Immune aging that cannot be underestimated: old age may lead to ineffective vaccines.
Original Zhao Bei Ten-Point Science
Because of the aging immune system, vaccines are less effective for the elderly. Scientists believe that it is more important and more widely used to develop drugs that can enhance the immune function of the elderly than to develop vaccines for the elderly.

Along with skin aging, there is also the immune system. | Figure worm creativity
Author | Doctor of Immunology, Zhao Bei
Recently, many deaths caused by influenza vaccine in Korea have attracted attention. As of October 31st, the death toll rose to 83, of which 71 were over 70 years old (accounting for 85.5%). In addition to the possible quality problems of the vaccine itself, it also reminds us of the fact that the role of the vaccine for young people and the elderly is different.
This is also a difficult point in the development of COVID19 vaccine.
Increasing age, and aging immune system
As people get older, we experience a series of physical changes, such as hearing loss, skin relaxation, joint injury and so on, and even the vitality of the immune system gradually decreases. This phenomenon is called "immune aging". This is also the reason why the elderly have become the main targets of infection and death in Covid-19.
In the face of the out-of-control epidemic in COVID-19, USA, and the emergence of the second round of epidemic peak in Europe, vaccine research and development is in full swing in various countries, which is expected to be a life-saving straw to reverse the situation.
However, vaccines, a means of "actively mobilizing the human immune system to prevent real virus attacks", are usually far less effective in the elderly population-the immune response of the elderly to vaccines is often weaker. That is, the immune system of the elderly is more difficult to be mobilized by vaccines.
This means that vaccines may not protect those who need protection most.
So, how does the immune system age?
Our bodies are naturally resistant to most pathogens. Although the environment is full of pathogens, we still live well most of the time.
The human immune system is divided into innate immunity and acquired immunity. The former is universal immunity. When the body encounters foreign objects (such as skin and mucous membrane), innate immunity will respond quickly. However, although it responds quickly, its ability is limited and it is often broken. For example, when it meets Covid-19, it can’t hold on.
The latter is the acquired immunity of the body, that is, for some pathogens that have not been seen before, the body must first fight with it and learn from it before it can gain immunity to it. The power of acquired immunity is very powerful. As long as the body can withstand the attack of pathogens in "learning" and meet the same pathogens in the future, it will not be a problem at all. For example, infectious diseases such as smallpox and chickenpox, if you get it once, you will generally not get it again.
When the body is invaded by foreign pathogens, such as viruses, innate immunity and acquired immunity will cooperate to resist.
In the innate immune system, immune cells, such as phagocytes and natural killer cells, will recognize or even devour the virus first, and secrete a large number of cytokines to summon more immune cells with different functions to join the battle. Some of these cells, such as phagocytes and dendritic cells, will also transmit the antigens of these viruses (substances that can cause antibody production) to the subsequent T cells and B cells, which are representatives of acquired immune cells.

T-cells and B-cells (shown here as antibodies produced by B-cells) are representatives of immune cells, and they are named after mature parts. The former is mature in thymus (English) and the latter is mature in bone marrow (English). Both are star immune cells. | Figure worm creativity
These two kinds of cells can not only produce antibodies and cytokines to quickly destroy the virus, but also form specific memory cells, so that they can respond quickly after encountering the same virus again.
When the immune system destroys the virus, immune cells will gather locally in the body, forming redness, swelling and heat pain, which is what we usually call inflammation. Proinflammatory factors secreted during this period, such as interleukin -1 and tumor necrosis factor α, can promote the elimination of pathogenic microorganisms, but excessive inflammation may lead to cytokine storms and even life-threatening. Another kind of anti-inflammatory factor, such as interleukin -10, can prevent excessive inflammation and maintain the balance of the body environment.
These factors together constitute our immunity.
And what will happen to our immune function as we get older? What is the impact on vaccine development?
Compared with young people, the immune aging of the elderly is mainly manifested in two aspects:
The initial number of T cells and B cells decreased. Vaccine mainly stimulates B cells to produce antibodies. Only when there are a large number of B cells with high diversity of receptors in the body, the greater the probability of recognizing antigens, and the targeted (directional) antibodies and memory B cells can be formed. -The decrease of B cells will undoubtedly weaken this effect.
Chronic low-grade inflammation is easy to occur after vaccination. The aging and necrotic cells in the elderly can not be removed in time, which will stimulate the immune system continuously, causing immune cells (such as macrophages) to continuously secrete pro-inflammatory cytokines, and the immune response cannot be terminated. The consequence is that the immune system can’t respond the next time the pathogenic microorganism attacks the human body, that is, immune dysfunction.
These lead to different effects of vaccines in the elderly and young people.
Vaccine research and development under "immune aging";
A special vaccine or an auxiliary drug to reverse aging?
For Covid-19, there are about 50 kinds of vaccines being tested in the world, but scientists are still not sure whether the vaccines are equally effective for the elderly.
One of the vaccines "mRNA-1273" being developed by Moderna, a biological company located in Cambridge, Massachusetts, USA, produced antibody levels similar to those of younger subjects in 40 subjects over the age of 56.
However, Pfizer and BioNTech, pharmaceutical companies located in Mainz, Germany, found in the first phase of the experiment that the antibody level induced by the vaccine "BNT162b2" was only half that of young people. It is certain that the antibody level produced by the elderly after vaccination is higher than that caused by the virus infection of their peers, but this is still not enough to explain whether the antibody induced by "BNT162b2" is enough to protect the elderly from the real virus attack.
Most of the vaccines being developed have elderly subjects, but more than half of the 18 latest candidate vaccines have no elderly subjects in clinical trials, which greatly increases the potential risks of vaccines to the elderly.

