Tag Archives: polio

The American Public’s Response to the 2014 West African Ebola Outbreak: Update

A premise of my August 10, 2014 blog entry was that public fear of Ebola in the United States has been disproportionate to the actual threat that the virus poses here (1). The piece also discussed the factors that shape the public’s reaction to particular viral diseases. The viruses discussed were Ebola, influenza, polio, and HIV.

For a sense of my earlier argument, consider that influenza kills on average about 40,000 Americans (and 500,000 people world wide) yearly. In contrast, at the time of the August 10 blog entry, the current Ebola outbreak was estimated to have killed about 1,000 people in total. Moreover, the largest previous Ebola outbreak, which occurred in Uganda in 2000, claimed 244 lives. Furthermore, up to the time of the earlier posting, Ebola had killed a total of about 2,000 people since it first emerged in 1976. All Ebola outbreaks occurred in Africa, and no Ebola infection had ever occurred in the United States. In each of the previous Ebola outbreaks, the virus ran its destructive course and then “disappeared.” Yet the American public is far more troubled by Ebola than it is by influenza. Indeed, an influenza vaccine is available to prevent influenza, yet all too few individuals avail themselves of it. And, while no one has yet contracted Ebola in the United States, the public has been clamoring for an Ebola vaccine.

Subsequent to my earlier blog entry, several key developments have taken place, one of which has been receiving virtually minute-by-minute cable news coverage. As most everyone knows, Thomas Duncan, a Liberian, arrived at the Dallas/Fort Worth International Airport on September 20; a day after he boarded an airplane in Monrovia, Liberia. Ten days later, Duncan was diagnosed with Ebola at the Texas Health Presbyterian Hospital in Dallas. Mr. Duncan was the very first person in the current outbreak to be diagnosed with Ebola outside of Africa, and he was the very first person to develop symptoms in the United States.

A second key development is that the Centers for Disease Control and Prevention (CDC) now predicts that the current outbreak in West Africa might be vastly more devastating than any previous Ebola outbreak. The CDC reported on September 23 that, in a worst-case scenario, African Ebola cases could reach 1.4 million in four months time. [It is not entirely clear why the current outbreak has been so devastating. But, the earlier Ebola outbreaks happened in rural African villages, where infected individuals had fewer contacts. The current outbreak has spread to more densely populated urban areas, where infected individuals might come into contact with more people over a wider area.]

How might these new developments affect the premise of the earlier piece? Read on.

We begin by considering the implications of Mr. Duncan entering the United States, while carrying the Ebola virus. First, in the modern era of world-wide jet travel, a virus outbreak could spread across the globe in a day’s time (2). Second, airport screening is inherently porous. Moreover, it may be particularly so in the case of Ebola since the incubation period for symptoms to emerge can be as long as 21 days. Thus, an Ebola-infected individual, who is symptom-free, might board an airplane and later disembark anywhere in the world, and afterwards develop symptoms. In fact, Mr. Duncan was screened for fever at the airport in Monrovia; a standard practice there. His temperature was normal, and he was allowed to board his flight out of Liberia.

Airport screening must also rely on travelers being aware of their exposure to the virus, and on their integrity to report their exposure. In this regard, Duncan also stated on an airport form in Monrovia that he had not been exposed to Ebola. It is not clear whether Duncan knew that he had been exposed. Regardless, Liberian officials announced plans to prosecute him when he returns to Liberia, and Texas prosecutors too are considering bringing charges against him. [Duncan was exposed on September 15 in Monrovia, while playing the part of a Good Samaritan. He helped a pregnant woman, stricken by Ebola, get to a hospital. But, the woman was turned away by the hospital because of lack of space in its Ebola ward. She was taken back home and died later that evening. Duncan’s condition in Dallas has been critical for the past several days.]

Some in Congress, and others on the campaign trail, have been calling for banning passengers arriving from West Africa. However, federal officials have rejected that notion. Importantly, such a step would prevent medical workers and other assistance from reaching Africa. And it is crucially important that this not happen. Aside from ethical and humane considerations, the way to finally end the threat of Ebola in the United States is to stop the epidemic at its source (see below).

