Using the same clinical specimen obtained from Mayali, Theiler began to further attenuate what was already known to be a rather weak pathogen. This was accomplished by passaging the newly discovered virus repeatedly through mice (much as Pasteur had done with rabies virus to create his vaccine decades before).27, 28 The passaging did indeed weaken the virus, yielding a vaccine that retained the ability to elicit a protective immune response without causing disease. The vaccine was soon deployed throughout Africa and other regions where mosquito control had not been sufficient to eliminate the disease. In appreciation for his contributions, Theiler was awarded the only Nobel Prize ever awarded solely for the discovery of a new vaccine.29
Double Jeopardy
Despite the success in controlling yellow fever all those years ago, one of its closest flavivirus cousins is the fastest-growing infectious disease in the world and is certain to grab future headlines in a hotter, wetter, and more densely packed world. Dengue is another mosquito-borne flavivirus with a penchant for urban and semi-urban areas in both tropical and subtropical climates.30 The name of the virus is derived from the Swahili word Ka-dinga pepo, which roughly translates into “disease caused by the devil that causes terrible pain.”31 This appellation accurately reflects the symptomology of dengue, which has also been referred to as “break-bone fever,” reflecting the extraordinary arthralgia (joint pain) that is a primary symptom of infection. This pain can cause permanent damage to the joints, giving the disease the additional moniker of Dandy fever, based on the fact that previously afflicted patients were said to acquire a stance and walking style comparable to a wealthy fop.32, 33
A dark joke about dengue fever is that the disease can strike only twice. The first time a person becomes infected, they want to die. The second time, they do.
Deconstructing the statement, dengue infection causes a series of symptoms collectively known as a viral hemorrhagic fever. In the days following initial exposure to the contagion (generally arising from the bite of an infected mosquito), the patient may suffer flulike symptoms, which include high fever, general malaise, and the beginnings of muscle and joint pain. Over time, the pain greatly increases and is accompanied by loss of appetite, nausea, and vomiting.
What distinguishes hemorrhagic fevers from simple fevers is that the former triggers a powerful immune response. This might, at first glance, seem like a positive thing, since, as we have seen, the job of the immune system is to eliminate foreign invaders like dengue virus. However, the type of response triggered by dengue virus is so acute and exaggerated that it tends towards utter destructiveness. Much as we have seen with bacterial endotoxins, a vigorous activation of the immune system can trigger the production (or, using the scientific term, “dumping”) of massive amounts of cytokines, chemicals designed to alert the body to the presence of an infectious invader. One job of these cytokines is to “loosen” the blood vessels to allow immune cells to gain access to the tissues. This is a beneficial reaction when, for example, an infection is localized to a specific site. When a person cuts him- or herself and thereby exposes the body to external pathogens, the loosening of the blood vessel lining near a site of infection will allow immune cells to enter and accumulate, thus speeding the clearance of the infection.
The problem with dengue and other viral hemorrhagic fevers is that the cytokines are conveyed en masse into the bloodstream and lymph systems throughout the body. The results tend to be rapid and lethal. For example, a sudden rush of cells out of the circulation and into tissues can cause rapid swelling (and much of the pain associated with the disease). Despite the fact that the blood mostly remains inside the body, the rapid blood loss can cause a form of shock like that seen with gunshot or accident victims. In extreme cases, the loosening of the blood vessels can be sufficiently extreme that blood begins to seep out of the body altogether. Consequently, an infected patient can begin bleeding from the eyes, ears, mouth, rectum, genitals, or other sensitive parts of the body that are rich with tiny blood vessels near the body’s surfaces. These responses are identical to those made famous by Richard Preston in The Hot Zone, an outstanding chronicle of early studies of Ebola virus infection (although the accounts overdramatized the symptoms a bit, since most patients do not bleed out or live long enough to experience liquefaction of vital organs).34
Returning to dengue, assuming the patient survives this first encounter with dengue virus, the body’s immune system eventually reverts to its more beneficent role of developing protective antibodies and T cells, and the virus is eliminated. However, any relief experienced by the patient is sadly temporary because a second exposure to dengue virus (even years later) will cause the same set of symptoms, only magnified manifold because the immune system (and the cytokine storm) has been trained to recognize the pathogen and thus will convey an even more vigorous response that in turn amplifies the symptoms. The result of a second infection is invariably death.
