Between Hope and Fear

by Michael Kinch

  Compounding these natural problems, human activity is changing both the rate and types of infections that one can expect in the future. For example, the warming of the planet increases the range of tropical infectious organisms and the vectors (e.g., mosquitoes, ticks, and bats) that harbor them. As population rates increase in underdeveloped nations, so does encroachment upon the natural reservoirs of these vectors, rendering it more likely that humans will encounter pathogens that have long existed but have been blissfully unaware that humans might provide their next meal. Compounding this further, urbanization, combined with greater availability and speed of travel, means that an infection in one place can be broadcast widely before the public health system becomes aware of its existence. No example of these mutually reinforcing dangers is more representative of this change than antibiotic-resistant bacteria. It is with this example that we will conclude our story, adding an ironic twist.

  Vaccines and Autism: A Different View

  The growth of drug-resistant infections has been the source of growing concern for many decades, and the potential for a “post-antibiotic world” is rapidly becoming a reality. As we have already discussed, resistance to these miracle drugs known as antibiotics accompanied their introduction in the 1940s. This resistance is a natural outcome of the overuse of antibiotics combined with the propensity of bacteria to swap plasmids that encode for resistance mechanisms (recall toxin-antitoxin from an earlier chapter). The consequences of these actions frequent the news cycles with reports of “superbugs,” flesh-eating bacteria, and drug-resistant forms of many different diseases. Prominent among the latter is a wave of drug-resistant forms of tuberculosis. These threaten the return of a disease once known as “consumption”—one of the world’s most deadly diseases—whose victims have included Eleanor Roosevelt, Frederic Chopin, and George Orwell.

  The final victim is symbolic of the Orwellian twist to our story. The same structure that gave rise to antibiotics undercut the deployment of vaccines that might have prevented some of the drug resistance we face today. Continuing with the example of tuberculosis, we encounter the character of Leon Charles Albert Calmette, a French physician who learned bacteriology from Emile Roux and started a branch of the Pasteur Institute in Saigon (then a part of French Indochina).49 Upon his return to France, Calmette began studying what we now call Mycobacterium tuberculosis, a bacterium discovered by Robert Koch that was responsible for the disease of “consumption” (a.k.a. tuberculosis). Specifically, Calmette and his colleague, Camile Guerin, began to grow tuberculosis bacteria on potato slices soaked in glycerin and bile. The bacteria that could survive under these conditions were weakened by repeating the process for more than a dozen years (from 1908 until 1921).50 The attenuated Bacille Calmette Guerin (or BCG) strain of bacteria had a bit of a rough start when early testing caused the deaths of seventy-two infants in Lubeck, Germany, in 1930.51 In the subsequent follow-up, it was revealed that the BCG strain had become contaminated with a more virulent natural form of tuberculosis during its manufacturing and the more aggressive contaminant caused the disaster. This inauspicious start unsurprisingly rendered many physicians and parents wary about the BCG vaccine. Ultimately, the need for the vaccine was eroded by the introduction of antibiotics in the years during and immediately after the conclusion of the Second World War.

  The widespread availability and low cost of antibiotics decreased the attractiveness of many vaccines. In our analysis of innovative vaccines, we found the number of different bacterial pathogens that could be targeted with vaccines grew rapidly from 1900 until 1940 and barely changed thereafter despite an ever-increasing discovery of new bacteria that cause various diseases. A pharmaceutical industry that had relied upon the development and deployment of new vaccine products instead embraced new antibiotic wonder drugs, and with an average of three new antibiotics being introduced each year from the 1950s through the 1980s, the concept of resistance seemed no more likely than the sky falling.

  As the years passed, circumstances changed. A glut of newly introduced antibiotics and increasing generic competition arising from the inexpensive marketing of older medicines fractured the market. New drugs could not command high prices, and the rate of new antibiotic introduction plummeted. Indeed, our work at Washington University revealed new antibiotic approvals dropped by more than 90 percent from the 1990s onwards. At the same time, the well-worn drugs of the past had become so overused that drug-resistant bacteria underwent selection in a manner that would have made Darwin proud. The result, as a casual glance at the headlines will reveal, is that most antibiotics will have limited effectiveness in the future. Compounding the problem, the expertise and personnel that developed earlier generations of antibiotics have largely atrophied. Even if an economic model could be made to support the development of new antibiotics, the pharmaceutical industry is ever less able to seize upon the opportunity.

  Returning to tuberculosis, a suitable, albeit imperfect vaccine exists. However, the low prevalence of tuberculosis during the antibiotic era has generally meant that public health officials do not routinely advise parents to immunize their children with BCG. As tuberculosis continues a relentless drive towards antibiotic resistance, the use of BCG might have to be reconsidered. Even better, a new generation of tuberculosis vaccines that improves upon the safety and efficacy of a vaccine that was developed almost a century ago using potato slices could undoubtedly be achieved.

  In a truly ironic twist, vaccines might also provide an opportunity to decrease the incidence of autism and developmental disorders. The idea is that vaccines tend to be scalpels, whereas antibiotics are blunt objects. Extending the analogy, a tuberculosis vaccine such as BCG should selectively eliminate a disease-causing organism with no beneficial value to humans, whereas penicillin depletes both the bad actors and the beneficial organisms of the human microbiome.

