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7.7: Specific acquired immunity - Biology

7.7: Specific acquired immunity - Biology


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What triggers specific immune responses? Antigens

Antigens trigger specific immune responses. When this occurs, it is referred to as “autoimmune” disease.) A bacterium can trigger production of antibodies and thus the bacterium is called “antigenic”. Each of these different parts is called an “antigenic determinant” or “epitope”. In class however, we will use the general term “antigen” to describe the part of a microbe to which antibodies bind.

Humoral immunity and antibodies/immunoglobulins

In humans, there are 5 classes of antibodies (ab) also called immunoglobulins (Ig). The predominant class and most versatile antibodies are called “IgG”. They represent approximately 70-80% of the antibodies in a human and can be found in blood and other tissue fluids.

Structure of IgG

igG is made of 4 polypeptide or protein chains. These chains are organized to forma a roughly “y” shaped molecule. The tipes of the arms are called “antigen-binding sites”. The arm tips have grooves with a specific shape and size which permit the antibody to bind to complementary antigen. Once bound to the antigen, the antibodies carry out several beneficial functions.

Functions of Antibodies

  1. agglutination of cells: inhibit movement of pathogens, increase phagocytosis by neutrophils and macrophages (agglutination=”clumping”)
  2. neutralization: antibodies binding to pathogen adhesins block attachment of pathogens to host cell surface receptors thus block colonization and disease. Antibodies can also bind toxins, preventing the toxin from binding host cells (antibodies to toxins are called “antitoxins”)
  3. opsonization: recall opsonization (literally “preparing to eat”) is the process in which a pathogen is coated with a “sticky” substance such as complement, making the coated pathogen easier for the phagocytic cells to attach to and kill the pathogen. Antibodies can also opsonize pathogens. When an antibody binds to the surface of a pathogen, the antibody “tail” sticks outward (the antibody tail is called the Fc fragment). Phagocytic cells have surface receptors which can bind to the antibody tails, permitting them to attach easier to the pathogen, thus increasing pathogen killing.
  4. Complement activation: when antibodies bind antigens, the antibodies can trigger activation of the complement pathway. Recall activation of the complement pathway has several advantages including:
    • triggering inflammation (increase blood flow, increase delivery of phagocytic cells, chemical gradients to guide phagocytic cells to sites of invasion)
    • complement proteins also act as opsonins thus help increase phagocytic killing of pathogens
    • complement proteins help guide phagocytic cells to site of injury/invasion
    • complement proteins can form membrane attack complexes “MAC attack” to help kill invading microbes by lysis.

Classes of antibodies

As mentioned earlier, IgG is one of 5 antibody classes in humans. The other classes include:

  • IgM: a large pentamer (5 parts), the first antibody produced in specific immune reactions. So large it is difficult to leave blood vessels. Can activate complement, can cause agglutination but NOT opsonic
  • sIgA= secretory IgA a dimmer (2 parts): VERY important antibody in mucous secretions. Important role in binding pathogens or toxins on mucous membrane to inhibit attachment to host cells. Essential component of specific mucosal immunity
  • IgE: important in allergic/hypersensitivity reactions. Bind to mast cells, help trigger release of histamine when allergen is encountered.
  • IgD: surface receptor on B lymphocytes

Which cells make antibodies? B-lymphocytes/plasma cells

When humoral immunity is triggered, antibodies are produced by B lymphocytes. Lymphocytes are one type of white blood cell or leukocyte which functions in the immune system. B lymphocytes are so named because they were first identified in chickens (!). Lymphocytes originate in bone marrow then mature under guidance of special chemicals produced in different environments. Upon maturation they will carry out different functions. In chickens, lymphocytes which mature under the chemical influence of the “Bursa of Fabricus” mature into “B” (Bursa) lymphocytes. Humans lack a Bursa of Fabricus. It is thought B lymphocytes may mature in the bone marrow of human or in lymphoid tissue associated with the intestine (GALT=gut associated lymphoid tissue)

B lymphocytes are programmed to produce antibodies when stimulated by the appropriate antigen (more later). Once the B lymphocytes are stimulated, they mature into antibody producing plasma cells.

Clonal Selection, Expansion and Memory Cells

How are we able to specifically respond to the antigens of an invading pathogens? The key is the surface receptors on our lymphocytes. We have an incredible variety of lymphocytes circulating in our blood stream and through our lymphatic system. Each lymphocyte carries a different surface receptor. Each surface receptor can bind to a different antigen. Once the surface receptor binds its specific antigen (selection), it helps trigger the lymphocyte to start dividing (clonal expansion) and to start maturing into a functional lymphocyte. When a lymphocyte starts dividing, it divides into two populations of cells: effector cells and memory cells.

