Tag Archives: poliomyelitis

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

The American media has been extensively covering the current West African Ebola outbreak. Consequently, the American public is anxious that the epidemic might spread to the United States; a worry likely fueled by Ebola’s horrible symptoms, which can include extensive internal and external bleeding (although not the liquefying of internal organs depicted in disaster movies), and by a fatality rate that has been as high as 90% in the developing world.

Yet aside from two American medical workers, Dr. Kent Brantly and missionary Nancy Writebol, who were infected in Africa, and returned to the United States for treatment at Emory University Hospital, no other Americans have been infected with Ebola. Moreover, public health experts, speaking through the media, have repeatedly assured the American public that the chance of an Ebola epidemic here at home is extremely slight. [One reason is that Ebola is not highly contagious, as it is transmitted only by direct contact with body fluids from an infected person. Moreover, infected individuals cannot transmit Ebola to others until they begin to express symptoms themselves. For these reasons, an Ebola outbreak in the United States should be quickly contained by isolating infected individuals. What’s more, supportive care in American hospitals would dramatically decrease the likelihood of any infection being fatal.]

Consider the following facts. By August 6, the current Ebola outbreak was estimated to have killed about 1,000 persons. The largest previous Ebola outbreak, which occurred in Uganda in 2000, claimed 244 lives, and Ebola has killed a total of about 2,000 people since it first emerged in 1976. All Ebola outbreaks occurred in Africa, and no Ebola infection has ever occurred in the United States. In each of the previous Ebola outbreaks, the virus ran its destructive course and then “disappeared.”

In contrast, consider that seasonal influenza claims on average about 40,000 lives annually in the United States alone, and 500,000 lives worldwide. And, the influenza virus reappears in a somewhat different immunological guise each and every year. Yet with the exception of those occasions when a seemingly exotic new influenza strain emerged (e.g., the H1N1 swine flu of 2009), the public seems rather indifferent to influenza. Indeed, even the 1918 influenza pandemic (which claimed 196,000 American lives in the single month of October, 1918, and 50,000,000 lives worldwide) did not cause any panic. And, despite the fact that a vaccine is available to prevent the flu, all too many individuals pass up that opportunity to protect themselves.

So, how might we account for the disparity between public apprehensions regarding an Ebola outbreak in Africa, versus public complacency regarding influenza here at home? Perhaps we simply take for granted that influenza will appear every year, and afterwards we forget about it. We even confuse influenza with the much less severe common cold, saying we have the flu, when we are merely experiencing the sneezes and sniffles of a cold.

We might think that the public is more worried by newer emerging viruses (e.g., West Nile virus, the SARS virus, and Ebola), than by actually more dangerous older ones (e.g., measles and influenza), at least in part because the newer viruses are relatively unfamiliar. Also, the current spate of post-apocalyptic movies, the 24-hour news coverage on cable television, and continuous commentary on social media, have each fostered public concern over new emerging infectious agents. But, that can’t be all, since it does not explain the intense fear that polio elicited in America until the Salk and Sabin polio vaccines appeared in the mid to late 1950s; decades before cable television and social media? I was a young teenager in the early 1950s, and remember well the panic that set in every summer when the newspapers reported the first polio cases of the season. What’s more, panic increased dramatically if a neighbor or schoolmate were stricken. You were kept home from school, and couldn’t even play outside. Yet the number of poliomyelitis cases was on average “only” about 20,000 per year, which was about half the average number of influenza fatalities. [The peak year for poliomyelitis was 1952, when there were 57,879 cases.]

So, how might we account for the difference in the public’s concern for polio, versus its relative lack of concern for influenza? A possible reason for the greater fear engendered by poliomyelitis was that the paralytic disease struck mainly children, adolescents and young adults, whereas influenza threatens mainly the elderly. People are usually much more emotionally invested in their children’s well being than in their parents or even themselves.

Yet the public did worry about influenza on occasions when a novel new influenza strain appeared (e.g., the H1N1 swine flu strain that emerged in 2009). Here is another situation in which influenza caused alarm. Unusual circumstances led to flu vaccine shortages in the United States during the winter of 2004/2005. When news of the vaccine shortage first broke in October 2004, there was panic as many individuals clamored for the limited vaccine dosages then available, which, as a matter of policy were being reserved for people at highest risk (e.g., the elderly and the immunologically compromised). But, as small numbers of extra doses began to trickle in from outside sources, demand for the vaccine suddenly disappeared. Indeed, there actually was a surplus, with many doses going to waste.

The outbreak of HIV/AIDS in the early 1980s was one of the defining moments of our time, and merits a longer posting of its own. In brief, because of the association of AIDS with human sexuality in all its forms, the media of that more prudish time had difficulty speaking openly and frankly about the disease. For instance, it used the term “body fluids” to avoid mentioning “semen,” leading to misinformation regarding how the then invariably fatal disease is transmitted. Also, AIDS was associated with intravenous drug abuse. That fact, together with homophobia, resulted in infected individuals (including hemophiliacs who were infected via the contaminated blood supply) being blamed for their illness, and there was blatant discrimination against them. About 15,000 Americans still die from AIDS each year.

The above examples, taken together, point up that the public’s response to infectious disease is shaped by a variety of factors. Furthermore, we might expect that as more and more people crowd into urban areas, and also intrude into once remote areas, new exotic viruses, as well as the older familiar ones, will continue to threaten the human population.

One final point: Whereas the American media has extensively discussed the risk (or non-risk) to Americans from the West African Ebola outbreak, it has barely mentioned America’s responsibility to the West African nations attempting to deal with the outbreak there. And aside from the moral issue, it is clearly in our own self interest to address an epidemic early, at its source, rather than to allow it to spread. [Donald Trump praised Brantly and Writebol for helping out in Africa, but argued that they should not be brought back for treatment because of the risk imposed. He said, “People that go that far away to help are great but must suffer the consequences!”]

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Opening Pandora’s Box: Resurrecting the 1918 Influenza Pandemic Virus and Transmissible H5N1 Bird Flu

The 1918 influenza pandemic killed an estimated 50 million people worldwide, making it the deadliest epidemic in human history. And despite the passage of nearly a century, a number of unexplained mysteries remain concerning the 1918 pandemic virus. A mystery important to our story is that the 1918 virus suddenly and inexplicably disappeared from the world in the early 1920s. And, since influenza virus was not even identified until the 1930s, no samples of the 1918 influenza strain were isolated at the time of the pandemic. Therefore, the 1918 pandemic virus did not exist in the world until it was “resurrected” nearly 80 years later by Jeffery Taubenberger and his colleagues, who used new, state-of-the-art molecular techniques to accomplish that feat.

More recently, in 2011, two independent research groups, one led by Yoshihiro Kawaoka and the other by Ron Fouchier, modified an H5N1 bird flu (see Aside 5) from a form that does not spread between humans, to forms that very well might. The unmodified avian virus has thus far infected only about 600 humans, in almost all instances by close contact with a diseased bird. But, and importantly, the avian virus killed more than half of the infected humans; a fatality rate far greater than that of even the 1918 pandemic virus. Thus, the resurrection of the 1918 pandemic virus, and the creation of transmissible H5N1 avian influenza, may have brought into the world pathogens with the potential to unleash extraordinary devastation.

These stories are compelling scientifically, historically, and for the public policy issues that they raise. As usual, we begin with some background.

The initial outbreak of the 1918 influenza pandemic occurred in March of that year, at an Army training camp outside of Boston. Yet by the fall of 1918 it was being referred to as the “Spanish” flu, probably because Spain, as a non-combatant in World War I, then in its final year, did not censor news of the pandemic. The combatants, on the other hand, fearing that news of the pandemic might cause panic that might undermine their war efforts, repressed news of it.

By the end of the winter of 1918-1919, two billion people around the world contracted the pandemic influenza strain and, as noted above, estimates of the total number of fatalities range as high as 50 million. That amount is about twice as many as would die of AIDS worldwide during the entire first twenty years of the AIDS epidemic. Moreover, the 1918 influenza pandemic killed more people in a single year than the four-year bubonic plague that ravaged Europe from 1347 to 1351. In the United States alone there were an estimated twenty million cases (out of a population of 100 million at the time) and 850,000 dead, including 196,000 people killed during the single month of October1918.

spanish fluRed Cross workers remove victims of the 1918 influenza pandemic from a house in St. Louis.      St. Louis Post-Dispatch

[Aside 1: Influenza virus pandemics also occurred in 1957 (the “Asian” flu) and 1968 (the “Hong Kong” flu). However, those pandemics were much less devastating than the pandemic of 1918. The number of deaths in the United States from those latter flu pandemics is estimated to be 70,000 and 50,000, respectively.]

