 2020;10:e041834. doi:10.1136/bmjopen-2020-041834.

Funding and collaborations

The ongoing research efforts are jointly coordinated by the LIH, the Integrated Biobank of Luxembourg (IBBL), the Laboratoire National de Santé (LNS), Research Luxembourg, the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg, the Centre Hospitalier de Luxembourg (CHL), the Fonds National de la Recherche Luxembourg, the Fondation André Losch and the Luxembourg Government.

About the Luxembourg Institute of Health (LIH)

The Luxembourg Institute of Health (LIH) is a public biomedical research organization focused on precision health and invested in becoming a leading reference in Europe for the translation of scientific excellence into meaningful benefits for patients.

LIH places the patient at the heart of all its activities, driven by a collective obligation towards society to use knowledge and technology arising from research on patient derived data to have a direct impact on people’s health. Its dedicated teams of multidisciplinary researchers strive for excellence, generating relevant knowledge linked to immune related diseases and cancer.

The institute embraces collaborations, disruptive technology and process innovation as unique opportunities to improve the application of diagnostics and therapeutics with the long-term goal of preventing disease.

About Research Luxembourg

Research Luxembourg is a unified agile team of thought leaders working to learn, explore and make an impact to shape a better future. By connecting all players in Luxembourg and abroad, Research Luxembourg aims to become a leader in research and innovation focusing on four research priority areas: (1) Industrial and Service Transformation; (2) Personalised Healthcare; (3) Sustainable and Responsible Development; (4) 21st Century Education

Research Luxembourg is a joint initiative of the main actors in Luxembourg public research with the support of the Luxembourg Minister of Higher Education and Research, including Luxembourg Institute of Health (LIH); Luxembourg Institute of Socio and Economic Research (LISER); Luxembourg Institute of Science and Technology (LIST); the Luxembourg National Research Fund (FNR); Luxinnovation; the University of Luxembourg (uni.lu).

Special proteins in the blood that are produced in response to a specific antigen and play a key role in immunity and allergy. Full medical glossary
A substance that prompts the immune system to fight infection with antibodies. Full medical glossary
A substance that acts against viruses, for example and antiviral drug. Full medical glossary
A substance that can be measured to help healthcare professionals to assess normal processes, disease processes or a person's response to treatment. Full medical glossary
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Invasion by organisms that may be harmful, for example bacteria or parasites. Full medical glossary
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