  1. Effector cells: these lymphocytes start immediately “to work”, they carry out the specific function of the lymphocyte. For example B lymphocyte effectors are the B lymphocytes which actually start producing antibodies (they have the specific name “plasma cells” when they start making antibodies)
  2. Memory cells: these memory lymphocytes do not start to work immediately. Instead, their job is to “live long” and “remember” the antigen which first triggered the immune response, if it is ever encountered again. The memory cells increase the number of lymphocytes which could respond to the antigen if it is ever encountered again. The memory cells are also “primed” to trigger a faster immune response the second time the antigen is encountered. The memory cells are what proved us with “immunological memory”, the reason vaccines work and the reasons some people develop “life-long” immunity once they recover from some infectious diseases. When memory cells are subsequently triggered by exposure to the same antigen that triggered the first (primary) immune response, the memory cells trigger a “secondary” immune response.

The secondary immune response is faster, stronger and longer lasting than the primary immune response.

Are only B lymphocytes involved in antibody production?

Although it would make our lives easier as students if only B lymphocytes were involved in antibody production, the process is much more complicated. The BEST humoral immunity is triggered when antigens trigger activation of 3 types of leukocytes/WBC’s. The 3 types of cells are called:

  1. Antigen-Presenting Cell or “APC”; a macrophage is a classic example of an APC
  2. T helper lymphocyte: The MOST IMPORTANT cell of our immune system. T helpers literally help all the other cell of the immune system to function properly. The T helpers have a surface molecule called “CD4”. For this reason, T helpers are also called “CD4+” cells or “CD4+” lymphocytes. Tragically, HIV targets and destroys our CD4+ T helper lymphocytes, thus crippling our immune system, causing AIDS. (note: T lymphocyte originate in the bone marrow then travel to the thymus gland where they mature into T (thymus) lymphocytes)
  3. B lymphocyte: the actual antibody producer

Note

There 3 cells interact with specific antigen and produce chemical messengers which enable each to carry out specific functions. Although we will briefly go over the process in lecture, what is most important to remember is that B cells need T helper lymphocytes to produce memory cells and to “switch” to IgG production.

Summary of how APC. T helper and B lymphocytes interact with antigen to trigger antibody production-YOU DO NOT NEED TO KNOW DETAILS:

  1. APC ex macrophage phagocytizes a pathogen (example a bacterium). The macrophage hydrolyzes the pathogen, processes the pathogen antigens, binds the pathogen antigens to a special molecule called the MHC-II molecule and “presents” the pathogen antigen on the surface of the macrophage linked to the MHC-II molecule.
  2. A T helper lymphocyte with a complementary surface receptors binds to the pathogen antigen “presented” on the MHC-II molecule of the macrophage. This binding and chemicals (interleukins) which the macrophage synthesizes helps to “activate” the Th helper lymphocyte. The Thelper starts to divide, forming effector cells and memory cells.
  3. Meanwhile, a B lymphocyte with surface receptors for the same antigen (IgD molecules) has also bound antigen from the pathogen and is partially activated. The B lymphocyte brings the antigen into its cell, processes them and binds them to MHC-II molecules and (just like the macrophage), “presents” the pathogen antigen on its surface, linked to the MHC-II molecule.
  4. One of the activated effector T helpers (from step 2 above) encounters the B lymphocyte and using its complementary surface receptor (T cell receptor or TCR), binds the pathogen antigen the B lymphocyte is presenting on its surface. This holds the T helper in close contact with the B lymphocyte. The T helper secretes chemicals (interleukins) to further activate the B lymphocyte. Now the B lymphocyte can start dividing, forming antibody producing plasma cell and B memory cells.

The Human Immune System and Infectious Disease

All living things are subject to attack from disease-causing agents. Even bacteria, so small that more than a million could fit on the head of a pin, have systems to defend against infection by viruses. This kind of protection gets more sophisticated as organisms become more complex.

Multicellular animals have dedicated cells or tissues to deal with the threat of infection. Some of these responses happen immediately so that an infecting agent can be quickly contained. Other responses are slower but are more tailored to the infecting agent. Collectively, these protections are known as the immune system. The human immune system is essential for our survival in a world full of potentially dangerous microbes, and serious impairment of even one arm of this system can predispose to severe, even life-threatening, infections.


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INTRODUCTION

Each year malaria infects about one-half billion people, killing 1 million to 2 million and severely dampening economic development (44, 123, 133, 289, 321a, 321b). The parasitic Plasmodium species causing malaria persist and even flourish despite the availability of tools for prevention, control, and treatment. Those tools consist of an array of drugs, diagnostics, and insecticides and a detailed understanding of the breeding site preferences of the many anopheline mosquito vectors. Despite the tremendous strides in biotechnology during the past 5 decades and the application to malaria of the many breakthroughs in molecular biology, genetics, immunology, and vaccinology by talented researchers, useful vaccines of any type evade us. This review examines one factor that may contribute substantially to this failure: inadequate understanding of naturally acquired immunity (NAI).

