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Consequential Epidemiology: Facing the Enemy, Fighting for the Future

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By Kelly M. Pyrek

While today’s headlines remind us that we are living in a fractious, potentially dangerous time, our deadliest enemy may not be a dictator with a finger on the trigger, but an invisible invader that silently travels in bodily fluids, on air currents, in insects and animals, and lies in wait for its opportunity to infect and annihilate.

Lest the scenario seem too dire, infectious diseases expert and renowned epidemiologist Michael T. Osterholm, PhD, MPH, insists there are many actions we can take – as healthcare professionals, government officials, policy-makers, researchers and even consumers – to fend off these infectious and insidious marauders and set a better course toward stewardship for the future.

However, that requires acknowledging lack of past foresight and shaking off the apathy that hampers effective planning and preparedness. Discomfiting as it is to acknowledge epic epidemiologic fails in the distant and recent past, it is necessary so that the lessons of yesterday can be applied to the infectious threats of today. Osterholm, founder and director of the Center for Infectious Disease Research and Policy (CIDRAP) at the University of Minnesota, asserts that “we tend to go from crisis to crisis without ever anticipating them or finishing the job in the end,” and that “without policy, research has nowhere to go.”

Long an advocate of forecasting, Osterholm adds that, “The only way we are going to confront and deal with the ever-present threat of infectious disease is to understand those challenges so that the unthinkable does not become the inevitable.” These words of wisdom are part of Osterholm’s advice in his new book, Deadliest Enemy: Our War Against Killer Germs (Little, Brown & Company, 2017), in which he emphasizes the need for a common-sense approach to global scourges. Public health science is based on statistics and probabilities and it is the cornerstone of risk management related to infectious diseases. Both throughout his 40-year career and in the book, Osterholm advocates for a real-world assessment of risks related to pathogenic organisms. While it’s impossible to plan for everything in life, Osterholm is a huge proponent of forecasting and foreseeing and then applying our collective knowledge based on past experience, the latest scientific calculations and modeling, and an improved approach to pharmaceutical therapy development and management. In his book, Osterholm calls for a reasoned approach to infectious diseases: “…We don’t always make rational decisions about where to put our resources, where to direct our policy, and frankly, where to direct our fear.”

The “crisis agenda” which Osterholm outlines in the book includes four orders of priorities:
1. Confront head-on those microbes that are considered to be pathogens of pandemic potential (and in Deadliest Enemy, Osterholm identifies influenza and antibiotic/antimicrobial resistance as the most significant challenges currently
2. Prevent high-impact regional outbreaks such as Ebola and coronavirus.
3. Prevent the use of microbes for intentional harm, specifically bioterrorism.
4. Prevent endemic diseases that continue to have a significant impact including malaria, TB, diarrheal disease and AIDS.

As Osterholm writes, “It is the range of possible results from the changeability and mixing of influenza strains that makes it the king of infectious microbial beasts. While it can be almost as mild as a common cold, it can also be just as fearsome and deadly as smallpox, and even easier to catch. That is why this particular beast terrifies epidemiologists.” He continues, “There’s another crucial difference between influenza and all the other ‘maybe’ point-source diseases such as Ebola, that form the basis of every plague novel and outbreak movie. As infectious disease epidemiologists, we all know that pandemic influenza is the one infectious disease that will happen. It has happened at least 30 times since the 16th century and our modern world presents all the ingredients for an imminent return.”

At this point in our evolutionary relationship with pathogens, Osterholm says our major concern should be pandemic influenza, which can be particularly crippling to the just-in-time society in which we live.

“I still worry more about pandemic influenza than anything else because it could happen tomorrow,” Osterholm confirms. “It was somewhat of a painful irony that I wrote both the chapter on H7N9 and the potential scenario that could unfold, and for the best part of the last six months, we have really almost been on the cusp of that with H7N9 in China.  This fifth wave has been remarkable, both in terms of what we are seeing in human illness and in terms of changes within the virus, and it is of great concern.  I think the world is waking up to the fact that we face a fundamental change in the way influenza occurs in the world – the increase in poultry production has resulted in this dynamic change in the transmission of avian viruses. So, thinking about what a pandemic could do today -- and we laid that out in the book – it’s very sobering.”

