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INSIDEthis issue : Essential Weapons in the Fight Against Disease

The safer should be chosen 1 Germ theory and rabies averted 2 Magic bullets and devouring cells 3 In pursuit of 4 Subunit and conjugate vaccines 5 safety 7 Recombinant vaccines 8 Taking its toll 9 The future of vaccines 10 Acknowledgments Vaccines: Essential Weapons in the Fight Against Disease Author, Margie Patlak Scientific Advisor, Nilabh Shastri, PhD, University of California Berkley

BREAKTHROUGHS IN BIOSCIENCE COMMITTEE Paula H. Stern, PhD, Chair, Northwestern University Feinberg School of Aditi Bhargava, PhD, University of California San Francisco David L. Brautigan, PhD, University of Virginia School of Medicine Blanche Capel, PhD, Duke University Medical Center Rao L. Divi, PhD, National Cancer Institute, National Institutes of Health Marnie Halpern, PhD, Carnegie Institution for Science Edward R. B. McCabe, MD, PhD, March of Dimes Foundation Loraine Oman-Ganes, MD, FRCP(C), CCMG, FACMG, Sun Life Financial Sharma S. Prabhakar, MD, MBA, FACP, Texas Tech University Health Sciences Center R. Brooks Robey, MD, FASN, FAHA, White River Junction VA Medical Center and Geisel School of Medicine at Dartmouth Scott I. Simon, PhD, University of California Davis ad hoc Committee Member, Herman Staats, PhD, COVER: Vaccines are powerful weapons in the fight Duke University Medical Center against disease. They have averted more than 100 million cases of disease in the United States and continue to prevent 2.5 million deaths globally every year. By BREAKTHROUGHS IN BIOSCIENCE answering some very basic questions, such as what PRODUCTION STAFF enables a guinea pig to defend itself against a toxin, how do starfish and other animals without stomachs Managing Editor, Anne M. Deschamps, PhD, Senior Science process their foods, and what protects fruit flies from Policy Analyst, FASEB Office of Public Affairs fungal infections, researchers laid the foundation for an impressive vaccine armory to fight infectious diseases and cancers. Cover illustration: © Michael Linkinhoker, Link Studio, LLC

This article was developed in collaboration with The American Association of Immunologists. VACCINESVaccines: Essential Weapons in the Fight Against Disease

An ounce of prevention is worth a pound of cure. − Benjamin Franklin

Imagine a world in which playgrounds and pools are closed because of polio BENJAMIN FRANKLIN epidemics, and elementary school playmates are dying from Perhaps the most poignant or whooping cough, while others are advocate for variolation permanently left deaf, blind, or sterile (inoculation with the live due to measles, mumps, or meningitis. virus) was Benjamin Only a generation or two ago that Franklin. Franklin writes in his world was a frightening reality that autobiography, “I lost one of my contributed to one out of five children sons, a fine boy of four years old, never reaching adulthood in the United by the small-pox, taken in the common way. I long regretted States. Repeated epidemics swept bitterly, and still regret that I had through the world, killing as many as not given it to him by inoculation. one-quarter of the population, many This I mention for the sake of of whom were healthy and vibrant parents who omit that operation, before an infectious disease led them on the supposition that they to their graves. should never forgive themselves if a child died under it; my Fortunately, that world no longer example showing that the regret exists because of tremendous progress may be the same either way, and made in vaccine development and Image credit: Joseph-Siffrein Duplessis that, therefore, the safer should application. There are now more than (Public domain), via Wikimedia Commons be chosen.” two dozen vaccines that can prevent death or disability from infectious diseases such as influenza, polio, meningitis, and measles. Vaccines Although the first vaccines stemmed are showing promise in clinical tests. have prevented more than 100 million from observations made centuries In an age when global travel facilitates cases of disease in this country alone ago that survivors of epidemics were the rapid spread of deadly epidemics and continue to prevent 2.5 million naturally immune to the same disease, and -resistant infections are deaths worldwide each year—the current vaccine successes come from becoming more and more common, equivalent of averting about 7,000 the efforts of hundreds of researchers vaccines are increasingly important deaths each day. With the exception over the last century and a half. By as powerful weapons against of safe drinking water, no other pursuing basic research, they uncovered infectious disease. single health measure has saved so what causes disease, how our immune many lives as vaccines. Vaccines system fights such illnesses, and ways also are highly cost effective. Routine The safer to harness and enhance our natural vaccinations administered to US should be chosen ability to combat infection. children between 1994 and 2013 are It is May of 1796 and, along with the estimated to save $295 billion in direct Basic research also fuels advances blooms of flowers, a deadly smallpox health care costs and an additional $1.3 in vaccines and underlies recent epidemic is sweeping across England. trillion in indirect costs ranging from breakthroughs, including innovative The disease is called the “speckled missed work to permanent disability. HIV, , and Ebola vaccines that monster” because of the disfiguring