Bearing in mind the sheer devastation of the 1918 pandemic, consider Taubenberger’s following comments from 1997: “It is curious that the (1918) pandemic doesn’t seem to be part of the cultural memory, at least in the United States, although it was a huge event with a huge impact. Everyone hears about the Black Death in the 1300s, yet here was an infectious disease only 85 years ago that killed 40 million people and for some reason we don’t know about it.”

It also is rather curious that while the 1918 influenza pandemic killed an astonishingly large number of people, it did not cause any public panic. Apropos that, in my last posting, Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science, I noted that the annual poliovirus outbreaks, in the pre-vaccine days of the 1940s and 1950s, did cause widespread public panic. Moreover, that was so despite the fact that poliomyelitis actually caused fewer fatalities than were caused by seasonal influenza, to which the public then and now seems rather indifferent.

Another of the mysteries associated with the 1918 pandemic is that the first cases in March 1918 were relatively benign. Then, in August, the mild infection suddenly changed into something astonishingly lethal. Initial outbreaks of the new lethal variant of the virus occurred almost simultaneously in three locations; France, Sierra Leone, and Boston, and then spread worldwide. The changed virus struck with a ferocity that stunned medical professionals.

Influenza’s genetic variability is a well known characteristic of the virus. [Indeed, it is the reason why the flu vaccine needs to be re-formulated each year.] Regardless, it is not clear how the 1918 pandemic virus suddenly became so deadly. Many of the fatalities resulting from our yearly seasonal influenza epidemics are due to pneumonia caused by opportunistic bacterial pathogens. And, while bacterial pneumonia also killed many during the 1918 pandemic, the 1918 virus itself was quickly lethal in many individuals. Some patients had massively hemorrhaged lungs, and were effectively drowning in their own blood; a scenario more reminiscent of the pathology of Ebola virus than of the fevers and aches typically associated with seasonal influenza infections.

Indeed, the 1918 pandemic virus was utterly unique in how quickly it could kill; literally overnight. There are anecdotes of people leaving for work in the morning feeling fine, and then succumbing on their way. One story tells of four women in a bridge group playing together until 11:00 in the evening. By morning, three of them had died.

Another puzzling feature of the 1918 virus was that it tended to kill the hale and hearty; individuals between the ages of 25 and 34, in the primes of their lives. In contrast, seasonal influenza epidemics cause the most fatalities in the elderly, the very young, the chronically ill, and people with weakened immunity.

The lower mortality rates among the elderly during the1918 pandemic is possibly explained by their prior exposure to an influenza strain serologically related to the 1918 pandemic virus, thus providing them with a measure of protective immunity against the pandemic virus. [On this point, and others related to the biology of influenza virus, see chapter 12 of Virology: Molecular Biology and Pathogenesis.]

The higher mortality rate among individuals between the ages of 25 and 34 is sometimes attributed to the fact that the pandemic occurred during the last year of World War I; a time when many individuals in this most susceptible group were living in crowded army camps, which predisposed them to the opportunistic bacterial infections responsible for many of the influenza fatalities in the pre-antibiotic era. Yet the virus itself was extraordinarily lethal, as noted above. Moreover, the “crowded army camp theory” can not explain why the same pattern of disease was seen in the populations of countries that did not participate in the war. So, these mysteries remain.

Recalling that the 1918 pandemic virus was absent from the world after the early 1920s, we now tell the story of Jeffery Taubenberger. In March of 1997, Taubenberger and his colleagues at the Armed Forces Institute of Pathology (AFIP) in Washington, D.C. startled virologists when they reported the sequence of the hemagglutinin (HA) gene of the 1918 pandemic virus. So, how was Taubenberger able to sequence the HA gene of a virus that was nonexistent for nearly 80 years?

[Aside 2: Influenza HA proteins are located in the viral envelope. They bind to the receptor on the target cell, and then promote fusion of the viral envelope with the plasma membrane of the target cell.]

[Aside 3: Jeffery Taubenberger is currently at the National Institute of Allergy and Infectious Diseases. The Armed Forces Institute of Pathology closed its doors in September 2011. It was founded in 1862 as a museum for specimens taken from American Civil War casualties. Over the years, the Institute’s specimen collection became legendary, and it became known for its role in diagnosing difficult civilian, as well as military cases. Moreover, its staff has included some of America’s greatest pathologists.]

Taubenberger was hired by the AFIP to create a state-of-the-art molecular pathology laboratory. Towards that end, his unit, which included molecular biologist Ann Reid, developed new procedures to recover nucleic acids from tissue samples that were fixed in formaldehyde and embedded in paraffin. Although pathologists routinely examine fixed tissues, molecular analysis of those specimens had not been possible, since the fixation can destroy nucleic acids.

Taubenberger’s initial involvement with influenza was not based on an interest in influenza per se. Instead, his intention was merely to showcase his Institute’s new procedures, and also its vast collection of specimens that had been assembled over the past century. With those purposes in mind, Taubenberger and Ann Reid put in a request for fixed tissue samples from soldiers who had succumbed during the 1918 flu pandemic.

Expecting a long wait, Taubenberger and Reid were themselves surprised when the Institute’s automated recovery system successfully retrieved their samples from the 3 million others in the AFIP collection, within a few seconds of receiving their request. The samples contained flecks of tissue from soldiers killed by the flu pandemic 80 years earlier. They were taken by doctors who, of course, had no knowledge at the time of what might be causing the soldiers’ illness.

Their interest now aroused, Taubenberger and Reid began to screen paraffin-embedded, formaldehyde-fixed patient specimens for influenza sequences, using then new, extremely sensitive molecular techniques (reverse- transcription polymerase chain reaction [RT-PCR] amplification of HA gene fragments). They hoped to increase their chance of success by focusing on specimens that showed severe lung disease. The rationale was that these samples would have come from victims who died quickly, before the virus might have cleared. [Influenza generally clears the lungs within days of the infection.] Regardless, they looked in vain for a year, until they came to a sample from Private Roscoe Vaughn, who died in September 1918 at Fort Jackson, SC., during the peak of the pandemic. In Private Vaughn’s fixed cells they found small segments of influenza-like RNA. Then, to be certain that these RNA segments were indeed from the 1918 pandemic virus, they resumed their search for positive samples until they found one from a soldier who died at Camp Upton, NY, also in September 1918. After thus confirming that their samples contained RNA segments from the actual 1918 pandemic virus, they were able to generate the complete sequence of it’s HA gene. Interestingly, the HA gene of the 1918 pandemic virus was unlike that of any other influenza HA gene that had been sequenced to date.

Having thus succeeded at reconstructing the HA gene of the 1918 virus, the next step would be to reconstruct its entire genome. However, from the very small amounts of tissue in the formaldehyde-fixed autopsy samples, Taubenberger doubted ever being able to do so. What follows is my favorite part of the story.

Dr. Johan Hultin, a 73-year-old retired pathologist, unexpectedly provided a solution to the AFIP group’s dilemma. Years earlier, in 1951, when Hultin was a graduate student at the University of Iowa, he attempted to grow live influenza virus from Alaskan Inuit victims of the 1918 pandemic, whose bodies remained buried in the Alaskan permafrost over the subsequent years. It was Hultin’s hope that the virus might have been preserved in those frozen victims. However, all his attempts to grow the virus were unsuccessful.

Hultin’s failure caused him to abandon his graduate studies and, instead, become a pathologist. Then, in 1997, after he was already retired, he happened to read the report from Taubenberger’s group describing how they reconstructed the HA gene of the 1918 pandemic virus. The report rekindled Hultin’s memories of his own earlier attempts in 1951 to grow the virus. Now, excited by his thought that the frozen bodies of the Alaskan victims might contain influenza genome fragments, from which it might be possible to reconstruct the entire genome, he wrote to Taubenberger, offering to return immediately to Alaska to obtain fresh specimens. Taubenberger agreed and, thus, Hultin eagerly returned to Alaska in 1997. There, he deliberately took tissue samples from a particularly obese woman, hoping that the combination of her fat and the permafrost might have preserved the influenza genomes. Hultin’s reasoning may indeed have saved the day, since Taubenberger’s group was able to generate the entire genome of the 1918 virus from these samples and, subsequently, to grow up the virus itself.