The dawn of scientific understanding of malaria occurred on 6 November 1880, when Alphonse Laveran observed a male gametocyte exflagellating in a blood smear from an Algerian patient with malaria. This event marked the identification of plasmodia as the cause of malaria (181). Working in India in 1897, Ronald Ross identified plasmodial oocysts in the guts of mosquitoes fed on parasitemic birds, thereby implicating mosquitoes as the vector of malaria (261). William George McCallum confirmed plasmodial exflagellation as a process of sexual reproduction in 1897 (200, 201), and Batistta Grassi et al. confirmed anopheline mosquitoes as the vector of human malaria in 1900 (130).

Human malaria has persisted through the development of miracle drugs and insecticides, a global eradication effort, and 30 years of intensive efforts to develop a practical vaccine. Not only does malaria persist it thrives. Today the global malaria situation is “serious and becoming worse” according to the WHO. The incidence and range of malaria, which were pushed to lows in about 1965 (the zenith of dichlorodiphenyltrichloroethane spraying campaigns), now increase sharply in areas of endemicity and spread into areas where control or eradication had been achieved. Worse still, this resurgence has been in progress for 40 years. Even as early as 1978 the historian Gordon Harrison wrote of the persistence of malaria in the face of such vigorous efforts to attack it, �ilure so universal, so apparently ineluctable, must be trying to tell us something. The lesson could be of course that we have proved incompetent warriors. It could also be that we have misconstrued the problem”(140). Three dominant factors account for the failure to maintain control: (i) parasite resistance to safe and affordable antimalarials, (ii) the almost complete demise of vector control programs in developing tropical and subtropical countries, and (iii) the failure to develop a practical vaccine that prevents malaria. Inadequate understanding of the mechanisms of naturally acquired clinical immunity against plasmodia may be an important factor contributing to the failure to develop a practical vaccine. We explore this possibility by examining the genesis and character of the current state of understanding of NAI.

In 1980, Bruce-Chwatt (50) wrote, “Malaria immunity may be defined as the state of resistance to the infection brought about by all those processes which are involved in destroying the plasmodia or by limiting their multiplication. Natural (innate) immunity to malaria is an inherent property of the host, a refractory state or an immediate inhibitory response to the introduction of the parasite, not dependent on any previous infection with it. Acquired immunity may be either active or passive. Active (acquired) immunity is an enhancement of the defense mechanism of the host as a result of a previous encounter with the pathogen (or parts thereof). Passive (acquired) immunity is conferred by the prenatal or postnatal transfer of protective substances from mother to child or by the injection of such substances.”

In humans, various types of acquired or adaptive immunity against plasmodia have been defined: (i) antidisease immunity, conferring protection against clinical disease, which affects the risk and extent of morbidity associated with a given parasite density (ii) antiparasite immunity, conferring protection against parasitemia, which affects the density of parasites and (iii) premunition, providing protection against new infections by maintaining a low-grade and generally asymptomatic parasitemia (171-174, 276). Here, protection is defined as objective evidence of a lower risk of clinical disease, as indicated by both the absence of fever (axillary temperature of 㸷.5ଌ) with parasitemia and lower densities of parasitemia.

Across sub-Saharan Africa where the disease is holoendemic, most people are almost continuously infected by P. falciparum, and the majority of infected adults rarely experience overt disease. They go about their daily routines of school, work, and household chores feeling essentially healthy despite a population of parasites in their blood that would almost universally prove lethal to a malaria-naive visitor. This vigor in the face of infection is NAI to falciparum malaria. Adults have NAI, but infants and young children, at least occasionally, do not. NAI is compromised in pregnant women, especially primigravidae, and adults removed from their routine infections apparently lose NAI, at least temporarily. Interventions that reduce exposure below a level capable of maintaining NAI risk the possibility of catastrophic rebound, as occurred in the highlands of Madagascar in the 1980s, with epidemic malaria killing more than 40,000 people (259). Routine exposure to hyper- to holoendemic malaria protects a majority of individuals while killing a minority. Aggressive interventions that consider only that vulnerable minority risk compromising or eliminating the solid protection against severe malaria in the majority.

This review summarizes what is understood about naturally acquired and experimentally induced immunity against malaria, with the help of evolving insights provided by biotechnology, and places these insights in the context of historical, clinical, and epidemiological observations. Apart from the practical importance of understanding NAI with respect to attacking holoendemic malaria, we also undertake this task to emphasize that NAI may be a good model for vaccine development. Consider a vaccine that allows infants and young children the same immunity enjoyed by their older siblings and parents: no disease with natural boosting, lifelong. Even if that concept were to be rendered superfluous by a safe eradication strategy, a more thorough understanding of NAI would almost certainly arm vaccinologists with other concepts to explore and adapt to specific populations. The exploration of NAI is key to the rational development and deployment of vaccines and other malaria control tools for almost any population at risk and, ultimately, a necessary foundation upon which to develop strategies of eradication by any means.


7.7: Specific acquired immunity - Biology

Lyme disease, if not treated promptly with antibiotics, can become a lingering problem for those infected. But a new study led by researchers from the University of Pennsylvania has some brighter news: Once infected with a particular strain of the disease-causing bacteria, humans appear to develop immunity against that strain that can last six to nine years.