1 Figure 1 – Portrait of Edward Jenner inoculating boy: Jenner’s smallpox Figure 2 – Louis Pasteur vaccine slashed the incidence of smallpox in half throughout the world by the supervising rabies inoculation: time he died in 1823. Image credit: Wellcome Images/Science Source Pasteur’s discovery that injections of weakened viruses or protected people from the disease led to his successful creation of vaccines scars it leaves behind. It is killing more Four years after Jenner’s success, for rabies and other diseases. than three-quarters of infants, and one- physicians are using the revolutionary Image credit: National Library third of its survivors end up blind. smallpox vaccine throughout England of Medicine Hearing tales that milkmaids are and much of Europe, as well as in naturally immune to the disease after the nascent US. By the time Jenner suffering a milder cow pox rash, the dies in 1823, his vaccine has slashed animalcules” under his microscope English country physician Edward the incidence of smallpox in half a century before Jenner began Jenner hopes to offer similar natural throughout the world. By 1979, vaccinating. No one made the link protection to his patients. He finds a smallpox is eradicated worldwide, between Leeuwenhoek’s microbes young dairymaid with cowpox blisters such that smallpox vaccinations are and disease, but that changed in the and uses a lancet to insert the pus no longer deemed necessary for the 1870s when an epidemic began killing from her blisters under the skin of an general public. silkworms. The French chemist Louis eight-year old boy. The boy develops Jenner was unaware that microbes Pasteur had previously discovered a fever and loses his appetite, but he triggered disease and was acting that certain bacteria spoiled the broth fully recovers ten days later. That merely on the anecdotal observation of the fermenting grains and grapes summer Jenner gives the boy a similar that milkmaids were protected from used to make beer and wine. So the inoculation, but this time with pus smallpox. Further progress in vaccines silk industry in southern France asked taken from a fresh smallpox blister. wouldn’t come until nearly a century Pasteur if he could also figure out the As Jenner expected, the boy stays later when researchers began solving source of the epidemic in silkworms healthy and is one of the first to be an ancient puzzle: what causes that was destroying their operations. successfully vaccinated for smallpox. infectious diseases and how do our Pasteur’s microscopic observations of Jenner’s vaccine works because, bodies naturally fight them? the diseased worms and eggs revealed unknown to anyone at the time, the telltale spores of a parasitic fungus virus that causes smallpox is so closely and led him to the correct hypothesis related to the cowpox virus that the Germ theory and rabies averted that the disease could be prevented by experimental vaccine triggers an selecting silkworm eggs not infected immune response offering protection As late as the mid-nineteenth by the spores. from both. The term vaccination was century, infectious disorders were initially used to describe inoculation attributed to poisonous vapors, Shortly thereafter, Pasteur proposed his against smallpox using the cowpox planetary influences, or bad smells. germ theory, which postulated that all virus, but the term today signifies Anton van Leeuwenhoek gleefully infectious diseases were caused by tiny inoculation against any disease. reported seeing what he called “living organisms invisible to the naked eye

Breakthroughs in Bioscience 2 called germs. The German physician made further refinements to the germ theory, set forth methods to determine whether a particular agent is responsible for disease, and triggered a worldwide hunt for disease-causing germs. Twenty years later, Pasteur, Koch, and other researchers had uncovered the origin of many common deadly diseases, such as leprosy, , cholera, and the plague. It was while trying to uncover the cause of an epidemic of cholera in chickens that Pasteur made one of the most important discoveries in the history of vaccines. He noticed by chance that old, weakened cultures of the causative bacteria he had isolated from infected chickens lost the capacity to cause major disease in poultry; however, chickens inoculated with the weakened bacteria no longer succumbed to more virulent strains in Figure 3 – : Metchnikoff discovered that cells called the wild. He put this basic finding into could engulf microbes and then digest them with enzymes in specialized sacs action in the 1880s, purposely using called phagosomes. This process is called phagocytosis and is a critical weapon drying, heating, and other techniques of the . Illustration: © Michael Linkinhoker, Link Studio, LLC. to create weakened strains of microbes.