After Taubenberger and his co-workers successfully brought the 1918 pandemic virus “back to life,” they then tested its virulence in mice. Not surprisingly, the pandemic virus was extraordinarily lethal in the mouse model. However, the explanation for the exceptional virulence of the virus was not revealed by its genetic sequence per se. But, once the technology was available to recover gene sequences of the 1918 virus, it became technologically feasible to identify which genes of the 1918 virus accounted for its extreme virulence. Some readers may need to read the following brief aside to fully appreciate this part of the story.

[Aside 4: Most viruses contain all of their genes on a single chromosome. In contrast, the influenza genome is comprised of eight distinct single-stranded RNA segments. Five of these segments encode a single protein, while three of these segments encode two different proteins. The segmented nature of influenza genomes has important consequences in nature, as follows.

If a cell were simultaneously infected with two different influenza strains, then the genomic segments of the two strains might randomly re-assort to produce brand new strains. Indeed, this is precisely how pandemic strains are believed to arise in nature. In those instances, a human influenza genome re-assorts with the genome of a zoonotic virus, usually an avian one. In fact, the 1918 pandemic virus is at least partly avian in origin.]

Bearing in mind that influenza viruses contain segmented genomes (Aside 4), and that re-assortment of genomic segments between different strains occurs in nature, several research groups, each working independently, sought to determine which of the genomic segments of the 1918 pandemic virus might be responsible for its extraordinary virulence. In brief, it was possible to experimentally substitute each of the genomic segments of a benign influenza strain with the corresponding genomic segment of the 1918 pandemic virus. [The individual influenza gene segments were reverse transcribed and then inserted into individual plasmids. Recombinant viruses were then generated by microinjecting different combinations of these plasmids into cells in culture.] These viruses were then screened for their virulence in mice.

The results of these experiments showed that several different genes from the 1918 virus contributed to its virulence. These included the viral genes that encode two of the envelope proteins; the HA protein described above and the neuraminidase (NA), which promotes virus release from cells. The viral polymerase also contributed to its virulence.

An early hypothesis to explain the virulence of the 1918 pandemic virus was based on the contention that the virus acquired and expressed the HA gene, and perhaps the NA gene as well, of an avian influenza strain. Consequently, there might have been little if any immunity in the human population against the pandemic virus. However, Taubenberger’s group found that laboratory-generated recombinant viruses, which contained both the HA and the NA proteins of the 1918 pandemic virus, induced higher levels of inflammation in the mouse model than were induced by more benign influenza viruses. That is, the laboratory-generated recombinant viruses were actually more immunogenic than benign influenza strains. While this finding might not have been predicted, it actually is consistent with the extreme lung pathology seen in humans during the pandemic. At any rate, more research still needs to be done to better understand the virulence of the 1918 virus.

Taubenberger’s group also found some important differences between the viruses in samples from individuals infected early in the 1918 pandemic, when the virus was relatively benign, and the viruses in individuals infected after the virus became vastly more virulent. In the earlier cases, the HA protein was more like that found in avian influenza strains, while later cases had an HA protein somewhat more like that found in human influenza strains. Presumably, the avian HA gene underwent changes that adapted the virus to disseminate and spread more easily in its human host.

[Aside 5: There are 16 known serologically distinct types of the influenza HA protein in nature; only three of which, H1, H2, and H3 are found in human influenza strains. There are nine known serologically distinct types of the NA protein, of which N1, N2, and N3 are most commonly found in human strains. The 1918 pandemic virus was an H1N1 strain. Pandemic viruses generally arise when a current seasonal human strain acquires a new HA gene from an avian influenza. Other genes also may be acquired from the avian virus in addition to the HA gene. Thus, the 1957 Asian flu was H2N2, and the 1968 Hong Kong flu was H3N2. See the following aside.]

[Aside 6: In April 2009, a novel H1N1 virus (see the above aside), which originated in swine, was found in humans in the United States, Mexico, Canada, and elsewhere. Although this virus turned out to be relatively benign, its emergence caused widespread panic, due in part to the non-stop updates of new cases in the media, which created the false impression that a killer pandemic was sweeping through the country.

In May, 2009, Vice President Joe Biden told a national TV audience that he would tell members of his own family not to go anywhere where they might be in a confined space, such as an airplane, subway or classroom. But, in fairness to Biden and the media, it was net yet clear that the virus was relatively mild.

Initially, the virus was referred to as the swine flu. But, Biden’s boss, President Barack Obama, in deference to the U.S. pork industry (people were afraid they might catch the virus by eating pork), began to deliberately call this virus “the H1N1 virus.” The new designation stuck. And while it does characterize the 2009 swine flu, it likewise characterizes the vastly more lethal 1918 pandemic virus, as well as a current seasonal influenza strain. Thus, the 2009 virus was hardly the H1N1 virus.

The world was of course fortunate that the 2009 H1N1 swine flu outbreak turned out to be relatively mild. Many millions of people might have been killed. Will the public remember the episode and, consequently, be complacent in the face of a future outbreak, doubting the credibility of government warnings?]

An earlier influenza outbreak, which indeed startled virologists, took place in 1997, when the first cross-species transmission of an avian H5N1 influenza to a human was documented. The patient, a child succumbed, and there were additional lethal human infections that followed. Indeed, the H5N1 virus killed about half of the individuals it infected; a fatality rate far greater than that of even the 1918 pandemic virus. Fortunately, during the past 17 years, the virus has not adapted to spread readily from person to person. Instead, the vast majority of the 600 humans, who were estimated to have been infected, acquired the virus by close contact with diseased birds.

Next, in September 2011, Yoshihiro Kawaoka at the University of Wisconsin and Ron Fouchier of Erasmus Medical Center in Rotterdam, shocked virologists when they announced that they and their colleagues had created variants of the H5N1 virus that could be transmitted between ferrets; often considered a good model for transmission in humans. What’s more, Fouchier’s group deliberately modified the virus so that it might be transmitted through the air; a very significant modification, since transmission of avian influenza viruses between their avian hosts is via the fecal-oral route, whereas mammalian influenza viruses are transmitted via the respiratory route.

Kawaoka’s group randomly mutated the HA gene of the H5N1 virus, until they found mutations that caused it to attach to human receptors, instead of to bird receptors. Then, they replaced the HA gene from the 2009 H1N1 “swine flu” strain (Aside 6) with the mutated H5 HA gene, thereby creating a virus that contained the mutated avian HA gene, and the remaining genes from the 2009 H1N1 virus. In contrast, Fouchier’s group examined the possibility that the H5N1 virus might acquire the ability to transmit via the respiratory route by mutation alone; without re-assortment. They began by giving the H5N1 virus three mutations previously identified in the HA genes of the 1918, 1957, and 1968 pandemic viruses.

Fouchier’s virus indeed was lethal in ferrets. In contrast, Kawaoka’s virus did not kill the animals, and was no more pathogenic in ferrets than the 2009 H1N1 swine virus. But, recombinant viruses that that arise in nature might have unpredictable and very different pathogenicities. And, bear in mind that both research groups in fact demonstrated that H5 avian viruses might acquire the ability to infect mammals.

Now, consider that the resurrected 1918 pandemic virus is essentially identical to the virus that claimed up to 50 million lives during the 1918 pandemic. Moreover, consider that up to now H5N1 viruses have not been able to readily transmit between humans. But, if either of the H5N1 viruses developed in Wisconsin and Rotterdam is indeed transmissible between humans, while retaining a measure of its virulence, it might be even more life-threatening than even the 1918 pandemic H1N1 virus.

In view of the above, one may well ask what reasons could possibly justify creating such potentially dangerous viruses. A common rationalization is that these experiments provide insights into the genetic changes that might happen in nature to generate deadly pandemic viruses. A potential benefit of that knowledge might then be to enable surveillance against the emergence of such viruses, thus providing a window of opportunity to develop strategies to cope with the threat and minimize its consequences.

But regardless of the possibly enormous benefits that might result from the types of experiments described above, one could easily imagine important arguments against doing these experiments. Clearly, resurrecting the 1918 pandemic virus brought an extremely deadly pathogen back to life. And, the experiments in Rotterdam and Wisconsin may likewise have given rise to very lethal viruses. Moreover, the accidental release of these viruses, even from the most secure facility, is not all far-fetched. In this regard, in 2003 and 2004 the SARS virus “escaped” from three different Asian laboratories. Furthermore, while these experiments might be done safely in a very few laboratories in the United States and Europe, there is no global mechanism to insure that they would be done safely elsewhere. What’s more, there is concern that terrorist groups might gain possession of these viruses, or perhaps even replicate the work that gave rise to them.