  In a series of scientific reports and a recent book targeting the general population, the director of the Human Microbiome Program at New York University, Martin Blaser, conveyed a theory that one outcome of the overuse of antibiotics is a disruption of the normal microbial component of the human body.52, 53 Using the bacterium Heliobacter pylori as an example, Blaser proposes that antibiotics have altered the microbiome in such a manner that, to paraphrase the title of one chapter of his 2014 book, Missing Microbes, it has rendered many people “fatter and taller” than might be expected or be considered healthy.54 Indeed, antibiotics have been used for decades to fatten and increase the overall size of livestock prior to slaughter (which has also contributed to the development of drug-resistant bacteria). Likewise, Blaster postulated that an altered microbiome might have links with increasing rates of autism and other developmental disorders.

  As we have already seen, the link of any causation to autism is complex. Oversimplifications have been abused repeatedly by desperate parents or charlatans advocating a link with vaccines. Thus, any claims as to causation must stand up to rigorous scrutiny that often takes years or decades of intensive, peer-reviewed work. Nonetheless, early reports suggest that the microbiomes of autism patients differ from those of “healthy” counterparts. Furthermore, a fecal transplant, the process of transferring the healthy gut bacteria from a non-disease patient to a disease-bearing individual, may show promise in ameliorating some of the symptoms of autism. It is essential to point out that this early study is small, akin to the size that Wakefield used to support his bogus claims, but hopefully not biased. Additional investigation will be needed to assess whether the results can be reproduced and expanded.

  Were such findings to hold, utilizing vaccine-based scalpels to selectively eliminate disease-causing bacteria and viruses may convey considerable advantages over chemical treatment such as antibiotics. Indeed, one advantage has already been established with the introduction of the first pneumococcal vaccines in the 1980s. Streptococcus pneumoniae was first isolated in 1881 by Louis Pasteur and, in parallel, by George Miller Sternberg (the commanding officer of a
young Walter Reed). The disease was a leading killer across the world, and the first, crude vaccines were developed in 1909. Greatly improved versions of the vaccine were introduced in the 1980s, and an unexpected consequence was a 47 percent plunge in the overall use of antibiotics in children.55 In a world facing increasing rates of infection from drug-resistant bacteria such as Clostridium difficile, Pseudomonas aeuruginosa, and others, which are currently treated with the blunt objects known as antibiotics, new generations of safe and effective vaccines could convey benefits well beyond their intended applications by decreasing the overall need for antibiotics.

  It will not be easy. Throughout this book, we have witnessed that virtually every introduction of a new vaccine has been countered by skepticism, if not outright hostility. From the time before the first vaccines (since variolation does not qualify as such), vaccines have encountered resistance, often from unexpected sources. The fears have ranged from the reasonable opposition that variolation can itself be deadly to the irrational fears that a cowpox-based vaccine might cause the recipient to sprout horns and begin to graze in a meadow. No one might have predicted the extreme responses to DPT and MMR precisely because the motivations behind the opposition were based on fabricated data or ulterior motives.

  Other unexpected reactions have included charges that the vaccine created to eradicate cervical cancer, a sexually transmitted disease, was instead intended to promote promiscuity. Perhaps the most damning response is an utter lack of response by many otherwise intelligent individuals, who elect not to receive an influenza vaccination because it is inconvenient for their schedule or because they don’t care for needles (even in the face of an intranasal option).

  Thus, the rosy scenario painted above, of a future where vaccines act as scalpels to selectively eliminate certain obnoxious pathogens, must face certain realities. First, any new vaccines must and indeed should face considerable scrutiny to ensure they are safe. Based on past experiences, some of which have been reviewed herein, vaccine manufacturers have been responsible for self-inflicted wounds, which have lingered long in individual and institutional memories. Given immunity generally lasts for years, this may require extensive and expensive needs for assessing safety.

  Furthermore, the vaccines must be sufficiently efficacious, and, under extreme circumstances, certain trade-offs must be considered. We have already experienced this with the mumps vaccine. Older versions of the mumps vaccine were associated with decreased duration of efficacy, so that individuals receiving this vaccine could become sensitive to infection with mumps within a few short years after vaccination. This risk is particularly high in the current environment, where the “herd immunity” of the population is crumbling because of the misplaced efforts of anti-vaccinator extremists.

  The growth of a small but dangerous anti-vaccine resistance is instructive. Much greater care must be taken to train physicians, especially pediatricians, about the importance of proper vaccination and how to discuss the fears, both rational and otherwise, that they will inevitably confront with understandably anxious parents, who might have been exposed to inaccurate propaganda from the vocal anti-vaccine lobby. Inaccurate rumors must be dispelled, and accurate information conveyed in its stead. Much care must be taken to respect the sensitivities of their patients (and parents) while conveying that the danger to children, and indeed the much wider community, is fundamentally threatened by a failure of even one parent to have his or her child immunized.