While working on weakening the virus inactivation. These, too, prompted seek out and destroy specific toxins that causes rabies, he was approached a natural immune response. like magic bullets, which prompted by a physician desperate to save the Behring to coin the term “anti-body.” life of a nine-year-old boy bitten by a Magic bullets Ehrlich imagined that , rabid dog. Pasteur gave the young lad and devouring cells with the specificity of a key to a lock, a dozen injections of weakened rabies fit around and blocked the action of Further progress in fighting virus. The boy survived because the foreign substances called diseases with vaccines awaited a injections triggered his immune system that circulate in the . (See the basic understanding of the immune to fight the disease before it took hold Breakthroughs in Bioscience article, system and how it naturally responds in his body. Luckily, rabies, unlike “Magic Bullets and Monoclonals: to infections. Fortunately, that most viruses, has a particularly long An Tale.”) Once a highly got underway by the close of the incubation period, enabling vaccines specific antibody recognizes and nineteenth century when the German to be effective when given soon after latches on to the it fits, the scientist Emil Behring stunned his exposure to the virus. immune system is stimulated to colleagues by showing he could Shortly thereafter, researchers created produce this type of antibody in large protect a guinea pig from deadly several vaccines by weakening numbers to fight infection, Ehrlich diphtheria toxins using a shot of serum or killing the microbes that cause postulated. This response came to be gathered from another guinea pig tuberculosis, typhoid fever, and known as adaptive immunity. Antigens that had recently recovered from cholera. Vaccines for diphtheria, that provoke an immune response, it the same disease. , and whooping cough followed was later discovered, were not limited after it was discovered that the toxins This led his colleague, chemist Paul to circulating toxins made by microbes produced by their causative microbes Ehrlich, to postulate that there must but included the proteins and sugars could be safely injected after chemical be agents in the blood that could that protrude from the cell walls or

3 He noted, “I fetched a few rose thorns and introduced them under the skin of some beautiful starfish larvae as transparent as water. I was too excited to sleep that night in the expectation of the result of my experiment.” That result was that hordes of phagocytes had migrated toward the thorns and were gobbling them up. Metchnikoff’s discovery of phagocytes Figure 4 – and Elie and the rapid innate immune response Figure 5 – Dorothy Horstmann Metchnikoff: Ehrlich (left) and was another powerful arm to immune and Isabel Morgan: Two women Metchnikoff (right) shared the 1908 defenses, in addition to the slower, contributed significantly to the in or Medicine development of a successful polio for their discoveries of how the antibody-dependent adaptive response vaccine. Yale University researcher immune system fights infections. described by Ehrlich. The two men Dorothy Horstmann (left) showed Ehrlich’s breakthrough on antibodies shared the Nobel Prize in 1908 for how polio is transmitted, and Isabel and Metchnikoff’s discovery of cells their basic research that provided Morgan (right) of Johns Hopkins that can devour microbes caused the foundation for and University revealed that inoculation progress in vaccines to blossom. with killed polio virus protected Image credits: National Library of triggered a rancorous debate at the monkeys from the disease. Medicine (Ehrlich) and Wikipedia time about which arm was most Image credits: Yale University, Harvey Commons (Metchnikoff) important for immune defenses. This Cushing/John Hay Whitney Medical debate wasn’t fully settled until a Library (Horstmann) and The Alan century later with other Nobel-prize Mason Chesney Medical Archives of The Johns Hopkins Medical capsules of microbes. There are also winning discoveries that dramatically Institutions (Morgan) more hidden internal components of changed the pace of vaccine research. microbes that become accessible to But before then, researchers had to antibodies, but only after some of meet a few other challenges to make University collected blood, nasal, and the microscopic invaders have been progress in vaccine development, oral samples from people with the destroyed and digested by specialized including understanding how viruses disease in the 1940s. The research on cells discovered by another colleague like polio cause disease, learning how these samples and Horstmann’s further of Ehrich’s, the Russian zoologist to grow viruses in large quantities, and experiments on chimpanzees revealed Elie Metchnikoff. making vaccines against bacteria more a surprise finding—poliovirus was effective in small children. Metchnikoff was trying to understand transmitted not nasally but orally and how primitive marine worms that lack traveled briefly in the blood before stomachs digest their food. Spending In pursuit of polio entering the central nervous system. continuous hours at his microscope The same year Ehrlich and Metchnikoff This led Johns Hopkins University and aided by that bind to and won the Nobel Prize, Viennese scientists bacteriologist Isabel Morgan to show thus allow subcellular structures to be and Erwin Popper in 1949 that a killed poliovirus vaccine visualized, Metchnikoff discovered that discovered the virus that caused polio, protected monkeys from the disease. an infectious disease that in severe cases specialized cells in the inner cavities The same year, John Enders, Thomas can result in paralysis or death. Progress of these worms send out finger-like Wellner, and Frederick Robbins in developing a vaccine for polio was projections that completely engulf and reported a new technique for culturing delayed by the mistaken assumption that then digest food particles. He called large quantities of poliovirus in the virus entered the body via the nasal these cells phagocytes and proposed animal tissues. This was a big advance passages where it infected nerves that that they were produced by animals because researchers needed such carried it into the brain and spinal cord. to devour foreign invaders, thus an abundant supply of poliovirus “performing a protective role against Haunted by images of children to develop and test vaccines for it. injurious agents.” This discovery encased in breathing machines, called Unlike bacteria, viruses had been formed the basis of innate immunity. iron lungs, and hoping to learn more notoriously difficult to grow in the lab. His next experiment transformed him from those with mild polio, Dorothy Building on Morgan’s findings and the from a zoologist into a pathologist. Horstmann and her colleagues at Yale new tissue culturing technique, Jonas