So what is the bottom line? The issue is not simply whether the research is dangerous. It clearly is. And, the issue is not simply whether the research holds the promise of real and important benefits. While some potential benefits may have been overstated, they yet may one day be considerable. Thus, the real question is whether the potential benefits of the research outweigh its here-and-now risks. Experts have taken opposite positions on this question, and a heated debate goes on.

Yet a new issue arose with regard to the H5N1 experiments; specifically, whether or not the work ought to be reported in scientific journals. This issue arose over concern that the transmissible H5N1 variants might fall into the hands of individuals or groups with evil intentions or, perhaps, even be made by them. Consequently, in December 2011, the U.S. National Science Advisory Board for Biosecurity (NSABB) made the unprecedented recommendation to censor the papers that reported the work of the Rotterdam and Wisconsin groups. The papers were, at the time, under review at Nature and Science. The NSABB worried that publication of “the methodological and other details could enable replication of the experiments by those who would seek to do harm.” Thus, the NSABB recommended that the general conclusions of the papers, but not their methodologies, might be published. Later, in February 2012, a World Health Organization committee recommended that the studies be published in full.

As might be expected, there is no consensus in the scientific community over this censorship issue. On the one hand, constraints on communication are inherently incompatible with free scientific inquiry and would hinder progress in a field that significantly impacts human health. Moreover, would scientists devote years to investigating dangerous viruses, only to have their work censored in the end? On the other hand, should not the scientific community bear at least some responsibility for keeping the fruits of its research from being misused by those who would do harm? Few scientists would prefer to have individuals who are not practicing scientists, and who don’t always understand the science, making these judgments in their place. [I find it interesting that these other individuals are often referred to as bioethics, biosecurity, or bioterror “experts,” and wonder what makes them so.]

References

Herfst S, Schrauwen EJ, Linster M, Chutinimitkul S, de Wit E, Munster VJ, Sorrell EM, Bestebroer TM, Burke DF, Smith DJ, Rimmelzwaan GF, Osterhaus AD, Fouchier RA. 2012. Airborne transmission of influenza A/H5N1 virus between ferrets. Science 336:1534-1541.

Imai M, Watanabe T, Hatta M, Das SC, Ozawa M, Shinya K, Zhong G, Hanson A, Katsura H, Watanabe S, Li C, Kawakami E, Yamada S, Kiso M, Suzuki Y, Maher EA, Neumann G, Kawaoka Y. 2012. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature 486:420-428.

Taubenberger JK, Reid AH, Krafft, AE, Bijwaard, KR, and Fanning TG. 1997. Initial genetic characterization of the 1918 “Spanish” influenza virus. Science 275:1793-1796.

 

Jonas Salk and Albert Sabin: One of the Great Rivalries of Medical Science

Paralytic poliomyelitis was one of the world’s most feared diseases during the first half of the 20th century. However, the dread of poliovirus ended abruptly with the advent of the poliovirus vaccines in the 1950s. This posting tells the stories of the key players in the race to develop a polio vaccine. In particular, it features the rivalry between Jonas Salk and Albert Sabin, the two main contenders in the pursuit. While their vaccines together have led to the near disappearance of poliovirus worldwide, neither was recognized by the Nobel committee for his achievement. We begin with some background.

Poliovirus has long been especially interesting to me, both as a virologist and personally as well. The reason is that I was a child and young teenager during the annual polio epidemics of the 1940s and early 1950s, and can vividly remember the panic that set in early every summer of the pre-vaccine days, when the first neighbor or schoolmate was stricken. You were kept home from school and couldn’t even play outside. A visit to a hospital in those times was associated with the pitiful sight of young polio victims in the iron lungs that filled the wards, and even the hallways of hospitals back then.

iron lung

Not even the emergence of AIDS in the early 1980s evoked fear comparable to that brought on by poliomyelitis. Yet despite the dread of poliomyelitis, the disease actually struck many fewer victims than was commonly perceived by the public. The number of poliomyelitis cases in the United States was typically 20,000 to 30,000 per year in the 1940s and 1950s, while influenza still typically kills 40,000 to 50,000 Americans annually. Yet most individuals, then and now seem indifferent to influenza. What’s more, even the 1918 “Spanish Flu” epidemic, which was arguably the most devastating epidemic in human history, did not cause any panic, despite the fact that during the single month of October 1918, it killed 196,000 people in the United States alone! Estimates of the total number killed worldwide by the 1918 Spanish Flu range between 20 million and 50 million.

So, how can we explain the terror brought on by poliomyelitis? It wasn’t simply because poliovirus struck suddenly, without any warning. So did the “Spanish Flu.” Rather, paralytic poliomyelitis mainly struck children, adolescents and young adults. In contrast, influenza mainly threatens the elderly. And, in truth, most parents are far more emotionally invested in their children’s well-being than in that of their parents or themselves. Furthermore, the sight of a child in an iron lung or leg braces (affected legs became atrophied and deformed) was truly heart rending.

The fear evoked by poliomyelitis was permanently ended in the United States and in much of the developed world as well, by the emergence of Salk’s killed polio vaccine in 1955. Sabin’s live attenuated vaccine followed soon after. [Live vaccines generally contain attenuated (weakened) variants of the virulent virus, which can replicate and induce immunity, but which cannot cause disease.] The response of the public to Salk’s vaccine was so great that he was hailed as a “miracle worker.” Nevertheless, and despite the fact that the vaccines created by Salk and Sabin have nearly ridden the world of poliovirus, neither man would ever be recognized by the Nobel committee.

salk Salk’s public acclaim was resented by his colleagues.

Most virologists of the day strongly favored live vaccines over killed ones, based on the belief that only a live vaccine could induce a level of immunity sufficient to protect against a challenge with live virulent virus. Indeed, the effectiveness of live vaccines had been established much earlier by Jenner’s smallpox vaccine (1798) and Pasteur’s rabies vaccine (1885). Jenner’s smallpox vaccine actually contained live cowpox virus, which was similar enough immunologically to variola to protect against smallpox, while not being able to cause smallpox itself. Pasteur’s rabies vaccine contained live rabies virus that was attenuated by passages through rabbit spinal cords. [Adapting the virus to grow in rabbits attenuated its virulence in humans, while not impairing its ability to induce immunity.] So, bearing in mind the well-established precedence of attenuated vaccines, why did Salk seek to develop a killed vaccine?

In 1941, Thomas Francis, one of the great pioneers of medical virology, working at the University of Michigan, developed a killed influenza vaccine. Providentially, in the same year, Jonas Salk (recently graduated from NYU medical school) came to Francis’ laboratory for postgraduate studies. In Francis’ lab, Salk learned his mentor’s methods for producing his killed influenza vaccine and assisted in its field trials.

Salk’s experience in Francis’ laboratory led him to believe in the potential of a killed poliovirus vaccine. And, Salk learned practical procedures from Francis that would be valuable in his pursuit of that objective. These included the use of formaldehyde to kill the virus, the use of adjuvants to enhance the immunogenicity of the killed vaccine, and protocols for conducting field tests.

In contrast to Salk, Sabin firmly believed that a live attenuated vaccine would be vastly superior to a killed one. And, although Salk won the race to produce an actual vaccine, Sabin had been doing polio research well before the younger Salk emerged on the scene. Indeed, Sabin made several important contributions to the field; some of which are discussed below. For now, we mention that in 1936, Sabin and colleague Peter Olitsky demonstrated that poliovirus could be grown in cultured human embryonic nervous tissue. While this might appear to be a key step towards the development of a vaccine, Sabin and Olitsky feared that nervous tissue might cause encephalitis (inflammation of the brain and spinal cord) when injected into humans.

sabinAlbert Sabin, who developed the live polio vaccine.

John Enders, at the Children’s Hospital of Boston, is the next key player in our story. Enders believed that poliovirus should be able to grow in non-nervous tissue, particularly tissue from the alimentary canal, as suggested to him by the amount of the virus that was present in the feces of many patients. So, in 1948, Enders, and colleagues Thomas Weller and Frederick Robbins, succeeded in growing poliovirus in cultured non-nervous tissue, including skin, muscle, and kidney. As a result of Ender’s work, sufficient amounts of poliovirus could now be grown, free from the hazards of nervous tissue, thereby enabling the mass production of a vaccine.