In a 2012 review published in The Lancet Infectious Disease, Osterholm and co-authors questioned the effectiveness of influenza vaccines, concluding that, “Influenza vaccines can provide moderate protection against virologically confirmed influenza, but such protection is greatly reduced or absent in some seasons. Evidence for protection in adults aged 65 years or older is lacking. LAIVs consistently show highest efficacy in young children (aged 6 months to 7 years). New vaccines with improved clinical efficacy and effectiveness are needed to further reduce influenza-related morbidity and mortality.” As Osterholm, et al. summarized, “Seasonal influenza is an important public health and medical challenge. Pandemic influenza would cause a substantial burden of disease and seriously threaten the global economy. Based on a track record of substantial safety and moderate efficacy in many seasons, we believe the current influenza vaccines will continue to have a role in reduction of influenza morbidity until more effective interventions are available. However, evidence for consistent high-level protection is elusive for the present generation of vaccines, especially in individuals at risk of medical complications or those aged 65 years or older. The ongoing public health burden caused by seasonal influenza and the potential global effect of a severe pandemic suggests an urgent need for a new generation of more highly effective and cross-protective vaccines that can be manufactured rapidly. New vaccines based on novel antigens that differ from the presently licensed vaccines are in development. Active partnerships between industry and government are needed to accelerate research, reduce regulatory barriers to licensure, and support financial models that favor the purchase of vaccines that provide improved protection. Active pursuit of this goal now will save lives every year and when the next influenza pandemic occurs. In the meantime, we should maintain public support for present vaccines that are the best intervention available for seasonal influenza.”

Osterholm recalls the reaction that The Lancet paper created: “In 2012, when I published a paper on the limited effectiveness of flu vaccines and said how their availability will always be very limited during a pandemic, there were people who compared me to Andrew Wakefield and the measles vaccine and that I was somehow undermining the whole system. We must understand our limitations to understand why we need new and better vaccines. I think that concept is now actually a norm because people no longer disagree with the fact that we have challenges with our current flu vaccines. The question is how we get around it. Now there is a recognition that we can likely build much more effective flu vaccines that can target many different influenza strains with one vaccine and that these may have durable protection over many years, if not decades.  We have called them game-changing flu vaccines, while others have called them more broadly protective vaccines but at least the awareness is there. Now we must actualize getting it done.  As I pointed out in the book, the U.S. spent more than a billion dollars on HIV vaccine research -- which I fully support -- but the point is that the U.S. only spent $35 million total on better flu vaccines. That provides a perspective on how we have lost sight of a looming influenza pandemic.  We need to refocus but this is not going to happen without the pharmaceutical industry’s participation; they don’t necessarily see an international market and they don’t see how they can achieve a return on their investment because vaccine development is not going to be cheap. This requires government and philanthropical organizational investment, and hopefully we are getting closer to that. I think we have almost been derailed over the course of the last six months due to other governmental priorities.”

Osterholm points to a CIDRAP-produced report, The Compelling Need for Game-Changing Influenza Vaccines: An Analysis of the Influenza Vaccine Enterprise and Recommendations for the Future, referred to as the CCIVI, for CIDRAP Comprehensive Influenza Vaccine Initiative. The CCIVI report identified four reasons for the collective failure to secure 21st century influenza vaccines, including failure to make the case for new vaccines; lack of research and development to bring new influenza vaccines to fruition; lack of a business pathway to overcome financial disincentives of current vaccine manufacturers to end their annual vaccine sales market and adopt a market for a once-a-decade vaccine; and finally, a lack of a governing body to help make new influenza vaccines a reality.

As Osterholm writes in Deadliest Enemy, “There can be no greater bang for the buck than investing in what I call a game-changing influenza vaccine. In any given year, or even in any given decade, the probability of a major influenza pandemic is low. As a possibility for some unknown point in the future, it is virtually a dead certainty.”

But perhaps too many people are betting on their lives in this high-stakes game of chance. 

“Look at where we are with coronaviruses,” Osterholm says. “I am absolutely certain that we are going to see this virus making its way to the Horn of Africa and it is going to get into the camels there; all the camel traffic is basically from the Horn of Africa to the Arabian Peninsula. Once MERS or a MERS-like virus infects 7 million camels in Somalia, we’re going to see an outbreak take off and it will be devastating. Now, we can anticipate this scenario, as this is not rocket science; and yet what are we doing? So, we’re not learning from previous outbreaks. I gave my first lecture on Zika almost 14 months before it hit the Americas, and so it is coming, get ready! That’s what I fear we are not learning from outbreaks such as Ebola.”