Breakthroughs in Bioscience 4 Figure 6 – Polio ward: Because polio caused paralysis of breathing muscles, many children with the disease had to spend time in the breathing machines depicted here. Image credit: New York Public Library/Science Source Figure 7 – Subunit vaccine: Instead of using an entire microbe in its formulation, subunit vaccines only contain the parts from inside or Salk of the University of Pittsburgh by the pioneering cell culturing outside of the microbe thought to developed the first successful polio techniques for which Enders, Weller, trigger an effective immune response. vaccine in 1955. This vaccine led to and Robbins won the 1954 Nobel Illustration: © Michael Linkinhoker, a tenfold decrease in the incidence Prize in Physiology or Medicine. Link Studio, LLC of the disease and was followed by an even more effective oral vaccine Subunit and sepsis (bloodstream infection), and developed by Albert Sabin that used conjugate vaccines a weakened form of the poliovirus. meningitis and came on the market in Horstmann, Morgan, Salk, and Sabin Armed with a basic understanding of 1946. Meningitis is a serious infection all received research support from how the body naturally defends itself of the brain and spinal cord most a private foundation created by against microbial invaders, researchers common in young children and causes President Franklin Delano Roosevelt began to fine-tune vaccines and death in 10 to 15 percent of those who called the National Foundation for experiment to see how little foreign are infected. Many survivors are left Infantile Paralysis, later renamed material was needed to elicit an effective disabled due to permanent neurologic March of Dimes. immune response. Instead of whole, damage caused by the infection. weakened, or killed microbes, only Globally, pneumonia kills nearly one Thanks to both the Salk and Sabin small portions (subunits) of microbes million children less than five years polio vaccines, the world is now on were used in their vaccines. The goal of age each year, and in the US, about the verge of eradicating polio as it was to make subunit vaccines comprised one million people are hospitalized eradicated smallpox years ago. Since of these key portions that could with pneumonia annually. 1988, polio infections have decreased adequately protect against disease but by 99 percent, and more than five Pneumococcus bacteria have an with a minimum of troublesome side million people have been saved from outer coating of sugar molecules that effects, such as fever and discomfort at paralysis. Polio vaccines were soon stimulate production of antibodies in the injection site. followed in the 1960s by vaccines animals. Researchers created several for measles, mumps, and rubella, The first subunit vaccine was subunit vaccines for meningitis and more recently by a vaccine for developed for the pneumococcus and pneumonia using different chickenpox. These were enabled bacteria responsible for pneumonia, combinations of these sugars. The

5 Figure 8 – Overview of Immune Response: When a pathogen enters the body, Toll-like receptors on dendritic and other cells recognize surface molecules (patterns) widely shared by microbes (1- Innate Immune Response). These “first responder” cells then display the intruder’s antigens to the helper T cells (1 – Adaptive Immune Response). Helper T cells orchestrate the immune response by activating B cells (A1). Activated B cells develop into memory B cells, sentries that stick around after an initial response to prevent reinfection by the same pathogen (A2), or plasma cells, cells that produce large numbers of antibodies that bind to invading microbes (A3). Antibody coated microbes are subsequently destroyed by phagocytes (A4). Helper T cells can also activate cytotoxic T cells, which detect infected cells and kill them (C1). Illustration: © Michael Linkinhoker, Link Studio, LLC