[Aside: Enders, Weller, and Robbins maintained their tissue samples in culture using the roller culture procedure, in which a horizontally positioned bottle is laid on its side and continuously rotated around its cylindrical axis. In comparison to the older process of growing tissues in suspension, the roller culture method enabled the prolonged maintenance of the tissues in an active state and, consequently, the growth of large amounts of virus. For readers who read Renato Dulbecco and the Beginnings of Quantitative Animal Virology (on the blog), note that Dulbecco developed procedures for growing pure cell types as flat adherent monolayer cultures, thereby making possible quantitative plaque assays of animal viruses.]

In 1954, Enders, Weller, and Robbins shared the Nobel Prize in Physiology or Medicine for their contribution described above. What’s more, the Nobel award to Enders, Weller, and Robbins was the only Nobel award ever given in recognition of polio research! Ironically, Ender’s true interests actually lay elsewhere; with measles. He would later develop a measles vaccine. [Enders has been referred to as the “Father of modern vaccinology.”]

The next key player of note in our story is not a person but, rather, a foundation; the “National Foundation for Infantile Paralysis,” which led and financed the crusade against polio in the pre-NIH days of the 1950s. The National Foundation was actually an outgrowth of the Georgia Warm Springs Foundation, a charitable organization founded by Franklin D. Roosevelt, himself crippled by polio. However, after Roosevelt became president of the United States, he was too polarizing a figure (particularly after his “court-packing” scheme in 1937) to head up a philanthropic organization. Consequently, in 1938, Roosevelt announced the formation of the nonpartisan National Foundation for Infantile Paralysis.

roosevelt Photos of Franklin Roosevelt in a wheel chair are rare and were not shown to the public, which was generally unaware that he was paralyzed from the waist down.

[Aside: The National Foundation was initially funded by the contributions of wealthy celebrities who attended Roosevelt’s yearly birthday bashes. At one of these fundraisers, the vaudevillian, Eddie Cantor, jokingly urged the pubic to send dimes directly to the president. And, bearing in mind the fear evoked by polio, the public, perhaps not recognizing the joke, did exactly that, flooding the White House with nearly three million dimes. And so, the slogan “March of Dimes,” for the Foundation’s grass-roots fund-raising campaign, came to be. And, it was not coincidental that a dime (the Roosevelt dime) was issued in 1946 to memorialize the late president.

In 1950, a March of Dimes chapter in Phoenix, Arizona held a “Mother’s March on Polio,” in which volunteers went door-to-door raising money for polio research. People were urged to leave their porch lights on to show that the volunteers would be welcome. The Phoenix initiative soon spread to other locals, and the Mother’s March became a nationwide annual event.]

The role of the National Foundation went beyond merely raising money for research. It also attempted to provide direction to the research, which often placed it at odds with its grantees. This was the case because Harry Weaver, the director of research at the National Foundation, was focused on bringing a vaccine to the public. In contrast, most of the Foundation’s grantees were largely motivated by their desire to understand basic virological issues, such as poliovirus transmission, replication, and dissemination. What’s more, they believed that there was still too much to be known about poliovirus and poliomyelitis before a vaccine might be a realistic possibility.

[Aside: Apropos the sentiment of some poliovirus researchers that there was too much yet to be known before a polio vaccine might be possible, Jenner’s 1798 smallpox vaccine was developed a half century before the germ theory of disease was proposed, and 100 years before the actual discovery of viruses. It was based on the empirical observation that milkmaids seemed to be “resistant” to smallpox; apparently because they had been exposed earlier to cowpox. The initial smallpox vaccine simply contained matter from fresh cowpox lesions on  the hands and arms of a milkmaid. It was then serially passed from one individual to another; a practice eventually ended because of the transmission of other diseases. And, Pasteur’s 1885 rabies vaccine too was developed before viruses were recognized as discrete microbial entities.]

Sabin’s objection to the Foundation’s priority of having a vaccine available as quickly as possible was somewhat more personal. Since a killed vaccine should be more straightforward and, therefore, quicker to develop than an attenuated one (see below), Sabin believed that Weaver’s sense of the urgent need for a vaccine would lead him to favor supporting Salk’s killed vaccine over his attenuated one. Moreover, Sabin felt that he was being shunted aside. And, Since Sabin remained firm in his belief in the superiority of a live vaccine; he also felt that Weaver’s main concern of having a vaccine available as quickly as possible, would compromise the efficacy of the vaccine that would be implemented in the end.

[Aside: Back in the Enders laboratory, Thomas Weller and Frederick Robbins wanted to enter the polio vaccine race. But, Enders viewed the project as boring and routine; a view pertinent to the question of why Salk and Sabin were never recognized by the Nobel Committee. Furthermore, Enders didn’t believe that a killed vaccine could ever provide adequate protection against polio, or that a live vaccine would be possible without years more of research.]

Sabin’s worry that a killed vaccine would be faster to develop than an attenuated one was borne out when, in1953, Salk was preparing to carry out a field-test of his killed vaccine. Yet Sabin and other poliovirus researchers remained inclined to move slowly, placing them in opposition to Harry Weaver’s sense of urgency. Moreover, Sabin and the other polio investigators were also piqued at the National Foundation for promoting Salk’s vaccine to the public and, also, for promoting Salk himself as a miracle worker. The Foundation’s reason for publicizing Salk was to stir up public enthusiasm for its fund raising campaigns. And Salk indeed was becoming the symbol of the miracles of medical research to an admiring public.

In fairness to the polio researchers who dissented with the National Foundation’s single minded emphasis on bringing a vaccine to the public, there were valid reasons for believing that the Foundation might be moving too quickly. So, consider the following excerpts from a letter that Sabin wrote to his rival, Salk: “…this is the first time they (the Foundation) have made a public statement based on work which the investigator has not yet completed or had the opportunity to present…in a scientific journal…Please don’t let them push you to do anything prematurely or to make liters of stuff for Harry Weaver’s field tests until things have been carefully sorted out, assayed, etc., so that you know what the score is before anything is done on a public scale.”

While Sabin’s advice to Salk seems eminently sensible, Sabin had never before shown any inclination to look out for Salk’s interests. So, might Sabin be sending a non-too-subtle warning to Salk that he could either play by the traditions of the scientific community, or face the consequences of playing to the interests of the Foundation? For his part, Salk was well aware of what was happening and he was indeed embarrassed by the adulation of the press; correctly sensing that it was compromising his standing with his colleagues.

[Aside: The media, in the person of the legendary broadcaster, Edward R. Murrow, provided Salk with a notable and very satisfying moment in the public spotlight. During an April, 1955 interview on the CBS television show See it Now, Murrow asked Salk: “Who owns the patent on this vaccine?” To which, Salk replied: “Well, the people, I would say. There is no patent. Could you patent the sun?”

While Salk’s answer to Murrow endeared him even more to the public, some colleagues questioned whether it might have been disingenuous. Both the University of Pittsburgh, where Salk carried out his work, and the National Foundation, which financed it, indeed had been looking into the possibility of patenting Salk’s vaccine. But, when patent attorneys sought to determine if there was a basis for a patent, Salk readily acknowledged that his vaccine was, for the most part, based on tried and true procedures developed by others.

In point of fact, Salk’s critics held him in low esteem largely because there was little about his vaccine that was innovative. Indeed, Sabin once quipped: “You could go into the kitchen and do what he (Salk) did.” But in fairness to Salk, he never claimed that his vaccine was unique. Instead, in the face of much skepticism, his point had always been that a killed vaccine could protect against polio. He persevered and he was right.

Note that Sabin too gave his vaccine to the world gratis.]

By 1954, field tests of Salk’s vaccine went ahead on a massive scale, involving nearly 1.5 million schoolchildren nationwide. The tests were overseen by Thomas Rivers, an eminent virologist who, at the time, was Director of the Rockefeller Institute. Like most virologists, Rivers favored a live vaccine as the ultimate solution to polio. Nevertheless, he believed that the world couldn’t wait ten or more years for an ideal vaccine, when a satisfactory one might be available at present.

With 57,879 cases of poliomyelitis in the United States in 1952, the peak year of the epidemic, Harry Weaver’s sense of the urgent need for a vaccine was widely shared by the public. Unsurprisingly then, the public eagerly supported the 1954 field test of Salk’s vaccine, as indicated by the fact that 95% of the children in the test received all three required vaccinations. [Killed vaccines require multiple doses. That is so because the first dose only primes the immune system. The second or third dose then induces the primed immune system to produce protective antibodies against the virus. Inoculation with a live vaccine resembles a natural infection and, consequently, a single dose is sufficient to induce immunity.]

