VACCINES
The Foundation of Public Health
As Alex Langmuir briefed us on the new oral polio vaccine in the summer of 1962, the future was hidden from me. It would take years for me to appreciate how important vaccines would be in my life. My mother had left me the baby book she bought before my birth in early 1936. It lists only two vaccines to be given to me, diphtheria toxoid and smallpox vaccine. That number, as of this writing, has increased to eighteen routinely given and another dozen for use under special circumstances or for those going to other countries to live or travel.
It has gradually become apparent that vaccines are the foundation of public health. Unlike antibiotics, which must be administered each time a person has an infection and which frequently lose effectiveness against certain organisms, vaccines often provide lifetime protection without developing resistance. Vaccines have become so effective that parents often forget the power of the preventable illness because it is rarely seen, and they become lax or even hostile to the notion of vaccinating their children.
The concept behind vaccines is to fool the immune system. In some cases, a living organism, basically harmless for most but not all people, is introduced into the body, and the immune system develops antibodies to fight that organism. But the harmless organism is so close to a pathogen that causes problems that the person now has immunity to the dangerous one.
The first such vaccine was for smallpox. It required no manipulation in the laboratory. Instead, Edward Jenner, practicing medicine in Berkeley, England, observed that milkmaids were protected against smallpox if they had a minor infection on their hands caused by a virus acquired from the teats of cows. Cows would have lesions on their udders and teats, due to a virus later called cowpox virus, but they were not otherwise sick. Milkmaids would get lesions on their hands but no general illness. Yet they were protected against smallpox. This protection was a huge benefit, derived from a natural development and the power of keen observation. Apparently, some milkmaids recognized this, and one even told Jenner she was protected against smallpox because of the lesions on her hand.
Jenner, over the period of a dozen years, observed the experiences of the milkmaids during smallpox outbreaks until he was sure the observation was correct. On May 14, 1796, Jenner was ready to apply his theory, based on those observations. He took material from the hand lesion of milkmaid Sarah Nelmes and, cutting into the skin of 8-year-old James Phipps, he inserted the pus from the cowpox lesion. James developed a fever and recovered. Some weeks later, Jenner inoculated the boy with material from a smallpox patient’s pustules. James did not develop smallpox. The cowpox had protected him. We are pleased with the safeguards we have today with ethics committees overseeing such experiments, but we also cannot help but be pleased that Jenner’s work presented public health with the first real tool that could be used to prevent disease. From that perspective, May 14, 1796, was the birth date of modern public health.
Building on this first observation, science developed vaccines by using the actual organisms but modifying them so that they would still stimulate the production of antibodies but would not cause disease. In 1937, a scientist working at the Rockefeller Foundation did just that with a strain of the virus causing yellow fever.
Yellow fever viruses cause a severe illness characterized by fever, chills, nausea, muscle pain, and oftentimes liver involvement and jaundice—hence, the name. Death is common. Even today, with a safe and effective vaccine, the WHO estimates that approximately 30,000 people die of yellow fever each year.
Deaths are especially common in populations not previously exposed to the virus. The early history of Europeans in West and Central Africa is replete with reports of very high death rates from yellow fever in explorers, military troops, missionaries, and traders. While Africa was often referred to as the “white man’s grave,” what is often missed is that it was also the “black man’s grave.” Local populations might seem to fair well during a yellow fever epidemic, but that was because of a high price of death and illness in childhood that left survivors relatively immune to the disease.
Yellow fever viruses are transmitted by the bite of a mosquito, usually Aedes aegypti. The viruses apparently traveled from primates to humans in Central Africa, from there to West Africa, and finally to the Americas with the slave trade. While we think of it as a tropical disease, New York City had an outbreak in 1668. An outbreak in Philadelphia in 1793 led to thousands of deaths and the flight of George Washington and the national government from the then-capital of the United States.
The anxiety can be imagined. No one knew what caused the disease or how it spread; therefore, outbreaks led to panic as people tried to flee the area of the first cases. Some towns would lose a quarter of their population. The social disruption is evident from an outbreak in Memphis in 1878, when people boarded a steamship to head north in hopes of avoiding the outbreak, only to be refused permission to disembark because areas north of Memphis feared the disease. The passengers were trapped on the boat for several months before they could disembark.
Construction of the Panama Canal started in January 1881 but was abandoned, partly because of the high death rates from yellow fever.
But the mysteries of the disease were about to yield to science. Carlos Finlay, a Cuban physician, proposed in the early 1880s that mosquitoes might transmit the disease. (Sixteen years later, Sir Ronald Ross, working in India, would discover the role of mosquitoes in the spread of malaria.) Yellow fever was so devastating in the Spanish American War that the United States developed a team, headed by Walter Reed, to research the problem. The team confirmed Finlay’s belief that mosquitoes were an essential ingredient in the transmission of yellow fever from person to person.
At last there was an explanation, and mosquito control now made it possible to actually complete the Panama Canal. (It also allowed Wade Hampton Frost and his team to control an outbreak of yellow fever in New Orleans, even before the first frost killed the mosquitoes.)
