• 24 Feb, 2024

Four years after the first serious cases of pneumonia emerged in Wuhan in December 2019, nearly 7 million people have died from COVID-19, and nearly 65 million are still struggling with the mysterious effects of the infection. A syndrome called long-term corona.

by Ekaterina Pesheva,
Harvard Medical School

But in the wake of the pandemic, medical scientists have gained new insights into the immune system that are reshaping long-held beliefs about human immunity. These insights are made possible by the scale of infectious disease, which affects hundreds of millions of people, and the unprecedented ability to study how viruses interact with their human hosts using sophisticated tools that were not available 20 years ago.

Scientists say this new knowledge could have an impact on how we think about, diagnose, and treat other infectious and non-infectious diseases. Some of them are still unknown.

"This may be a golden age for human immunology, but it is relatively under-researched because we have few tools to do it," said Shiv Pillai, professor of medicine at Harvard Medical School and Massachusetts General Hospital and principal investigator at the Institute. Lagoon. He said. "This was a major global effort that gave us a new way to look at disease from an immunological perspective. Of course, I'm still learning."

The most exciting insights include a deeper understanding of immune memory, immune longevity, and outcomes following COVID-19 infection.
Immunity is not a dichotomy

"One of the most important insights coming from the pandemic is the realization that the waning of immune responses induced by mRNA vaccines may not be limited to these vaccines," said Pillay, principal investigator for the Massachusetts Pathogen Preparedness Consortium, which leads the HMS. "It is," he said. (Mass CPR).

This may also apply to other vaccines that were previously thought to induce lifelong immunity.

mRNA vaccines are a completely new method of vaccination. There is a rapid and robust but unstable response to symptomatic COVID-19 disease. mRNA vaccine protection against death and severe disease remains strong over time, but protection against symptomatic infection is less durable.

This is largely because viruses undergo mutations to evade the defenses of the immune system, an evolutionary competition between host and pathogen.

But Pillay added that this is because the human immune system takes a long time to develop long-term immune memory against pathogens.

This memory becomes stronger each time the immune system encounters a virus, either through vaccine or natural exposure. Something similar can happen with smallpox and measles.

“We thought, oh, we're either going to get measles or chicken pox, or we're going to get the vaccine and be immune for life. But there is increasing evidence that this is not the case,” Pillay said. For example, a recent study found that the number of cases of shingles (herpes zoster) has increased over the past 60 years for reasons that are still unclear.

The causative agent, the varicella-zoster virus, is also the cause of chickenpox or chickenpox infection in children.

One possible explanation is that the relatively low levels of circulating virus in recent years have resulted in previously asymptomatic infections, naturally "boosting" the immune system of previously infected or vaccinated individuals.

"The reason we think this is because we vaccinate or recover from infection earlier, but because the infection is still persistent, we can all be reinfected multiple times, often without realizing it, and come back stronger," he said.

"Most of us have probably been reinfected multiple times and have developed very good immunity."

Therefore, the idea that a single encounter with a pathogen leads to lifelong immunity may need to be reconsidered. The same can apply to vaccines.

The protection that some vaccines offer and their effectiveness against viruses weaken over time. Pillai vaccine, mRNA, etc.

He emphasized that it saves lives. But the idea of ​​providing one-stop protection may have to be abandoned. According to Pillai, vaccines remain the most important and safe means of strengthening the immune defense. But they are not perfect.

"What COVID has taught us is that we don't fully understand the power of immune memory in humans and that we may need to revise our common views about the power of immunity," Pillay said. Is the immunity due to the vaccine alone or is it a natural boost from the vaccine and exposure? Is it possible to achieve complete immunity against pathogens that spread easily after mutation? It will probably never happen.

However, serious diseases can be prevented by vaccination."

A new platform for the treatment of cancer, etc.

COVID mRNA vaccines work by teaching the body to make a safer version of the SARS-CoV-2 protein and the immune system to recognize and stop it, which then works when it comes into contact with the real virus.

This approach, first used successfully against SARS-CoV-2, has evolved into plans to use the body's immune response to create its own "cures" for a variety of infectious diseases and several types of cancer. Different forms of heart disease, rare diseases such as cystic fibrosis, and some autoimmune diseases. COVID-19 sheds light on another puzzling situation

The consequences of SARS-CoV-2 infection have strikingly similar characteristics to post-treatment syndromes such as Kawasaki disease, fibromyalgia, and Lyme syndrome, some of which are of limited duration, while others may lead to post-infection clusters of long term. there is. Symptom.