The field test of Salk’s vaccine was unprecedented in its size. What’s more, it was supported entirely by the National Foundation, which strenuously opposed outside interference from the federal government. In actuality, the Foundation considered federal funding for polio research to be a “Communistic, un-American…scheme.”

[Aside: President Dwight Eisenhower, a Republican and a fiscal conservative, also believed that the federal government had no proper a role in health care. Consequently, Eisenhower took little interest in his Department of Health, Education, and Welfare (HEW). What’s more, Eisenhower’s Secretary of HEW, Oveta Culp Hobby, was even more conservative in that regard than Eisenhower himself. In 1955, after the field trials showed the Salk vaccine to be a success, and with the public clamoring for it, there were insufficient amounts of the vaccine available to meet the public’s demands. Thus, even some Republicans were stunned to learn that the Eisenhower administration had taken no actions whatsoever to watch over production of the vaccine or its distribution, believing that this was in the province of the drug companies. When pressed on this, Mrs. Hobby responded: “I think no one could have foreseen the public demand.”

Not surprisingly, American drug companies lobbied intensely to keep vaccine production under their own control. A different scenario played out in Canada, where the government viewed polio as a national crisis, and took control of its vaccination program, with overwhelming public support.]

All did not go well for Salk and his vaccine after the successful 1954 field tests. In April 1955, more than 200,000 children were inoculated with a stock of improperly inactivated vaccine made by Cutter Laboratories; one of the five companies that produced the vaccine in 1955. [The others were Eli Lilly, Parke-Davis, Wyeth, and Pitman-Moore.] The Cutter vaccine caused 40,000 cases of abortive poliomyelitis (a form of the disease that does not involve the central nervous system), and 56 cases of paralytic poliomyelitis; 5 of which were fatal. What’s more, some of the children inoculated with the Cutter vaccine transmitted the vaccine virus to others, resulting in 113 more cases of paralytic poliomyelitis and 5 fatalities.

A congressional investigation blamed the “Cutter incident” on the NIH Laboratory of Biologics Control, for insufficiently scrutinizing the vaccine producers. In point of fact, the NIH did little testing on its own. Instead, it mainly relied on reports from the National Foundation, whose agenda was to proceed with the vaccinations. Yet the NIH did have an early, in-house warning of potential problems with the Cutter vaccine, which it failed to act on. Bernice Eddy, a staff microbiologist at the NIH, reported to her superiors that the Cutter vaccine caused paralysis when inoculated into monkeys. However, no action was taken in response to Eddy’s warning. [In 1959, Eddy discovered simian virus 40 (SV40) in monkey kidney tissue that was used for vaccine production. By that time, live SV40 had unknowingly been injected into hundreds of millions of people worldwide; perhaps the subject of a future blog posting.]

Salk was exonerated of any fault in the Cutter incident. Moreover, after that episode, not a single case of polio in the United States would be attributed to Salk’s vaccine. Nevertheless, while Salk’s killed vaccine was perfectly safe when properly prepared, the Cutter incident led to the perception that it was unsafe. Consequently, Salk’s killed vaccine was eventually replaced by Sabin’s live attenuated one. Ironically, as we will see, the perception that Salk’s vaccine was dangerous led to its replacement by a more dangerous one.

Sabin’s work on his live polio vaccine began in 1951 and, like Salk; he was supported by the National Foundation. Sabin’s task was more difficult than Salk’s because it is more straightforward to kill poliovirus, than it is to attenuate it. [The attenuated virus must be able to replicate in the digestive tract and induce immunity, yet be unable to damage the nervous system.] But Sabin persisted, sustained by his conviction that a live vaccine would invoke stronger, longer-lasting immunity than a killed vaccine. Sabin attenuated his vaccine by successive passages through monkey tissue, until the live virus could no longer cause paralysis when inoculated directly into chimpanzee spinal cords.

[Aside: At this early date, live-vaccine-proponents could not have known that only a live vaccine could activate T-cell mediated immunity, which is generally necessary to clear a virus infection. Instead, their preference for live vaccines was based on the simpler, but correct notion that inoculation with a live vaccine would more closely approximate a natural infection. Also, since the vaccine virus is alive, vaccinated individuals might transmit it to unvaccinated ones, thereby inducing immunity in the latter as well. On the other hand, the attenuated vaccine poses a deadly threat to individuals with impaired immune systems, such as AIDS patients and individuals on immunosuppressive regimens following organ transplants.]

In 1954, a successful small-scale test of Sabin’s vaccine was carried out, which involved thirty adult human prisoners at a federal detention facility. The promising outcome of this test warranted a larger field-trial of Sabin’s vaccine. But, several obstacles stood in the way. First, the National Foundation was not inclined to support another massive field trial, now that Salk’s vaccine was already in use. Second, the Foundation was still reeling from the Cutter incident, and had no inclination to be caught up in another such debacle. Third, it would be virtually impossible to conduct the trials in the United States, since millions of American children had already been inoculated with Salk’s vaccine. The ensuing course of events was rather remarkable.

By 1956, poliomyelitis had become a serious public health crisis in the former Soviet Union. Consequently, a delegation of Russian scientists came to the United States to meet with Salk and consult with him on how to produce his vaccine. However, the Russians were disposed to meet with other polio researchers as well. Thus, Sabin seized this opportunity to invite the Russians to visit his laboratory at the University of Cincinnati, where he was able to tout his live vaccine to them. Sabin’s pitch was apparently effective, as he secured an invitation from the Russians to visit the Soviet Union, where he spent a month, further hyping his vaccine.

[Aside: While Sabin was in Russia, the Russians requested from him a sample of his live vaccine. So, when Sabin returned to the United States, he sought permission from the State Department to send the Russians the samples they requested. The State Department approved the request; but it did so over objections from the Defense Department, which was concerned that the vaccine virus might have “biological warfare applicability.”]

With the incidence of poliomyelitis on the rise in the Soviet Union, the Soviet Health Ministry needed to quickly decide which vaccine to adopt; Salk’s or Sabin’s. The Russians were already producing the Salk vaccine, but were unable to consistently maintain its efficacy from one batch to another. So, the Soviets invited Salk to visit Russia, so that he might help them to solve the problems they were having producing his vaccine.

Salk then made a decision that he would long regret. Because of pressure from his wife to spend more time with his family, Salk turned down the Russian invitation. The upshot was that the Russians turned instead to Sabin. In 1959 they vaccinated 10 million children with vaccine strains sent to them by Sabin. Soviet results with the Sabin vaccine were so promising that the Soviet Health Ministry decided to then use it to vaccinate everyone under 20 years of age. A total of seventy-seven million Soviet citizens were vaccinated with Sabin’s vaccine, vastly exceeding the number vaccinated during field trials of the Salk vaccine in the United States.

The U.S. Public Health Service did not endorse the Sabin vaccine for use in the United States until 1961. By then, the Salk vaccine had virtually eliminated polio from the country. Nevertheless, Sabin’s vaccine supplanted Salk’s in the United States and in much of the rest of the world as well.

Yet all did not go well with Sabin’s vaccine either. As noted above, after the Cutter incident, there were no cases of poliomyelitis in the United States that could be attributed to Salk’s vaccine. In contrast, Sabin’s vaccine caused about a dozen polio cases per year, a frequency of about one case per million vaccinated individuals. At least some of these cases resulted from the ability of the attenuated virus to revert to a more virulent form. What’s more, reverting viruses posed a threat to non-vaccinated individuals in the population. For instance, in 2000/2001, there were 21 confirmed cases of poliomyelitis in the Dominican Republic and Haiti, which were traced to a single dose of the Sabin vaccine that was administered during the preceding year. [As noted in an above Aside, since the Sabin vaccine is alive, vaccinated individuals might transmit the vaccine virus to unvaccinated individuals.]

In actual fact, the few cases of poliomyelitis that now occur in the West are vaccine-related, resulting from the rare reversions of Sabin’s vaccine. Ironically, the Sabin vaccine, which played a crucial role in the near eradication of polio from the world, had become an obstacle to the complete eradication of the virus. In 2000, the U.S. Centers for Disease Control (CDC) recommended the complete return to the Salk vaccine in the United States. However, the Sabin vaccine would continue to be used in much of the developing world.

[Aside: Several polio hotspots remain in the world. Three major ones are Pakistan, Afghanistan, and Nigeria. Recent outbreaks have also occurred in Syria and Somalia. In each of these instances, social and political climates make it difficult to carry out eradication campaigns.