Considering that it was only a matter of time before Ebola-infected individuals might pass through screening procedure and arrive in the United States, the CDC and hospitals and health departments around the country have been preparing for that event. And, since people with Ebola are not contagious until symptoms develop, and contracting the virus requires contact with a sick person’s bodily fluids (e.g., blood or vomit), an Ebola outbreak should be quickly contained here by carrying out basic public health procedures (i.e., isolating infected individuals, and tracing and isolating their contacts).

That said, there is much that is troubling about the response of local and federal health officials in the incident involving Mr. Duncan in Dallas. The first time that Duncan came to the emergency room at Texas Health Presbyterian Hospital, he told a nurse that he had just been in Liberia. [Liberia, Guinea, and Sierra Leone are the three West African countries where Ebola is rampant]. However, this information was not transmitted to the doctors who treated Duncan. Believing that Duncan had a low-grade fever from a viral infection, they sent him home with antibiotics (hmm?). The hospital later released a statement blaming a flaw in its electronic health records system for its decision to send Duncan home. There were separate “workflows” for doctors and nurses in the records, so that doctors were not aware Duncan had come from Africa.

Three days after Duncan was sent home from the Dallas hospital, he came back with worsening symptoms. This time, he was placed in isolation, and both the CDC and a state lab in Texas then confirmed his condition as Ebola. Alarmingly, 114 people, including several schoolchildren, were believed to have been in contact with Duncan during the few days between his first visit to the hospital and his return and isolation there.

The number of people being monitored in Dallas has since dropped to ten, and none of these individuals has shown signs of infection. Regardless, public anxiety mounted after Duncan’s diagnosis was announced and his contacts were quarantined. Reports of worried Dallas parents keeping their children home from school were reminiscent of the public’s response to the polio outbreaks of the 1950s (1).

Astonishingly, the four people, who Duncan had been living with until his hospitalization, were forced to remain in the apartment they had been sharing. The apartment had not been sanitized, and the sheets and towels that Duncan had been using remained there. The explanation offered by the Texas health commissioner was that officials had encountered “a little bit of hesitancy” in finding a contractor willing to clean the apartment. And, while county officials visited the apartment, they did so without wearing protective gear. The four people Duncan was living with have since been moved from the potentially contaminated apartment.

Important lessons should have been learned from the missteps in Dallas. And, despite those missteps, no one in Dallas appears to have contracted Mr. Duncan’s infection. Thus, we might remain optimistic about the ability of our public health system to contain an Ebola outbreak anywhere in the United States. Moreover, that optimism might be bolstered by the example of Nigeria, the most populous nation in Africa (177,000,000 individuals), which recently contained its first Ebola outbreak. Interestingly, Nigeria’s outbreak grew from a single airport case, and it was contained using basic public health procedures. Nigerian health workers made nearly 18,500 face-to-face visits to monitor the nearly 900 people who had contact with known cases. Incidentally, the Bill & Melinda Gates Foundation financed the creation of the Ebola Emergency Operations Center, which oversaw the Nigerian response. With the best public health infrastructure in the world, we ought to be able to do as well here.

Although the epidemic in Nigeria was contained, the epidemic rages out of control only a few hundred miles away, in the epicenter comprised of Liberia, Sierra Leone, and Guinea. These underdeveloped and poverty-stricken nations have altogether inadequate public health systems that are overwhelmed by the scale of their epidemics. Thus, the Nigerian experience is not applicable in those countries, which desperately need massive international assistance.

President Obama announced on September 16 that the United States would send about 3,000 American military personnel, including doctors, to Liberia and Sierra Leone, to help construct Ebola treatment centers there, and to train up to 500 health-care workers per week. Importantly, and as noted above, irrespective of ethical and humane considerations, the epidemic must be stopped at its West African source, before we might be entirely safe from it here. But that will not be an easy or quickly realized task, since current estimates are that it will require as many as 30,000 health-care workers to bring the West African epidemic under control. The international community will need to become engaged in that effort to a vastly greater extent than it has to date.

