rubella_virus_vaccine
A computer rendering of the Rubella virus. Newscom

What the Hard Lessons of Rubella Teach Us About a Zika Vaccine

Feb 22, 2017
Ideas
Wadman is the author of The Vaccine Race

Imagine that you are pregnant, unexpectedly. You are terrified, but not because you don’t want a baby. You are in fact, happily married, and you have been intending to start a family soon. Rather, you are terrified because an epidemic of a viral disease is raging around you. It is a disease that is often so mild that people aren’t aware that they have it. But when it infects a woman early in her pregnancy, it devastates the fetus, shrinking its head and addling its brain. There is no effective treatment and there is no vaccine.

I am not describing the plight of a pregnant woman in northeastern Brazil, or that of a worried woman from Oregon or Omaha returning from a honeymoon in Puerto Rico. I am not talking about the Zika virus that, as of February 2, has led to the births of at least 2,656 infants with brain damage in 28 countries. Rather, the terrified Everywoman pictured above lived in the United States in 1964, when an epidemic of rubella, commonly known as German measles, infected some 12.5 million people, or 1 in 15 Americans. The injuries inflicted on fetuses by the 1964 epidemic makes the current Zika plague look mild. Before it was over in 1965, some 20,000 American babies were born damaged. (This would be equivalent to roughly 34,000 babies proportionate to today’s much larger US population.) The virus was also responsible for more than 8,000 miscarriages, stillbirths and babies born only to perish within the first month of life.

While Zika has so far demonstrated a predilection for the brain, rubella infects virtually every fetal organ: the long, thin fibers of the lens of the eye; the delicate inner ear, the seat of hearing; the lining of the heart; the small blood vessels that feed what should be a growing brain with oxygen and nutrients. By the time the 1964 epidemic ebbed, this virus less than two millionths of an inch in diameter had resulted in more than 8,000 deaf babies; nearly 4,000 newborns who were both deaf and blind; and 1,800 who were intellectually disabled. About 6,600 infants had other manifestations of congenital rubella, most typically serious heart defects. Often, babies were born with several of these disabilities.

The demand for a vaccine was immediate and intense.

The fear in the air in 1964 wasn’t confined to pregnant women who broke out in rubella’s signature pink-red rash, with its accompanying fever and swollen lymph nodes. Any woman who conceived knew she might be carrying a disease that doesn’t cause symptoms in up to two-thirds of those infected. There was no easily available blood test for infection; the one that was accessible to the determined and the enterprising took several, excruciating weeks to return results.

Some 5,000 women — generally those who were whiter, wealthier and better-connected — sought and obtained abortions. This was not easily done at a time when the procedure was illegal, except to save the life of the mother and in a handful of other, tightly-circumscribed situations, in 49 of 50 states. (Pennsylvania’s 1939 law did not even contain the life-of-the-mother exception.) All the same, the authorities tolerated the fact that, even before the rubella epidemic, major medical centers quietly conducted abortions, sanctioned by committees of doctors who passed muster on the case of each supplicating woman.

In Philadelphia in 1964, a determined young physician and virologist named Stanley Plotkin began racing to make a rubella vaccine before the next epidemic. Large rubella outbreaks occurred regularly, every six to nine years. That meant that another epidemic could arrive as soon as 1970.

The 32-year-old Plotkin worked at the Wistar Institute of Anatomy and Biology, an elegant brownstone in the heart of the University of Pennsylvania campus. He was one of the few doctors who knew how to test blood or throat swabs for rubella infection, and he had been inundated with requests from agonized couples, and even potential grandparents.

“Dear Sir,” began one letter he received in careful cursive on a plain half-sheet of paper. “Could you let me know is it dangerous or fatal. I have a daughter pregnant 3 months and had the measles. Is the danger over of injury to baby? It is no [sic] 4 month. Please let me know?”

Occasionally, his tests on pregnant women led to follow-up letters that were a joy to write. But more often, they left a painful uncertainty, often because women didn’t find him until several weeks after they fell ill; his results were less reliable the more time elapsed after infection. “I suspect the problem is that we did not see the patient until 18 days after the onset of the rash,” he wrote to one doctor who had sent a worried pregnant woman to him.

When a test came back positive and a couple decided to abort, Plotkin asked permission to try to capture the virus from the aborted fetus. He captured a hardy rubella virus this way, and set about making a vaccine by growing the virus in cells that his Wistar Institute colleague, Leonard Hayflick, had developed from the lungs of a fetus legally aborted in Sweden in 1962.

Plotkin grew the virus through several generations in the fetal cells, aiming to weaken it to the point that it would provoke the production of protective antibodies in vaccinees, but not cause the disease. (Adapting to lab life commonly weakens viruses.) Plotkin tested his new vaccine in toddlers at St. Vincent’s Home for Children, a Philadelphia orphanage run by the Catholic Church; he had won approval to run trials at the orphanage from the Archbishop of Philadelphia, John Joseph Krol. In approaching the staunchly anti-abortion archbishop, Plotkin chose not to mention that he had captured the virus from one aborted fetus and grown it in cells from another.

It emerged that Plotkin had not weakened the virus enough. In the first trial, many of the toddlers broke out in rashes and spiked fevers; vaccinated children passed the virus to unvaccinated controls. But after several more rounds of growth in the lab, and after more trials in children at the orphanage and at the Hamburg State School and Hospital, an institution for the intellectually disabled, his results showed that Plotkin had an effective vaccine. (Today, federal laws and regulations prevent scientists from testing drugs and vaccines, except in rare circumstances, on powerless, institutionalized children. But in the mid-1960s, this was standard practice.)