As recently as March 2014, militants attacked a polio vaccination team in northwest Pakistan, detonating a roadside bomb and then opening fire on their convoy, killing 12 of their security team, and wounding dozens more. Some Pakistani religious leaders denounced the vaccination campaign in Pakistan as a cover for spying or as a plot to sterilize Muslim children.

In the developed world there is a very different problem. Ironically, the great success with which the polio vaccines eradicated the virus in the West has created conditions there in which poliomyelitis might make a most unwelcome return. That has come about because too many parents in the developed world now view polio as ancient history, and have become complacent about having their children vaccinated. What’s more, some parents are heeding unsubstantiated warnings that the risks of vaccines are greater than the risks of the viruses. Consequently, the frequency of vaccinated individuals in the West is declining to the point where the West may be susceptible to outbreaks sparked by imported cases. These issues will be discussed at length in a subsequent posting.]

We turn now to an issue raised at the outset of this posting; neither Salk nor Sabin was recognized by the Nobel Committee for his contribution. That is so, despite the fact that their individual efforts, taken together, have virtually eliminated polio from the world.

Max Theiler, at the Rockefeller Institute, is relevant regarding the Nobel issue, and for several other reasons as well. First, Theiler took an early interest in Sabin’s career during Sabin’s years at the Rockefeller (1935 to 1939). Second, during those years Theiler was working on a live attenuated vaccine for yellow fever. Like most virologists of the day, Theiler believed that only a live vaccine could provoke significant long-lasting immunity. And, Theiler’s thinking on this matter likely influenced Sabin’s later approach to a polio vaccine. Thirdly, and important in the current context, in 1951 Theiler was awarded the Nobel Prize in Physiology or Medicine for his yellow fever vaccine. Fourth, Theiler’s Nobel Prize was the only one ever awarded for the development of a virus vaccine!

Why was Theiler’s Nobel award the only one ever given for the development of a virus vaccine? In addition, recall that John Enders, Thomas Weller, and Frederick Robbins shared the 1954 Nobel Prize for Physiology or Medicine, for demonstrating that poliovirus could be propagated in non-nervous tissue. Moreover, the Nobel Prize shared by Enders, Weller, and Robbins was the only one ever given in recognition of polio research! Why weren’t Salk and Sabin recognized as well? Didn’t they also contribute substantially “to the benefit of mankind;” a standard for the award, as specified by Alfred Nobel?

Apropos these questions, it may be relevant that Alfred Nobel also specified that the prize for physiology or medicine should recognize a “discovery” per se. With that criterion in mind, the Nobel committee may have viewed the contributions of Salk and Sabin as derivative, requiring no additional discovery. In contrast, the discovery of Enders, Weller, and Robbins, refuted the previously held belief that poliovirus could be grown only in nervous tissue; a breakthrough that paved the way to the vaccines.

But then, what was there about Theiler’s yellow fever vaccine that might be considered a discovery? Hadn’t Pasteur developed an attenuated Rabies vaccine in 1885? And, what of Jenner’s earlier 1798 smallpox vaccine, comprised of live cowpox virus?

To the above points, Sven Gard, at the Karolinska Institute, and a member of the Nobel committee for Physiology or Medicine, wrote the following in his evaluation of Theiler’s prior 1948 Nobel nomination: “Theiler can not be said to have been pioneering. He has not enriched the field of virus research with any new and epoch-making methods or presented principally new solutions to the problems, but he has shown an exceptional capacity to grasp the essentials of the observations, his own and others, and with safe intuition follow the path that led to the goal.”

Despite the seeming inconsistency between Gard’s comments and Nobel’s instruction that the prize be awarded for a discovery, Gard nonetheless concluded that Theiler’s contributions indeed merited the Nobel award. [Incidentally, Theiler’s 1948 Nobel nomination was a detailed six-page-long document, written and submitted on his behalf by Albert Sabin!]

To the same point, Hilding Bergstrand, also at the Karolinska Institutet, and chairman of the Nobel Committee for Physiology and Medicine, said the following during his otherwise laudatory speech honoring Theiler at the 1951 Nobel Prize ceremony: “The significance of Max Theiler’s discovery must be considered to be very great from the practical point of view, as effective protection against yellow fever is one condition for the development of the tropical regions—an important problem in an overpopulated world. Dr. Theiler’s discovery does not imply anything fundamentally new, for the idea of inoculation against a disease by the use of a variant of the etiological agent which, though harmless, produces immunity, is more than 150 years old.”

Even Theiler himself agreed that he had not done anything fundamentally new. But then, what might Bergstrand have had in mind when referring to Theiler’s discovery? Perhaps it was Theiler’s finding that passage of the Asibi strain of yellow fever virus in chick embryos, which were devoid of nervous systems, generated viable, non-neurotropic attenuated yellow fever virus. If so, then did that discovery fulfill the condition for the Nobel award, as specified by Alfred Nobel? And, if that is the case, then might this discovery have been what makes Theiler’s contribution more worthy than those of Salk and Sabin in the eyes of the Nobel committee? [A more detailed account of Max Theiler’s yellow fever vaccine, particularly with regard to the “discovery” noted here, can be found in The Struggle Against Yellow Fever: Featuring Walter Reed and Max Theiller, now on the blog.]

The seemingly trivial distinction between the worthiness of Theiler’s contribution from that of Salk and Sabin, suggests that we may need to look elsewhere for answers to why Salk and Sabin were bypassed by the Nobel committee. One reason suggested in the case of Salk is that in the elitist world of big-time science, he had never spent time at a prestigious Research institution like the Rockefeller. Yet he did carry out postgraduate studies in association with the eminent Thomas Francis. So perhaps he was passed over by the Nobel committee because it did not see anything innovative about his vaccine. Or, perhaps it was because he allowed himself to be promoted as a celebrity by the March of Dimes, thereby causing resentment among his colleagues.

But, how then might we explain the case of Sabin? Sabin had not been used by the National Foundation to promote its fund-raising. And, he had done research at the Rockefeller Institute. Moreover, Sabin made seminal contributions to the poliovirus field before and after beginning his vaccine work. As noted above, Sabin and Peter Olitsky demonstrated that poliovirus could be grown in cultured human embryonic nervous tissue. Moreover, Sabin provided experimental evidence that the poliovirus port of entry is the digestive tract, rather than the respiratory tract, as was previously thought. And, Sabin established that the incidence of poliomyelitis tended to be highest in urban populations which had the highest standards of sanitation.

[Aside: Sabin’s finding, that the poliovirus route of entry is via the alimentary tract, validated the premise that poliomyelitis might be prevented by a live oral vaccine. In contrast, Salk’s killed vaccine needed to be injected. An advantage of a vaccine being administered by the oral route, particularly in developing countries, is that trained medical personnel are not required for its administration. On the other hand, the killed vaccine is safer. The few cases of poliomyelitis that now occur in the West are vaccine-related, resulting from rare reversions to virulence of the attenuated virus.]

[Aside: Why was the incidence of poliomyelitis highest in urban populations that had the highest standards of hygiene? Polio infection tends to be milder in the very young, perhaps because they are partially protected by maternal antibodies. But, in areas with high standards of hygiene, infection tends to occur later in life, when maternal antibodies have waned, and the infection can then be more severe.

Before this was appreciated, poliomyelitis was thought to originate in the slums and tenements of cities, and then spread to the cleaner middle-class neighborhoods. Thus, during polio outbreaks in New York City, there were instances when slums and tenements were quarantined, and city dwellers fled to the suburbs, all to no avail.]

Were Sabin’s discoveries noted above, taken together with his vaccine, worthy of a Nobel Prize? In any case, Sabin indeed had been nominated for the Nobel award by numerous colleagues, including Enders. So, why was Sabin never awarded the Nobel Prize? Perhaps the Nobel committee could not recognize Sabin without also recognizing Salk, which it may have been reluctant to do for reasons noted above. Or, as has been suggested, the continual back-and-forth carping between supporters of Salk and Sabin may ultimately have diminished enthusiasm in Stockholm for both of them.

Salk (in 1956) and Sabin (in 1965) each received the prestigious Lasker Award for Clinical Research (often seen as a prelude to the Nobel) and, earlier, in 1951, Sabin was elected to the U.S. National Academy of Sciences. In contrast, Salk was the only prominent polio researcher not elected to the Academy. And regarding the Nobel Prize, Salk once joked that he didn’t need it, since most people thought he had already won it.

