How targeting killer T cells in the lungs could lead to immunity against respiratory viruses

Summary:

A significant site of damage during COVID-19 infection is the lungs. Understanding how the lungs' immune cells are responding to viral infections could help scientists develop a vaccine. Now, a team of researchers has discovered that the cells responsible for long-term immunity in the lungs can be activated more easily than previously thought. The insight could aid in the development of universal vaccines for influenza and the novel coronavirus.

Source:

Salk Institute

First human trial of COVID-19 vaccine finds it is safe and induces rapid immune response

Summary:

A study of 108 adults finds that the vaccine produced neutralizing antibodies and T-cell response against SARS-CoV-2, but further research is needed to confirm whether the vaccine protects against SARS-COV-2 infection.

FULL STORY

The first COVID-19 vaccine to reach phase 1 clinical trial has been found to be safe, well-tolerated, and able to generate an immune response against SARS-CoV-2 in humans, according to new research published in The Lancet. The open-label trial in 108 healthy adults demonstrates promising results after 28 days — the final results will be evaluated in six months. Further trials are needed to tell whether the immune response it elicits effectively protects against SARS-CoV-2 infection.

"These results represent an important milestone. The trial demonstrates that a single dose of the new adenovirus type 5 vectored COVID-19 (Ad5-nCoV) vaccine produces virus-specific antibodies and T cells in 14 days, making it a potential candidate for further investigation," says Professor Wei Chen from the Beijing Institute of Biotechnology in Beijing, China, who is responsible for the study. "However, these results should be interpreted cautiously. The challenges in the development of a COVD-19 vaccine are unprecedented, and the ability to trigger these immune responses does not necessarily indicate that the vaccine will protect humans from COVID-19. This result shows a promising vision for the development of COVID-19 vaccines, but we are still a long way from this vaccine being available to all."

The creation of an effective vaccine is seen as the long-term solution to controlling the COVID-19 pandemic. Currently, there are more than 100 candidate COVID-19 vaccines in development worldwide.

The new Ad5 vectored COVID-19 vaccine evaluated in this trial is the first to be tested in humans. It uses a weakened common cold virus (adenovirus, which infects human cells readily but is incapable of causing disease) to deliver genetic material that codes for the SARS-CoV-2 spike protein to the cells. These cells then produce the spike protein, and travel to the lymph nodes where the immune system creates antibodies that will recognize that spike protein and fight off the coronavirus.

The trial assessed the safety and ability to generate an immune response of different dosages of the new Ad5-nCoV vaccine in 108 healthy adults between the ages of 18 and 60 years who did not have SARS-CoV-2 infection. Volunteers were enrolled from one site in Wuhan, China, and assigned to receive either a single intramuscular injection of the new Ad5 vaccine at a low dose (5 × 1010 viral particles/0·5ml, 36 adults), middle dose (1×1011 viral particles/1.0ml, 36 adults), or high dose (1.5 x 1011 viral particles/1.5ml, 36 adults).

The researchers tested the volunteers' blood at regular intervals following vaccination to see whether the vaccine stimulated both arms of the immune system: the body's 'humoral response' (the part of the immune system that produces neutralising antibodies which can fight infection and could offer a level of immunity), and the body's cell-mediated arm (which depends on a group of T cells, rather than antibodies, to fight the virus). The ideal vaccine might generate both antibody and T cell responses to defend against SARS-CoV-2.

The vaccine candidate was well tolerated at all doses with no serious adverse events reported within 28 days of vaccination. Most adverse events were mild or moderate, with 83% (30/36) of those receiving low and middle doses of the vaccine and 75% (27/36) in the high dose group reporting at least one adverse reaction within 7 days of vaccination.

The most common adverse reactions were mild pain at the injection site reported in over half (54%, 58/108) of vaccine recipients, fever (46%, 50/108), fatigue (44%, 47/108), headache (39%, 42/108), and muscle pain (17%, 18/108). One participant given the higher dose vaccine reported severe fever along with severe symptoms of fatigue, shortness of breath, and muscle pain — however these adverse reactions persisted for less than 48 hours.

Within two weeks of vaccination, all dose levels of the vaccine triggered some level of immune response in the form of binding antibodies (that can bind to the coronavirus but do not necessarily attack it — low-dose group 16/36, 44%; medium dose 18/36, 50%; high dose 22/36, 61%), and some participants had detectable neutralising antibodies against SARS-CoV-2 (low-dose group 10/36, 28%; medium dose 11/36, 31%; high dose 15/36, 42%).

After 28 days, most participants had a four-fold increase in binding antibodies (35/36, 97% low-dose group; 34/36 (94%) middle-dose group, and 36/36, 100% in high-dose group), and half (18/36) of participants in the low- and middle-dose groups and three-quarters (27/36) of those in the high-dose group showed neutralising antibodies against SARS-CoV-2.