In the early twentieth century, the Rockefeller Foundation became interested in the problem, and after World War I the foundation expanded yellow fever work to Africa with a laboratory near Lagos, Nigeria. It was to be both productive and tragic. One member of the group, Adrian Stokes, a pathology professor from London, was the first victim of yellow fever. The next was Hideyo Noguchi, a physician from Japan who worked at the Rockefeller Institute. His autopsy was performed by William Young, who also died of yellow fever. Global health work was high risk at that time. But they did not give up.
Then a series of breakthroughs permitted the isolation of a virus and transport of that virus in a frozen state to New York. Work at the Rockefeller Institute with cell cultures led to the development of the 17D yellow fever vaccine by Theiler and Haagen. Theiler, from South Africa, hired in 1930 from Harvard by the Rockefeller Foundation, received a Nobel Prize in 1951 for his work.
The vaccine is so protective that many thought yellow fever eradication would be a reasonable undertaking. The WHO supported such a program, only to find that primates are also infected with the virus. Indeed, workers and hunters in the forests are often the link between primate transmission and human outbreaks. Short of immunizing primates (not impossible if oral vaccines are developed that could be included in food baits of various kinds), eradication is not possible, and efforts are now focused on protecting populations living in yellow fever–endemic areas, as well as travelers to those areas.
For reasons not totally clear, Asia has been spared from the virus. Public health workers are always concerned that a traveler could introduce the virus and that, because the appropriate mosquitoes are already in Asia, a massive outbreak could ensue. For that reason, Asian countries are very strict about travelers showing proof of vaccination. It takes no special insight to predict that, at some time in the future, yellow fever will spread to Asia.
The vaccine inventory now contains many other live vaccines that have been modified to avoid disease. They are capable of multiplying in the person receiving the vaccine so that the immune system develops antibodies. Measles, mumps, and rubella (MMR) vaccines are examples of such live vaccines.
Polio Vaccine
Another category of vaccines includes organisms that have been killed so that they cannot cause the disease, and yet the immune system recognizes them as a threat and develops antibodies to fight them as if they were live invaders.
The Salk vaccine, is an example. Physicians Tom Weller, John Enders, and Fred Robbins were working on improving the ability to identify and grow viruses in the laboratory. It was while working on techniques to grow chickenpox viruses in cell cultures, in 1949, that Tom Weller found that poliovirus would replicate in the culture materials he was attempting to develop for chickenpox virus. He immediately shifted his focus to polioviruses, and the team was able to grow unlimited quantities of the virus in the lab.
The ability to grow large quantities of the poliovirus allowed Jonas Salk to develop a vaccine based on killing the virus and inoculating the killed virus. Within three years, he had a vaccine shown to be effective in producing antibodies in a small study. But would it protect against polio? Salk was not convinced that a field trial was even necessary. He was certain that the ability of the vaccine to produce antibodies was proof that it would protect against polio disease. In his mind, it would be immoral to have a control group, who would remain unvaccinated. But his mentor, Thomas Francis, the first person to isolate an influenza virus, simply said, “That is not the way science works.” Francis agreed to organize the field trial in 1953, and in two years, with the help of 1.8 million children, countless volunteers, and superb organization, Thomas Francis had an answer.
Yet a third type of vaccine is in common use. For some illnesses, the organism does not cause the illness but rather a toxin produced by the organism, for example, tetanus. Acquiring a tetanus spore does not automatically lead to illness. However, when the tetanus organism produces a toxin, tetanospasmin, which affects the nerves that lead to muscles, illness results. This neurotoxin causes the muscles to contract, leading to spasms. Often the jaw muscles are affected first (hence, the name lockjaw) with life-threatening results when respiratory muscles become involved. This toxin is second only to botulinum in potency, and yet it is totally neutralized by antibodies and therefore disease can be prevented. A vaccine derived from the toxin allows each person to develop his or her own protection, even in the face of an environment loaded with tetanus organisms.
The tetanus vaccine is one of the best vaccines in our arsenal. Attempts to see how long the vaccine provided protection led to studies in World War II veterans who developed tetanus over the years after the war. In most cases, it was found that the veterans, for various reasons, had not actually received the vaccine; in fact, some admitted to having others receive the vaccine for them because they were so adverse to needle sticks.
Gradually, various vaccines became routine. However, vaccines such as smallpox vaccine, diphtheria toxoid, tetanus toxoid, and pertussis vaccine were generally administered by doctors, and the patients paid for those vaccines. They were not purchased by public health programs seeking widespread coverage. This all changed on April 12, 1955.
Today, it is almost impossible to understand the fear that gripped people in the mid-twentieth century as they contemplated polio. The fear was similar to that felt by Africans and Indians in the 1970s for smallpox or Americans in 2014 in the face of Ebola disease. An anthropologist who lived through a smallpox outbreak with the Tiv people of Nigeria said the only comparison that could be understood by those outside the outbreak might be the experience of war.
The fear of polio grew during the first half of the twentieth century. Epidemics were rare until the end of the nineteenth century because children often acquired the viruses in the first year of life, when passive immunity from their mothers allowed the virus to grow in their intestine; maternal immunity prevented the virus from entering the central nervous system (hence, no paralysis). As hygiene improved, the risk of exposure to polio in the first year decreased and children began to acquire the wild virus after they had lost maternal immunity, often upon entering school. Most cases were therefore in young children, and the disease acquired the name infantile paralysis. Over time, the virus was no longer ubiquitous and might be introduced to a community only after several years had passed and a group of susceptible children had accumulated. Outbreaks resulted, and the age of patients increased. By midcentury, epidemics during summer months became common, and some of those paralyzed were adolescents and young adults.