Could the overlap of symptoms mean that these conditions share common biological mechanisms that unfold when the virus interacts with other organs and organ systems? That's the question MassCPR researchers are pursuing to understand the mechanisms of long-lived COVID-19, which can lead to so many cases of viral infection.

The "original sin" of the immune system can be a virtue

The pandemic has led to a deeper understanding of immune fingerprinting, a key feature of immunity. When our body first comes into contact with a virus, it forms a long-term memory of it. These initial encounters shape subsequent responses not only to single viruses but also to similar pathogens.

This type of immune labeling is classically described as the "primary antigen sin", meaning the first encounter with a specific antigen that directs the immune system to the pathogen in question.

When the immune system encounters a new virus, instead of rapidly producing antibodies highly specific to the new virus, it retains its initial resemblance to its first memory - a distant, vaguely blind person. he is. If a stranger claims to know you, think of him as a friend.

Immunoprinting can generate a protective immune response against viruses that resemble the original antigen. This is because some of these new viruses are similar to the original antigens that created the memory. However, imprinting the immune system can prevent the formation of a rapid immune response to new viruses or previously observed mutated parts of the virus.

This slightly reduces the accuracy of basic defense.

MassCPR researcher Duane Wesemann, an associate professor of medicine at HMS and an immunologist at Brigham and Women's Hospital, argues that such an approach may be too simplistic.

"We're getting closer to a deeper understanding of the immune fingerprint, and I think that could teach us big lessons from the COVID-19 pandemic," Wesemann said. "Of course, infectious diseases are scary, but if you put that aside and look at how the immune system processes information and how the biology works, it's very interesting."

The memory of the first encounter is stronger and can cause the original version of the virus to be picked up for life, Wesemann said. Subsequent exposures may cause the immune response to expand to include new strains, but initial antiviral reactivity remains elevated.

This may mean that people are more susceptible to infection when previously encountered viruses mutate and are not recognized by antibody-producing immune cells.

However, Wezemann points out that exposure to a virus early in life generally provides long-term protection against serious diseases caused by similar strains of the virus.

This is true even if the response is not strong enough to prevent symptomatic infection later in life. For example, labeling such immunity as good or bad cannot reflect the nuance and complexity of the phenomenon, other than a dichotomy, he says. What about COVID-19?

Evidence shows that when people infected with or vaccinated against the original Wuhan strain of SARS-CoV-2 were challenged with the latest strain, they had higher levels of antibodies against the original strain and lower levels of antibodies against the new strain. It is not infected with any kind of virus.

However, studies have shown that prior exposure to SARS-CoV-2 through infection and/or vaccination reduces disease severity in subsequent infections.

Studies have also shown that previous vaccination does not prevent new responses to mutated parts of the virus.

The limitations of immune imprinting can be overcome by vaccine fortification with higher doses of vaccine antigens, multivalent vaccines that respond to different variants, or adjuvants that enhance the immune response.

First, Wezemann suggests that antibody production based on the immune system's memory of previous exposures is a quick and cost-effective way to generate rapid protection when a quick response in the face of uncertainty is more important than a highly accurate response.

The immune system has the evolutionary advantage of having a broad repertoire and a long memory of previous exposures. This is a way to avoid the risk of future encounters with pathogens. The immune system could unlock memories and destroy cells that contain memories of previous contact with the virus, but that doesn't happen, Wezeman explained. Retention of these old "files" increases the likelihood that at least some of the long-lived antibody-producing cells will recognize parts of the virus that were not previously present.

Generating new antibodies that are highly adapted to a new virus takes time and energy. This is a valuable resource in high-risk situations where speed of reaction is critical.

Therefore, the immune system uses two ways to respond. One is a rapid but imprecise response based on existing defense mechanisms, and the other is a slower, more precise response that gradually builds an arsenal to attack new viruses.

"The immune system is smart enough to know it needs speed and accuracy," Wesemann said. "But to do both, you have to sacrifice initial accuracy for speed."

According to Wezeman, antigenic original sin may be a virtue. That is, it may be an evolutionarily refined optimum for speed, accuracy, and adaptation in the face of uncertainty.