Importantly, the Ad5-nCoV vaccine also stimulated a rapid T cell response in the majority of volunteers, which was greater in those given the higher and middle doses of vaccine, with levels peaking at 14 days after vaccination (low-dose group (30/36; 83.3%), medium (35/36, 97.2%), and high-dose group (35/36, 97.2%) at 14 days).

Further analyses showed that 28 days after vaccination, the majority of recipients showed either a positive T cell response or had detectable neutralising antibodies against SARS-CoV-2 (low-dose group 28/36, 78%; medium-dose group 33/36, 92%; high-dose group 36/36, 100%).

However, the authors note that both the antibody and T-cell response could be reduced by high pre-existing immunity to adenovirus type 5 (the common cold virus vector/carrier) — in the study, 44%-56% of participants in the trial had high pre-existing immunity to adenovirus type 5, and had a less positive antibody and T-cell response to the vaccine.

"Our study found that pre-existing Ad5 immunity could slow down the rapid immune responses to SARS-CoV-2 and also lower the peaking level of the responses. Moreover, high pre-existing Ad5 immunity may also have a negative impact on the persistence of the vaccine-elicited immune responses," say Professor Feng-Cai Zhu from Jiangsu Provincial Center for Disease Control and Prevention in China who led the study.

The authors note that the main limitations of the trial are its small sample size, relatively short duration, and lack of randomised control group, which limits the ability to pick up rarer adverse reactions to the vaccine or provide robust evidence for its ability to generate an immune reaction. Further research will be needed before this trial vaccine becomes available to all.

A randomised, double-blinded, placebo-controlled phase 2 trial of the Ad5-nCoV vaccine has been initiated in Wuhan to determine whether the results can be replicated, and if there are any adverse events up to 6 months after vaccination, in 500 healthy adults — 250 volunteers given a middle dose, 125 given a low dose, and 125 given a placebo as a control. For the first time, this will include participants over 60 years old, an important target population for the vaccine.

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Materials provided by The Lancet. Note: Content may be edited for style and length.

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Suppressed Immune System

Your immune system helps your body tell the difference between its own healthy cells and abnormal or foreign cells, and organisms that can threaten your body. The immune system is constantly checking the cells in the body for foreign proteins that allow it to detect and destroy bacteria, fungi, and viruses.

Similarly, the immune system also checks our cells to make certain that they are not presenting proteins that are suspicious for cancer. If they do find cells that are presenting inappropriate proteins, they assume they are cancer and destroy them. This process of checking cells is called immunosurveillance.

The immune system can be weakened or suppressed by certain cancers, UV radiation, special drugs for organ transplants, and the human immunodeficiency virus (HIV) that causes AIDS. When the immune system is not functioning properly, we are at risk to develop cancer as well as infections.

Scientists have found that people who are on immunosuppressant medications for an organ transplant are much more likely to develop basal and squamous cell cancers. In some studies, the risk is 20 to 60 times greater than in the general population.1

The risk for melanoma in immunosuppressed individuals is less clear. Some studies have found that the rate is 6 times that of the general population.1 However, other studies found a threefold increase.2 Still another study did not find a statistically significant difference.3 One likely reason for the differences among these studies is that melanoma occurs less frequently than the other skin cancers, and few studies have followed patients long enough to determine the full effect of immunosuppression on melanoma.

Although HIV suppresses the immune system, it is not clear that being HIV-positive puts someone at a higher risk for developing melanoma.4,5 Nevertheless, there is some suspicion that HIV increases the risk of melanoma, along with the risk of basal cell carcinoma and squamous cell carcinoma.

Boost Your Immune System

your Immune System

YOUR IMMUNE SYSTEM

All living organisms are continuously exposed to substances that are capable of causing them harm. Most organisms protect themselves against such substances in more than one way — with physical barriers, for example, or with chemicals that repel or kill invaders. Animals with backbones, called vertebrates, have these types of general protective mechanisms, but they also have a more advanced protective system called the immune system. The immune system is a complex network of organs containing cells that recognize foreign substances in the body and destroy them. It protects vertebrates against pathogens, or infectious agents, such as viruses, bacteria, fungi, and other parasites. The human immune system is the most complex.

Although there are many potentially harmful pathogens, no pathogen can invade or attack all organisms because a pathogen's ability to cause harm requires a susceptible victim, and not all organisms are susceptible to the same pathogens. For instance, the virus that causes AIDS in humans does not infect animals such as dogs, cats, and mice. Similarly, humans are not susceptible to the viruses that cause canine distemper, feline leukemia, and mouse pox.

