Immunology and Vaccination

Summary

The function of vaccination is to induce immunity in humans and other animals to protect against disease-causing organisms. Vaccination is generally carried out by injecting attenuated or inactivated microorganisms, such as bacteria or viruses, or the inactivated toxins produced by bacteria. The first vaccinations were directed against smallpox during the eighteenth century and involved the use of cowpox virus, similar but not identical to the virus that caused smallpox. Modern vaccinations often use purified components of the organism rather than the entire bacterium or virus, producing similar immunity without the danger of side effects or illness.

Definition and Basic Principles

Immunology is the science that studies the reactions of immune cells within the body to foreign molecules referred to as antigens. The majority of immune cells are represented by populations of white blood cells, or leukocytes, found circulating within the bloodstream and lymphatic system. Although all immune cells originate and mature largely within the bone marrow, they undergo differentiation into highly specialized categories. Monocytes and neutrophiles are phagocytic cells circulating in the bloodstream and lymphatic system that function to ingest and digest both foreign antigens from outside the body and old or dying cells within the body. Monocytes mature within tissues and organs, such as the spleen and lymph nodes, into a class of cells called macrophage, transport the ingested antigens to the cell surface, and present the digested molecules to a second class of white cells called B and T lymphocytes. Only those lymphocytes that express a receptor specific to the presented antigen will respond, with B cells differentiating into plasma cells that secrete antibodies directed against the original antigen.

The principle underlying vaccination is that administration of a killed or attenuated form of bacterium, bacterial toxin, or virus will produce antibodies against the target, producing immunity in the individual against the bacterial or viral antigens. If the person is later exposed to the same microorganism or toxin, the presence of preexisting antibodies will protect against infection or poisoning.

Background and History

Immunitas originally referred to the freedom from taxes among ancient Romans. The Greek historian Thucydides, who described the medical concept of freedom from disease—immunity—in his description of the plague (actually probably a typhoid fever epidemic) in Athens in 430 Before the Common Era, noted that individuals who survived “were never attacked twice.”

An understanding of the cellular basis for immunity was not reached until late in the nineteenth century. However, the principle of prior exposure to a disease resulting in immunity had been known since about 1000 Common Era, when the Chinese carried out a practice called variolation. In this practice, a person inhaled dried crust from the pocks that developed on smallpox victims. If they developed only a mild form of the disease, the most common outcome, the person was immune for life. The practice traveled to Eastern Europe and then England by the early eighteenth century. Although variolation was generally successful, sometimes it resulted in the person contracting smallpox.

The first successful active immunization is ascribed to Edward Jenner, an English country physician who, in the 1790s, tested a belief common among local dairymaids—that prior exposure to a mild cowpox infection of the udder on a cow provided immunization against smallpox. Beginning in 1796, Jenner carried out tests in which he intentionally infected people by applying cowpox “lymph” obtained from a lesion to small slits cut in the arms of volunteers. During a subsequent epidemic, none of the inoculated individuals developed smallpox. Jenner called the practice “vaccination,” from vacca, Latin for cow.

How It Works

An understanding of the cellular mechanism underlying successful vaccinations did not begin until the late nineteenth century and was the outcome of both a scientific and a nationalistic rivalry between French and German scientists. The major proponent of a cellular theory of immunity was the Russian scientist Élie Metchnikoff. While studying the differentiation of cells in animals, such as starfish larvae, Metchnikoff observed that the insertion of a wooden splinter into the larvae resulted in the infiltration of both large and small white blood cells. He called these macrophages, “large eaters,” and microphages, “small eaters.” Microphage later became known as neutrophils. Metchnikoff subsequently joined the laboratory of French scientist Louis Pasteur, where he became a proponent of the cellular theory of immunity.

The competing theory was defined by the German school and became known as humoral immunity. Robert Koch, Emil von Behring, and their associates noted that blood plasma obtained from animals previously exposed to etiological agents of disease or to bacterial toxins could directly kill bacteria or neutralize these toxins. Behring and Paul Ehrlich applied their discovery in developing the first vaccines against diphtheria. Soluble proteins, including antibodies, became the basis for humoral immunity.