In 1952, the United States reported almost 58,000 cases of polio. More than 3,000 of these patients died, and more than 20,000 persons were left with various degrees of paralysis. Scientists were working overtime to find an answer to this problem. Interest was also heightened because of the paralysis of President Franklin Roosevelt. Clearly, everyone was at risk, even the rich such as Roosevelt.
The National Foundation for Infantile Paralysis was established. Eddie Cantor suggested the phrase “The March of Dimes,” based on a popular news program shown at theaters called The March of Time. Contributions of dimes flowed into the White House, and research efforts were accelerated.
Jonas Salk was one scientist funded by the organization, and he established that three types of the virus existed. But then he benefited from the breakthrough by John Enders, Tom Weller, and Fred Robbins, when they demonstrated that the virus could grow under laboratory conditions. These three later received the Nobel Prize for their findings.
The killed vaccine was soon ready for a field trial, but the logistics would prove difficult. Even in epidemics, only a small percentage of children would show evidence of illness, and even fewer (less than 1 percent) would show the characteristic paralysis; therefore, an enormous study was required to have sufficient numbers of children with paralysis. So Francis, before the age of computers, had to assemble a team of 20,000 medical personnel, 64,000 school personnel, and 220,000 volunteers. With that as a core, he then enrolled 1.8 million schoolchildren into this massive study. It was said that file cabinets lined hallway after hallway at the University of Michigan.
On April 12, 1955, ten years to the day after the death of Franklin D. Roosevelt, Francis faced an overflow audience at Rackham Auditorium, including scientists and noted journalists, such as Edward R. Murrow and Fred Friendly. He summarized the two-year study in four words: “safe, effective and potent.” Pandemonium ensued, as reporters tried to get to phones. The next day a grateful nation spontaneously put signs in windows that read, “Thank you, Dr. Salk.”
Salk once related to me the story of that day. He said Murrow interviewed him on CBS television and asked, “Who owns the patent on this vaccine?” Salk answered, “Well, the people, I would say. There is no patent. Could you patent the sun?” That night at dinner, Murrow presented Salk with a watch that he wore for the rest of his life. Murrow said, “Young man, today you have lost your anonymity.”
It was a great day in public health, and it changed medical history. But in a real sense, a greater day would occur within the week.
A Social Contract
On April 11, 1953, President Eisenhower named Oveta Culp Hobby to be the first secretary of the new Department of Health, Education, and Welfare (HEW). She was an accomplished manager as the head of the Women’s Army Corps during World War II. She had made it clear that socialized medicine would not get any support from her.
But now the polio vaccine was declared effective, and people assumed there would be a government plan for its distribution. The public clamored, and President Eisenhower asked Secretary Hobby for a plan.
Secretary Hobby announced that she would seek an appropriation to buy polio vaccine for poor children. Soon, a senator responded by saying that no American children should have to declare themselves poor to be protected from polio, and he would seek an appropriation to provide polio vaccine for all children and pregnant women. This is the day that vaccines went from only protecting the recipient to a social contract that attempted to protect society. It was the beginning of a public health immunization program for this country. Three months later, that senator, Senator Lister Hill, introduced bill S. 2501 authorizing the government to buy polio vaccine.
A decade later, President Lyndon Johnson used the same logic of a social contract to commit the United States to the global eradication of smallpox.
The Cutter Incident
Paul Offit has chronicled the tragedy that quickly overtook the joy of that University of Michigan announcement (1). There was a time when Dr. Salk had questioned the need for a field trial. Tommy Francis had overruled that idea, and now everyone was happy that he had. Because within the month, the value of the field trial would become obvious to all.
Only six days after the University of Michigan press conference, on April 18, 1955, Josephine Gottsdanker drove her two children to the pediatrician to get the new vaccine. She had seen Edward R. Murrow’s interview with Jonas Salk, and she wanted her children protected. The family went on vacation, but as they returned, on April 26, her daughter complained of a headache. She soon developed paralysis. And, as Offit points out, 40,000 other children also developed symptoms after getting the Salk vaccine; 200 were paralyzed, and 10 died. What was going on? (1).
Alex Langmuir immediately put his officers on the case. Overnight, at the request of the surgeon general, Langmuir developed a national polio surveillance system to detect cases of polio as rapidly as they developed and then to get information on every case. How old were the patients, when did symptoms begin, where and when did they get vaccine, and which manufacturer made the vaccine they received? The polio surveillance system was quickly developed and improved as the outbreak was investigated.
This was the second national surveillance system developed in this country. The first had been instituted five years earlier for malaria; it revealed that malaria had quietly disappeared in this country. We now have dozens of national surveillance systems for many conditions. But it was the polio surveillance system that demonstrated the value and power of aggregate data.
