11.12A: Natural Active Immunity - Biology

Naturally acquired active immunity occurs when a person is exposed to a live pathogen, develops the disease, and then develops immunity.

Learning Objectives

  • Compare and contrast: active natural and active artifical immunity

Key Points

  • Once a microbe penetrates the body’s skin, mucous membranes, or other primary defenses, it interacts with the immune system.
  • Active immunization entails the introduction of a foreign molecule into the body, which causes the development of an immnune response via activation of the T cells and B cells.
  • The principle behind immunization is to introduce an antigen, derived from a disease-causing organism, that stimulates the immune system to develop protective immunity against that organism, but which does not itself cause the pathogenic effects of that organism.

Key Terms

  • immunity: the state of being insusceptible to a specific thing.
  • vaccination: inoculation with a vaccine in order to protect a particular disease or strain of disease.

Immunity is the state of protection against infectious disease conferred either through an immune response generated by immunization or previous infection, or by other non-immunological factors. There are two ways to acquire active resistance against invading microbes: active natural and active artificial.

Naturally acquired active immunity occurs when the person is exposed to a live pathogen, develops the disease, and becomes immune as a result of the primary immune response. Once a microbe penetrates the body’s skin, mucous membranes, or other primary defenses, it interacts with the immune system. B-cells in the body produce antibodies that help to fight against the invading microbes. The adaptive immune response generated against the pathogen takes days or weeks to develop but may be long-lasting, or even lifelong. Wild infection, for example with hepatitis A virus (HAV) and subsequent recovery, gives rise to a natural active immune response usually leading to lifelong protection.

In a similar manner, administration of two doses of hepatitis A vaccine generates an acquired active immune response leading to long-lasting (possibly lifelong) protection. Immunization (commonly referred to as vaccination) is the deliberate induction of an immune response, and represents the single most effective manipulation of the immune system that scientists have developed. Immunizations are successful because they utilize the immune system’s natural specificity as well as its inducibility. The principle behind immunization is to introduce an antigen, derived from a disease-causing organism, that stimulates the immune system to develop protective immunity against that organism, but which does not itself cause the pathogenic effects of that organism.

Immune systems are the purveyors of homeostasis and orchestrators of relationships among hosts, mutualists, commensals and pathogens of multipartite organisms, termed holobionts. Immunity underpins the health and survival of these holobionts—withstanding disruption and re-establishing homeostasis in the face of biotic and abiotic perturbations. Physiological trade-offs operating under evolved constraints drive distinct manifestations of immunity and underpin resistance. Variation in immunity therefore likely has a strong influence over coral survivorship under climate-change pressures.

Traditionally, innate immunity was recognized as the system used by invertebrates as a non-specific response to non-self 1 . But non-specificity and non-self may be out-dated concepts innate immune systems have targeted responses and memory 2,3 , and many organisms are not discrete ‘self’ entities with borders to defend 4 . Corals are complex mutualisms among multicellular partners and associated microbiota, which influence coral physiology sensu latu 5,6 . Corals and their plethora of mutualists, including the light-harvesting and energy-providing algae Symbiodinium spp. that live inside coral cells, enable all associates to thrive in often nutrient-poor tropical warm waters and build complex reef structures 7 . Homeostasis of these coral holobionts 8 therefore hinges on the immune system accepting mutualists and being vigilant of imposters while managing the housekeeping: clearing dead cells and selecting and maintaining an appropriate commensal microbiota 9 .

With climate change impacting the entire global marine ecosystem, as well as millions of people, biologists are racing to develop novel approaches to better conserve, restore and manage coral reefs 10 , which have endured significant impacts since the early 1980s 11 . To be effective, we need to fully explore, and embrace, the intricacies and complexities of coral holobiont health 12 . This will require understanding the role of immunity in maintaining and degrading homeostasis, inclusive of mutualisms and under environmental change 13,14 .