The finding doesn’t give people who have already had the disease license to wander outside DEET-less, however. At least 16 different strains of the Lyme disease bacterium have been shown to infect humans in the United States, so being bit by a tick carrying a different strain of the disease is entirely possible. But the discovery does shed light on how the immune system recognizes and builds a defense against the pathogen and could inform future attempts to design a vaccine that would protect against multiple strains of the disease.

The study, published in the April issue of Infection and Immunity, was led by Dustin Brisson, an assistant professor in the Department of Biology in Penn’s School of Arts and Sciences, and Camilo E. Khatchikian, a postdoctoral associate in Brisson’s lab. They collaborated with Robert B. Nadelman, John Nowakowski, Ira Schwartz and Gary P. Wormser of New York Medical College.

When someone notices the telltale bull’s-eye rash that can signal Lyme disease, the infected person may receive antibiotics from a physician but generally will not know what strain of Borrelia burgdorferi caused the infection. But a 2012 study by Wormser’s group, published in the New England Journal of Medicine, reported on 17 patients who had been infected multiple times with Lyme disease and had the strain of each infection cultured and identified.

"The point of the paper published in the New England Journal of Medicine was to see if there is evidence that these recurrent infections were in fact caused by subsequent tick bites and not by a relapse of the original infection,” Brisson said. “That study overwhelmingly confirmed that they were new infections only one patient was infected by the same strain multiple times.”

The only patient infected by the same strain twice actually had Lyme disease four times in six years, contracting strain K twice, five years apart, with an infection by a different strain in between.

“In the present study, we wanted to see if so few patients were infected by the same strain multiple times because they were protected against subsequent infections with the same strain.”

The Penn-led team used two statistical approaches to answer this question.

The first involved calculating the probability of arriving at the data obtained from the 17 patients who had multiple Lyme disease infections by chance alone.

“If there was no strain-specific immunity, then there should be a random distribution of strains in patients, and you would expect several of the patients to be affected by the same strain twice,” Brisson said. “But only one patient was.”

Using multinomial probabilities, similar to rolling a die many times, the team found it would be nearly impossible to arrive at the data presented by the 17 patients if no strain-specific immunity were present. The same held true no matter if the calculations assumed it was equally likely that a patient would be infected with any strain of B. burgdorferi, or if the “die” was weighted based on the prevalence of each strain in New York state.

In a second statistical test, the researchers used the data from the 17 patients in what is known as a stochastic model to determine the expected number of total infections during a set period of time as well as the expected number of infections of the same strain during that time period.

The model allowed the researchers to vary assumptions such as the presence or absence of type-specific immunity, the duration of immunity and the length of time a patient was “available” to having been bitten by a tick -- in other words, the time from the first visit to the clinic to the last visit, or from the first visit to the completion of the study.

The results of all of their simulations indicated that strain-specific immunity would need to last a minimum of four years in order to result in the suite of infections that the 17 patients acquired. And parameterizing the model with actual data from 200 patients who had been infected at least once with a known strain of B. burgdorferi, the simulation indicated that immunity lasts in the range of six to nine years.

While studies in mice had suggested that strain-specific immunity might exist, this is the first time it’s been investigated in humans who have acquired infections naturally.

“If you infect a mouse with one strain and then clear it with antibiotics, it can’t be infected again with the same strain but can be with a different strain,” Brisson said “But mice only live for a year or so. No one had explored if immunity persists over the course of many years.”

The fact that the strain-specific immunity is lasting has implications for vaccine design.

“If you could make a vaccine that covers several of these strains,” Brisson said, “you could substantially reduce the probability of infection in vaccinated people. The vaccine could last several years, perhaps requiring a booster once every several years.”

Brisson noted that there is likely to be variation in the strength and duration of immunity among people and perhaps even among strains of the Lyme bacterium. His group is also investigating whether becoming infected and generating an immune reaction against one strain could offer protective cross-immunity against other strains.


Herd Immunity: Strength in Numbers

Herd immunity is the idea that an entire community can be protected from an illness by immunizing a certain percentage of individuals.

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Herd immunity, otherwise known as community immunity or the herd effect, is the way in which an entire community can be protected from an illness by immunizing a certain percentage of individuals. If enough people in the population are immune to a disease, then it is less likely to spread, thus shielding those who are unprotected.

Illness and Immunity

Diseases occur when people are infected with pathogens like bacteria or viruses. A person&rsquos immune system detects these intruders and responds by producing antibodies that fight the pathogen. Illnesses can be passed from person to person, and if enough people get sick it can lead to an outbreak. However, if a particular number of people in a population are immune, then the pathogen&rsquos chain of transmission is broken and the disease cannot be passed around as easily. As a result, the disease becomes rarer over time and can even be eliminated altogether.