Two Kinds of Immunity

All animals possess a primitive system of defense against the pathogens to which they are susceptible. This defense is called innate, or natural, immunity and includes two parts. One part, called humoral innate immunity, involves a variety of substances found in the humors, or body fluids. These substances interfere with the growth of pathogens or clump them together so that they can be eliminated from the body. The other part, called cellular innate immunity, is carried out by cells called phagocytes that ingest and degrade, or “eat'' pathogens and by so-called natural killer cells that destroy certain cancerous cells. Innate immunity is nonspecific — that is, it is not directed against specific invaders but against any pathogens that enter the body.

Only vertebrates have an additional and more sophisticated system of defense mechanisms, called adaptive immunity, that can recognize and destroy specific substances. The defensive reaction of the adaptive immune system is called the immune response. Any substance capable of generating such a response is called an antigen, or immunogen. Antigens are not the foreign microorganisms and tissues themselves; they are substances — such as toxins or enzymes — in the microorganisms or tissues that the immune system considers foreign. Immune responses are normally directed against the antigen that provoked them and are said to be antigen-specific. Specificity is one of the two properties that distinguish adaptive immunity from innate immunity. The other is called immunologic memory. Immunologic memory is the ability of the adaptive immune system to mount a stronger and more effective immune response against an antigen after its first encounter with that antigen, leaving the organism better able to resist it in the future.

Adaptive immunity works with innate immunity to provide vertebrates with a heightened resistance to microorganisms, parasites, and other intruders that could harm them. However, adaptive immunity is also responsible for allergic reactions and for the rejection of transplanted tissue, which it may mistake for a harmful foreign invader.

Lymphocytes — Heart of the Immune System

Lymphocytes — a class of white blood cells — are the principal active components of the adaptive immune system. The other components are antigen-presenting cells, which trap antigens and bring them to the attention of lymphocytes so that thev can mount their attack.

How lymphocytes recognize antigens

A lymphocyte is different from all other cells in the body because it has about 100,000 identical receptors on its cellular membrane that enable it to recognize one specific antigen. The receptors are proteins containing grooves that fit into patterns forrned by the atoms of the antigen molecule — somewhat like a key fitting into a lock — so that the lymphocyte can bind to the antigen. There are more than 10 million different types of grooves in the lymphocytes of the human immune system.

When an antigen invades the body, normally only those lymphocytes with receptors that fit the contours of that particular antigen take part in the immune response. When they do, so-called daughter cells are generated that have receptors identical to those found on the original lymphocytes. The result is a family of lymphocytes, called a lymphocyte clone. with identical antigen-specific receptors.

A clone continues to grow after lymphocytes first encounter an antigen so that, if the same type of antigen invades the body a second time, there will be many more lymphocytes specific for that antigen ready to meet the invader This is a crucial component of immunologic memory.

How lymphocytes are made

Like all blood cells, lymphocytes are made from stem cells in the bone marrow (see Blood, "Composition"). (In fetuses, or unborn offspring, lymphocytes are made in the liver.) Lymphocytes then undergo a second stage of development, or processing, in which they acquire their antigen-specific receptors. By chance, some lymphocytes are created with receptors that happen to be specific to normal, healthy components of the body. Fortunately, a healthy immune system purges itself of these lymphocytes, leaving only lymphocytes that ignore normal body components but react to foreign intruders. If this purging process is not completely successful, the result is an autoimmune (literally "self-immune") disease in which the immune system attacks normal components of the body as though they were foreign antigens, destroying healthy molecules, cells, or tissues.

Some lymphocytes are processed in the bone marrow and then migrate to other areas of the body — specifically the lymphoid organs (see Lymphatic System). These lymphocytes are called B lymphocytes, or B cells (for bone-marrow-derived cells). Other lymphocytes move from the bone marrow and are processed in the thymus, a pyramid-shaped lymphoid organ located immediately beneath the breastbone at the level of the heart. These lymphocytes are called T lymphocytes, or T cells (for thymus-derived cells).

These two types of lymphocytes — cells and T cells — play different roles in the immune response, though they may act together and influence one another's functions. The part of the immune response that involves B cells is often called humoral immunity because it takes place in the body fluids. The part involving T cells is called cellular immunity because it takes place directly between the T cells and the antigens. This distinction is misleading, however, because, strictly speaking, all adaptive immune responses are cellular — that is, they are all initiated by cells (the lymphocytes) reacting to antigens. B cells may initiate an immune response, but the triggering antigens are actually eliminated by soluble products that the B cells release into the blood and other body fluids. These products are called antibodies and belong to a special group of blood proteins called immunoglobulins When a B cell is stimulated by an antigen that it encounters in the body fluids, it transforms, with the aid of a type of T cell called a helper T cell (see "T cells"), into a larger cell called a blast cell. The blast cell begins to divide rapidly, forming a clone of identical cells.

Some of these transform further into plasma cells — in essence, antibody-producing factones. These plasma cells produce a single type of antigen-specific antibody at a rate of about 2,000 antibodies per second. The antibodies then circulate through the body fluids, attacking the triggering antigen.