Public health workers toiled around the clock and quickly demonstrated that the postvaccine cases were heavily concentrated in California and Idaho. A number of companies were producing the vaccine, but Langmuir quickly realized that the people with paralysis had shared one thing. They had received vaccine made by Cutter Laboratories. The Francis field trial had demonstrated both the safety and the effectiveness of the vaccine. This made it possible for Langmuir to provide assurance that vaccines made by other companies were safe to use. Langmuir demonstrated the power of the epidemiologic approach by predicting what the epidemic curve of cases would look like, given the number of doses of Cutter vaccine given, and what the secondary attack rate would be due to new cases resulting from contact with the vaccine-induced case-patients. He was close on both counts. What was the problem? The process for killing the poliovirus was incomplete. Relatively few live viruses survived to make it into the vaccine vial, but it was enough to cause illness in some of the thousands of children receiving vaccine from that company.
The Cutter incident was a vivid reminder of the need for federal regulations on vaccine safety and for oversight to enforce such regulations. It also demonstrated the absolutely crucial need for field trials to establish the safety, efficacy, and potency of vaccines. But from the CDC’s perspective, it also demonstrated the need for a federal program to collect and interpret data from the entire country and the need to provide guidance on the use of vaccines. This incident also established the reputation of the EIS.
Polio incidence in the United States declined by more than 95 percent from 1955 until 1961, when the new Sabin oral vaccine was introduced. The Salk vaccine was a killed product (with the exception of that which caused the Cutter incident); by contrast, the Sabin vaccine was a live but attenuated virus that could be given orally with a sugar cube. The vaccine virus would then multiply in the intestine of the recipient. Despite the small risks of acquiring polio from the oral vaccine, it was adopted in the United States because of its ease of administration. It was also believed that it had the benefit of providing immunity in the intestine. This would reduce transmission of the wild virus if acquired by children who had received the oral vaccine. This attribute of oral vaccine was overestimated, but it took years to discover that the Salk vaccine also provided considerable intestinal immunity, although slightly less than the oral Sabin vaccine.
In 1979, the United States experienced its last polio outbreak. Polio cases occurred in the unimmunized Amish communities in Pennsylvania. Several things were significant about this outbreak. Not only was it the last outbreak in the United States but also it was the first time CDC scientists were able to fingerprint a poliovirus. They were able to show that a single strain of wild poliovirus was responsible for all the cases. Second, as the outbreak spread to other Amish communities in other states, it was possible to show that only one strain was still involved. Third, polio cases were not identified outside the Amish community, providing some reassurance that it was not exceptionally easy for the virus to reestablish after it had disappeared from a geographic area. Fourth, it was possible to trace the virus backward; it had been introduced from within a religious community in Canada, traveling there from a religious community in the Netherlands, which had received the virus from the Middle East. But finally, and of great importance, the Amish taught an important lesson regarding the social contract of vaccines. For religious reasons, they had not immunized their children. When they realized their children presented a risk to non-Amish children, they immediately agreed to a polio immunization campaign.
This last lesson continues to reverberate decades later. As polio, measles, and whooping cough cases declined, parents lost their fear of the diseases. Soon they concentrated on only one side of the equation, the risk of the vaccine. All vaccines have some inherent risks, although these have declined as the vaccines have gotten purer and better over the years. Nonetheless, enough parents have decided against immunization to increase once again the risk of the diseases. In 1989 and 1990, the United States suffered thousands of cases of measles and dozens of resulting deaths.
Improving the National Immunization Program
In 1977, President Jimmy Carter was inaugurated. Early in his tenure, the Carters invited Senator Dale Bumpers and his wife Betty for dinner at the White House. The two wives had become friends when both were First Ladies, Mrs. Carter in Georgia and Mrs. Bumpers in Arkansas. They shared many interests but one was the need to protect more children with the vaccines that were becoming increasingly available. Now at the dinner table, the two women became excited over the prospect of improving the immunization status of children throughout the country.
The next morning, President Carter called his new secretary of HEW, Joseph Califano, to discuss what it would take to improve the national immunization program. Secretary Califano called me, not to discuss what it would take but rather to say we were going to do it. He suggested we set a goal of 90 percent coverage with childhood vaccines by a child’s entry into school.
I, in turn, went to Don Millar, the head of the CDC Immunization Program, and asked him what it would take to reach 90 percent immunization levels? Don had considerable experience with immunization and the barriers to good programs, both domestically and internationally, as head of the Smallpox Eradication / Measles Control Program in West and Central Africa. He had worked in the polio programs in which the Sabin live polio vaccine was given on special Sunday clinics. Even our best, concentrated efforts rarely saw immunization rates exceed 90 percent. His response to the 90 percent goal was typically concise and well reasoned. He said, “I would not like to see that in my job description!” But he agreed that a 90 percent target should be attempted, and the next day it was in his job description.
In typical Millarian fashion, Don rose to the occasion, energizing immunization programs around the country to acquire more staff, increase coverage targets, involve education departments and PTA programs, and increase the news coverage on the diseases and the immunization programs. Everything advanced. The public health structure continued to improve management, evaluation, surveillance, and outcomes. States without school-entry requirements worked on ways to involve political leaders. Only seventeen states had school-entry immunization requirements, but over the next few years, activists were able to get politicians to pass such requirements in all states. Education leaders joined the coalition, and over time, the figures inched up more than 90 percent and then even to the 95 percent level. Don had incredibly gifted immunization leaders. Physicians Alan Hinman, Walt Orenstein, Steve Cochi, and others were zealots. They understood the benefits of protecting children with vaccines, and they wanted every child to enjoy that benefit.