There are two ways people can become immune to a disease: through natural exposure or through vaccination. In both cases, the human immune system recognizes any pathogens that it has been exposed to before and is able to produce antibodies much faster to ward off sickness. This is why an adult who has already had chickenpox (varicella) as a child is unlikely to contract the disease a second time. A new type of vaccine stimulates immunity using artificial mRNA, or messenger RNA. Messenger RNA is essential to the process that reads DNA to make the building block of proteins, amino acids. The mRNA vaccine replicates part of a pathogen, which is then injected into the body, triggering the immune system to develop antibodies against it.

Natural exposure to a disease is one way of achieving immunity, but it is risky for obvious reasons: it relies on getting sick in the first place, in the hopes that the immune system is strong enough to fight the illness and recover. Vaccination, on the other hand, is a relatively safe and effective option for immunization.

Vaccination has a long history with accounts of smallpox (variola) innoculation methods being practiced by as early as the 16th century in China and India. Smallpox was a common disease that killed countless people and left those who survived with disfiguring scars. These early vaccination methods involved rubbing the pus from the scab of someone infected with smallpox into an uninfected person's arm. This techinque was popularized in the United States by Puritan minister Cotton Mather in a 1721 smallpox outbreak in Boston, Massachusetts. Mather learned the technology from Onesimus, a West African man he kept enslaved. But this method had a relatively high mortality rate.

In the 18th century, English scientist Edward Jenner enhanced this technique. Instead of innoculating people with a healthy sample of the smallpox virus, Jenner innovated using a related, and less harmful, pathogen. He noticed that milkmaids who had contracted cowpox&mdasha similar but less aggressive disease&mdashdid not seem to get sick during smallpox outbreaks. He theorized that the two viruses were similar enough that exposure to cowpox would immunize an individual against smallpox.

Jenner decided to test his theory by inoculating a young boy with cowpox. He extracted pus from the blister of a milkmaid infected with cowpox and wiped it into a cut on the boy's arm. The boy fell ill but soon recovered. Jenner then purposely infected the boy with the deadly smallpox virus. Luckily for the boy, Jenner's theory was correct: His exposure to cowpox had made him immune, and he did not contract the disease.

Thankfully, medical science has come a long way since then. Today&rsquos vaccines work by injecting a weakened or modified version of a pathogen, or a synthetic snippet of mRNA based on the pathogen, to stimulate an immune response without inducing sickness. If an individual is exposed to the target pathogen in the real world, that person&rsquos immune system knows how to make the antibodies required to fight off the disease.

Vaccination is largely safe and it provides an uncomplicated way to confer herd immunity. Occasionially, vaccines can cause allergic reactions and unwanted side effects, and not everyone is a suitable candidate for every vaccine.

For herd immunity to take effect, a certain percentage of the population must be immunized. This threshold of how many people are required to stop a disease from spreading is different for every disease and depends on many factors, including how easily it spreads and whom it infects.

One of the statistics used to calculate this threshold is the &ldquobasic reproduction number&rdquo of a pathogen, known as R0. It represents the number of people one contagious person can, on average, be expected to infect in a community of unprotected individuals. The more contagious a disease is, the higher R0 will be. A higher R0 means more people need to be immunized for herd immunity to take effect.

For example, measles (Measles morbillivirus) is a highly contagious virus that can quickly be spread through the air. It has an R0 of 12&ndash18 and requires 95 percent of the population to be vaccinated before herd immunity kicks in. Polio, on the other hand, is less contagious and has an R0 of five to seven, meaning that only 80&ndash85 percent of the population needs to be immunized against polio for herd immunity to work.

Why Does It Matter?

Thanks to the effects of herd immunity, vaccines protect more people than just the individuals who receive them. If enough members of the population are immunized, then people who do not receive vaccines are less likely to get sick.

For example, seasonal influenza is a contagious disease that kills 36,000 people per year in the United States alone. While having the flu is unpleasant at the best of times, it is potentially deadly for people with weakened immune systems, including children and the elderly. Flu shots are available, but their effectiveness depends on a strong immune response. As a result, the vaccine is least effective at immunizing those who need it most: people with weakened immune systems. If strong and healthy people get vaccinated, then flu outbreaks can be contained and vulnerable demographics are protected.

Herd immunity is important because it contains outbreaks and protects the most vulnerable members of society from potentially deadly diseases. It is impossible to vaccinate every single person on the planet, but if enough people are vaccinated, then herd immunity can lead to diseases being stamped out entirely. Thanks to vaccinations and the herd effect, smallpox was officially declared as eradicated in 1980&mdashalmost two centuries after Edward Jenner discovered the first vaccine. Unfortunately, the growth of the anti-vaccination movement in recent decades has led to a resurgence in deadly childhood illnesses such as measles and pertussis.

Arguments against vaccination are not based on peer-reviewed scientific research or evidence, but they have risen steeply in popularity since the mid-20th century and have resulted in the resurgence of preventable, once-eradicated diseases like measles.


By Gypsyamber D’Souza and David Dowdy | Updated April 6, 2021

When the coronavirus that causes COVID-19 first started to spread, virtually nobody was immune. Meeting no resistance, the virus spread quickly across communities. Stopping it will require a significant percentage of people to be immune. But how can we get to that point?