Understanding the dynamics and limitations of coral holobiont immunity is essential for accurately interpreting stress experiments and for elucidating appropriate target genes for assisted evolution of more resilient corals. To stimulate research, I challenge the dogma of coral bleaching as a general stress response distinct from immunity. I also propose the Damage Threshold Hypothesis of Coral Holobiont Susceptibility, a related concept to that described previously for insects 15 , to conceptualize immune-dynamics under homeostasis and with perturbations.

Active immunity

Individuals rely on active immunity more so than passive immunity. Active immunity is created by our own immune system when we are exposed to a potential disease-causing agent (i.e., pathogen). Most of the time, we are exposed to these potential pathogens naturally throughout the course of our day — in the air we breathe, the food we eat, and the things we touch. Luckily, most of these exposures are to agents that will not result in disease, either because they are harmless or because our immune system works to neutralize them.

In addition to “fighting off” these pathogens, active immunity is important because it lasts a long time in the form of immunologic memory. Immunologic memory consists of B and T cells that can recognize a particular pathogen (see "Adaptive immune system"). These cells circulate at low levels in our bodies and if “activated” by recognizing that pathogen in their travels, they quickly start to multiply and signal other elements of the immune system to activate as well. Memory cells are crucial for two reasons. First, they allow our immune systems to respond quickly. Second, they are specific for the pathogen, so the immune response is ready the moment the pathogen is encountered (see "Immunologic memory").

Because we don’t know about most of the work our immune system does, we often do not think about how busy it is. But, the reality is that like our hearts and lungs, our immune system is constantly working to keep us healthy. This effort is evidenced by the fact that our immune system generates grams of antibodies every single day!

Vaccines contribute to active immunity by providing us with a controlled way to create an immune response. When a vaccine is introduced, our immune system treats it like any other exposure. It works to stop the “assault” and, in the process, immunologic memory develops. Because vaccines are designed such that they do not cause illness, we gain the benefits of the exposure without the risks associated with fighting off a natural infection. In this way, vaccines offer our immune systems a chance to “train” for a future encounter and provide us with a “shortcut” to protection. We gain the immunity that follows surviving a natural infection without having to pay the price of natural infection.

What is passive immunity and how is it acquired?

While active immunity occurs when an individual produces antibodies to a disease through his or her own immune system, passive immunity is provided when a person is given antibodies. This can happen in utero or through antibody-containing blood products—such as immune globulin, or a substance made from human blood plasma�ministered when immediate protection from a specific disease is needed. 𠇏or example, when a mother’s antibodies cross the placenta to the fetus or when people are given antibodies as treatment for rabies,” explains Dr. Meyer. Immune globulin can also provide protection against hepatitis A in instances when a hepatitis A vaccine is not recommended,

The major advantage to passive immunity𠅊nd the reason why it&aposs sometimes used as a treatment against diseases—is that it provides immediate protection. But passive immunity doesn&apost last as long as active immunity, and loses effectiveness within a few weeks or months, per the CDC.

Of course, this passive immunity may also be helpful when it comes to COVID-19—primarily through the potential use of convalescent serum or blood plasma collected from those who have previously recovered from COVID-19. This means, according to Dr. Meyer, "giving antibodies from the blood of people who have recovered from COVID-19 to people who are actively ill in order to prevent complications and hasten recovery." But the use of convalescent plasma isn&apost exactly new it&aposs also been used as a treatment option in a variety of other infectious diseases, including Ebola, Middle East respiratory syndrome (MERS), SARS, and even the H1N1 and H5N1 infections, according to research presented in JAMA. That same research found that, for five critically-ill patients with COVID-19, convalescent plasma treatment resulted in "an improvement in clinical status" in all patients, concluding that convalescent plasma may be a helpful treatment for those with critical cases of COVID-19.

Convalescent plasma as treatment for COVID-19 specifically is still being studied, and is not yet recommended as routine treatment𠅋ut while it&aposs not yet been approved for use by the US Food & Drug Administration, the FDA did provide guidance to health care professionals and investigators administering or studying the use of convalescent plasma for treatment of COVID-19, according to a press release shared Monday, April 13. In addition to those guidelines. the FDA also approved Johns Hopkins University to test blood therapies for COVID-19 using plasma from recovering patients. "Researchers hope to use the technique to treat critically-ill COVID-19 patients and boost the immune systems of health care providers and first responders," researchers from Johns Hopkins University said in a press release.

