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Infectious diseases & pandemics

[Fall 2013 Centennial issue]

Today, noncommunicable diseases account for two-thirds of all deaths globally. But in low-income nations, three largely preventable infectious diseases—lower respiratory infections, diarrheal infections, and HIV/AIDS—are the leading killers, with malaria, tuberculosis, and neonatal infections close behind. And as recent headlines have shown, new infections—from SARS to bird flus to deadly new strains of E. coli—continually emerge. From its very beginning, Harvard School of Public Health has bolstered efforts to control the most common and the most vicious infections in every corner of the world—with pivotal discoveries in the lab and advances in interventions on the ground.

Three deadly scourges

Smallpox

William Foege had a problem—a big problem. It was December 1966. Foege, who graduated from the School with an MPH in 1965, was serving in a remote part of eastern Nigeria on a medical mission and as a consultant to the U.S. Centers for Disease Control and Prevention (CDC). His assignment was daunting: to help rid that part of the world of smallpox, a painful, disfiguring infection that was one of humankind’s most devastating scourges. Health authorities believed that to achieve eradication, 80 to 100 percent of regional populations had to be inoculated.

But in Foege’s jurisdiction, vaccine was in short supply. When smallpox erupted in a nearby village, Foege had to figure out how to hold back the epidemic. Spreading out maps of the district and working with two-way ham radios, he contacted missionaries and asked them to dispatch runners throughout the region to learn where else the disease had broken out. Using this information and analyzing family travels and market contacts, he made an educated guess about where the epidemic would jump. The task required, as he once recalled, imagining “how a smallpox virus bent on immortality” would behave. Foege’s team took an unusual approach, targeting for vaccination only residents in the affected villages and in villages where the disease would likely strike.

Miraculously, four weeks later, though less than 10 percent of the population had been immunized, the outbreak screeched to a halt. Six months later, the entire region was smallpox-free. “Surveillance/containment,” as the method came to be known, revolutionized the smallpox eradication campaign by saving money and time. When the World Health Organization (WHO) officially declared smallpox eradicated in 1980, it was in no small part because of Foege’s daring calculations.

A woman in Ethiopia is vaccinated against smallpox in the 1970s as the global eradication campaign nears an end.

A woman in Ethiopia is vaccinated against smallpox in the 1970s as the global eradication campaign nears an end.

It was just the start of Foege’s game-changing career. From 1984 to 1990, he led a partnership of U.N. agencies and nongovernmental organizations that raised worldwide immunization levels from 20 percent to 80 percent for six major childhood diseases—“the largest peacetime mobilization in the history of the earth,” according to James Grant, then the director of UNICEF. As CDC director from 1977 to 1983, Foege witnessed the emergence of Legionnaires’ disease, toxic shock syndrome, Lyme disease, the deadly E. coli O157:H7 strain, and HIV/AIDS. In 2012, Foege was awarded the Presidential Medal of Freedom, the highest civilian award in the United States.

Mobilizing an international team of scientists and government officials in a targeted attack on a single microbe, the war on smallpox demonstrated for the first (and, to date, the only) time that it was possible to extinguish a pathogen through deliberate human activity. In October 1977, a hospital cook in Somalia contracted smallpox from two Ethiopian children who had fled to Somalian refugee camps after their nation’s civil war—the last case of naturally occurring smallpox on earth. Three years later, the WHO declared smallpox—an infection that had killed an estimated 300 million people in the 20th century alone—gone for good.

Polio

The iron lung pulled back thousands of polio victims from the brink of death.

The iron lung pulled back thousands of polio victims from the brink of death.

At the beginning of the 20th century, major epidemics of poliomyelitis were virtually unheard of. But within a few decades, it was the fifth-leading cause of infectious disease death in the United States, claiming thousands of lives each year in nearly annual epidemics. The 1952 polio epidemic was the worst outbreak in the nation’s history; of 57,628 reported cases, 3,145 died and 21,269 were left struggling with mild to disabling paralysis.

Called “the summertime scourge,” polio often flared in the midst of the idyllic rituals of summer. Because water was believed to be a route of transmission, swimming holes, pools, and ponds were closed when epidemics erupted. But the threat loomed everywhere. As Philip Roth wrote in his 2010 novel Nemesis, “We were warned not to use public toilets or public drinking fountains or to swig a drink out of someone else’s soda-pop bottle or to get a chill or to play with strangers or to borrow books from the public library or to talk on a public pay phone or to buy food from a street vendor or to eat until we had cleaned our hands thoroughly with soap and water.”