vaccines, however, protected older cells did was unknown. That changed of infectious diseases because they children and adults from the diseases when Jacques Miller was trying lacked a key subset of . but not infants and small children who to understand how a virus caused Miller and others went on to show that needed the protection most. in mice. It was thought that although they look identical, there are the virus infected the thymus, a small Why? two major types of lymphocytes: B organ located near the heart that many cells and T cells. Both types of cells The answer to that question came from deemed unnecessary. Miller removed originate in the bone marrow, but B the serendipitous findings of a young the thymus from newborn mice cells mature in the bone marrow while medical researcher working at the expecting it would make them immune T cells mature in the thymus. The job National Institutes of Health (NIH) in to the virus and prevent leukemia. of the B cell is to produce antibodies, the 1960s. Prior to that time, scientists Instead, he accidentally discovered and T cells are essential conductors of knew that blood contained cells called that absence of the thymus made the an immune response. Some T cells, lymphocytes, but what exactly these animals more susceptible to all types called T helper cells, commandeer

Breakthroughs in Bioscience 6

VACCINE SAFETY

By the time the Food and outbreaks are especially Administration (FDA) approves prevalent in areas that offer vaccines for the market, most exemptions for parents to enroll have undergone clinical tests on their children in public schools thousands of people, including without vaccinating them. children. These tests require reporting any serious side effects This recent trend is disturbing to the agency. Once vaccines because, as vaccination are in widespread use, there is rates decrease, people with continued surveillance for any compromised immune systems side effects that may be linked and infants too young to be to them, with reporting of such vaccinated will succumb to effects to the Vaccine Adverse deadly infections spread by the Events Reporting System jointly unvaccinated. Vaccines protect maintained by the FDA and the not only individuals but entire Centers for Disease Control and communities, offering what is Prevention (CDC). The CDC also known as herd immunity. As an has other extensive databases article in The Economist noted, “A from a collaboration of large large vaccinated population forms managed care agencies that a fence around those who are it can use to quickly detect susceptible, keeping diseases away. and explore possible adverse In communities where anti-vaccine reactions to vaccines. One such sentiment is strongest, the fence is database is called the Vaccine falling down.” Safety Datalink. A notable example is a recent In extremely rare cases, the registry and databases may outbreak of measles traced back to California’s Disneyland that reveal serious side effects such Figure 9 – Herd immunity diagram spread infection to 17 other states that the FDA will require a Image credit: National Institute of Allergy and Infectious and caused 12 infants too young vaccine to be taken off the Diseases, NIH market. For example, a vaccine to be vaccinated to suffer from for rotavirus, an organism that the disease. A 2013 study found can cause life-threatening diarrhea from a fraudulent and unethical study that between 2004 and 2008 nearly half in small children, was immediately taken that was later retracted. of US children younger than two years of off the market in 1999 when an analysis age received vaccines late or not at all, With so many vaccines now recommended of reports to the registry revealed that and these children were 21 percent more for small children, some parents worry about one out of 100,000 doses of the likely to be hospitalized than children about overwhelming their babies’ immune vaccine was linked to the development who were vaccinated on schedule. Due to systems and try to delay certain vaccines of intestinal blockages—a side effect too low vaccination rates, 2014 had the most to lessen the load at one time. Yet studies infrequent to be detected in tests of the confirmed cases of measles (644) since vaccine before it entered the market. show vaccines are as safe when used in combination as used singly, and the 2000 when the CDC declared the illness Many children will experience some thousands of germs a baby’s immune nearly eliminated in the US. minor vaccine side effects, such as fever system is bombarded with on a daily The problem is that parents are not and discomfort at the injection site. basis is considerably more than what he scared of the disease, according to But the risks of serious side effects are or she will ever get from recommended Paul Offit, a physician at Children’s extremely small and pale in comparison vaccine schedules. Hospital of Philadelphia who treated to the risks of the disease itself. For example, the risk of a brain infection It is more worrisome that vaccines may children sickened by the disease in a (encephalitis) with the measles vaccine become a victim of their own success, 1991 epidemic brought on by parents is one in three million, but the risk of as parents forget the dreaded diseases who did not vaccinate their children. encephalitis from a measles infection is for which they offer protection and opt “These children would come in covered one in one thousand. Some proposed not to vaccinate their children. There are in rashes, struggling to breathe and often side effects of vaccines, such as autism, problematic new trends in this regard, extremely dehydrated,” he wrote in a have no credible data to support them. including recent outbreaks of whooping recent editorial in . Unfortunately, misinformation came cough and measles in children. These “It was like being in a war zone.”