The information in this story is accurate as of press time. However, as the situation surrounding COVID-19 continues to evolve, it&aposs possible that some data have changed since publication. While Health is trying to keep our stories as up-to-date as possible, we also encourage readers to stay informed on news and recommendations for their own communities by using the򠳜, WHO, and their local public health department as resources.

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Immunologic Memory

The effectiveness of adaptive immunity is largely a result of its ability to recognize invading microbes encountered previously and to mount an enhanced and accelerated response against them. The more an animal encounters an antigen, the greater will be its immune response. Immunologic memory depends on the presence of persistent populations of memory cells that accumulate as an animal ages. These memory cells may be very long-lived or, more likely, turn over very slowly. As a result, animals may make small amounts of antibodies to vaccine antigens for many years after vaccination. Cell-mediated memory is also due to the development of very long-lived populations of memory T cells. The effectiveness of vaccines in inducing long-lasting immunity depends in large part on their ability to induce memory cell populations.

Active Humoral Immunity

Active humoral immunity refers to any form of immunity that occurs as a result of the formation of an adaptive immune response from the body&rsquos own immune system. Active immunity is long term (sometimes lifelong) because memory cells with antigen-binding affinity maturation are produced during the lymphocyte differentiation and proliferation that occurs during the formation of an adaptive immune response. It also refers to the effector functions of antibodies, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.

Active immunity can either be naturally-occurring or passive. Natural active immunity generally occurs as a result of infection with a pathogen, in which memory cells that remember the antigen of the infectious agent remain in the body. Artificial active immunity is the result of vaccination. During vaccination, the body is exposed to a weakened form of a pathogen that contains the same antigens as the live pathogen, but cannot mount an infection against the body in its weakened state. Vaccinations have become an effective form of disease prevention that is especially useful in preventing diseases that would normally have a high risk of mortality during an infection, where relying on natural active immunity would prove dangerous. However, active immunity does not work to protect against all pathogens, because many can mutate and change their antigen structure over time, which enables them to evade the defenses of immunological memory.

How the strep bacterium hides from the immune system

The graphical abstract: pathogen Group A Streptococcus camouflaging as red blood cells. Credit: Dorota Wierzbicki

A bacterial pathogen that causes strep throat and other illnesses cloaks itself in fragments of red blood cells to evade detection by the host immune system, according to a study publishing December 3 in the journal Cell Reports. The researchers found that Group A Streptococcus (GAS) produces a previously uncharacterized protein, named S protein, which binds to the red blood cell membrane to avoid being engulfed and destroyed by phagocytic immune cells. By arming GAS with this form of immune camouflage, S protein enhances bacterial virulence and decreases survival in infected mice.

"Our study describes a completely novel mechanism for immune evasion," says corresponding author David Gonzalez of the University of California, San Diego. "We believe the discovery of this previously overlooked virulence factor, S protein, has broad implications for development of countermeasures against GAS."

GAS is a human-specific pathogen that can cause many different infections, from minor illnesses to very serious and deadly diseases. Some of these conditions include strep throat, scarlet fever, a skin infection called impetigo, toxic shock syndrome, and flesh-eating disease. An estimated 700 million infections occur worldwide each year, resulting in more than half a million deaths. Despite active research, a protective vaccine remains elusive.

To date, penicillin remains a primary drug of choice for combatting GAS infections. But the rate of treatment failures with penicillin has increased to nearly 40% in certain regions of the world. "Due to the high prevalence of GAS infection and the decreasing efficacy of the available set of countermeasures, it is critical to investigate alternative approaches against GAS infection," Gonzalez says.

One alternative approach is to develop novel anti-virulence therapeutics. To avoid immune clearance, GAS expresses a wide variety of molecules called virulence factors to facilitate survival during infection. But the function of many of these proteins remains unknown, hindering the development of alternative pharmacological interventions to combat widespread antibiotic resistance.