Turning to crisis agenda item No. 2, those high-impact regional outbreaks such as Ebola and coronavirus, it’s clear that this is the most significant area to which past experience can be applied. Yet, Osterholm begins his chapter on Ebola by asking, “Why were we surprised in 2014?” Although first identified in 1976, Osterholm says Ebola’s surprise attack was multifactorial and adds, “Ebola virus didn’t change. Africa changed. This simple fact had infinitely complex implications for this outbreak and will have for any yet to come.” Additionally, Osterholm says, “… because of its rarity, Ebola hadn’t been factored into individual threat matrices as malaria, TB, AIDS and vaccine-and diarrheal diseases had.”

“The Ebola situation in Africa is a gas tank waiting to blow up,” Osterholm says. “In the U.S., there may be a few cases but it’s never going to be a huge clinical problem here; it may be more of a public relations problem than anything else. Yet everyone in the U.S. almost went off the deep end as if what happened in Freetown was going to happen here. We don’t yet understand in the U.S. what kills us versus what hurts us versus what concerns us versus what scares us and sometimes they are all very different.  We, in the U.S., haven’t had an outbreak like Ebola. But something else could impact us, and so you can’t respond effectively if you wait until that one does happen and then try to respond. It’s like having done no hurricane evacuation planning until the hurricane is now upon you.  It doesn’t work.”

Zika virus could have been the next microbiological “hurricane” for the U.S.; as of the time of writing, currently there are 215 symptomatic Zika virus disease cases reported and cumulatively, there have been 5,423 symptomatic Zika virus disease cases reported to the Centers for Disease Control and Prevention (CDC). “People are saying that Zika is almost gone and that is not true,” Osterholm says. “All we need to do for proof of that is look at the situation with chickungunya. Brazil experienced its initial wave in 2014-2015 and yet it just reported something like 100,000 new cases, so chickunmgunya is back with a vengeance in Brazil. These things cycle and so Zika may have a reduced number of cases but as we see with other viruses, it’s going to come back and there is still a very large part of the world that is vulnerable.  Some people will be surprised again when it comes back; in 2018 or 2019 we could have a hell of an outbreak in the Americas.” In Deadliest Enemy, Osterholm alludes to a “fragmented leadership” in vector-borne disease control and says he supports a fledgling coalition that could united countries with a vested interest in preventing mosquito-borne diseases, and Aedes-transmitted illnesses in particular.

Such efforts are imperative, Osterholm says, especially considering the false sense of security that many cultivate when the U.S. escapes so many outbreaks that it observes happening elsewhere. “Look at what is happening in Yemen right now,” Osterholm says. “We have the largest cholera outbreak in human history underway right now.  I’ll grant you that in the days before sanitation, cholera was a very important disease in the overall disease-risk picture. In the old days, because the transportation around the world was so much slower, we didn’t see widespread cholera. We didn’t have the explosive population numbers then like we do today.  You hardly hear about cholera in the U.S.; the port in Yemen was closed in the recent political conflict to limit supplies to rebels and now healthcare professionals can’t get the medical supplies they need. It doesn’t affect us in the U.S. so people are not talking about it.  There is the potential for some of these pathogens to land in the U.S. and do real harm.”

Some pathogens do reach U.S. shores before they are studied for their ability to mutate. As Osterholm writes in Deadliest Enemy, “The one previous time that the Ebola virus appeared in America was in a holding building for laboratory-bound macaque monkeys in Reston, Va. In 1989. This outbreak as the backdrop for Richard Preston’s 1995 bestseller, The Hot Zone. Though all the monkeys died of the disease or were euthanized to prevent spread, the Reston strain – which is different from the one that caused the outbreak in West Africa – turned out not to be infectious to humans. Unfortunately, this has not been the case for the four other known strains. In Reston, the humans lucked out.”

As Osterholm writes in Deadliest Enemy, “In 2012, a team of Canadian researchers showed that Zaire Ebola, the same strain that caused the virus in west-central Africa, could be transmitted via the respiratory route from pigs to monkeys, both of whose lungs are very similar to those of humans. If airborne transmission of Ebola virus to and by humans were to occur, it would be a game changer. That is a very, very big deal. Though I was criticized as being alarmist for bringing this up in a New York Times op-ed I wrote in September 2014, I considered it – and still consider it – a possibility we cannot and should not dismiss.” In 2015, Osterholm was among 19 authors of a review on Ebola virus transmission that was published in the microbiology journal mBio in which they stated, “A fair amount of evidence suggests that (respiratory transmission of Ebola viruses) could be possible, even without dramatic evolution or genetic changes in Ebola viruses.” 