It was in the mid-twentieth century that the basis for immunization was established as a combination of both cellular and humoral immunity. Phagocytosis is indeed carried out by several classes of white blood cells, while antibodies are produced by a class of white cells called B lymphocytes. The actual immune mechanisms involve a complex interaction between these classes of cells and their soluble products in which the phagocytic cell presents the digested antigen on its surface to the appropriate lymphocyte. The end result is that B lymphocytes mature and differentiate into an end-stage antibody-producing factory called a plasma cell. Each plasma cell produces a single type of antibody, selected based on possessing a receptor specific to the antigen presented by the phagocyte.

Vaccine Production. Vaccine production is based on the activation of lymphocytes through exposure to bacterial or viral antigens (proteins), the result of which is the production of antibodies or the stimulation of phagocytic cells. Vaccines have historically been produced by three major mechanisms: the use of inactivated or killed microorganisms, the use of attenuated or cross-reacting organisms, or the use of purified portions of microorganisms in recombinant vaccines. The smallpox vaccine is an example of a cross-reacting organism. The cowpox virus is similar enough to smallpox that the immune response is protective against both.

Most viral vaccines have used attenuated strains of the original virus, selected either by passage through nonhuman animals or cells or by artificial selection on the basis of avirulence, an inability to cause disease. The strains of poliovirus vaccines developed by Albert Bruce Sabin, as well as vaccines against rabies, chickenpox, measles, and mumps, all consist of attenuated viruses. The polio vaccine developed by Jonas Salk is a formalin-killed virus. A later generation of viral vaccines, those directed against viruses, such as hepatitis B and human papillomavirus (which causes warts and cervical cancer), are subunit types consisting of surface proteins obtained from the virus, which through DNA recombination are linked to harmless carrier proteins. Vaccines directed against tetanus toxin are similar to those originally developed by Behring and Ehrlich against diphtheria toxin. The toxin is chemically modified and injected.

The principle behind all vaccinations is the same. Exposure to the agent results in an immune response within the individual. Antibodies are produced, and cellular immunity is activated. The response is already in place in the event of future exposure to the same organism or toxin. In most cases, immunity is long-lasting, though periodic boosters are recommended to ensure a proper level of immunity.

Autoimmune Disease. In principle, the immune response is directed only against foreign agents that could potentially cause disease. However, in certain circumstances, alterations in immune regulation take place, and antibodies are produced against the person's own tissues. The precise molecular mechanism that triggers autoimmune function is unclear. Some diseases run in families or are gender-specific (women are more likely to contract certain autoimmune diseases), and other illnesses may be triggered by cross-reaction with viral or bacterial antigens. The tissue involved depends on the type of autoantibody produced, but the mechanisms for damage are similar.

Autoimmune diseases are placed into two major categories, organ-specific or systemic, reflecting the sites or systems involved. Examples of organ-specific diseases include type 1 diabetes, in which the B cells of the pancreatic islets of Langerhans are targeted; Crohn's disease, a form of inflammatory bowel disease; and multiple sclerosis, characterized by inflammation of tissue in the central nervous system. Systemic autoimmune diseases include systemic lupus erythematosus, in which antigen/antibody complexes lodge in different organs, and rheumatoid arthritis, characterized by immune complexes that lodge in joints or bone. Although the type of antibody may differ in autoimmune diseases, pathologies are similar in that each activates the complement pathway, components of which include degradative enzymes that contribute to inflammation and tissue destruction.

Applications and Products

Vaccine Production. Historically, vaccines fell into two categories: live vaccines in which the agent was altered to be unable to cause disease but still able to replicate in the human host, triggering the immune response, and killed vaccines in which the organism was identical to the parent strain but unable to replicate. Each had advantages. Live vaccines produced a greater response and often a lifelong immunity, and killed vaccines would not result in reversion to the wild strain, causing disease. For example, before they were discontinued in 1990, the Sabin strains of attenuated poliovirus had a reversion rate of about one in one million persons inoculated in the United States (US), resulting in about ten vaccine-associated cases of polio per year.