In the interim, considering that Ebola does not spread nearly as easily as the viruses in doomsday movies do (recall that Ebola can be contracted only by contact with the bodily fluids from a person who has developed Ebola symptoms), and considering the asserted excellence of the public health infrastructure in the United States, Ebola still poses less of a threat here than influenza does, and less of a threat than several other viruses as well. [See the Postscript, below.]

References

(1) The American Public’s Response to the 2014 West African Ebola Outbreak, posted on the blog August 10, 2014.

(2) Carlo Urbani: A 21st Century Hero and Martyr, posted on the blog February 11, 2014.

Related

Peter Piot: The Discovery of Ebola Virus, posted on the blog September 2, 2014.

Postscript

As long as the epidemic lasts, new developments are bound to happen that cause us to reevaluate our earlier perspective. Just yesterday, a nurse in Madrid became the first health worker known to contract Ebola outside of West Africa. She was infected while attending to a Spanish missionary who contracted the illness in Sierra Leone. The missionary was flown to the Carlos III hospital in Madrid, where he succumbed three days afterward. The nurse was in his room in the Madrid hospital only twice; once before his death, and once afterwards, and she was wearing protective gear. This incident, together with the episode in Dallas, causes us to question just how well prepared Western health care systems actually are to safely treat people with Ebola, while not endangering their health workers or the public.

Addendum: October 8, 2014

Thomas Duncan passed away today at the Texas Health Presbyterian Hospital in Dallas.

Also, an editorial in Nature this week (9 October 2014) makes several points that supplement the above discussion. In particular, “even in rich countries, inequalities in access to health care and cost-cutting in the health services can create vulnerabilities… Were Ebola to spread in underprivileged urban areas, it might not be so easy to control as US officials are making out. The uninsured, in particular, may think twice about going to see a doctor, and so hamper efforts to stem an outbreak.”

And, regarding the disproportionate and excessive coverage by the America media of Ebola here in the USA, “People who suspect they might have been in contact with someone infected with Ebola might now be reluctant to come forward in case their names are splashed all over the headlines. The public has a legitimate interest in knowing the places an infected person has frequented, for example, but there is a fine line between this and blatant voyeurism, invasion of privacy and sensationalism.”

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Remembering Ciro de Quadros and the Eradication of Polio in Latin America

Ciro de Quadros, who passed away at his home in Washington, D.C. on May 28, 2014, was a present-day hero, who ought to be much better known. In brief, de Quadros, a Brazilian epidemiologist, single-handedly initiated and then led efforts in the 1980s to eradicate polio from the Latin America continent.

The incidence of polio in Latin America had already been significantly diminished by the early 1960s via the introduction of Sabin’s vaccine. However, de Quadros insisted that epidemics would remain possible on the continent until mass immunization of the population might be achieved. He was particularly concerned with reaching unimmunized children who lived in the remotest areas. So, starting in 1985, in his role as an executive of the Pan American Health Organization (PAHO; a subsidiary of the United Nation’s WHO), de Quadros sent teams of health workers to 15 countries; some of which contained the most isolated and war-torn regions of Latin America.

El Salvador and Guatemala were particularly unstable at the time. So, in order to administer vaccinations in those nations, de Quadros first negotiated 24-hour cease-fire agreements between rebel and government forces. These so called “tranquility days” enabled health care workers to enter combat zones and carry out immunizations in relative safety.

In Peru, de Quadros was unable to secure cooperation from the Shining Path guerillas that operated there. So, he had his teams work around the areas controlled by the guerillas, and come back to those areas when the battle lines shifted elsewhere.

In 1994, the success of de Quadros’ immunization program led the PAHO to declare that polio had been officially eradicated from Latin American. The last reported case of polio on the continent occurred in 1991, in Pichanaki, Peru.