To address this gap in knowledge, Gonzalez and co-first authors Igor Wierzbicki and Anaamika Campeau of the University of California, San Diego, used a nanotechnology-based technique called biomimetic virulomics to identify proteins that are secreted by GAS and bind to red blood cells. This approach revealed a previously uncharacterized protein, which the researchers named S protein, because this type of protein is limited to members of the Streptococcus genus.

The researchers found that a mutant bacterial strain lacking S protein was less able to grow in human blood, and less able to bind to red blood cells, compared to the non-mutated strain. The mutant strain was also more readily captured and killed by phagocytic immune cells called macrophages and neutrophils. In addition, the absence of S protein vastly reshaped the bacterial protein landscape, decreasing the abundance of many known virulence factors.

Moreover, mice infected with GAS cells coated with red blood cells showed a 90% mortality rate, compared to 40% of mice infected with uncoated GAS cells. Infection with coated GAS cells also caused a more rapid decrease in body weight. "These findings suggest that S protein co-opts red blood cell membranes for molecular mimicry, or imitation of host molecules, to evade the immune response," Gonzalez says.

Additional experiments showed that infection with GAS caused a progressive decline in the body weight of mice and a 90% mortality rate. By contrast, all mice infected with mutant GAS lacking S protein survived infection, and their body weight stabilized and remained constant after a slight initial decline. Infection with mutant GAS also resulted in a lower concentration of bacteria in the bloodstream and organs, and promoted a robust immune response and immunological memory.

"Taken together, the results suggest that inactivation of S protein function makes GAS vulnerable to host immunity," Gonzalez says. "S protein influences virulence by capturing lysed red blood cell membranes to cloak the bacterial cell surface, which allows bacteria to circumvent host immunity. This novel evasion mechanism can be targeted for anti-streptococcal therapies."

Currently, Gonzalez and his team are examining the mechanism by which S protein binds to red blood cells. They are also studying the role that S protein plays in other important human pathogens, including Streptococcus pneumoniae, which causes pneumonia and other illnesses, as well as Group B Streptococcus or S. agalactiae—a bacterium that is a common cause of severe infections in newborns during the first week of life.

"Ultimately, the findings could lead to the development of a novel vaccine candidate," Gonzalez says. "Because of its pivotal roles in pathogenesis and immune evasion, and its conserved nature in Streptococci, S protein shows promising clinical potential as a target for the development of anti-virulence pharmacological interventions."

Which offers more protection: Vaccination or natural immunity?

Credit: Modern Healthcare

Let’s start by demonstrating the pandemic’s continuing politicization with the Tweets of the Senator from Kentucky.

Perhaps a more interesting question is whether there are advantages or disadvantages to natural versus artificial, i.e., vaccinated immunity?

The short answer is that it makes no difference to our immune system. Whether the antigen is a virus or bacteria, or a snippet of same, made by man, the immune system recognizes it as foreign and “does its thing.” Its thing, of course, is to develop an immune response. That transformation occurs in the bloodstream and lymph nodes irrespective of whether the antigen got in from our nose, mouth, digestive tract, lung, or via a needle.

That said, there are a few differences. Natural immunity requires enough antigen, viral or bacterial, to be identified and cause the immune system to respond. More antigen gives a more robust response. But that response varies several-fold – a mild case involving minimal symptoms may result in more of a half-hearted natural immunization than you would hope for.

Before considering the variability of response, let’s dig into the cost of natural immunity – you have to be infected and may suffer significant consequences. When looking at a lethal disease, like COVID-19, or infection with substantial morbidity, like brain damage from measles or paralysis from polio, the cost can be quite high. Vaccines are far safer than acquiring immunity by becoming ill. That is the tradeoff underlying the fight over letting herd immunity develop naturally. Herd immunity will develop, but there are going to be a lot of deaths along the way.

