How the COVID-19 Pandemic Fast-Tracked the Next Era of Immunology
The COVID-19 pandemic thrust immunology into the global spotlight. From the rapid rollout of mRNA vaccines to a growth in awareness of immune memory and a surge in autoimmune research, the COVID-19 pandemic not only strained global health systems but also highlighted the immune system’s complexity, power and vital role in public health. As we mark the International Day of Immunology – and five years since the pandemic was declared a global emergency – we reflect on the scientific breakthroughs made and how immunology is shaping our future preparedness.
The emergence of mRNA vaccines
Before 2020, messenger RNA (mRNA) vaccines were considered experimental, yet, within a year, they became one of the most widely used technologies to combat SARS-CoV-2. Luckily, researchers had already spent decades researching and developing mRNA vaccines, enabling this rapid transition – a process that would typically take years.
Like traditional vaccines, mRNA vaccines are designed to prevent infectious diseases by training the immune system to recognize and respond to a specific pathogen. However, the method by which they achieve this fundamentally differs.
Typically, traditional vaccines use inactivated viruses, weakened pathogens or isolated viral proteins (protein subunits) to elicit an immune response. In contrast, mRNA vaccines deliver genetic instructions that direct the body’s cells to produce a viral protein – typically one that is harmless on its own but easily recognized by the immune system (e.g., SARS-CoV-2 spike protein).
What is mRNA?
mRNA is a transient molecule that carries genetic information from DNA to ribosomes – the cell’s protein synthesis machinery. Ribosomes read the mRNA sequence and translate it into proteins that carry out essential functions throughout the body.
Importantly, the mRNA introduced by the vaccine is naturally degraded within a few days after delivering its instructions, just like endogenous mRNA.
The success of mRNA vaccines during the COVID-19 pandemic demonstrated the platform's flexibility, scalability and rapid development potential. These advantages are now driving research into mRNA-based vaccines for other infectious diseases, such as influenza, respiratory syncytial virus and human immunodeficiency virus, as well as therapeutic vaccines for cancer.
Immunological memory became in the public eye
Immunological memory is the basis of protective immunity provided by vaccines and previous infections. Upon first exposure to a pathogen – whether through natural infection or vaccination – a cascade of immune events occurs. This response includes the activation and proliferation of antigen-specific lymphocytes, some of which differentiate into long-lived memory cells. Upon re-exposure to the same pathogen, these memory cells generate a faster, more effective immune response, which often neutralizes pathogens before clinical symptoms arise.
For example, during SARS-CoV-2 infection, both T and B lymphocytes play critical roles in viral clearance and the generation of immunological memory. Memory B cells retain the ability to produce high-affinity antibodies, while memory T cells – particularly CD8⁺ cytotoxic T lymphocytes – are primed to recognize and destroy infected host cells.
However, research has revealed the challenges in achieving durable immunity during the COVID-19 pandemic. Both natural infection with SARS-CoV-2 and vaccination can generate protective immune responses, yet these responses may wane over time, necessitating booster immunizations to maintain protection.
Multiple epidemiological studies have now validated these immunological findings by observing that hybrid immunity (the combination of infected- and vaccine-induced immunity) resulted in more robust protection against COVID‐19 than either previous infection immunity or vaccine‐induced immunity. Each type of antigen exposure has distinct characteristics of immune memory, which are key to the observed protective immunity in each case.
The complexity of immune memory highlights the urgent need to improve public understanding of the cellular and molecular processes that underpin its formation and long-term maintenance. Public education on immunological memory is crucial for the effectiveness of vaccination and public health initiatives – not just for COVID-19 but for a broad range of infectious diseases. The COVID-19 pandemic has revealed both the strengths and shortcomings of our current knowledge, spurring renewed efforts to enhance vaccine design and immune monitoring strategies to ensure lasting protection.
Long COVID highlighted the immune system’s dark side
While the immune system is designed to protect the body from pathogens, not all immune responses are beneficial, with dysregulation leading to long-term harm. Long COVID, or post-acute sequelae of COVID-19 (PASC), exemplifies how an imbalanced immune response can result in persistent inflammation, fatigue and neurological symptoms. These observations have reignited scientific interest in immune-mediated chronic conditions and underscored the importance of maintaining immune homeostasis.
Several mechanisms underlie immune dysregulation in long COVID. Persistent inflammation, for instance, occurs when the immune system remains chronically activated even after the virus has been cleared. In some individuals, immune cells such as monocytes and T cells demonstrate altered activity, further perpetuating inflammation. The complement system, a key component of innate immunity, can also become hyperactivated, leading to thrombo-inflammation and damage to the endothelium – the thin layer of cells lining blood vessels. In turn, endothelial cell injury may contribute to the formation of microclots and vascular complications frequently observed in long COVID patients.
These immunological abnormalities give rise to a wide array of multi-systemic symptoms, including fatigue, cognitive impairment ("brain fog"), dyspnea and cardiovascular dysfunction. Beyond symptom persistence, prolonged immune dysregulation may increase susceptibility to additional complications, such as the development of autoimmune diseases. Collectively, these findings emphasize the need for a nuanced understanding of immune function and its regulation in the context of post-viral syndromes.
Autoantibodies became an unexpected villain
Recent studies have shed light on the immune system’s complex response to COVID-19, revealing that autoimmunity may play a critical role in disease severity. This is especially evident in severe cases, highlighting the need for deeper insight into autoimmunity in viral infections – particularly the role of autoantibodies.
Researchers found that patients with severe cases of COVID-19, particularly those who developed long COVID, had autoantibodies that neutralized interferons, which are critical in the body’s defense against viral infections. These autoantibodies, including antiphospholipid antibodies and rheumatoid factors, were linked to severe complications such as thrombosis. The study highlights how autoantibodies may contribute to the heightened risk of severe outcomes in COVID-19, offering insights into potential biomarkers for the early identification of at-risk patients.
Autoantibodies
Autoantibodies are antibodies that mistakenly target and react with a person's own tissues or organs.
A second study used a systems immunology approach to assess autoantibody levels in COVID-19 patients aged 50 and above. Those with severe disease had markedly higher levels of autoantibodies targeting multiple self-antigens. The findings suggest that age-related increases in autoimmune activity may worsen COVID-19 outcomes and point to autoantibodies as potential markers of severity, paving the way for targeted immunotherapies and improved screening.
By identifying autoantibodies as potential markers for at-risk patients and exploring their age-dependent effects, researchers have paved the way for more precise diagnostics and targeted therapies. As this field evolves, further exploration into autoimmunity’s role in viral infections may lead to novel strategies for managing severe COVID-19 and other autoimmune-related conditions.
Public trust in immunology needs ongoing investment
The COVID-19 pandemic not only elevated the visibility of immunology but also highlighted significant challenges in science communication. Misinformation, vaccine hesitancy and public fatigue underscored the need for sustained education and engagement, extending beyond crises and into everyday science policy.
Public trust in immunology plays a pivotal role in several ways. It empowers individuals to make informed health decisions, enhances their participation in public health discussions and supports adherence to public health guidelines, especially during health crises. Furthermore, trust in scientific expertise is essential for the successful implementation of new research, technologies and treatments. Scientific societies, such as the British Society for Immunology, acknowledge its critical role in fostering this trust by making research more accessible and engaging with the public.
Throughout the pandemic, immunology became a central topic of public conversation, raising awareness and revealing gaps in understanding. This highlighted the importance of ongoing communication and education to address challenges such as misinformation and vaccine hesitancy. Public trust in science is foundational for translating innovations from the laboratory into real-world applications, ensuring that breakthroughs in treatments and technologies can be effectively adopted and benefit society.