Interestingly, de Quadros had to fight an uphill battle to obtain support for his immunization efforts; even with the WHO, which preferred to use its limited resources to sustain primary health care. But, de Quadros forcefully maintained that vaccination is the starting point for effective primary health care, especially for children. And, while he was mainly concerned with polio, his vaccination teams also were prepared to immunize against measles, diphtheria, pertussis, tetanus, and tuberculosis.

Earlier in his career, in the 1970s, de Quadros was recruited by Donald A. Hendreson, then director of the WHO’s global smallpox eradication program, to help organize smallpox eradication in Ethiopia. In a phone interview with a NY Times reporter after de Quadros’ passing, Henderson recalled de Quadros’s steadfastness during Ethiopia’s civil war, when a half-dozen of his teams were kidnapped by rebels and one of his United Nations helicopters was commandeered along with its pilot. De Quedros helped negotiate the release of the health teams and the pilot, all of whom returned to their vaccination duties. Henderson noted that the helicopter pilot, who had vaccine aboard when he was hijacked, actually vaccinated the rebels who held him captive.

On May 2, 2014, less than one month before his death, de Quadros was honored by the PAHO/WHO as a Public Health Hero of the Americas. The award was presented to de Quadros by PAHO/WHO director Carissa F. Etienne, during an international vaccine symposium celebrating the 20th anniversary of the Sabin Vaccine Institute, where De Quadros was serving as Executive Vice President and Director of Vaccine Advocacy and Education. Etienne stated, “We at PAHO believe that no single person has done more to extend the benefits of immunization to people throughout the Americas.”

Dr. Carissa F. Etienne, Dr. Donald A. Henderson, Dr. Ciro de Quadros, Dr. Anthony Fauci, and Dr. Jon K. Andrus
Dr. Carissa F. Etienne, Dr. Donald A. Henderson, Dr. Ciro de Quadros, Dr. Anthony Fauci, and Dr. Jon K. Andrus

Etienne went on to say, “His (de Quadros’) leadership and vision were essential to our region’s becoming the first in the world to eradicate polio, a success story that inspired the global polio eradication campaign.” Also, de Quadros is regarded as a leader in the development of the surveillance and containment strategies that facilitated the eradication of smallpox worldwide, and he also directed measles eradication efforts in the Americas.

 

 

 

The Struggle Against Yellow Fever: Featuring Walter Reed and Max Theiler

The first part of this posting tells how a U.S. Army medical board, headed by Walter Reed, confirmed that the transmission of yellow fever requires a mosquito vector. The second part tells the story of the yellow fever vaccine developed by Max Theiler.

Bearing in mind the enormous benefit to mankind of the polio vaccines developed by Jonas Salk and Albert Sabin (1), and that Maurice Hilleman developed nearly 40 vaccines, including those for measles, mumps, and rubella (2), it would appear remarkable that Theiler was the only one of these four individuals to be recognized by the Nobel committee. In fact, Theiler’s 1951 Nobel award was the only one ever given for a vaccine! In any case, while Theiler’s vaccine was a major step forward in the fight against yellow fever, it came after a perhaps more dramatic episode in the struggle against that malady. But first, we begin with some background.

Yellow fever was another of mankind’s great scourges. Indeed, it was once the most feared infectious disease in the United States. And, while we might want to say that science has “conquered” yellow fever, that statement would not be entirely accurate. Unlike polio and measles, which have nearly been eradicated by the vaccines against them, that is not so for yellow fever. The reason is as follows. Humans are the only host for polio and measles viruses. Consequently, those viruses might be completely eradicated if a sufficient percentage of humans were to comply with vaccination regimens. In contrast, the yellow fever virus infects monkeys that range over thousands of square miles in Africa and the Amazon jungle. Thus, even with massive vaccination of humans, it would be impossible to eliminate the yellow fever virus from the world.

According to the World Health Organization’s estimates, there are still about 200,000 cases of yellow fever per year, resulting in about 30,000 deaths, about 90% of which occur in Africa. The yellow fever virus itself is the prototype virus of the flavivirus family of single-stranded RNA viruses, which also includes dengue hemorrhagic fever virus, Japanese encephalitis virus, and West Nile encephalitis virus, among others.

yellow fever map

Yellow fever is somewhat unique among the viral hemorrhagic fevers in that the liver is the major target organ. Consequently, the severe form of yellow fever infection is characterized by hemorrhage of the liver and severe jaundice. But, as in infections caused by other virulent viruses, most cases of yellow fever are mild.