Our understanding of how dengue fever infection has impacted people over time has been growing. Ancient accounts of an arthritis-causing infection have been unearthed in ancient Chinese texts and 17th-century Egyptian reports and have been assumed to be early written descriptions of dengue infection.35 However, it was not until a 1780 outbreak in Philadelphia that the disease received its first conclusive documentation. A report by the American physician Benjamin Rush (a Forrest Gump–like character, who befriended many of America’s Founding Fathers and thereby influenced an extraordinary number of events in the revolutionary and postrevolutionary United States) described a “bilious remitting fever” whose “more general name among all classes of people was the break-bone fever.”36
Despite these early accounts of dengue fever, its incidence remained low, with occasional high-profile outbreaks. For example, the queen of Spain was afflicted in 1801 following a period of protracted rain (which increased the local mosquito population) but survived.37 However, all this began to change in the second half of the 20th century as the global incidence began to skyrocket and has continued to do so at an alarming rate.38 Further, the geographic span of the outbreak has comparably expanded, with infections being recorded on all continents (excluding Antarctica), in part as a result of climate change, which continues to increase the range of its mosquito vectors. As of press time, no vaccine or antiviral treatment beyond supportive care for its symptoms has been developed to counter this rapidly growing scourge. While dengue is unquestionably growing in incidence (as evidenced by precise DNA and other epidemiological assessments), recent years have witnessed considerable confusion, as many other diseases mirror the symptomology of dengue.
Mkomaindo Hospital is a small structure located at the intersection of the A19 and B5 roads in the town of Masasi in the southern part of Tanzania, near its border with Mozambique. Even today, the hundred-bed hospital is staffed by no more than twenty clinical officers (CO), a title certifying two years of training. It serves 300,000 regional patients. Despite the hospital supporting a local CO training college, the turnover rate is very high, since most trainees quickly leave Mkomaindo for the lures of the capital, Dar-es-Salaam, and its higher pay and amenities.
The current two-story building lacks running water and stable electricity and yet is a marked improvement over its immediate predecessor, a rickety structure torn down in 1952. The hospital is the only source of medical support for the regional population. Its construction was overseen by two remarkable women doctors. Dr. Frances Taylor had come to Masasi in 1922 and would remain as the only physician in the area for most of the four decades of her missionary service. At the time the new hospital was being built, Dr. Taylor had the relative luxury of working with another English-trained missionary-physician by the name of Marion C. Robinson.
Starting in late 1951 and extending into the early months of 1952, the fortune of having two staff physicians was nonetheless stretched to the limit by an outbreak of a new disease. Although most of the infected survived, the disease was characterized by high fever and joint pai
n, which caused patients to stoop over as a consequence of debilitating arthritis triggered by the infection. After the worst of the crisis had passed, Dr. Robinson realized that this disease was unlike any other she had treated, including dengue fever, and reached out to a colleague at the Yellow Fever Research Institute in Entebbe.
Dr. William Hepburn Russell Lumsden was a Scottish physician who had trained in Glasgow, receiving his medical degree in 1938 and specializing in tropical medicine.39 This choice of careers proved fortunate for his homeland, since Britain was soon inundated with a world war that saw Dr. Lumsden serving as a commanding officer in charge of malaria field units in the European, Middle Eastern, North African, and Asian theaters of war. He served in Palestine, Transjordan, North Africa, Italy, India, and Sicily. Indeed, in this last location, Lumsden’s career and life were nearly ended when the truck he was riding in struck a land mine and was blown off the road. Months after the declaration of peace, Lumsden accepted a position in Entebbe, where he would remain for the next nine years.
On a fateful day in 1952, Lumsden learned about the situation in Masasi and agreed to work with Dr. Robinson to investigate its causes. They worked diligently over the coming years and, in 1955, introduced the world to their new discovery.40, 41 The epidemic in Tanganyika was not dengue but rather a new virus they named chikungunya, which is the local Makonde language word for ‘that which bends up.’ Like the etiology of dengue, this name reflects a primary symptom of the disease, which reflects the joint pain and dysfunction suffered by the afflicted.