7 Figure 11 – Baruch Blumberg: Figure 10 – Conjugate vaccine: Conjugate vaccines combine pieces of the Baruch Blumberg discovered that bacteria’s sugar coat with a protein carrier to enhance the immune response proteins shed by the hepatitis B virus to the bacteria. Illustration: © Michael Linkinhoker, Link Studio, LLC. could be used to make an effective vaccine for the disorder. This led to the first vaccine made without cultivating the microbe that caused it. B cells to produce antibodies that latch in infants and other young children Image credit: Fox Chase Cancer Center onto the antigens of foreign intruders who have never been exposed to and mark them for destruction. Helper the pathogen. T cells also foster the production Fortunately, in the early twentieth humankind since the beginning of of cytotoxic T cells, which detect century, researchers found that when recorded history. Hepatitis B causes and kill infected cells and stimulate the sugar component of the pneumonia acute infection (hepatitis), and in some, the production of “memory” B cells, can lead to chronic infection, causing sentries that stick around after bacteria was linked (conjugated) to a fatigue, jaundice, abdominal pain, an initial response to respond more protein, it triggered greater production and liver damage, which can result quickly to re-infections by the of antibodies. Revisiting this finding, in liver failure or cancer. Children same microbe. John Robbins and colleagues at NIH hypothesized that the added protein infected at birth or during infancy By the 1970s, scientists knew that an elicited the critical immune response are particularly prone to developing effective and long-lasting immune from helper T cells. They then linked chronic hepatitis B infection. response to a pathogen involved not the sugar antigen from the bacteria that A hepatitis B vaccine got its start in just producing antibodies but activating cause meningitis to the protein toxin T cells as well. Using this basic the 1960s when Baruch Blumberg, a made by the diphtheria bacteria. This first information, the stymied vaccine makers specialist in genetics, wondered why sugar-protein conjugate vaccine entered discovered that the sugar antigens on people were prone to certain diseases. the market in 1987 and proved highly the outside of bacteria did not stimulate With support from NIH, he combed effective in preventing meningitis in a T cell response but rather directly through blood samples collected from children as young as two months of age. stimulated B cells. This explained ethnically diverse people around the Similar conjugate vaccines that improved why the meningitis and pneumonia world to search for genetic clues the effectiveness of pneumonia vaccines vaccines were only effective for older that might explain susceptibility to for small children came on the market children and adults— the vaccines disease. In the process, he accidentally about the same time. made individuals previously infected discovered something that later won with the pathogens or similar microbes him the Nobel Prize—people infected better able to fight re-infection. But the Recombinant vaccines with hepatitis B had in their blood vaccines did not stimulate T cells, which Another type of vaccine that large quantities of particles that contain are needed to mount a quick, effective, revolutionized targeted proteins found in the outer coat of the and long-lasting immune response hepatitis B, a disease that had plagued hepatitis B virus.