Interestingly, the name “yellow fever” does not have its origin in the yellowing of the skin and eyes that is characteristic of severe disease. Instead, it has its origin in the term “yellow jack,” which refers to the yellow flag that was flown in port to warn approaching ships of the presence of infectious disease.

Yellow fever originated in Africa. It is believed to have been brought to the New World by slave ships in the year 1596. As noted above (and discussed below), yellow fever transmission, from an infected individual or primate to an uninfected one, requires a specific vector, the Aedes aegypti mosquito. The sailing ships of the day inadvertently transported the disease across oceans via the mosquito larvae in their water casks.

Before getting to our stories proper, we note a pair of intriguing instances in which yellow fever profoundly affected New World history. In the first of these, yellow fever was a key factor that led Napoleon to sell the Louisiana Territory to the United States in 1803; an act that doubled the size of the United States. It happened as follows. After Napoleon seized power in France, he reinstated slavery in the French colony of Saint Domingue (now Haiti); doing so for the benefit of the French plantation owners there. In response, the rather remarkable Toussaint Breda (later called Toussaint L’Ouverture, and sometimes the “black Napoleon”) led a slave revolt against the plantation owners. In turn, in February 1802, Napoleon dispatched an expeditionary force of about 65,000 men to Haiti to put down the revolt. The rebellious slaves, many fewer in number than the French, cleverly retreated to the hills, believing that the upcoming yellow fever season would wreak havoc on the French force. And, they were correct. By November 1803, the French lost 50,000 of the original 65,000 men to yellow fever and malaria. Thus, in 1804, Napoleon had to allow Haiti to proclaim its independence, and then become the second republic in the Western Hemisphere. Moreover, there is evidence suggesting that Napoleon’s actual purpose in dispatching the expeditionary force was to secure control of France’s North American holdings. With his expeditionary force decimated by yellow fever and malaria, that was no longer possible and, consequently, Napoleon sold France’s North American holdings (the Louisiana Purchase) to the United States.

louisiana purchaseThe Louisiana Purchase, in green.

Second, in 1882, France began its attempt to build a canal across the Isthmus of Panama. However, thousands of French workers succumbed to yellow fever, causing France to abandon the project. The United States was able to successfully take up the task in 1904; thanks to the deeds of the individuals in part I of our story, which now begins.

In May 1900, neither the cause of yellow fever, nor its mode of transmission was known. At that time, U.S. Army surgeon, Major Walter Reed, was appointed president of a U.S. Army medical board assigned to study infectious diseases in Cuba, with particular emphasis on yellow fever. Cuba was then thought to be a major source of yellow fever epidemics in the United States; a belief that was said to have been a factor in the American annexation of Cuba.

ReedMajor Walter Reed

When Reed’s board began its inquiry, a prevailing hypothesis was that yellow fever might be caused by the bacterium Bacillus icteroides. However the board was unable to find any evidence in support of that notion.

Another hypothesis, which was advanced by Cuban physician Dr. Carlos Juan Finlay, suggested that whatever the infectious yellow fever agent might be, transmission to humans requires a vector; specifically, the mosquito now known as Aedes aegypti. Reed was sympathetic to this idea because he noticed that people who ministered to yellow fever patients had no increased risk of contracting the disease, which indicated to Reed that people did not pass yellow fever directly from one to another.

Reed, as president of the medical board, is generally given major credit for unraveling the epidemiology of yellow fever. Yet there were other heroes in this story as well. Finlay, whose advice and experience were invaluable to Reed’s board, was one. He was the object of much ridicule for championing the mosquito hypothesis, at a time when there little evidence that might support it. In any case, Reed, in his journal articles and personal correspondences, gave full credit to Finlay for the mosquito hypothesis.