Success led to additional objectives. One was to exceed 95 percent; a second was to achieve that percentage by age 2, rather than wait for school entry. And a third objective seemed almost beyond our reach: Could we actually interrupt measles transmission in the United States?
Interrupting Measles Transmission
The last objective resulted in a lively debate. Measles is so easily transmitted that it almost seems mysterious. Introduce one child with measles into a room of susceptible children, and more than 75 percent are likely to become ill after one incubation period. Some scientists argued that to even declare such an objective would lead to ridicule and that we would hurt the reputation of the CDC by failing such a target, and failure would be inevitable.
When Dave Sencer suggested a measles eradication goal some years earlier, many did indeed ridicule the idea. Others maintained, more persuasively, that we would never understand the actual barriers to interrupting the transmission of this virus unless we sought the ultimate objective, stopping its spread. After considered deliberation, we decided to interrupt measles transmission in the United States.
We reserved a thirty-minute segment each week to review what we had achieved and what we had learned about measles. Like the peeling of an onion, each week brought a new problem, not fully understood in the past, but each week also brought possible solutions. That was the payoff of this weekly investment of time by an array of CDC talent. For all of our worry, we never discovered a problem that did not have an eventual solution.
The first problem was the realization that military recruits were a source of measles virus spread. As new recruits went on their first home leave, they often took the virus back to their homes. The military solved this with a single change. From then on, they would immunize all new recruits, regardless of their history of measles disease or measles immunization. Within the first year, the problem of the military as a source of civilian infections was identified and totally resolved.
Next, the immunization program discovered that transmission was occurring from preschool programs, which had not been included in the school-entry requirements. States then methodically changed their requirements to include preschool programs. This was a multiyear project.
Each solution made another problem more visible. Soon, for example, we found that transmission was occurring in college and postgraduate programs. But the problems were getting smaller and more discrete. An outbreak of measles resulted from a wrestling match; thus, it became clear that close contact gives the measles virus an added chance to spread. A wedding involving two important Romany families held in Spokane, Washington, drew families from around the country, and the virus spread as they returned home. Each problem identified a group requiring special attention.
A baffling outbreak involved children who had visited Disneyland. The affected children had attended on different days, leading us to believe that the index case-patient must actually work at the park. (While this was undoubtedly true, the index case-patient was not identified.) It is possible to work while sick with measles, if you are not too ill. And you can avoid identification if you are dressed as a Disney character.
But soon we realized that such outbreaks had masked our biggest, remaining risk: imported cases. These constituted the core of the remaining measles problem. The United States was experiencing, on average, two importations of measles a week from other countries—a fact that had always been obscured by indigenous transmission.
With this information, the Pan American Health Organization continued to improve measles immunization programs in the Americas. Soon we went weeks without a case. The United States reached the point that measles was no longer accepted as a childhood disease, and the presence of cases became front-page news. It took five years of effort to stop endemic transmission of measles in the United States, but for a quarter of a century, all measles cases in this country have been the result of importation. Choosing the ultimate objective was the only way to make this possible.
In summary, vaccine-preventable deaths have drastically declined in the United States, thanks to a national immunization program that involves politicians and government and health workers at every point from national, state, county, and city levels. It is a grand coalition of public and private organizations. This has been a wonderfully successful program for the country.
There are other vaccine success stories. These include the reduction of pneumonia and meningitis when Haemophilus influenzae vaccine was introduced. And the elimination of the dreaded congenital rubella syndrome in newborns, when rubella vaccine, given to enough children, halted transmission of the virus in this country. The United States has also been blessed by the reduction of deaths from influenza and pneumonia in the young and in the elderly.
The development of an anticancer vaccine against human papillomavirus (HPV) presents another opportunity to seek an ultimate solution. This virus is often silent after acquisition through sexual contact but can later cause cancer in both men and women. The most prevalent of these cancers is cancer of the cervix. As a result, many programs have focused on girls and young women before they become sexually active. However, the real challenge is to stop transmission of the virus, and, as with measles, our objective should be breaking virus transmission and nothing less. The combination of an HPV vaccine and early screening for carcinoma of the cervix means that there should never be another death from cervical cancer in this country.
A View of Vaccine History
It was at the 1995 memorial service for Dr. Jonas Salk, at the Salk Institute in San Diego, that I developed a startling mental picture of the entire history of immunization programs. For the occasion, Dr. Charles Merieux had traveled from France, and he reviewed the history of immunizations. He talked about the movement from eighteenth-century England and Edward Jenner, to nineteenth-century France and Louis Pasteur and then to twentieth-century America and Jonas Salk.
I immediately thought about my visit to the home of Dr. Merieux in France, where he showed me a picture on his wall. He said, “That is my father, working in the lab. And the man standing next to him is Dr. Louis Pasteur!” That moment is riveted in my mind because it was Louis Pasteur, while on a visit to London, who changed our nomenclature. He noted, in a speech, that the word vaccine refers specifically to the virus used to protect against smallpox, namely vaccinia virus, and that the word vaccination refers to the inoculation of vaccinia virus. However, Pasteur suggested that from this time forth, we could honor Edward Jenner by referring to all immunizing agents as vaccines and the application of those agents as vaccinations. With that, I could visualize the entire history from Jenner to Pasteur to Merieux and now Salk.