Live or attenuated vaccines were originally created by passage in nonhuman animals or cell cultures in a laboratory. This was particularly true for vaccines for viruses, including those against rabies, polio, measles, mumps, rubella, and chickenpox. Because viruses develop random mutations, variant strains were selected based on sensitivity to pH (acidity-alkalinity), elevated temperatures (fever), or their inability to infect specific tissues. The Sabin poliovirus strains represent a prototype of attenuated viruses, being temperature-sensitive and incapable of infecting tissue in the central nervous system. Later methods of developing attenuated strains have involved active modification of viral genetic material or the creation of recombinant viruses in which those genes necessary for replication have been deleted.

Most viruses can be grown in cell culture for vaccine production. Animal cells are easy to maintain in the laboratory, and viruses for vaccines can be grown to the necessary concentrations. Influenza viruses are exceptions, one reason why quick production of yearly influenza vaccines has been difficult. The influenza virus genome consists of eight individual segments; coinfection of cells with two different strains, often involving viruses from two different species, such as humans and birds, routinely creates a new recombinant strain that is not recognized by the human immune system. Influenza viruses do not grow well in cell culture, so vaccines must be produced using viruses grown in eggs. The lead time necessary to produce sufficient quantities of vaccine for the influenza season, which begins in the fall, is about six months. Therefore, health agencies, such as the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), must decide in late winter which strains are most likely to produce an outbreak later that year.

Monoclonal Antibodies (mAB). Exposure to antigens, such as those found on bacteria or viruses, triggers the production of a large number of different antibodies, each specific for a particular molecular determinant on an organism. In the 1960s, it was discovered that persons with multiple myeloma, a cancer of plasma cells, produced large quantities of homogeneous antibodies.

British scientists Georges J. F. Köhler and César Milstein found that because myeloma cells, like those of most cancers, are immortalized, they could artificially fuse myeloma cells with immune cells of known specificity to produce a clone of “immortal” cells producing identical antibodies. Because these cells represented a clone, the product became known as monoclonal antibodies.

Because antibodies can, in theory, be generated in the laboratory against any target, monoclonal antibodies can be used as a probe for detecting any cellular molecule. Initial applications used monoclonal antibodies to detect cell surface proteins to identify cell types or the maturation stage of cells during differentiation. Because these surface proteins exhibited clustering, they became known as cluster of differentiation (CD) proteins. Nearly two hundred cluster of differentiation proteins are now known.

The ability of monoclonal antibodies to bind surfaces on specific cells has led to their use in diagnosing or treating certain types of cancers. Immuno-conjugates are prepared by chemically attaching a toxin or radioisotope to a monoclonal antibody and injecting the molecule into a patient. The binding of the conjugated monoclonal antibody to the tumor cell kills the target. Although, in theory, immunotherapy could be applied to many forms of cancer, most tumors do not express proteins unique to that type of cancer. Cancer vaccine research continues. In 2024, therapeutic cancer vaccines had been approved for prosate, bladder, and melanoma cancers. Furthermore, by 2023, the US Food and Drug Administration (FDA) had approved immunotherapy to treat about twenty types of cancers.

Careers and Course Work

As is true for most careers in medical science, students generally begin by earning a Bachelor of Science degree in a field, such as biology or biochemistry. The undergraduate program should include courses in general biology, chemistry (particularly organic chemistry), microbiology, genetics, and biochemistry. An understanding of the human immune system is vital, so courses in immunology, virology, and pathogenic microbiology should be included. Universities, such as Rice University in Texas and Johns Hopkins University in Maryland, offer courses related to vaccination and immunology.

