Tag Archives: influenza

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.”

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!”]

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.