Acting Assistant Surgeon Major James Carroll was another hero. As a member of Reed’s board, Carroll volunteered to be bitten and, promptly, developed yellow fever. Major Jesse Lazear, also a board member, asked Private William Dean if he might be willing to be bitten. Dean consented, and he too contracted yellow fever. Fortunately, Dean and Carroll each recovered. Not so for Lazear. After allowing himself to be bitten, he died after several days of delirium.

Lazear’s contribution to gaining recognition of the mosquito hypothesis went significantly beyond his tragic martyrdom. When Reed examined Lazear’s notebook after his death, Reed found that it contained several key observations. First, Lazear had carefully documented that in order for a mosquito to be infected; it had to bite a yellow fever patient within the first three days of the patient’s illness. Second, twelve days then had to elapse before the virus could reach high enough levels in the insect’s salivary glands to be transmitted to a new victim.

The observations of the board, up to then, convinced Reed and the others that the mosquito hypothesis indeed was correct. Yet Reed knew that more extensive controlled experiments would be needed to convince the medical community. So, he directly supervised those experiments, which involved twenty-four more volunteers, each of whom may rightly be considered a hero.

Just as Reed benefited from Finlay’s insights, William C. Gorgas, Surgeon General of the U.S. Army, applied the findings of Reed’s board to develop vector control measures to combat urban yellow fever; first in Florida, then in Havana, Cuba, and next in Panama, where those measures enabled the United States to complete the canal in 1914. The last urban yellow fever outbreak in the United States occurred in New Orleans in 1905, and the last in the New World occurred in 1999 in Bolivia.

The vector control strategy works for urban yellow fever because the Aedes aegypti mosquitoes have a very short flight range and, consequently, the female mosquito does not stray far from the source of her blood meal before laying her eggs. Thus, it is only necessary to control the vector population in the immediate vicinity of human habitation. In practice, this is accomplished by draining potential mosquito breeding sites such as swamps and ditches, and destroying water-collecting objects such as discarded tires.

After Reed’s board was disbanded, he made yet another key contribution to the wiping out of yellow fever. The focus of the board had been on the means of yellow fever transmission; not with the infectious agent itself. In 1901, at the suggestion of William Welch, an eminent Johns Hopkins pathologist, Reed and James Carroll (who nearly died of yellow fever after being experimentally infected while in Cuba), asked whether yellow fever might be caused by a filterable virus. Indeed, they found that they could infect volunteers by inoculating them with filtered serum taken from yellow fever patients. What’s more, theirs was the very first demonstration of a human illness being caused by a filterable agent. That is, yellow fever was the first human illness shown to be caused by a virus. [Pasteur developed an attenuated rabies vaccine in 1885, more than a decade before the discovery of viruses. Remarkably, this most brilliant of experimentalists did not recognize that he was dealing with a previously unknown, fundamentally distinct type of infectious agent; the topic of a future posting.]

[Aside: Walter Reed spent the early years of his Army career at different posts in the American west. The Mount Vernon Barracks in Alabama, which served as a prison for captured Apache Native Americans, including Geronimo, was a particularly interesting stop for Reed. Captain Walter Reed, serving as post surgeon in the 1880s, looked after Geronimo and his followers.]

Part II of this posting concerns the development of Max Theiler’s yellow fever vaccine. But first, here is a bit more background.

Vector control measures ended yellow fever epidemics in most, but not all urban centers worldwide. Outbreaks have not occurred in the United States for more than a century. However, jungle yellow fever still persists in areas of Sub-Saharan Africa and, to a lesser extent, in tropical South America. Individuals who are infected in the jungle by wild mosquitoes can then carry the virus to densely populated urban areas, where Aedes aegypti mosquitoes can transmit the virus from one individual to another. [Vector-mediated, human-to-human transmission happens because the level of yellow fever virus in the blood of an infected person becomes high enough for the infected person to transmit the virus to a biting mosquito. In this regard, the yellow fever virus is an exception to the generalization that humans are a “dead end” host for arthropod-borne (arbo) viruses.]