The Bachelor of Science degree is sufficient for an entry-level position, but advanced training is necessary for someone wishing to be more than a technician. Historically, most research in the field of immunology has taken place in universities, often in association with medical schools or research institutes. A student wishing to pursue such research most commonly enters a graduate program in which faculty members are carrying out studies in a relevant area. The laboratory director may focus their research in developing a recombinant vaccine. The work often involves initial testing of efficacy and safety in nonhuman animals. A Doctorate is necessary for working at the level of university faculty or laboratory director.

Development and marketing of any prospective vaccine requires a significant source of funding, which may be available through government grants but more likely involves funding from pharmaceutical companies. A Master's degree in an area of science, such as chemistry or biochemistry, is the minimal requirement in industry for vaccine research and development, while a Doctorate is preferred. Aspirants can work as pharmacologists, epidemiologists, vaccine research scientists, and safety physicians.

Social Context and Future Prospects

The effective control of most childhood infectious diseases by the end of the twentieth century has caused the fear of such diseases to all but disappear among most modern populations. As some segments of European, British, and American populations have grown up in a time in which childhood infectious diseases appeared to be a thing of the past, many of these people do not fully understand the devastating nature of these diseases and question the value of vaccines. Also, the sheer number of recommended vaccinations has created concern among parents, some of whom are afraid their children's immune systems could be overwhelmed. Although no evidence for a link between autism and vaccination has been found, some parents still believe that such a link exists due to a false study published by Andrew Wakefield in 1998. Although this study has been disproven and Wakefield stripped of his medical license, this belief has remained in society and continued to be proliferated through social media.

Though measles is a disease that was considered effectively eradicated in 2000, the worst outbreak of measles in twenty years occurred in 2014, with the CDC reporting twenty-three outbreaks and a total of 667 cases from twenty-seven states. Critics of the anti-vaccination movement claimed that the reoccurrence of such diseases can largely be blamed on the large number of children who have not received the vaccinations that had been proven to work in the past. In a detailed report, the CDC highlighted the largest outbreak that year, consisting of 383 cases, occurred among unvaccinated Amish communities in the state of Ohio. In 2015, the United States experienced yet another large outbreak of measles, resulting in 189 cases from twenty-four states, which was linked to an amusement park in California. Once again, it was argued that the disease would not have spread to such an extent if everyone had received the measles vaccination and did not get infected by others with the disease traveling into the country. In 2019, more than 1,200 new measles cases were reported in the country. Between 2020 and May 2024, over 300 new cases of measles were reported. 

Future immunizations are likely to rely less on whole virus or bacterial vaccines and more on acellular or subunit vaccines. Side effects resulting from the pertussis vaccine, generally mild fever or inflammation but occasionally a more serious problem, led to the development of an acellular pertussis vaccine using only bacterial proteins. Similar vaccines, some containing only genetic information for the production of viral proteins, are likely to be used against other diseases in the future. For example, vaccines containing genetic material, such as mRNA (messenger ribonucleic acid), were developed in 2020. These vaccines were made against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic that started in 2019. After reacting with a viral protein, mRNA in the vaccine makes the immune system recognize the antigen leading to antibody production.

Immunization against some agents, such as influenza viruses, which undergo yearly changes, will probably involve some form of combination vaccines, incorporating proteins that are common to most major strains of the virus. The simplicity of world travel in the twenty-first century means scientists must take a worldview of new strains, as an outbreak in a few countries can rapidly develop into a worldwide pandemic. For example, COVID-19, first detected in Wuhan, China, in 2019, spread via travelers to almost every country in the world and hence was declared a pandemic by WHO in 2020.

The ability of the human immunodeficiency virus (HIV) to undergo rapid mutations, even within the same individual, means a vaccine against acquired immunodeficiency syndrome (AIDS) remains unlikely in the foreseeable future. However, in the early twenty-first century, the development of HIV vaccines using mRNA, viral vector, and broadly neutralizing antibodies (bNAbs) by the International AIDS Vaccine Initiative (IAVI) was under research.

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