In this Q&A, Gypsyamber D’Souza, PhD ’07, MPH, MS, and David Dowdy, MD, PhD ’08, ScM ’02, explain how the race is on to get people immune by vaccinating them before they get infected.

What is herd immunity?

When most of a population is immune to an infectious disease, this provides indirect protection—or population immunity (also called herd immunity or herd protection)—to those who are not immune to the disease.

For example, if 80% of a population is immune to a virus, four out of every five people who encounter someone with the disease won’t get sick (and won’t spread the disease any further). In this way, the spread of infectious diseases is kept under control. Depending how contagious an infection is, usually 50% to 90% of a population needs immunity before infection rates start to decline. But this percentage isn’t a “magic threshold” that we need to cross—especially for a novel virus. Both viral evolution and changes in how people interact with each other can bring this number up or down. Below any “herd immunity threshold,” immunity in the population (for example, from vaccination) can still have a positive effect. And above the threshold, infections can still occur.

The higher the level of immunity, the larger the benefit. This is why it is important to get as many people as possible vaccinated.

How have we achieved herd immunity for other infectious diseases?

Measles, mumps, polio, and chickenpox are examples of infectious diseases that were once very common but are now rare in the U.S. because vaccines helped to establish herd immunity. We sometimes see outbreaks of vaccine-preventable diseases in communities with lower vaccine coverage because they don’t have herd protection. (The 2019 measles outbreak at Disneyland is an example.)

For infections without a vaccine, even if many adults have developed immunity because of prior infection, the disease can still circulate among children and can still infect those with weakened immune systems. This was seen for many of the aforementioned diseases before vaccines were developed.

Other viruses (like the flu) mutate over time, so antibodies from a previous infection provide protection for only a short period of time. For the flu, this is less than a year. If SARS-CoV-2, the virus that causes COVID-19, is like other coronaviruses that currently infect humans, we can expect that people who get infected will be immune for months to years. For example, population-based studies in places like Denmark have shown that an initial infection by SARS-CoV-2 is protective against repeat infection for more than six months. But this level of immunity may be lower among people with weaker immune systems (such as people who are older), and it is unlikely to be lifelong. This is why we need vaccines for SARS-CoV-2 as well.

What will it take to achieve herd immunity with SARS-CoV-2?

As with any other infection, there are two ways to achieve herd immunity: A large proportion of the population either gets infected or gets a protective vaccine. What we know about coronavirus so far suggests that, if we were really to go back to a pre-pandemic lifestyle, we would need at least 70% of the population to be immune to keep the rate of infection down (“achieve herd immunity”) without restrictions on activities. But this level depends on many factors, including the infectiousness of the virus (variants can evolve that are more infectious) and how people interact with each other.

For example, when the population reduces their level of interaction (through distancing, wearing masks, etc.), infection rates slow down. But as society opens up more broadly and the virus mutates to become more contagious, infection rates will go up again. Since we are not currently at a level of protection that can allow life to return to normal without seeing another spike in cases and deaths, it is now a race between infection and injection.

What are the possibilities for how herd immunity could play out?

In the worst case (for example, if we stop distancing and mask wearing and remove limits on crowded indoor gatherings), we will continue to see additional waves of surging infection. The virus will infect—and kill—many more people before our vaccination program reaches everyone. And deaths aren’t the only problem. The more people the virus infects, the more chances it has to mutate. This can increase transmission risk, decrease the effectiveness of vaccines, and make the pandemic harder to control in the long run.

In the best case, we vaccinate people as quickly as possible while maintaining distancing and other prevention measures to keep infection levels low. This will take concerted effort on everyone’s part. But if we continue vaccinating the population at the current rate, in the U.S. we should see meaningful effects on transmission by the end of the summer of 2021. While there is not going to be a “herd immunity day” where life immediately goes back to normal, this approach gives us the best long-term chance of beating the pandemic.

The most likely outcome is somewhere in the middle of these extremes. During the spring and early summer (or longer, if efforts to vaccinate the population stall), we will likely continue to see infection rates rise and fall. When infection rates fall, we may relax distancing measures—but this can lead to a rebound in infections as people interact with each other more closely. We then may need to re-implement these measures to bring infections down again.

Will we ever get to herd immunity?

Yes—and hopefully sooner rather than later, as vaccine manufacturing and distribution are rapidly being scaled up. In the United States, current projections are that we can get more than half of all American adults fully vaccinated by the end of Summer 2021—which would take us a long way toward herd immunity, in only a few months. By the time winter comes around, hopefully enough of the population will be vaccinated to prevent another large surge like what we have seen this year. But this optimistic scenario is not guaranteed. It requires widespread vaccine uptake among all parts of the population—including all ages and races, in all cities, suburbs, and countrysides. Because the human population is so interconnected, an outbreak anywhere can lead to a resurgence everywhere.

This is a global concern as well. As long as there are unvaccinated populations in the world, SARS-CoV-2 will continue to spread and mutate, and additional variants will emerge. In the U.S. and elsewhere, booster vaccination may become necessary if variants arise that can evade the immune response provoked by current vaccines.