  A more difficult challenge faces the public health community, lawmakers, and regulators in their attempts to restart a sputtering vaccine industry. It is crucial for lawmakers, regulators, and indeed the entire general public to place themselves in the shoes of a vaccine manufacturer, if only via a simple thought experiment. Imagine that you are an executive at a large pharmaceutical company and you have a choice of where to invest limited research and development dollars. You could choose a designer medicine for a sick population, such as those with cancer, which will garner a price tag of five or six digits. This drug would take, on average, ten to fifteen years to develop and cost about a billion dollars.

  Alternatively, you could develop a vaccine for an infectious disease. Whereas the cancer drug is being administered to sick patients in need of a cure, the vaccine is administered to healthy people, many of whom will never encounter the infectious disease you seek to prevent. The product you seek to develop is a commodity, intended to be administered to a mass population rather than to a subset of needy patients. Your pricing structure must reflect this. This fact precludes a five- or six-digit price tag. Moreover, your pricing assumption may not include factors beyond your control. For example, any perceived side effect arising at or near the time your vaccine is administered, may be attributed to your product. Despite the fact you have spent enormous resources and time to assure that the vaccine is safe, this may all be neutralized by a string of coincidences, or, worse still, the active intervention of a bad actor such as Andrew Wakefield. These perceptions (or realities) will substantially decrease your market size and may jeopardize the sustainability of the product and even your company.

  By spending just a few moments contemplating such decisions, it is easy to understand why drug manufacturers view vaccine products as less attractive than conventional medicines. Compounding the problem, the drug development community itself is shrinking rapidly, as are the resources devoted to research and development, largely because of industry consolidation meant to restrain a persistent decrease in efficiency.

  What can be done? In a word: incentives. If vaccine manufacturers can be assured stable markets through advanced market commitments, they are more likely to address unmet medical needs. The stability of the market could be assured if regulators and legislators required immunization at the national level. Such actions are a commonsense approach to ensure that herd immunity sustainably protects the population. However, true to the cliché, common sense is increasingly rare as it pertains to current trends in vaccine mandates. Rather than insisting that individuals be immunized against diseases that threaten the population, a more libertarian approach has held sway in which individuals can exempt themselves or simply ignore the advice of physicians and public health boards. Indeed, the individual appointed in 2017 to lead the public health infrastructure in the United States advocates that the federal government reverse its long-standing advocacy of vaccines and instead return such responsibilities to individual states.56 Such an approach could be disastrous in terms of herd immunity. As we have seen in the example of mumps, it would threaten not just those individuals who make the unwise decision not to immunize but the entire community as well. Such trends must be reversed, both to protect the population and to ensure that manufacturers remain confident enough of the market potential to ensure competition that favors further improvements in the safety, efficacy, and breadth of products that prevent the myriad disease-causing organisms that we face.

  For many emerging diseases, as well as those that are reemerging due to antibiotic-resistant bacteria, additional incentives may be necessary to entice innovators to develop novel vaccines. In the case of the West African Ebola virus outbreak of 2014, quick responses by the scientific and biopharmaceutical communities facilitated the rapid identification and testing of vaccines meant to arrest a fast-growing epidemic before it could spread even further. On one hand, much of the work was initiated after the proverbial horse had left the barn. On the other hand, the Ebola crisis demonstrated the value of incentivizing experimental therapies and vaccines in a just-in-time manner (that was quite literally true in this case).

  The regulators and developers of future vaccines for emerging and reemerging diseases could learn much from the 2014 Ebola crisis. First, incentives could be placed upon the development of certain vaccines. The incentives might be passive, such as ensuring market exclusivity for a longer period, or more active, such as providing tax breaks for a fraction of the research and development costs for vaccines that address particularly im
portant needs. Such incentives do work, as evidenced by the extraordinary growth in drugs meant to target low-incidence diseases in the years following congressional passage of the 1983 Orphan Drug Act.57 Such incentives might be made more powerful by increasing cooperation between vaccine manufacturers and the epidemiologic community. For example, the Centers for Disease Control and Prevention could help prioritize the pathogens for which vaccine treatments are developed. The incentives provided by governmental agencies could include provisions such as those in the Orphan Drug Act but might also include additional incentives as conveyed by social impact bonds.

  In July 1988, an economist by the name of Ronnie Horesh was asked to present at a conference of the New Zealand Branch of the Australian Agricultural Economics Society held at Lincoln College in Canterbury, New Zealand.58 Horesh’s expertise was social and environmental policy, but the impact of his presentation would comparably apply to many other fields. What Horesh proposed on this winter day was that the public sector should establish a contract that is payable to a recipient that meets certain predefined outcomes. The beauty of the program was that the payer would not have to expend funds until the payer had obtained their desirable goal. This concept, known as a “social impact bond” or “pay for success bond” was the subject of discussion for a few decades thereafter. It was finally tested in March 2010 when British justice secretary Jack Straw announced an impact bond meant to reward innovators who could decrease inmate recidivism at Peterborough Prison.59 Within six months, a group of investors had posted £5 million pounds in an effort that could return £8 million, an attractive profit in a time when bank interest rates hovered at and occasionally below zero percent.60