Antibodies attack antigens by binding to them. Some antibodies attach themselves to invading microorganisms and render them immobile or prevent them from penetrating body cells. In other cases, the antibodies act together with a group of blood proteins, collectively called the complement system, that consists of at least 30 different components. In such cases, antibodies coat the antigen and make it subject to a chemical chain reaction with the complement proteins. The complement reaction either can cause the invader to burst or can attract scavenger cells that "eat" the invader.

Not all of the cells from the clone formed from the original B cell transform into antibody-producing plasma cells; some serve as so-called memory cells. These closely resemble the original B cell, but they can respond more quickly to a second invasion by the same antigen than can the original cell. T cells. There are two major classes of T cells produced in the thymus: helper T cells and cytotoxic, or killer, T cells. Helper T cells secrete molecules called interleukins (abbreviated IL) that promote the growth of both B and T cells. The interleukins that are secreted by lymphocytes are also called lymphokines. The interleukins that are secreted by other kinds of blood cells called monocytes and macrophages are called monokines. Some ten different interleukins are known: IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, interferon, lymphotoxin, and tumor necrosis factor. Each interleukin has complex biological effects.

Cytotoxic T cells destroy cells infected with viruses and other pathogens and may also destroy cancerous cells. Cytotoxic T cells are also called suppressor lymphocytes because they regulate immune responses by suppressing the function of helper cells so that the immune svstem is active onlv when necessary.

The receptors of T cells are different from those of B cells because they are "trained" to recognize fragments of antigens that have been combined with a set of molecules found on the surfaces of all the body's cells. These molecules are called MHC molecules (for major histocompatibility complex). As T cells circulate through the body, they scan the surfaces of body cells for the presence of foreign antigens that have been picked up by the MHC molecules. This function is sometimes called immune surveillance.

Immune Response

When an antigen enters the body, it may be partly neutralized by components of the innate immune system. It may be attacked by phagocytes or by preformed antibodies that act together with the complement system. Often, however, the lymphocytes of the adaptive immune system are brought into play.

The human immune system contains approximately l trillion T cells and l trillion B cells, located in the lymphoid organs and in the blood, plus approximately 10 billion antigen-presenting cells located in the lymphoid organs. To maximize the chances of encountering antigens wherever they may invade the body, lymphocytes continually circulate between the blood and certain lymphoid tissues. A given lymphocyte spends an average of 30 minutes per day in the blood and recirculates about 50 times per day between the blood and lymphoid tissues.

If lymphocytes encounter an antigen trapped by the antigen-presenting cells of the lymphoid organs, lymphocytes with receptors specific to that antigen stop their migration and settle to mount an immune response locally. As these lymphocytes accumulate in the affected lymphoid tissue, the tissue often becomes enlarged — for example, the lymph nodes in the groin become enlarged if there is an infection in the thigh area.

Antigen-presenting cells degrade antigens and often eliminate them without the help of lymphocytes. If there are too many antigens for them to handle alone, however, the antigen-presenting cells secrete IL- 1 and display fragments of the antigens (combined with MHC molecules) to alert the helper T cells. The IL-1 facilitates the responsiveness of T and B cells to antigens and, if released in large amounts (as it is in the course of infections), can also cause fever and drowsiness. Helper T cells that encounter IL- 1 and fragments of antigens transform into cells called lymphoblasts, which then secrete a variety of interleukins that are essential to the success of the immune response. The IL-2 produced by helper T cells promotes the growth of cytotoxic T cells, which may be necessary to destroy tumorous cells or cells infected with viruses. The IL-3 increases the production of blood cells in the bone marrow and thus helps to maintain an adequate supply of the lymphocytes and lymphocyte products necessary to fight infections. Helper T cells also secrete interleukins that act on B cells, stimulating them to divide and to transform into antibody-secreting plasma cells. The antibodies then perform their part of the immune function.

The process of inducing an immune response is called immunization. It may be either natural — through infection by a pathogen — or artificial — through the use of serums or vaccines. The heightened resistance acquired when the body responds to infection is called active immunity. Passive immunity results when the antibodies from an actively immunized individual are transferred to a second, nonimmune subject. Active immunization, whether natural or artificial, is longer-lasting than is passive immunization because it takes advantage of immunologic memory.

Monoclonal Antibodies

Scientists can now produce antibody-secreting cells in the laboratorv by a method known as the hybridoma technique. Hybridomas are hybrid cells made by fusing a cancerous, or rapidly reproducing, plasma cell and a normal antibody-producing plasma cell obtained from an animal immunized with a particular antigen. The hybridoma cell can produce large amounts of identical antibodies — called monoclonal, or hybridoma, antibodies — which have widespread applications in medicine and biology.

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