Fortunately, people who live in high risk areas for yellow fever can be protected by vaccination. Indeed, the World Health Organization’s strategy for preventing yellow fever epidemics in high risk areas is, first, to mass immunize the population, and then to routinely immunize infants. [Vaccinated American or European visitors to West Africa or the Amazon need not be concerned about yellow fever. However, the risk to an unvaccinated person of acquiring yellow fever during a two-week stay at the height of the transmission season (July through October), is estimated to be 5%. Individuals wanting to enter or return from countries where yellow fever is endemic may need to show a valid certificate of vaccination. ]

Part II of our story, concerning Max Theiler and the development of the yellow fever vaccine now begins.

Even as late as the 1920s, some reputable bacteriologists remained unconvinced by the earlier findings of Reed and Carroll that yellow fever is caused by a filterable agent. Instead, they persisted in the belief that the illness is caused by a bacterium. The notion of a bacterial etiology for yellow fever was finally put to rest after A. H. Mahaffy in 1927 discovered that the yellow fever agent could be propagated and cause illness in Asian rhesus monkeys. With an experimental animal now at hand, yellow fever workers were able to prove conclusively that the disease is caused by a virus. [Mahaffy drew the virus he used in his experiments from a 28-year-old African man named Asibi, who was mildly sick with yellow fever. That isolate, referred to as the Asibi strain, will play an important role later in this anecdote.]

Regardless of the significance of the discovery that the yellow fever virus could be propagated in rhesus monkeys, Max Theiler had to contend with the fact that these monkeys were quite expensive; especially for a not yet established young investigator. [They cost the then princely sum of about $7.00 apiece.] As for mice, while they could be bred for pennies apiece, other researchers were not able infect them via the usual practice of inoculating them under the skin or in the abdomen. However, Theiler took a cue from Pasteur’s inability to propagate the rabies virus in laboratory rabbits until he put the virus directly into their brains. Thus, in 1929 Theiler attempted to do the same with yellow fever virus in mice.

TheilerlMax Theiler

Theiler’s attempts to infect the mice by intracranial injection were a success. All of the inoculated mice died within several days. Surprisingly, the dead mice did not display the liver or renal pathology characteristic of yellow fever. Instead, the mice appeared to have succumbed to inflammation of their brains. Thus, the yellow fever virus appeared to be neurotropic in mice. Also, Theiler himself contracted yellow fever from one of his inoculated mice. He was fortunate to survive.

A fortuitous result of Theiler’s perilous bout with yellow fever was that he had become immune to the virus, as revealed by the presence of antiviral antibodies in his blood. Importantly, Theiler’s acquired immunity to the virus validated the possibility of developing an attenuated yellow fever vaccine. And, in a sense, Theiler was inadvertently the first recipient of the nascent vaccine he soon would be developing.

Theiler also determined that the virus could be passed from one mouse to another. And, while the virus continued to cause encephalitis in mice, it caused yellow fever when inoculated back into monkeys; quite a unique and striking set of findings. But, and crucially significant, while continued passage of the virus in mice led to its increased virulence in those animals, the virus was concurrently losing its virulence in monkeys. [In 1930, Theiler moved from the Harvard University School of Tropical Medicine to the Rockefeller Foundation’s Division of Biological and Medical Research. The Rockefeller Foundation shared facilities with the Rockefeller Institute (now University); although it was otherwise administratively separate from it.]

Since the mouse-passed virus was becoming attenuated in monkeys, Theiler’s belief in the possibility of generating an attenuated yellow fever vaccine was bearing out. However, because the mouse-passed virus remained neurovirulent in mice, Theiler was reluctant to inoculate that virus into humans. In an attempt to solve this problem, Theiler turned from passing the virus in the brains of live mice and, instead, began passing the virus in mouse tissue cultures.

Theiler carried out seventeen different sets of trials to further attenuate the virus. In the 17th of these, Theiler used the wild Asibi strain, isolated earlier by Mahaffy. Initially, this virus was extremely virulent in monkeys, in which it caused severe liver damage. But, after passing the virus from culture to culture several hundred times, over a period of three years, a flask labeled 17D yielded the virus that was to become the famous 17D yellow fever vaccine.