As we saw with Zika, the whole of continental Africa was ablaze in revolutionary change and the unshackling of colonial bonds. These realities directly impacted Marion Robinson and the fate of chikungunya. In the months after publication of her seminal scientific articles with William Lumsden, Marion fell in love with an Anglican priest by the name of Mark Way. At the same time Robinson was battling a chikungunya outbreak, Way was being appointed bishop of the Anglican Masasi Diocese.42 However, Bishop Way’s battles had yet to begin, as he was soon assailed by his clergy with overt and subtle claims of micromanagement and racism. The local clergy revolted and Way, who was preparing a trip to the United Kingdom in late 1959 to marry Marion Robinson in their homeland, made the absence permanent with his resignation and the couple’s return to England.
The appointment of a new bishop who was known for his strong antiapartheid convictions was more to the liking of the local clergy.43 The new bishop, Ernest Urban Trevor Huddleston, was widely praised, but his appointment created its own crisis, as his authoritarian tendencies led to the loss of half the trained physicians in Masasi. This condition would deteriorate further in 1963, as evidenced by an open letter submitted by Huddleston to the entire Anglican community, pleading for a doctor to replace Frances Taylor, who herself was set to retire later that year. He further related that all attempts to replace Robinson over the past few years had failed (though not mentioning her by name), and he feared (rightfully so) that the same challenges would confront the looming retirement of Taylor.
These symptoms of a larger transition in African society and infrastructure would help propel the chikungunya virus well beyond its Tanganyika home. The virus was being experienced in India at the same time Bishop Huddleston was composing his open letter and would soon spread throughout the subcontinent and the entire Indian Ocean basin. From there, the virus expanded globally, being experienced throughout the world but too often being confused with dengue fever.44 This was more than a minor nuisance, as it confounded epidemiological understanding of both diseases and has led the medical community to appreciate we are simultaneously facing not one but two particularly dangerous pandemics in parallel.
The dangers from hemorrhagic fever viruses are not limited to dengue and chikungunya, as this classification and these horrific symptoms are shared by a frighteningly large and growing number of hemorrhagic fever viruses, which include many names that are increasingly familiar to physicians throughout the world. These viruses include Ebola, Marburg (which we met earlier), Lassa, Nipah, Hendra, Kyasanur Forest, Alkhurma, LCM, Omsk, Chapare, Lujo, and Sabi. Hemorrhagic fevers (each caused by a different pathogen) are associated with Venezuela, Argentina, Bolivia, Crimean-Congo, Kaysanur Forest, and the Rift Valley of east Africa, to name but a few. The simple reality is that the list of viral hemorrhagic fevers is a growing problem and is certain to worsen in the coming months and years.
Despite their rapid proliferation, modern medical science is almost entirely unprepared for this growth. At best, the most wealthy public health systems can try to address the symptoms of these diseases, but targeting their causation can only be accomplished by a type of medicine that has lost the attention of the pharmaceutical industry and is worryingly shunned by the general public: vaccines.
Hopes and Opportunities
Vaccines provide a very real hope for addressing dengue, chikungunya, and all the other viral hemorrhagic fevers. Although each pathogen provides its own set of scientific challenges, the experiences gained with yellow fever, not to mention the myriad vaccines successfully developed to date, demonstrate that it is feasible. Vaccines have saved millions (perhaps even billions of lives) and generate many billions of dollars in revenue each year for their manufacturers. Despite such impressive numbers and the fact that we know more about the breadth and destructive potential of the many lethal microorganisms in our environment, the field of vaccine production has largely stalled. Given ongoing trends in the business of vaccines, it might not continue in the future.
I initiated a project in early 2011 to document the sources of innovation in the pharmaceutical and biotechnology industries. As described in greater detail in A Prescription for Change, the rationale for doing so was to assess both the science and business of making new medicines and to see how both have changed over time.45 In parallel with our work to track the sources of all new medicines, we began to track the same information for vaccines. These studies revealed a total of 135 different passive (i.e., antibody) or active (i.e., vaccines) innovations. These breakthroughs provided much-needed immune-based therapies approved for use in the United States by the FDA or its predecessors.