Prolonged effort will be required to prevent major outbreaks until vaccination is widespread. Even then, it is very unlikely that SARS-CoV-2 will be eradicated it will still likely infect children and others who have not been vaccinated, and we will likely need to update the vaccine and provide booster doses on some regular basis. But it is also likely that the continuing waves of explosive spread that we are seeing right now will eventually die down—because in the future, enough of the population will be immune to provide herd protection.

What should we expect in the coming months?

We now have multiple effective vaccines, and the race is on to get people vaccinated before they get infected (and have the chance to spread infection to others). It is difficult to predict the future because many factors are at play—including new variants with the potential for increased transmission, changes in our own behavior as the pandemic drags on, and seasonal effects that may help to reduce transmission in the summer months. But one thing is certain: The more people who are vaccinated, the less opportunity the virus will have to spread in the population, and the closer we will be to herd immunity.

We have seen that the restrictions needed over time have varied as preventive measures have worked to drive infection rates down, but we have also seen these rates resurge as our responses have relaxed. Once we get enough people vaccinated to drive down infection rates more consistently, we should be able to gradually lift these restrictions. But until the vaccine is widely distributed and a large majority of the population is vaccinated, there will still be a risk of infection and outbreaks—and we will need to take some precautions.

In the end, though, we will build up immunity to this virus life will be able to return to “normal” eventually. The fastest way to get to that point is for each of us to do our part in the coming months to reduce the spread of the virus—continue to wear masks, maintain distance, avoid high-risk indoor gatherings, and get vaccinated as soon as a vaccine becomes available to us.

Gypsyamber D’Souza is a professor and David Dowdy an associate professor in Epidemiology at the Bloomberg School.


Introduction

Streptococcus pneumoniae is a leading cause of infectious disease related death, responsible annually for up to a million child deaths worldwide [1]. Pneumonia represents the greatest burden of disease caused by S. pneumoniae [2], and despite current vaccination strategies the burden of pneumococcal pneumonia remains high. Invasive pneumococcal disease (IPD) is the most severe form of S. pneumoniae infection and mainly affects very young children and older adults. This is attributed to an underdeveloped adaptive immune system in infants, and to waning natural immunity combined with co-morbidities in the older adult. A clear understanding of the mechanisms of natural-acquired adaptive immunity to S. pneumoniae is essential to characterise why both the young and elderly are at high risk of disease and for the development of effective preventative strategies. Vaccines based on the polysaccharide capsule of S. pneumoniae are highly protective against the capsular serotypes included in the vaccine preparation [3–5], and protection correlates with the level of anti-capsular antibody responses. It has generally been assumed that the type-specific anti-capsular antibodies that can develop in response to colonisation or episodes of infection are also the main mechanism of natural adaptive immunity against IPD [6, 7]. However, there is little good evidence supporting the concept that levels of anti-capsular antibodies predict risk of IPD in unvaccinated individuals.

As well as causing symptomatic disease, S. pneumoniae asymptomatically colonises the nasopharynx, affecting at least fifty percent of infants and approximately ten percent of adults [8]. Colonisation is an immunising event. In humans, it leads to antibody responses to capsular polysaccharide [9], but also induces both antibody [10–14] and cellular immune responses to protein antigens [15, 16]. Serum levels of antibody to multiple pneumococcal surface proteins rise in the first few years of life [13], and have been show to fall in older age for a limited number of antigens [17]. Similar adaptive immune responses are observed in mouse models of nasopharyngeal colonisation [11, 18–25]. In animal models, these anti-protein responses alone can be protective, with T-cell mediated immunity preventing re-colonisation and non-invasive pneumonia[15, 24, 25] and anti-protein antibody responses protecting against IPD [19, 20, 22, 24]. Recent human data suggests that Th17-cell mediated responses to protein antigens also play an important role in protection against colonisation in humans [26] with implications for vaccine design [27]. There are several converging lines of evidence from human studies which support the concept that naturally-acquired anti-protein antibodies can also protect against S. pneumoniae infections. Lower serum IgG levels to a range of pneumococcal proteins correlate with susceptibility to acute otitis media [28, 29] and respiratory tract infections in children [30]. Passive transfer of human serum from experimentally challenged human volunteers protected mice against invasive challenge with a different capsular serotype of pneumococcus [20], providing proof of concept that ‘natural’ antibodies against bacterial proteins induced through nasopharyngeal exposure can protect against IPD. Furthermore, the incidence of IPD falls after infancy for all serotypes of S. pneumoniae, irrespective of how commonly the serotype is carried in the nasopharynx [31] suggesting that naturally-induced adaptive immune mechanisms are serotype-independent. If the protection against IPD that develops naturally through colonisation requires anti-protein antibody responses rather than serotype-specific anti-capsular antibody, this would represent an important readjustment in our understanding of immunity to S. pneumoniae. It would have major implications for identifying subjects with an increased risk of infection, understanding mechanisms of immunosenescence that increase susceptibility to S. pneumoniae with age, and for guiding future vaccine design.