Our Debt to Hilleman
But there is yet another hero who must be recognized. Maurice Hilleman was born on a ranch in Montana. His twin sister died at birth, and his mother died two days later. Because of lack of money, Hilleman almost went to work after high school, without the chance of going to college. But a brother continued to urge him to find a way, and eventually he made it through college, graduating first in his class. He then received a PhD from the University of Chicago, where he demonstrated that Chlamydia organisms were not viruses, as thought, but rather bacteria. He was already thinking beyond the horizons of his teachers.
Why mention him here? I gave two Maurice Hilleman lectures during his lifetime, and he attended both of them. In the first, I referred to him as the Louis Pasteur of our time. In the second, I corrected myself. Hilleman was in a class by himself, exceeding any vaccine developer the world has ever seen. Over half of the vaccines reaching our children today either came out of his mind directly or were altered in some way by his ideas. He was a complex and compelling genius.
He was an exceedingly capable scientist, able to see things denied to others. He was an obsessive worker, who expected his coworkers to meet his standards. He was a difficult man to work with; he kept a row of “shrunken heads” in his office (constructed by his children) to represent the people he had fired. He was coarse and vulgar and could use profanity with as much ingenuity and directness as he used science. Roy Vagelos, former CEO of Merck, confirmed that Hilleman had failed the compulsory “charm school” course required of Merck supervisors. But his subordinates loved him. He got the most out of them but only because they were willing to give it to a man who outworked everyone.
He developed a vaccine against Japanese B encephalitis, and a vaccine against the Hong Kong flu. He went on to develop more than three dozen vaccines for humans and animals. Although his modesty would not allow him to put his name on a vaccine (such as the Salk vaccine or the Sabin vaccine), he did allow the mumps vaccine to be named the Jeryl Lynn strain after his daughter, from whom he isolated the virus. (He was awakened during the night because she had pain in her jaw. He immediately drove to his lab for equipment and returned to successfully culture the mumps virus for the first time.)
Hilleman developed the MMR vaccine. It is given to millions of children every month. A billion children vaccinated against measles in recent years make it possible to contemplate measles eradication in the world.
Hilleman also developed a hepatitis B vaccine. In many countries, this virus, acquired early in life, leads to liver cancer in adults. In some countries, it is the leading cause of death from cancer; therefore, it is a significant problem. Hilleman not only developed a vaccine but also originally surprised everyone by preparing the vaccine from the blood serum of gay men. He treated it with pepsin, urea, and formaldehyde.
The products of Hilleman’s mind have entered and changed the immune systems of the majority of the world’s population. It is almost beyond comprehension what this one person has meant for global health. And one remains troubled by how close he came to dying at birth like his twin sister, or how close he came to not continuing his education beyond high school. And one also thinks about his vaccines keeping other geniuses from dying in childhood.
After Hilleman’s death, at age 85, Ralph Nader wrote, “Yet almost no one knew about him, saw him on television, or read about him in newspapers or magazines. His anonymity, in comparison with Madonna, Michael Jackson, Jose Canseco, or an assortment of grade-B actors, tells something about our society’s and media’s concept of celebrity; much less of the heroic” (2).
But we knew him well at the CDC.
The Task Force for Child Survival
In late 1983, Jonas Salk and Robert McNamara talked with Jim Grant, head of UNICEF, to discuss how the improvements in the US Immunization Program could benefit immunization programs around the world. Their inquiries led to a meeting at the Rockefeller Center in Bellagio, Italy, in March 1984. The meeting included the directors of UNICEF, WHO, the United Nations Development Programme (UNDP), the World Bank, and USAID, among others. Rafe Henderson, who had been seconded from the CDC to develop the Expanded Program on Immunization at the WHO, also attended (3).
The meeting led to the development of a Task Force for Child Survival, headquartered in Atlanta and largely staffed by former CDC employees. The Task Force held quarterly meetings with the key representatives of UNICEF, WHO, UNDP, the World Bank, and the Rockefeller Foundation. This small group quickly agreed on steps to improve coordination to improve global immunization. More than that, it gave donors confidence that a global approach was being developed rather than multiple agencies working independently.a
Robert McNamara had argued that $100 million in new immunization money would change the world of immunizations. Attendees at the Bellagio meeting argued that could not happen without taking money from other global health programs. But they were wrong. Confidence in a global approach led to new resources, and Italy alone gave $100 million for immunization programs in Africa. They were so impressed with plans that they increased the gift to $120 million. UNICEF and WHO coordinated in new ways, working together in countries, putting out joint publications on evaluating programs and forming partnerships on research to improve efficiency and to present a single voice to countries. However, they could not agree on a name for the program. While the WHO referred to the program as the Expanded Program on Immunization, UNICEF continued to call it Universal Childhood Immunization. But it mattered not. There was unity of purpose, and immunization levels improved. Rafe Henderson always attended the quarterly meetings, representing the WHO; UNICEF would send its top immunization person, but often times Jim Grant himself would attend.
For six years, the Task Force met quarterly and approximately every eighteen months would have a larger meeting to include dozens of persons and groups involved in global immunization efforts. Each meeting was able to report on increasing levels of immunization, more coordination between agencies, tighter country programs, and growing excitement over the protection of children with vaccines. With increasing confidence, the group added oral rehydration therapy, micronutrient additions to the immunization program, child health programs of various kinds, and even family planning. It proved that there is a place for collaboration among groups assisting national and global efforts.