Our initial reaction to assessing the data was that 135 is a remarkably small number, particularly when one considers that many of the new products were simply improvements upon earlier versions of vaccines. Specifically, the 135 novel products altogether were able to prevent disease caused by a mere 28 different microbial pathogens.
Looking further, our studies revealed the number of companies devoted to vaccines expanded starting in the 1940s, reaching a peak of twelve different companies in 1970. Thereafter, a combination of industry consolidation, declining revenue potential, and increasing concerns about liability (arising from the experiences with DPT and MMR) cut in half the number of companies that develop new vaccines. Despite varied incentives to encourage new vaccine development to address rising problems such as Zika or dengue virus, the number of organizations focused on vaccines remains at a perilously low level.
Reflecting a larger trend of waning research and development by the pharmaceutical industry, more of the early research and development of new vaccines is being performed by relatively small upstart companies with names such as BioVex, Protein Sciences, and Acambis. Although start-up companies can bring new ideas and energy to a field, the relative reluctance of large, experienced companies to more fully engage in vaccine research could unnecessarily limit our ability to develop much-needed vaccines. All of these changes are occurring amidst an ever-increasing array of pathogens encountered as the planet grows warmer and more densely populated and when intercontinental travel can spread a disease at an unprecedented rate.
Consistent with these concerning trends, a comprehensive analysis revealed that the number of different pathogens that can be targeted with vaccines has not changed since the early 1990s. Extending this further, almost all the growth in developing vaccines to prevent infectious disease since the 195
0s has been focused upon viral diseases. A 2014 study by investigators at Brown University identified twelve thousand different outbreaks that affected forty-four million people worldwide from 1980 to 2013.46 To put this into perspective, the list of the world’s fastest growing infectious diseases discovered since 1980 includes but is not limited to: Lyme disease (discovered in 1982); Escherichia coli O157:H7 (1982) HIV/AIDS (1983), Rotavirus (type B in 1984 and type C in 1986), hepatitis c virus (1989), Hantavirus (1993), Hendra virus (1994), Vancomycin-resistant Staphylococcal aureus (1996), Nipah virus (1999), Human metapneumovirus (2001), and SARS (2003).47, 48 This list does not include other pathogens such as dengue virus, chikungunya, or pandemic influenza virus, which had been known to medicine years before and still do not yet have a protective vaccine.
A few years ago, I was dragged into the murky world of bioterrorism (and the development of countermeasures to protect the public) after serving under a boss who himself was a former head of the Defense Advanced Research Projects Agency (DARPA). This secretive agency is the research and development arm of the Defense Department and responsible for the introduction of Global Positioning Satellite (GPS) technology, the internet, and autonomous vehicles (as well as Area 51 and its antecedents). At the time, the US government was still reeling from the 2001 anthrax attacks on the media and Congress (attacks that we now know were launched by a military colleague developing a vaccine to anthrax). In a knee-jerk response, the government invested heavily in a variety of programs such as the 2004 Project BioShield Act, which allocated billions of dollars to support the development of countermeasures to protect against terrorist attacks.
Amidst all the uproar about man-made threats, my old boss stated calmly, “Nature is the worst terrorist of them all.” This accurate statement reflects the fact that the emergence of new infectious diseases does not require malevolent intent but can arise from a combination of natural and unnatural circumstances. The natural contributors include spontaneous mutations that allow a virus that had been restricted to animals (e.g., rinderpest), to take a new interest in humans (where it became measles) or for a chance encounter between a monkey and a human to facilitate the spread of HIV, launching one of the most deadly plagues our species has suffered. Likewise, influenza virus tends to undergo a natural shift every few decades that gives rise to a new form that had not been encountered for at least a few generations. Unlike the seasonal forms of influenza that are moderately deadly (killing thirty to fifty thousand Americans per year), these periodic and completely natural pandemic influenzas can kill tens or hundreds of millions and perhaps, given our globalized society, billions.
Between Hope and Fear Page 34