Poliovirus belongs to the enterovirus family, which infects the intestinal tract and is spread by the fecal-oral route. The infection was unusual because it actually claimed more lives as overall health conditions improved. In crowded tenements and rural slums, young children were exposed to the poliovirus within the first few years of life, when the disease causes few symptoms beyond a transient fever. By contrast, children of the middle and upper classes were protected from exposure to the virus during infancy. As they got older and went to school or summer camp or swam in public pools, they encountered large groups of children. First-time exposure to the poliovirus at an older age is more likely to trigger the most dreaded complications: muscle stiffness, pain, and eventual paralysis.

In the first half of the 20th century, medicine was virtually helpless in treating polio’s complications, including the tortured suffocation that followed paralysis of the chest muscles. But in the fall of 1928, the clinical picture brightened somewhat, when a Harvard senior with polio entered Boston’s Brigham Hospital. In his room sat a giant tin box with a hole at one end and a motor at the other. Its inventor was Philip Drinker, a quiet, modest engineer and professor of industrial hygiene at HSPH. The iron lung pulled back thousands of polio victims from the brink of death. Drinker’s contraption aided the young man’s respiration by increasing and decreasing the pressure inside its sealed compartment (the first polio victim to use the respirator, an 8-year-old girl, was revived but soon succumbed). Officially called the Drinker Respirator, it came to be known by a more descriptive name: the iron lung. In 1964, Drinker recalled this early clinical success with the Harvard senior: “After a long siege in the machine, he recovered quite well and is today after almost thirty years very much alive.”

The iron lung pulled back thousands of victims from the brink of death, and Drinker became an international celebrity. Scientists were soon to make an even more profound breakthrough. In the 1930s and ’40s, researchers were frantically working on a polio vaccine—but the science was stalled, because no one could grow the virus in a form that would permit mass production of vaccine.

HSPH's Thomas Weller, left, with Frederick Robbins, center, and John Enders received the 1954 Nobel Prize in Physiology or Medicine for discovering new methods to cultivate the poliovirus.

HSPH’s Thomas Weller, left, with Frederick Robbins, center, and John Enders received the 1954 Nobel Prize in Physiology or Medicine for discovering new methods to cultivate the poliovirus.

As a wave of polio swept the country in 1948, 32-year-old Thomas Weller was logging long hours in a lab at Harvard-affiliated Children’s Hospital, trying to develop a new way to culture viruses in test tubes. One day at the bench, when he was done injecting varicella, the chickenpox virus, into test tubes, he noticed four leftover flasks with human embryonic tissue suspended in a nutrient broth. He walked to the laboratory freezer and took out samples of poliovirus obtained from the brain of an infected mouse.

Weller inoculated the extra flasks with the poliovirus. Then he added an innovative twist to the experiment: Instead of discarding the tissue every one or two days and keeping the fluids—the usual protocol—he kept the tissues in the flasks and frequently replenished the nutrient fluids. That way, slow-growing viruses were not inadvertently thrown out.

The chickenpox cultures never took—but the polio cultures did, on Weller’s first try. The virus grew not only in brain tissue but also in cells derived from skin, muscle, and intestines. By finding a way to grow the virus in nonnervous tissue, Weller and his colleagues, John Enders and Frederick Robbins, paved the way for safe polio vaccines in the 1950s and ’60s. In 1949, Weller joined the HSPH Department of Comparative Pathology and Tropical Medicine, rising through the ranks as instructor, assistant professor, and associate professor.

In 1954, the three scientists shared a Nobel Prize in Physiology or Medicine. The prize came just months after Weller had been named the Richard Pearson Strong Professor of Tropical Public Health at Harvard, as well as chair of the department.

“These discoveries incited a restless activity in the virus laboratories the world over,” noted the award committee. “The tissue culture technique was rapidly made one of the standard methods of medical virus research.” The discovery made possible the creation of a polio vaccine.

Today—like smallpox 50 years ago—polio is the bull’s-eye of a global eradication campaign that rests on vaccination. Since the launch of the campaign in 1988, new cases have dropped more than 99 percent. In 2012, a total of 223 polio cases worldwide were reported, with most from countries where the infection remains endemic: Afghanistan, Nigeria, and Pakistan. (In 2013, in something of a setback, Pakistan and several African nations saw outbreaks.) This past April, the Global Polio Eradication Initiative presented a plan to eradicate the disease by 2018—a fitting epilogue to the School’s storied achievements.

HIV/AIDS

A World AIDS Day rally in Calcutta in November 2011. First held in 1988, when the United Nations General Assembly declared AIDS to be a global pandemic, World AIDS Day is now an annual event in most countries.

A World AIDS Day rally in Calcutta in November 2011. First held in 1988, when the United Nations General Assembly declared AIDS to be a global pandemic, World AIDS Day is now an annual event in most countries.

In June 1981, the CDC issued a report with a deceptively bland title: “Pneumocystis Pneumonia—Los Angeles.” It summarized the first five reported cases of the horrifying pandemic later named acquired immune deficiency syndrome: AIDS. Around the globe, millions were already silently infected.