Breakthroughs in Bioscience 8 These particles had no viral DNA so they could not cause infection, but they did stimulate an effective immune response to hepatitis B in people who received blood transfusions contaminated with the virus particles. Blumberg proposed the particles be used in a vaccine against hepatitis B. In 1981, FDA licensed the first vaccine for hepatitis B, which used heat and Figure 12 – Beutler, Hoffmann, Steinman: , Jules Hoffmann, chemicals to inactivate the virus in the and Ralph Steinman received the 2011 Nobel Prize in Physiology or Medicine for plasma of infected individuals, leaving their discoveries of the cells and receptors that play a critical role in the immune behind its outer coat proteins that system’s first line of defense. Their discoveries prompted the creation of safer stimulate an immune response. and more effective vaccines. Image credits: © HO/Reuters/Corbis (Beutler), Holger Motzkau (Hoffmann), The (Steinman) Subsequently, Maurice Hilleman of Merck genetically engineered yeast to produce the viral proteins and, immune responses with vaccines been studied for over 100 years. for the first time, made a vaccine for other killer diseases, including Other groups went on to further without cultivating the microorganism the ancient scourge malaria. For elucidate this response in humans responsible for the disease! Merck’s over a century, scientists had been and other mammals unsuccessful at producing an recombinant vaccine, which came Bruce Beutler at the University of effective vaccine for this disease, on the market in 1986, is 95 percent Texas Southwestern Medical Center which kills more than one million effective at preventing hepatitis B was trying to understand how bacterial people a year—mostly children under and has reduced the rate of chronic sugar-fat complexes trigger an extreme the age of five—and causes repeated infection in children from 15 to less immune response called septic shock debilitating bouts of illness in those than one percent. The vaccine also (blood poisoning). The body’s immune that survive. A new battle strategy was prevents liver cancer that can arise from defense must have a specific receptor a chronic hepatitis B infection. Because needed and, once again, basic findings that is activated by these foreign sugar- the recombinant hepatitis B vaccine is in immunology led the charge. fat complexes, Beutler reasoned. With safer, production of the plasma-derived support from NIH and the Howard vaccine was halted in 1990 and is no Taking its Toll Hughes Medical Institute, he searched longer available in the US. In the 1990s, Jules Hoffmann systematically through mouse mutants A similar procedure was used to make of the University of was that lacked the ability to react to these vaccines for other viruses that cannot puzzling over how animals that lacked sugar-fat complexes and discovered be grown in cell culture, including the T and B cells, such as insects or they had a mutation in a gene similar the starfish larvae that Metchnikoff human papilloma virus (HPV), which to the fruit fly’s Toll. This mouse gene experimented on, protected themselves can cause cervical cancer. The first coded for what is called a Toll-like from infection. With support from HPV vaccines came on the market receptor (TLR), which in normal mice France’s National Center for Scientific in 2006 and 2009. A newer vaccine triggers septic shock when activated. Research, Hoffmann did research on followed in 2015, which protects fruit flies that had a defective gene During the 1980s and 1990s, against more types of HPV, and is called Toll. These flies fell victim immunologist Ralph Steinman at expected to reduce the risk of cervical to fungal infections unlike normal Rockefeller University discovered cancer by 90 percent and lower the flies. Hoffmann discovered the Toll in mice a new cell with branch-like risk of vaginal, anal, and throat cancers gene codes for a specific cell surface extensions he called a dendritic cell. that are also caused by this virus. (See receptor that can detect certain With support from NIH, Steinman Breakthroughs in Bioscience article, features in microbes and send out and other scientists showed that when “Viruses, Cancer, Warts and All: The biochemical signals that prompt an components of bacteria, viruses, or HPV Vaccine for Cervical Cancer.”) immune response against the invaders. other pathogens are detected by the Despite all the progress made in Hoffmann’s discovery revealed the TLRs of dendritic cells, the cells the twentieth century, researchers genetic basis of the physiological mature, devour the intruders, and still were not able to elicit sufficient response to bacteria, which had travel to the lymph nodes. There, they

9 Image credits: Centers for Disease Control (Smallpox virus/vaccine, Tuberculosis culture, , Pneumococcal culture, Polio virus, Measles virus, Rubella virus, Hepatitis B virus, and Human Papilloma virus), National Library of Medicine (Pasteur, Salk, and Hilleman), ThinkStock (Typhoid toxin), Michigan Women’s Historical Center & Hall of Fame (Kendrick and Eldering), Wikimedia Commons/Creative Commons (Human Papilloma vaccine); Design: Michael Linkinhoker, Link Studio, LLC. display the intruders’ antigens like red furthered the development of more Control and Prevention (CDC), there flags to circulating T cells, which start effective vaccines. are now 27 diseases that are vaccine- to multiply, mature, and seek out the preventable, including close to a dozen Ten TLRs have been discovered in microbial antigens to trigger a full- childhood diseases whose incidence people. These receptors are not as fledged immune response. specific as those on T and B cells, which have dramatically decreased compared to when vaccines were unavailable. The discovery of TLRs and dendritic can zero in with exquisite precision on Each year in the US, vaccines are cells resolved the debate about which the antigens under attack. Instead, TLRs estimated to save the lives of 36,000 arms of the immune system—innate recognize molecular patterns broadly people, most of whom are children. or adaptive—were most critical for shared by pathogens, such as bacterial Largely because of vaccines, instead of mammalian immune defenses. They or viral sugars, proteins, and nucleic dying in infancy, most babies born today both were! Much weight had been given acids. By adding these compounds will live long and productive lives. to antibodies, but the first responders to or their mimics to vaccine antigens, infection—the phagocytes Metchnikoff investigators have been able to create Using advances in genetics and observed and dendritic cells—played a more effective vaccines. immunology, investigators continue key role in triggering later T and B cell to develop new kinds of vaccines that responses and antibody production. In The future of vaccines hold promise for better efficacy by 2011, Beutler, Hoffmann, and Steinman Vaccination has been remarkably eliciting immune responses similar won the Nobel Prize in Physiology successful over the past two centuries. to those that occur naturally upon or Medicine for their discoveries that According to the Centers for Disease entry of an intruding microbe. Some