“We are always learning how the bugs evolve,” Osterholm says. “Ebola is a good example of that.  I was pounded for talking about Ebola as a potentially airborne-transmitted agent even though we have the examples of Ebola Reston where we have seen dramatic changes in this virus. I don’t know if it would ever become an airborne pathogen, but I don’t want to find out.  We wouldn’t have to find out if in fact we just actualized an Ebola-prepared world plan that involved effective vaccines; the Merck vaccine is the most limited one as a monovalent but if you look at GSK and the J&J vaccines, they are quite good. Wouldn’t it be great if we never had to find out if Ebola could become an airborne pathogen? And so, to me, that’s just the kind of common-sense application of science and resources needed to stave off an outbreak. But the world is still not prepared and I know this sounds remote, but I’m certain it’s going to happen.”

Osterholm continues, “Look at smallpox – our country is better prepared because Secretary Thompson made sure we have a much better smallpox vaccine and that it was stockpiled. However, a smallpox outbreak could happen on a worldwide basis where due to faster global transportation it gets transmitted very quickly, and we wouldn’t be ready at all. While we must attend to pathogens such as MRSA and other important garden-variety agents in places such as hospitals, it is the catastrophic agents that have a way to bring the world to its knees. At least let’s be prepared to take those off the table by being prepared. To me that’s my common-sense risk assessment picture – I don’t want to prepare for the last war every day until the next war and we find out we were preparing for the wrong one.”

Turning to crisis agenda item No. 3, bioterrorism and weaponized organisms, as Osterholm writes in Deadliest Enemy, “In spite of biological warfare’s long history … in the more than a decade and a half since the anthrax attack, our state of unreadiness and denial has remained more or less the same. What has changed, though, is our grain-of-function capability. Tools to fundamentally alter how a virus or bacteria kills, or even potentially transmits, that did not exist in 2001 are mow in the hands of many thousands of scientists…” Osterholm says he worries about anthrax, smallpox and “any microbe that we can change through our new hyper-lab tools to be readily transmissible to people or animals and resistant to current treatments for vaccines.” As he observes in Deadliest Enemy, “Despite the fact that it has harmed no one in almost 40 years, smallpox remains one of the scariest monsters on earth.”

Osterholm says, “Our challenge is that we always seem to be a day late a dollar short in our anticipated response.  A year ago, when I wrote about getting ready for the return of the smallpox virus, it was a yawner for most people, yet two months ago the University of Alberta announced that they had just constructed horsepox virus de novo – that is the same size virus as smallpox. The researchers used horsepox so as not to be accused of bringing back smallpox if anything went wrong; if you can make horsepox you can make smallpox. That should have been a wake-up call. Is anyone planning if there is a return of smallpox in the world? So many of these things are foreseeable.”

Osterholm embraces what he calls “consequential epidemiology,” the idea that “by attempting to change what could happen if we don’t act, we can positively alter the course of history, rather than merely record and explain it retrospectively.”  As Osterholm says, “The adoption of this approach requires resources and fortitude, and it’s more difficult to accomplish to create and sustain a long-term priority program when the particular pathogen or disease is not in the news every day. As an example, look at this year’s March on Science, which everyone thought would be a revolution and ultimately direct greater attention to the importance of science. But it just got quiet since then, and I think a fatigue factor sets in. But I consider myself to be the tortoise in the race here, I’m not real fast but I’m not going to give up.  The challenge in our healthcare institutions is that everyone can experience the adrenaline rush when there’s a new exotic bug that enters the scene, and this is where in the book I talk about our confusion between what kills us versus what hurts us, etc.  If you look at the so-called garden-variety bugs, they are increasing in their resistance to drugs and so infection prevention as well as antibiotic/antimicrobial stewardship programs are critical because day after day after day, we are preventing a cumulative number of deaths and serious illnesses and in the long run they far exceed the epidemiological bumps that occur with some of these exotic bugs. The garden-variety bugs often are not sexy, and they don’t often raise the adrenaline level but they are critical nonetheless and have to be balanced with the exotics.”