The Summit for Children
On September 30, 1990, the United Nations had a one-day “Summit for Children.” The program was the product of Jim Grant’s enthusiasm and included seventy-one heads of state, to that point the largest gathering of heads of state the world had ever seen. Children in national dress escorted heads of state to their seats.
The heads of state were permitted five minutes to comment on what they had done and what they planned to do to improve child health in their countries. I watched from the audience as peer pressure increased the leaders’ promises during the day. Jim Grant declared that immunization levels had improved from about 15 percent six years earlier to the point that 80 percent of children were now receiving at least some of the childhood immunizations. He said this was the greatest peacetime effort the world had ever seen.
A grand coalition such as this requires that heads of agencies are committed. When Jim Grant died and Halfdan Mahler retired as head of the WHO, keeping the same level of commitment was no longer possible. The new director of UNICEF, Carol Bellamy, pursued other objectives and reduced the immunization budget. The new WHO director, the physician Hiroshi Nakajima, found collaboration with other agencies very difficult. The Task Force played a diminished role. Through the 1990s, immunization rates continued to stagnate, and the global coalition that had been so successful through the 1980s was disintegrating. The Task Force for Child Survival became the Task Force for Global Health, and under the leadership of Dr. Mark Rosenberg, it has become one of the most successful nonprofit agencies in the world as it directs products worth billions of dollars each year to neglected diseases of poor countries. In 2016, the Task Force was awarded the Hilton Humanitarian Award that not only acknowledged the Task Force’s impact but also was accompanied by a $2 million award to enhance its activities.
A New Global Coalition
In 1998, the World Bank initiated meetings to revitalize the global immunization program, and, in November 1999, the Bill & Melinda Gates Foundation brought life back into the idea of a coalition with the formation of the Global Alliance for Vaccines and Immunization (GAVI). But the alliance went far beyond the modest objectives of the Task Force of 1984. With a pledge of $750 million over five years, the foundation wanted to improve the capacity to deliver vaccines, but it also wanted to add the lifesaving vaccines that were more expensive and had eluded the global community.
The global health community remained somewhat skeptical of the staying power of the foundation, and the matching grants expected early on were not materializing, despite the solid leadership of Tore Godal, the gifted global health worker from Norway, who had spent years working in the WHO and was now heading GAVI. Four years into the program, the Gates Foundation announced that it would renew its pledge for an additional five years. Immediately, Norway and the United Kingdom announced that they would make contributions. A new era in global immunization had arrived. And a former CDC and Task Force employee, Seth Berkley, became the second director of GAVI.
Fear of Autism
One of the most discouraging developments in the vaccine field has been the difficulty in maintaining the immunization levels that have been achieved. In part, this reflects the success of the program in reducing the diseases targeted. Parents no longer compare the risks of vaccine to the risk of the disease. Instead, they compare the risk of vaccine to zero because they cannot visualize the disease’s risks.
This problem is potentially correctable through education. In the early years of education on the risks associated with tobacco use, smoking rates were high for physicians. Although nicotine is very addictive, education was able to overcome addiction, and soon smoking rates dropped faster for physicians than for other occupations; the lowest smoking rates were seen in thoracic surgeons and pulmonary specialists, who daily saw the price of tobacco. But, interestingly, smoking rates did not go to zero, even in those groups. Nicotine addiction is powerful.
Education is also the approach required for vaccines. Pediatricians have been in the forefront of the effort to educate parents because they have seen the ravages of the diseases. But even some pediatricians are against immunization. Education is important but not sufficient.
In addition to education, laws and conventions are necessary to protect the largest numbers possible. School-entry requirements, military regulations, and national quarantine regulations all help immensely.
For more than thirty-five years, the custom has been to require consent for immunization. The reason is to make it clear that the parent recognizes the inherent complications of immunizations. It is now proving necessary to also contemplate informed consent from parents who decline immunization for their children. Such parents may need to demonstrate that their declination is truly informed and not simply a lack of knowledge or an antigovernment bias that leads them to accept undue risks for their children. Reminding new parents that their child avoided congenital rubella syndrome because other children had been immunized against rubella is important in explaining the social contract we have to protect our children and other children.
In the midst of all the positive actions that have improved child health, one of the most devastating negative stories concerns a physician from England, Andrew Wakefield, who published an article in the Lancet based on twelve children. He raised the question of whether MMR vaccine might be responsible for the increased incidence of autism. The fear of autism is so great that many parents began to refuse vaccinations.
Major studies were undertaken in response to this allegation, and all showed no increase in autism incidence in children who had received the vaccine as compared to those who had not received it. Then concern was raised that thimerosal, an antiseptic containing mercury, might be a problem. Thimerosal had been used in vaccines for many years to prevent bacterial overgrowth in multiple dose vials of vaccine.
Increasingly, single-dose syringes containing vaccines have been used, and they have not required the use of thimerosal. Dropping the use of this agent made no difference in the rates of autism.
As the science became clearer, three facts emerged. First, no evidence existed that vaccines were implicated in the increase in autism. Second, research continued to implicate prenatal factors, especially in the second trimester of pregnancy, rather than postbirth exposures as important in the development of autism. Third, the science could not easily counter the social fear that had now developed around the use of vaccines.