AIDS has been public health’s perfect storm. The human immunodeficiency virus (HIV) that triggers AIDS devastates the body’s protective systems, ushering in not only systemic symptoms such as fevers and weight loss but also opportunistic infections and cancers that would normally be kept at bay. In the U.S., where the infection is most common among gay men, homophobic backlash initially slowed the political commitment to tackling the disease. And HIV/AIDS has disproportionately struck the poorest nations in the world, with 69 percent of infections in sub-Saharan Africa.

From the start, as the immense proportions of the AIDS epidemic became apparent, HSPH helped lead a counterassault. The School’s laboratory discoveries have pointed the way for ongoing research into vaccines and treatments. Its epidemiologic modeling and data analysis helped describe the contours of the epidemic and the best interventions. And its public policy and human rights commitments have set standards worldwide.

When the epidemic first surfaced, Max Essex, now the Mary Woodard Lasker Professor of Health Sciences at HSPH, had been toiling away in relative obscurity on a virus known as FeLV (feline leukemia virus), which causes AIDS-like immunosuppression in cats. A veterinarian and virologist by training, Essex was one of the first to suggest that the mysterious agent causing AIDS was a retrovirus. His work sped the discovery of the AIDS virus by the National Cancer Institute’s Robert Gallo and the Pasteur Institute’s Luc Montagnier. In 1986, for his role in identifying the cause of AIDS, Essex shared, with Gallo and Montagnier, the prestigious Albert Lasker Medical Research Award.

Other crucial discoveries quickly followed. Collaborating with HSPH colleagues, Essex confirmed that the AIDS virus could be transmitted through blood transfusions. In 1985, he co-discovered, with Tun-Hou Lee, now professor of virology, the gp-120 surface protein, which is now used worldwide for blood
screening. In 1986, Essex, Phyllis Kanki, now professor of immunology and infectious diseases, and Richard Marlink, now executive director of the Harvard School of Public Health AIDS Initiative, discovered a second AIDS virus, HIV-2, which causes a million infections annually in West Africa. HIV-2 is less transmissible and less deadly than HIV-1. HSPH researchers have also identified a treatment program that prevents 99 percent of mother-to-child HIV transmission via breastfeeding.

Max Essex, the Mary Woodard Lasker Professor of Health Sciences

Max Essex, the Mary Woodard Lasker Professor of Health Sciences

Though U.S. President Ronald Reagan didn’t deliver a major address on AIDS until 1987, it was painfully clear to scientists that the infection was fast becoming the leading public health crisis of the century. In 1988, to promote an interdisciplinary approach to a battle that had to be waged on several fronts, Harvard President Derek Bok announced the creation of the University-wide Harvard AIDS Institute (HAI), with Essex as chair. In 1992—a time when the U.S. banned visas for people infected with HIV/AIDS—the HAI-organized eighth International AIDS Conference was scheduled to take place in Boston. To protest the discriminatory policy, Essex canceled the meeting, which was later moved to Amsterdam.

International collaborations have been the bedrock of the School’s basic research. In the early 1980s, HSPH established a presence in Africa to meet the challenges posed by the pandemic. The School established a model study in Senegal in the mid-1980s that is now one of the longest-running AIDS studies in Africa. HSPH also conducted the first HIV vaccine trial in southern Africa.

In 1995, HSPH biostatistician Stephen Lagakos founded the Center for Biostatistics in AIDS Research to bring innovative statistical techniques to clinical trials in HIV/AIDS, while at the same time honoring the needs and welfare of patients enrolled in these studies. In 1996, the School launched the Botswana–Harvard AIDS Institute Partnership, a research and training program that was the largest of its kind in Africa at the time, as well as the first dedicated HIV research lab in southern Africa.

The President’s Emergency Plan for AIDS Relief (PEPFAR) dramatically scaled up the School’s work in African countries hit hard by the disease. Beginning in 2004, HSPH received a total of $362 million from PEPFAR for work in Nigeria, Botswana, and Tanzania, led by Kanki. The School trained thousands of health care workers, developed monitoring and evaluation systems, refurbished and equipped clinics and labs, and collaborated with local hospitals and clinics. (See page 22.) Such progress gives scientists hope that the tide may be turning. “On the cusp of the fourth decade of the AIDS epidemic, the world has turned the corner—it has halted and begun to reverse the spread of HIV,” said a 2011 summary from UNAIDS.

Still, in 2013, the toll remains incalculable. The majority of HIV-positive individuals are unaware that they are infected. The virus is the leading cause of death globally among women of reproductive age. Most people living with HIV, or at risk for infection, do not have access to prevention, care, and treatment. And more than three decades into this shattering pandemic, there is no cure.

As HSPH enters its second century, it will continue to focus its research and education on stemming this relentless pandemic.

Madeline Drexler

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