One of the recurring messages in Osterholm’s book is the fact that something can be done about infectious disease threats. “I think people are paying attention to the growing problems, but what they need is a way to understand that there is something that they can do about it,” he says. “We do see ways in which we are becoming more empowered. For example, when the Centers for Medicare and Medicaid Services (CMS) underscored the importance of infection control by tying reimbursement to healthcare-acquired infections (HAIs), that made a big difference. Now with antibiotic stewardship it’s the same thing – those are the kinds of victories that we surely can have and must have.  At the same time, I think healthcare workers in general who are parents and grandparents, must understand there are bigger issues like flu vaccine, like antimicrobial issues, like preparedness for these genetically altered organisms and the potential for terrorism, that those too, are very important and if they don’t have the support of the general medical community, then it’s harder for government to be concerned. So, we need their advocacy very much. I heard this time and time again after 9/11, most of our resources were diverted to these bioterrorism agents and we ran short on resources for other routine infections and there is some real truth to that.  At the same time, 9/11 helped build some of the infrastructure, particularly state and local health departments, and the awareness of antibiotic resistance and so what we need to do is all come together under the shared agenda of infection prevention.  As I said in the book time and time again, we are all going to die, but what I hope we can do is make it so that we don’t have these early, painful, disabling conditions and deaths that occur and that we can all live a long life.”

In the book’s final chapter, titled “Battle Plan for Survival,” Osterholm tackles nine priorities within the aforementioned crisis agenda. Let’s take a quick look at some of these priorities.

Priority 1 is to create a Manhattan Project-like program to secure a game-changing influenza vaccine and vaccinate the world. As Osterholm observes, it is scientifically attainable, but the rest of the world will need to catch up to the financial and resource-heavy commitments that the U.S. could make here: “Our best guess is that we would need to invest $1 billion per year for seven to 10 years to make this happen,” he writes in Deadliest Enemy. “This is about what we currently invest each year in HIV vaccine research, and I believe we’d have a greater chance of the influenza vaccine working.”

Priority 2 is to support and expand the mission and scope of the Coalition for Epidemic Preparedness and Innovations (CEPI) to fast-track comprehensive public-private vaccine research, development, manufacturing and distribution for diseases of current or potential critical regional importance.

“In terms of lessons learned from the past, I think we are making some progress,” Osterholm says. “If you look at the three major reports that came out of the post-Ebola era – WHO, National Academy of Medicine and the Harvard and London schools -- all noted that very few preparedness-related action items have been acted upon.  CEPI is an example of where we are trying to do some things but it is so limited. We need a better-prepared world and there is no reason why we can’t imagine this.” As Osterholm writes in Deadliest Enemy, “When I look at the portfolio of critically needed vaccines and the resources that will be required to bring them to licensure, purchase and distribution, I believe an annual $1 billion infusion of support will provide a huge return on investment in terms of both lives saved and direct and indirect economic costs. All the parties are at the table to make this happen. It will be up to them to embrace and support this more aggressive approach.”

Similarly, several priorities address the need to fund, launch and maintain key alliances. Another priority is to recognize that TB, HIV/AIDS, malaria and other infectious diseases remain major global health problems. Additionally, the need to anticipate climate-change effects is an imperative, according to Osterholm, who writes, “While climate change may not influence the likelihood of a pandemic, it surely will have a major impact on the incidence of other infectious diseases. Think of infectious diseases as fire and climate change as fuel.”

Despite the chilling scenarios that Deadliest Enemy explores, Osterholm notes, “There are many things that we can do and that makes me optimistic,” he says. “My job in writing this book was not to scare people out of their wits but into their wits. One of the things that makes me want to get up every day and go to work is the fact that there is so much that we can do. My ongoing concern, however, is we will have one of these crises and we will ask ourselves, ‘why didn’t we prepare? We knew what to do and we knew how to do it. But we didn’t do it.” 

Osterholm acknowledges that the nine compelling priorities he puts forth in his book are ambitious and writes, “We know what we are suggesting will be difficult to implement and will require significant commitments of money, personnel, diplomacy, political power and courage. That doesn’t make it any less necessary. We shouldn’t have to wait for something to happen before we react. The dots are there to be connected. When we say we were surprised by Zika, we shouldn’t have been. When we say we were surprised by Ebola, or yellow fever or chickungunya, or so many others, we shouldn’t have been. And we shouldn’t be surprised if tomorrow’s crisis is caused by Nipah, Lassa, Rift Valley fever or a new coronavirus.”

References:
Osterholm MT and Olshaker M. Deadliest Enemy: Our War Against Killer Germs. Little, Brown & Company. 2017.

Osterholm MT, Kelley NS, Sommer A and Belongia EA. Efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis. The Lancet Infectious Diseases. Vol. 12, No. 1. Pages 36-44. January 2012.

 

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