If vaccines had been related to autism, knowing that would have been very important. Therefore, it was important to consider whether any evidence existed to suggest it. However, by the time the question was answered, untold harm had been done as parents heard the preliminary question but not the answer, and many had lost their confidence in vaccines.
On January 6, 2011, the British Medical Journal published an article by journalist Brian Deer, who examined the medical records of the twelve children cited in the Andrew Wakefield article (4). His findings:
The paper in The Lancet was a case series of 12 child patients; it reported a proposed “new syndrome” of enterocolitis and regressive autism and associated this with MMR as an apparent precipitating event. But in fact:
Three of nine children reported with regressive autism did not have autism diagnosed at all. Only one child clearly had regressive autism;
Despite the paper claiming that all 12 children were previously normal, five had documented pre-existing developmental concerns;
Some children were reported to have experienced first behavioral symptoms within days of MMR, but the records documented these as starting some months after vaccination;
In nine cases, unremarkable colonic histopathology results—noting no or minimal fluctuations in inflammatory cell populations—were changed after a medical school “research review” to “non-specific colitis”;
The parents of eight children were reported as blaming MMR, but 11 families made this allegation at the hospital. The exclusion of three allegations—all giving times to onset of problems in months—helped to create the appearance of a 14-day temporal link;
Patients were recruited through anti-MMR campaigners, and the study was commissioned and funded for planned litigation.
In an accompanying editorial (5), British Medical Journal editors wrote:
Clear evidence of falsification of data should now close the door on this damaging vaccine scare … Who perpetrated this fraud? There is no doubt that it was Wakefield. Is it possible that he was wrong, but not dishonest: that he was so incompetent that he was unable to fairly describe the project, or to report even one of the 12 children’s cases accurately? No. A great deal of thought and effort must have gone into drafting the paper to achieve the results he wanted: the discrepancies all led in one direction; misreporting was gross. Moreover, although the scale of the GMC’s 217-day hearing precluded additional charges focused directly on the fraud, the panel found him guilty of dishonesty concerning the study’s admissions criteria, its funding by the Legal Aid Board, and his statements about it afterwards.
Perhaps this is too much attention to the negative forces opposing immunization. But when one understands the importance of vaccines to the health of the world, understanding the hollowness of the antivaccination movement seems critical.
Wakefield lost his license to practice in the United Kingdom, but he moved to the United States and has continued talking to parents’ groups about the dangers of vaccines. He attempted to sue Deer and the Sunday Times, and lost.
Repeatedly, nature is shown to be a formidable foe when it comes to death and disease. But it is discouraging, as with this article by Wakefield, when the enemy turns out to be people seeking fame or profit.
Vaccination efforts will hopefully recover to deliver their promise, but the lesson must be heeded that parents throughout the world are likely to follow the European and American trends. Namely, parents can easily lose interest in certain vaccines when the diseases are no longer prominent.
There will always be charlatans to make public health work more difficult. The media are often more concerned with so-called balance than with truth. Over many decades, we have watched as reports on tobacco have summarized the work of scientists and then, “for balance,” the report ends with a quote from the Tobacco Institute, an organization funded by tobacco companies. This makes no logical sense. When confronted, reporters would tell me that this was necessary to show balance. My response was they should clearly label this as the other side of truth. Their ultimate argument was that readers were smart enough to read both sides and see the truth. My contention was that this was unlikely if the reporters themselves were unable to do that.
Likewise with vaccines. Reports by the American Academy of Pediatrics, the Advisory Committee on Immunization Practices, and researchers around the country are often balanced by comments from a publicity-seeking television personality, who has done untold damage by supporting Wakefield and claiming that vaccines cause autism.
The future of vaccines is exceptionally exciting. Without even entertaining thoughts of science fiction, it is totally predictable that we will eliminate much of the trauma experienced by children because of needles. Increasingly, vaccines will be given orally or transdermally. More vaccines will be combined to reduce the number of medical contacts necessary to protect children.
In addition, the number of vaccines will continue to increase. In seventy-five years, routine vaccines for children in the United States increased from two to eighteen vaccines, and another dozen are given under certain circumstances. My grandchildren will see this number increase to dozens.
Two vaccines are already in the category of anticancer vaccines, protecting against liver cancer and cancer of the cervix. Anticancer vaccines will multiply.
Vaccines will be developed against certain aspects of cardiovascular disease and diabetes, as we understand the role of infectious agents in later chronic diseases. We may even see vaccines that will reduce the desire for alcohol, opiates, and other agents so disruptive to life.
Because of vaccines, the number of diseases eliminated for all time will increase. In addition to smallpox, polio—despite all the social problems encountered with religious and terrorist groups (not to mention US intelligence agencies’ misuse of the program in an attempt to identify the house of bin Laden, an act that fueled backlash from terrorist groups, who have killed innocent vaccinators to vent their rage)—will cease to exist. Measles will follow and then the pace may accelerate as the world gains confidence in its ability to understand both the epidemiology of diseases and the sociologic conditions involved in the spread of diseases.
With the improvement of the science base, public health will have formidable challenges in educating people about the benefits of such vaccines and the implications of the social contract in using them.
a The story of the impact on global health that this small group grew to have is told in my upcoming book on the history of the Task Force for Child Survival.