Plotkin had competition in the rubella vaccine race, from Merck, from other companies, and from an inside-track vaccine candidate at the National Institutes of Health in Bethesda, Maryland, which in those days approved vaccines for the US market – a role now filled by the Food and Drug Administration. The NIH’s inscrutable vaccine czar was silently, inveterately opposed to making vaccines in Hayflick’s human fetal cells. This was probably not for religious reasons – he was known to roll his eyes when the staunchly Catholic NIH director offered prayers at public ceremonies. (Nonetheless, the cells would, with time, attract plenty of anti-abortion detractors.) Rather, the vaccine czar, Roderick Murray, seemed to suffer from a paralyzing scientific conservatism. Never mind that the fetal cells’ producer, Hayflick, had demonstrated their safety in scores of tests, and that Europeans were quickly embracing them for vaccine-making.

What followed was a thoroughly politicized vaccine race, in which Plotkin’s superior vaccine was sidelined in favor of the in-house NIH candidate. The NIH’s vaccine was handed off to Merck, tweaked slightly and then produced in vast quantities, in the cells of embryos from ducks that floated placidly on a custom-built pond at Merck’s research campus outside Philadelphia. The Merck vaccine was approved by NIH in 1969. Another, made in rabbit kidney cells by SmithKlineBeecham (now GlaxoSmithKline), quickly followed it to the US market.

In 1972, the FDA took over US vaccine regulation after a whistleblower-prompted Congressional probe revealed the NIH vaccine division’s gross deficiencies and Murray, its chief, was put out to pasture. But it would be 1979 before the FDA approved Plotkin’s vaccine and its inferior competitors vanished from the market. Plotkin’s vaccine is used, nearly worldwide, to this day. In the US, it is still produced in Hayflick’s fetal cells; it is the “R” in the “MMR” vaccine given to toddlers.

Hayflick’s human fetal cells also won widespread acceptance. Today, those cells and a group of similar fetal lung cells launched by the British in 1966 are used to make vaccines against rabies, chicken pox, shingles, polio, adenovirus and hepatitis A – and, of course, rubella.

In 2005, the Centers for Disease Control and Prevention declared that home-grown rubella had been eliminated from the United States. In 2015, the Pan American Health Organization announced the same achievement in the Western Hemisphere.

An Ohio opera singer named Betsy Graham MacConnell was likely the last US-born woman to give birth to a baby with congenital rubella. (Immigrants from countries that don’t vaccinate against rubella still occasionally give birth, stateside, to affected children.) In 2001, MacConnell’s daughter, Anna, was born blind, deaf and with serious heart defects. Anna got the best care available. Her parents — her father, Chip, is a whip-smart physician’s assistant — saw her through multiple surgeries, rejoiced when a cochlear implant gave her a degree of hearing and enrolled her in their local elementary school in Centerville, where she became something of a rock star. The whole school learned to sing the school song in sign language. But in 2012, not long after her eleventh birthday, Anna’s heart gave out. She died in a Cincinnati hospital, her family surrounding her and her service dog, a GoldenDoodle named Cadi, curled up in a corner of the room.

Anna’s mother Betsy had been vaccinated at age 3, in 1972, with one of the vaccines that were then on the US market.

Today, political interference in science is alive and well. Consider this: Late in February, 2016, then-President Obama asked Congress for $1.9 billion to fight Zika transmission and to develop a vaccine. It was not until seven months later, September 29, 2016, that Congress provided 60% of that amount. In the intervening time, 1,500 zika-affected babies were born, two dozen of them in the US. And by the time the funding bill containing the money passed, Zika had established a foothold in Miami.

The months of delay were due to one thing: partisan politics. Republicans on Capitol Hill balked at the $1.9 billion request and told the White House to repurpose funds already allocated to combating the even-deadlier Ebola virus. By late August, the administration had “borrowed” tens of millions of dollars designated to fight not only Ebola but malaria, tuberculosis, diabetes, mental health and heart disease — in order simply to get a promising Zika vaccine trial up and running. Needless to say, the money “borrowed” from the other diseases will never be paid back. Nor can the time be recovered, a particular tragedy in light of the World Health Organization’s announcement this month that no Zika vaccine is likely to be available to women of childbearing age until 2020.

In September, 2016, when the GOP finally produced a bill with $1.1 billion in new Zika funds, Democrats in Congress initially refused to approve it because its Republican authors excluded Planned Parenthood a woman’s health organization that uses 3% of its budget to conduct abortions – from a list of providers slated to get new money to distribute contraception to combat Zika’s spread. (The virus can be transmitted sexually.) Eventually, the Planned Parenthood wording was dropped and, amidst other political wrangling, the bill was passed and signed into law.

Fifty years of experience — and untold thousands of damaged babies — do not appear to have convinced us that when it comes to public health, science needs insulating from politics. There are signs that President Donald Trump may be open to change: Last August, as Congress dallied, he told The Miami Herald that lawmakers should free up the Zika funds, pronto. If he wants to avoid another Zika-like showdown, Trump could take a page from his one-time foe’s playbook. Hillary Clinton proposed Public Health Rapid Response Fund with reliable, predictable annual funding that would allow our public health agencies, scientists and hospitals to respond immediately, unencumbered by our increasingly partisan politics, when a new virus or any other public health threat emerges. And emerge they will. The only question is how well we will respond.

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Meredith Wadman’s book, The Vaccine Race: Science, Politics and the Human Costs of Defeating Disease, is out from Viking this month. Wadman is a reporter at Science magazine.


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