Breakthroughs in Bioscience 10 vaccines can be delivered into the skin this manner are expected to offer is promising, there are obstacles that with a microneedle, rather than via longer lasting protection. Researchers must to be overcome in order to move the traditional shot into a muscle. The are currently evaluating this type of them into clinical practice. Researchers expectation is that these intradermal recombinant vaccine for HIV, rabies, are currently studying DNA vaccines vaccines will be more effective and measles, among other diseases. for influenza, HIV, and herpes. because they will encounter more Some research groups are also Scientists have come a long way since immune response-stimulating dendritic investigating DNA vaccines, which Jenner’s first inoculation for smallpox. cells in the skin. Other vaccines build consist of just a small number of genes The remarkable progress in fighting on advances in genetic and protein that code for a pathogen’s antigens. infectious diseases was started by screening of microbes that have led When these genes are injected into scientists who had only their powers to the identification of new antigens. the skin, some cells take up the DNA, of observation. It then blossomed Such techniques have been applied to begin making the encoded antigen with the insights gleaned by curious make experimental vaccines offering molecules, and display it on their scientists over the past century protection against staph, strep, and own surfaces. Because these antigens pursuing answers to such basic pathogenic E. coli infections. stimulate the production of antibodies questions as what causes disease A new approach to making vaccines as well as the expansion of dendritic, and how do organisms naturally is to insert key antigens into the helper, and cytotoxic T cells, they protect themselves from pathogenic genetic material of weakened viruses. activate both innate and adaptive microbes. Exploration of these These viruses cannot cause disease immunity. The next time the immune questions by zoologists, chemists, yet are still able to infect cells, which system encounters the same antigens, molecular , geneticists, respond to the antigens they carry it destroys the pathogen before it has and immunologists revealed ways to the same way they would respond to a chance to cause disease. The DNA harness nature’s immune defenses a natural infection. Because of how vaccine contains such a small number and improve them, resulting in a well they mimic natural protection of microbial genes that it cannot revolution in the prevention of from infection, vaccines created in cause disease itself. While this work disease through vaccination. •

11 ADDITIONAL SUGGESTED READING

Gordon S. “Elie Metchnikoff: Father of natural immunity.” European Journal of Immunology. 38:3257-3264, 2008.

mLIVE January 25, 2015 “How 2 women scientists, helped by Grand Rapids, created whooping cough vaccine” by Sue Thoms (http://www.mlive.com/news/grand-rapids/index.ssf/2015/01/how_grand_rapids_led_by_two_wo.html)

Los Angeles Times April 10, 2005 “The Unsung Women in the Race for the Polio Vaccine” by David M. Oshinsky (http://articles.latimes.com/2005/apr/10/opinion/oe-oshinsky10)

The New York Times May 6, 2013 “A Forgotten Pioneer of Vaccines” by Richard Conniff (http://www.nytimes. com/2013/05/07/health/maurice-hilleman-mmr-vaccines-forgotten-hero.html)

http://www.vaccines.gov

The History of Vaccines (http://www.historyofvaccines.org/)

Finco O. and Rappouli R. “Designing Vaccines for the Twenty-First Century Society.” Frontiers in Immunology. 5:12, 2014.

BIOGRAPHIES

Margie Patlak writes about biomedical research and health from the Philadelphia region. She has written for Discover, Glamour, Physician’s Weekly, Consumer Reports on Health, The Washington Post, Los Angeles Times, Dallas Morning News, and numerous other publications. She frequently writes for the National Institutes of Health and the National Academy of Sciences and currently works with a number of trade journals, such as Endocrine News and the Journal of the National Cancer Institute. This is her tenth article in the Breakthroughs in Bioscience series.

Nilabh Shastri, PhD is a Professor of Immunology and Pathogenesis at the University of California Berkeley. He researches mechanisms of immune surveillance, specifically of intracellular pathogens. With support from the National Institutes of Health (NIH), he has developed novel methods to identify T cell activating peptide antigens in tissue transplants, microbes, parasites, and cancer cells. In addition, his group has made seminal discoveries in understanding antigen producing pathways. He serves on the Editorial Boards of the Journal of Experimental Medicine and Frontiers in Immunology and on many review panels at NIH. Dr. Shastri earned his PhD in biochemistry at the All India Institute of Medical Sciences and received postdoctoral training in cellular and molecular immunology at the University of California Los Angeles and Caltech.

THE BREAKTHROUGHS IN BIOSCIENCE series is a collection of illustrated articles that explain recent developments in basic biomedical research and how they are important to society. Electronic versions of the articles are available in html and pdf format at the Breakthroughs in Bioscience website at: www.faseb.org/breakthroughs

Breakthroughs in Bioscience 12 Published 2015, © Copyright, FASEB

This article was developed in collaboration with The American Association of Immunologists.

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