Passive transfer of pooled human immune globulin (IVIG) is an established treatment to prevent infections in individuals with primary antibody deficiency [32, 33], in whom S. pneumoniae is a leading cause of disease [34]. Previous investigations in mice have indicated that IVIG may protect against experimental IPD [35, 36]. Commercially-manufactured IVIG is pooled immunoglobulin G (IgG) from >1000 different donors [37], and therefore represents the pooled antibody responses acquired through natural exposure across a population. We have used IVIG to determine the targets of natural acquired immunity to S. pneumoniae and the relative functional importance of anti-capsular and anti-protein responses for prevention of IPD.


Immunological perspectives

One of the most striking results from the studies described above is that mutations in LLO that render strains prematurely cytotoxic are avirulent. Thus, just as it is commonly stated that successful pathogens have evolved to avoid killing their host, it is not beneficial for intracellular pathogens to kill their host cell. Indeed, the host has evolved innate and acquired mechanisms, including induction of apoptosis and the generation of antigen-specific cytotoxic T-cells, that result in killing of infected cells (Harty et al., 2000). Lysis by cytotoxic T-cells is an important acquired immunological effector mechanism to eliminate L. monocytogenes (Finelli and Pamer, 2000). This may provide an explanation for the observations that L. monocytogenes cytotoxic mutants are avirulent: premature killing of infected host cells may lead to extracellular bacteria that are readily killed by infiltrating phagocytes. This also provides a framework with which to understand why L. monocytogenes spreads from cell to cell i.e., to avoid cytotoxic T-cells and phagocytes. Consistent with this notion, L. monocytogenes mutants that cannot recruit Ena/VASP peoteins show a small virulence defect in naïve mice, but show a 400-fold virulence defect in the liver of immune mice (Auerbuch et al., 2001) and (unpublished data). Presumably, efficient cell-to-cell spread is necessary during a cellular immune response. Lastly, it should be noted that an immunodominant epitope recognized by Listeria-immune cytotoxic T-cells is derived from LLO (Vijh and Pamer, 1997). Perhaps the fail-safe properties of LLO that are necessary for pathogenesis, such as rapid degradation in the cytosol, also lead to entry of LLO into the host's cytosolic pathway of antigen processing and presentation. Thus, LLO lies at the interface of bacterial pathogenesis and cell-mediated immunity.


How long will COVID-19 immunity last?

The coronavirus SARS-CoV-2 has only been circulating in human hosts for five or six months, which means that there is simply no way to know whether immunity to the disease lasts longer than that. How long immunity lasts is a big question, Tsinghua's Dong told Live Science via email.

"Per our findings, we can only confirm that COVID-19 patients can maintain the adaptive immunity to SARS-CoV-2 for 2 weeks post-discharge," he wrote.

Evidence from other coronaviruses suggests that immunity probably lasts longer than that, Vabret said. Along with Mount Sinai colleagues Robert Samstein and Miriam Merad, Vibrat led more than two dozen doctoral students and postdoctoral researchers in an effort to review the avalanche of immunology research coming out about the coronavirus in journals and on preprint servers that host scientific papers before peer review. Studies of SARS-CoV-2's proteins and genetics suggest that the virus seems likely to induce a long-term immune response similar to that of other coronaviruses, like 2002's SARS 1, or Middle Easter respiratory syndrome (MERS), which arose in 2012.

Research on SARS 1 and MERS suggests that some level of antibody immunity persists for at least two or three years, starting high and gradually waning as time goes by, Samstein told Live Science.

The immune system also produces a type of immune cell called virus-specific T cells in response to coronavirus infection. Less is known about T cells compared with antibodies, Vabret and Samstein said, because they are more difficult to find in the blood and study. But other coronaviruses seem to trigger their production, and these T cells seem to last for years in those cases. In one study of SARS 1 published in the journal Vaccine, researchers found these memory T cells last for up to 11 years after infection.

Ultimately, researchers are still uncertain about what level of long-term immune memory is sufficient to protect against future coronavirus infection, and how long it takes for the immune system to drop below that level. It's not even clear whether someone with immunity could spread the coronavirus to others while fighting off a second infection, Vabret and Samstein said. If the immune response were strong enough to crush the virus quickly, the person probably wouldn't transmit it further, they said. A weaker response that allowed some viral replication might not prevent transmission, though, particularly since people without symptoms are known to pass the coronavirus around.

"We're taking lessons from the older viruses, but we don't know how much for sure how much is similar," Samstein said.

This uncertainty does not reduce hopes for a vaccine, though. One benefit of vaccines is that researchers can mimic the viral proteins that trigger the most effective immune response. Thus, vaccination can often induce immunity that lasts longer than immunity from falling ill.

"You can aim at inducing protection that would be better than what you would get from an infection," Vabret said.


Watch the video: Immune Cells Eating Bacteria Phagocytosis (May 2022).