Credit: AFP

For most immunities, vaccines not only are safer but produce a more robust response. This includes vaccines for HPV, tetanus, and pneumonia mumps is an exception. The other benefit of a vaccine over natural immunity is its standardization. First, unlike acquiring natural immunity, you can choose when you get vaccinated. Second, while natural immunity provokes a range of responses, vaccines are designed to create the most significant immune response without safety concerns.

For the COVID-19 vaccines, there remain two questions. How long will the immunity last? We don’t know yet, but only time will tell. Again, most vaccines confer equally long-lasting immunity. The two mRNA vaccines are targeted at the spike protein. Natural immunity can target the spike and other viral shapes, which might allow natural immunity to protect against some variants again, we do not know. What we do know is that getting your immunity by contracting COVID-19 is a crapshoot being vaccinated is exceedingly efficacious and safe.

“Because vaccines are made using parts of the viruses and bacteria that cause disease, the ingredient that is the active component of the vaccine that induces immunity is natural. However, critics point to other ingredients in vaccines or the route of administration as being unnatural.”

– Immune System and Health Children’s Hospital of Philadelphia

Vaccines include three common ingredients, an adjuvant, a stabilizer, and, often, a preservative. The Pfizer vaccine contains no adjuvant you might think of the first dose priming your immune system for the second although the first confers significant immunity. Instead of a stabilizer, the mRNA is wrapped in a bit of fat with some salts and sugar, called a nanoparticle. It contains no preservatives. Moderna’s vaccine is essentially the same, differing in the elements of the nanoparticle. Johnson & Johnson’s vaccine uses a different delivery method for the antigen. It makes use of an adenovirus –one that causes the common cold and that has been attenuated to cause no symptoms. It is stabilized using a sugar, and the preservative is a citrate commonly found in food.

“I believe that morally everyone must take the vaccine. It is the moral choice because it is about your life but also the lives of others.”

– Pope Francis

Catholics have raised concern about the J&J product because the vaccine’s production involves using a cell line obtained from aborted fetal tissue. The initial statements by local church officials were mixed messages. In 2005 the Vatican’s Pontifical Council of Life indicated that there were “Degrees of Cooperation with Evil” – that the further one was from the act of abortion, the less evil the involvement. The Pope has stated, and now the US Catholic leadership has concurred, that a devout Catholic should choose a different vaccine when given a choice. Still, when there is no choice, the Johnson & Johnson vaccination is “morally acceptable.”

But I will give the last word on the topic to ACSH friend Dr. Paul Offit – the Director of the Vaccine Education Center and professor of pediatrics in the Division of Infectious Diseases at Children’s Hospital of Philadelphia.

Dr. Charles Dinerstein, M.D., MBA, FACS is Senior Medical Fellow at the American Council on Science and Health. He has over 25 years of experience as a vascular surgeon. He completed his MBA with distinction in the George Washington University Healthcare MBA program and has served as a consultant to hospitals. While no longer clinically active, he has had his writing featured at KevinMD and Doximity. Follow him on Twitter @CRDtoday

A version of this article was originally posted at the American Council on Science and Health and has been reposted here with permission. The ACSH can be found on Twitter @ACSHorg

The GLP featured this article to reflect the diversity of news, opinion and analysis. The viewpoint is the author’s own. The GLP’s goal is to stimulate constructive discourse on challenging science issues.


Vaccines have been a revolution in modern medicine, helping to protect millions of people from infectious disease. They work by building up memory immunity to a target pathogen.

Vaccines are biological preparations comprised of dead/attenuated pathogens or antigens from their surfaces. These preparations alone cannot cause disease but can help our body to develop memory immunity, protecting us should we become infected with the live pathogen. The initial, innate immune response is relatively slow and is the reason why we often display symptoms of disease before our immune system has chance to kill the pathogen. Following this we develop adaptive immunity, through the specialisation of leukocytes, fine tuned to react to the encountered pathogen.

Vaccination aims to bypass slow, initial response so that when we are infected with disease causing material, our acquired immunity (from the vaccine) can kill an invading pathogen before they have chance to cause disease.

How effective are vaccines?