Theiler never gave a satisfactory accounting for the “D” in the “17D” designation, and for what, if anything became of A, B, and C. Regardless, the genesis of 17D was as follows. Theiler initially took an Asibi sample that had been multiplying in mouse embryo tissue and continued passing it in three separate types of minced chicken embryo cultures. One of these sets contained whole minced chicken embryos, and was designated 17D (WC). A second set contained chick embryo brain only, and was designated 17D (CEB). In the third set, the brains and spinal cords were removed from the otherwise whole chick embryo tissue cultures. This set, alone among all the sets, generated an attenuated virus that did not induce encephalitis when injected directly into monkey brains. Indeed, Theiler removed the central nervous systems from the chicken tissue in this set of cultures, in the express hope of generating just such an attenuated virus. And, by hook or by crook, the virus emerging from that particular set of passages became the vaccine that is now known simply as 17D.

Field tests of Theiler’s yellow fever vaccine were underway in 1937 in Brazil, and were successfully completed by 1940. In 1951 Theiler was awarded the Nobel Prize in Physiology or Medicine for developing the vaccine.

Next, we return to a point noted above, and discussed in two earlier postings. Neither Jonas Salk nor Albert Sabin were awarded Nobel prizes for developing their polio vaccines (1). And, Maurice Hilleman was never awarded a Nobel Prize, despite having developed nearly 40 vaccines, including those for measles, mumps, and rubella (2). Indeed, Max Theiler’s Nobel Prize for the yellow fever vaccine was the only Nobel Prize ever awarded for a vaccine! Why was that so?

Alfred Nobel, in his will, specified that the award for Physiology or Medicine shall be for a discovery per se; not for applied research, irrespective of its benefits to humanity. With that criterion in mind, the Nobel committee may have viewed the contributions of Salk and Sabin as derivative, requiring no additional discovery. [Hilleman’s basic discoveries regarding interferon should have been sufficient to earn him the award (2). The slight to him may have been because the Nobel committee was reluctant to give the award to an “industrial” scientist. Hilleman spent the major part of his career at Merck & Co.]

So, what was there about Theiler’s yellow fever vaccine that might be considered a discovery? Hadn’t Pasteur similarly developed an attenuated Rabies vaccine in 1885?

Perhaps the “discovery” was Theiler’s finding that passage of the Asibi strain of yellow fever virus in chick embryo cultures, which were devoid of nervous system tissue, generated attenuated yellow fever virus that was no longer neurovirulent in mice and monkeys. But, consider the following.

Theiler indeed believed that removing the brains and spinal cords from the chick embryo cultures in which 17D had been serially passed was the reason why the virus lost its neurovirulence. Nevertheless, as a serious scientist he needed to confirm this for himself. So, he repeated the long series of viral passages under the same conditions as before. But, this time, there was no loss of neurovirulence. Thus, a cause and effect relationship, between the absence of the brains and spinal cords from the tissue cultures and the emergence of non-neurovirulent virus, was not confirmed.

So, perhaps the Nobel committee merely paid lip service to the directives in Alfred Nobel’s will. In any case, Theiler’s 17D yellow fever vaccine has had a virtually unblemished safety record, and is regarded as one of the safest and most effective live-attenuated viral vaccines ever developed.

Theiler’s unshared 1951 Nobel award paid him $32,000. At the time, he resided in Hastings-on-Hudson; a village in Westchester County, NY, from which he commuted to the Rockefeller labs. Theiler’s next door neighbor in Hastings-on-Hudson was Alvin Dark, the star shortstop of the New York Giants. Nobel laureate Max Theiler was known to fellow commuters from Hastings-on-Hudson as the man who lives next door to Alvin Dark.

Virus Hunters, by Greer Williams (Alfred A, Knoff, 1960) was my major source for the material on Max Theiler.

1. Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science. On the blog.

2. Maurice Hilleman: Unsung Giant of Vaccinology. On the blog.