In 1963 Salk founded the prestigious Salk Institute for Biological Studies in La Jolla, California. Francis Crick (1), Renato Dulbecco (2), and Leo Szilard (3), each of whom is featured elsewhere on the blog, were among the eminent scientists recruited by Salk to the La Jolla campus. Bearing in mind Salk’s alienation from other medical researchers of the day, we might enjoy his remark “I couldn’t possibly have become a member of this institute if I hadn’t founded it myself.” Jonas Salk died of congestive heart failure in 1995 at the age of 80. He remains one of the most venerated medical scientists ever.

salk instSalk Institute for Biological Studies

[Aside: Salk married Dora Lindsay in 1939, right after he graduated from NYU medical school. But, the marriage eventually fell apart, and the couple divorced in 1968.

In 1970, Salk married the artist Francois Gilot, who had been the mistress of Pablo Picasso for nearly ten years and with whom she had two children. Salk and Gilot met in 1969, at the home of a mutual friend in Los Angeles. They remained married until Salk’s death in 1995.

The following is from an April 27, 2012 article in Vogue by Dodie Kazanjian, entitled Life after Picasso: Francois Gilot.

“On a trip to Los Angeles in 1969, a friend introduced her to Jonas Salk. She had no interest in meeting him—she thought scientists were boring. But soon afterward, he came to New York and invited her to have tea at Rumplemayer’s. ‘He didn’t have tea; he ordered pistachio and tangerine ice cream,’ she recalls. ‘I thought, Well, a scientist who orders pistachio and tangerine ice cream at five o’clock in the afternoon is not like everybody else!’ He pursued her to Paris and a few months later asked her to marry him. She balked. “I said, ‘I just don’t need to be married,’ and he said, ‘In my position, I cannot not be married.’ He gave me two pieces of paper and told me to write down the reasons why I didn’t want to get married.” She complied. Her list included: ‘I can’t live more than six months with one person’; ‘I have my own children’; ‘I have my career as a painter and have to go here and there’; ‘I’m not always in the mood to talk. Et cetera, et cetera, et cetera.’

Salk looked at the list and said he found it ‘quite congenial.’ They were married in 1970 and were together until he died in 1995. ‘It worked very well,’ she says, because after all we got along very well.’”]

Albert Sabin became president of the prestigious Weizmann Institute of Science in Israel, but stepped down in November 1972 for health reasons. He passed away in 1993 at the age of 86. Unlike in the case of Salk, and despite the fact that he never was awarded the Nobel Prize, Sabin’s standing among his colleagues always remained high.

Before concluding, we note two other important contenders in the quest for a polio vaccine. The first of these was Isabel Morgan, the daughter of the great geneticist, Thomas Hunt Morgan. Isabel Morgan nearly produced a killed polio vaccine before Salk succeeded in doing so. Working at Johns Hopkins, she generated formalin-inactivated poliovirus preparations that indeed protected monkeys against intracerebral injections of live poliovirus. However, Morgan gave up her research in 1949 to marry and raise a family. At that time, Salk had barely begun his work. But, if Morgan had remained in the race, Salk may yet have beaten her to the finish line, since she was reluctant to test her vaccine on human subjects.

Hilary Koprowski was the other noteworthy contender in the race to a polio vaccine. Koprowski was a Polish Jew who immigrated to Brazil in 1939, after Germany invaded Poland. He later came to the United States, where, in 1945, he was hired by Lederle Laboratories to work on a project to develop a live polio vaccine. Koprowski’s foray into polio had a few interesting happenings. Moreover, he went on to have a renowned career as a virologist. Thus, we discuss him in a bit more detail.

[Aside: Salk and Sabin also were Jewish. And Sabin too was born in Poland. In 1921 he immigrated with his family to the United States, at least partly to escape persecution of Jews in his birth-land.]

Koprowski began his work at Lederle before John Enders developed methods for growing poliovirus in monkey kidney cell cultures. Consequently, Koprowski attenuated his live vaccine by passaging it in mouse brains in vivo. In 1950, several years before Sabin’s vaccine was ready for testing, Koprowski found that his vaccine indeed protected chimpanzees from challenge with virulent poliovirus. Koprowski then tested his live vaccine in humans; first on himself, and then on 19 children at a New York State home for “feeble minded” children.

Koprowski was still an unknown figure in the scientific community when he made the first public presentation his test findings. This happened at a 1951 National Foundation roundtable that was attended by the major polio researchers of the day, including Salk and Sabin. The conferees were aghast upon hearing that Koprowski had actually tested his live vaccine, grown in animal nerve tissue, on children. Koprowski’s response was simply that someone had to take that step. Also, it didn’t help Koprowski’s standing with his academic colleagues that he was employed by Lederle. In those pre-biotech days, he was looked down on as a “commercial scientist.”

Human testing was of course a necessary step in the development of this or any human vaccine. What’s more, using cognitively disabled children as test subjects was a common practice back then. So, the actual concern of Koprowski’s colleagues was that he inoculated human subjects with a vaccine that was grown in animal brains. Koprowski also may have been treading on shaky legal ground, since it is not clear whether he ever obtained consent from the children’s parents.

[Aside: The only guidelines for such tests back then were the so-called Nuremburg Code of 1947, which was formulated in response to Nazi “medical” experiments. Informed consent was one of the Nuremburg guidelines, which, in the case of children, meant consent from a parent or guardian. Note that federal approval was not required to test vaccines or drugs in those days.]

Irrespective of whatever uproar Koprowski caused by testing his vaccine on helpless institutionalized children, he indeed had a live polio vaccine in 1949; several years before Salk and Sabin brought out their vaccines. However, Koprowski’s vaccine began its demise soon afterwards. A small field trial in Belfast showed that the attenuated virus could revert to a virulent form after inoculation into humans. But, bearing in mind that there was not yet any alternative to his vaccine, Koprowski firmly believed that the greater risks of natural poliovirus infections justified its use.

The fate of Koprowski’s vaccine was sealed in 1960, when the U.S. Surgeon General approved the Sabin vaccine for trial manufacture in the United States, while rejecting Koprowski’s vaccine on safety grounds. Tests showed that Sabin’s vaccine was the less neurovirulent of the two vaccines in monkeys. Sabin had carefully tested plaque-isolated clones of his attenuated viral populations for neurovirulence in monkeys, and he then assembled his vaccine from the least neurovirulent of these clones. Moreover, by this time millions of children in the Soviet Union had had been successfully immunized with the Sabin vaccine.

Koprowski left Lederle Laboratories in 1957 after clashing with its management. After that, he became Director of the Wister Institute in Philadelphia. He then transformed the then moribund Wistar into a first class research organization.

The relationship between Koprowski and Sabin was quite adversarial at the time their vaccines were in competition, but they later became friends. In 1976, Koprowski was elected to the U.S. National Academy of Sciences, an honor shared with Sabin, bit never afforded to Salk.

Here is one last bit on Koprowski. Recall that early lots of the Salk and the Sabin vaccines unknowingly contained live SV40, which had been injected into hundreds millions of people worldwide. While the unknown presence of a live tumor virus in a vaccine must be one of a vaccinologist’s worst nightmares, this finding did not attract the attention of the public. In contrast, a 1992 article in Rolling Stone, which attributed the emergence of HIV to Koprowski’s polio vaccine, created a sensation. The premise of the article was that Koprowski’s vaccine was produced in chimpanzee cells that were contaminated with simian immunodeficiency virus (SIV), which then mutated into HIV when inoculated into humans. As might be expected, there was no evidence to support that premise. Indeed, PCR analysis could not detect SIV or HIV in the supposedly contaminated vaccine lots, and records from Koprowski’s laboratory showed that his vaccine was never grown in chimpanzee cells. So, faced with the possibility of a lawsuit, Rolling Stone issued a retraction.

Readers, who enjoyed the above account of the rivalry between Jonas Salk and Albert Sabin, may also enjoy the account of the rivalry between Robert Gallo and Luc Montagnier in Who Discovered HIV? More on the same topic can be found in How the Human Immunodeficiency Virus (HIV) Got its Name. For a very different kind of rivalry, that between Howard Temin and David Baltimore, see Howard Temin: In From the Cold.

1. Howard Temin: “In from the Cold” On the blog.

2. Renato Dulbecco and the Beginnings of Quantitative Animal Virology On the blog.

3. Max Delbruck, Lisa Meitner, Niels Bohr, and the Nazis On the blog.