Vaccination is one of our most powerful tools against infectious disease and have been very successful at protecting us. One of the greatest successes in modern medicine is the polio vaccine, which after 3 doses offers 99% coverage and has all but eradicated poliomyelitis.

Above - the first peak in the graph represents an adaptive immune response following initial vaccination. Exposure to antigen following this initial vaccination, be it a booster or infection, stimulates an elevated immune response.

Scientists Uncover Evidence That a Level of Pre-Existing COVID-19 / SARS-CoV-2 Immunity Is Present in the General Population

The T cells, along with antibodies, are an integral part of the human immune response against viral infections due to their ability to directly target and kill infected cells. A Singapore study has uncovered the presence of virus-specific T cell immunity in people who recovered from COVID-19 and SARS, as well as some healthy study subjects who had never been infected by either virus.

The study by scientists from Duke-NUS Medical School, in close collaboration with the National University of Singapore (NUS) Yong Loo Lin School of Medicine, Singapore General Hospital (SGH) and National Centre for Infectious Diseases (NCID) was published in Nature. The findings suggest infection and exposure to coronaviruses induces long-lasting memory T cells, which could help in the management of the current pandemic and in vaccine development against COVID-19.

The team tested subjects who recovered from COVID-19 and found the presence of SARS-CoV-2-specific T cells in all of them, which suggests that T cells play an important role in this infection. Importantly, the team showed that patients who recovered from SARS 17 years ago after the 2003 outbreak, still possess virus-specific memory T cells and displayed cross-immunity to SARS-CoV-2.

“Our team also tested uninfected healthy individuals and found SARS-CoV-2-specific T cells in more than 50 percent of them. This could be due to cross-reactive immunity obtained from exposure to other coronaviruses, such as those causing the common cold, or presently unknown animal coronaviruses. It is important to understand if this could explain why some individuals are able to better control the infection,” said Professor Antonio Bertoletti, from Duke-NUS’ Emerging Infectious Diseases (EID) program, who is the corresponding author of this study.

Associate Professor Tan Yee Joo from the Department of Microbiology and Immunology at NUS Yong Loo Lin School of Medicine and Joint Senior Principal Investigator, Institute of Molecular and Cell Biology, A*STAR added, “We have also initiated follow-up studies on the COVID-19 recovered patients, to determine if their immunity as shown in their T cells persists over an extended period of time. This is very important for vaccine development and to answer the question about reinfection.”

“While there have been many studies about SARS-CoV-2, there is still a lot we don’t understand about the virus yet. What we do know is that T cells play an important role in the immune response against viral infections and should be assessed for their role in combating SARS-CoV-2, which has affected many people worldwide. Hopefully, our discovery will bring us a step closer to creating an effective vaccine,” said Associate Professor Jenny Low, Senior Consultant, Department of Infectious Diseases, SGH, and Duke-NUS’ EID program.

“NCID was heartened by the tremendous support we received from many previous SARS patients for this study. Their contributions, 17 years after they were originally infected, helped us understand mechanisms for lasting immunity to SARS-like viruses, and their implications for developing better vaccines against COVID-19 and related viruses,” said Dr Mark Chen I-Cheng, Head of the NCID Research Office.

The team will be conducting a larger study of exposed, uninfected subjects to examine whether T cells can protect against COVID-19 infection or alter the course of infection. They will also be exploring the potential therapeutic use of SARS-CoV-2-specific T cells.

Reference: “SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls” by Nina Le Bert, Anthony T. Tan, Kamini Kunasegaran, Christine Y. L. Tham, Morteza Hafezi, Adeline Chia, Melissa Hui Yen Chng, Meiyin Lin, Nicole Tan, Martin Linster, Wan Ni Chia, Mark I-Cheng Chen, Lin-Fa Wang, Eng Eong Ooi, Shirin Kalimuddin, Paul Anantharajal Tambyah, Jenny Guek-Hong Low, Yee-Joo Tan and Antonio Bertoletti, 15 July 2020, Nature.
DOI: 10.1038/s41586-020-2550-z