Some vaccines are being developed, which may have hidden dangers for the elderly. | Figure worm creativity
Facing the phenomenon of immune aging of the elderly, scientists are also actively looking for strategies.
Mainly includes the following two aspects:
(1) The first is how to enhance the immune response of the elderly induced by vaccines.
According to the experience in the research and development of influenza vaccine, the elderly are usually treated by increasing immune stimulating components (such as adjuvants) or increasing the dose of virus antigen to achieve the expected antibody level.
Other scientists have turned to developing drugs to enhance the immune system function of the elderly, that is, supplementing drugs at the same time of vaccination. This way aims to promote the rejuvenation of the immune system of the elderly, even reverse immune aging, and can also resist the virus more effectively when it is infected.
In the above two schemes, the research on reversing age, especially immune aging, has made some progress. In the past 20 years, scientists have found some key small molecular targets. One kind of anti-aging drugs acts on the protein molecule mTOR in the cell growth regulation pathway. Experiments show that inhibiting the expression of mTOR can prolong the life of Drosophila and even mice.
Joan Mannick, one of the founders of resTORbio, a biotechnology company in Boston, Massachusetts, USA, said that "mTOR participates in many biological regulation mechanisms, especially the process of human aging and organ dysfunction".
During his work at Novartis Institute in Cambridge, Massachusetts, Mannick published a study on mTOR protein in 2018, trying to answer the question "Can reducing the content of mTOR protein in the elderly improve the immune system function of the elderly?". 264 participants in the study received low-dose mTOR inhibitor or placebo respectively, and after six weeks, the infection rate of influenza virus and the effect of influenza vaccine were followed up. It was found that the number of people suffering from influenza in the elderly who received mTOR inhibitors decreased significantly, and the immune response caused by influenza vaccine was stronger.
Another study shows that mTOR inhibitor RTB101 can enhance the immune response of the elderly after coronavirus infection, and the elderly who receive mTOR inhibitor have lower coronavirus load and recover faster. At present, resTORbio is testing the preventive or therapeutic effect of RTB101 on Covid-19 infection in 550 elderly people over 65 years old in nursing homes.
In addition, at least four research teams are studying the therapeutic effect of rapamycin, another more mature mTOR inhibitor, on the elderly over 60 years old infected with COVID-19.
In addition, metformin, a drug for the treatment of type 2 diabetes, also inhibits the activity of mTOR protein. Clinical data from China and the United States show that diabetic or obese patients who take metformin have less symptoms of Covid-19 infection and lower mortality.
Carolyn Bramante, a researcher at the University of Minnesota in the United States, pointed out that people with diabetes and obesity show immune deficiency very similar to that of the elderly. At present, Bramante and his colleagues are conducting a study involving 1,500 people to explore whether taking metformin can prevent Covid-19’s infection or alleviate its symptoms. Although the mechanism is not clear, decades of clinical data show that metformin has high safety, can be used in children and even pregnant women, and the cost is very low, which are the advantages of metformin.
(2) The second key is how to avoid causing or how to terminate chronic inflammatory reaction.
Studies have found that losmapimod, an anti-inflammatory drug used to treat muscular dystrophy, can inhibit chronic inflammatory response and improve the body’s response when viruses or bacteria invade. A biological company in Cambridge, Massachusetts, USA recruited 400 volunteers to verify the therapeutic effect of losmapimod on patients with COVID-19. The drug may be able to treat symptoms such as respiratory failure after Covid-19 infection, thus saving patients’ lives.
Many scientists say that it is more important to develop drugs to enhance the immune function of the elderly than to develop COVID-19 vaccine for the elderly, and the latter is more universal, which can improve the protection effect of influenza vaccine, COVID-19 vaccine and even other vaccines in the future. A deep understanding of immune aging and its regulation mechanism and the development of related drugs will also have far-reaching implications for the treatment of other diseases such as diabetes and cancer.
In short, although there are always difficulties in vaccine development, known or unknown, scientists have been working hard and believe that methods will always be found.
(Editor Gao Peiwen)
Original information:
Cassandra Willyard, Nature vol 586, 15.10.2020
Reference information:
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Original title: "Immune aging that cannot be underestimated: old age may lead to ineffective vaccines"
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