Ready or Not, Here it Comes

Is the world ill equipped to handle infectious disease outbreaks? In his latest book, Michael Osterholm says yes, and explains why and what the world needs to do about it.

By Kristen Jill Kresge

In a 2015 TED Talk, Bill Gates said that “If anything kills over 10 million people in the next few decades, it’s most likely to be a highly infectious virus rather than a war. Not missiles, but microbes…we’re not ready for the next epidemic.”

In Deadliest Enemy, Our War Against Killer Germs, Michael Osterholm, founding director of the Center for Infectious DiseaseDeadliest Enemy 01 Research and Policy and regents professor at the University of Minnesota, and documentary filmmaker and author Mark Olshaker tackle how the global public health community needs to prepare for epidemics in the 21st century. They outline a nine-point Crisis Agenda to address the major infectious disease threats facing the world today from A to Z, or rather from AIDS to Zika.

The book opens with a chilling account of what it was like to be sitting around a table in the Director’s Conference Room at what is today the US Centers for Disease Control and Prevention (CDC) 36 years ago this month. It was June of 1981 and Osterholm and others were discussing two mysterious clusters of Pneumocystis carinni pneumonia (PCP) among otherwise young, healthy gay men in Los Angeles and New York City.

“None of us around the table that day in Atlanta realized that we were bearing witness to an epochal moment in history: the world’s transition into the era of AIDS,” Osterholm writes in the book.

James Curran, under whose leadership a task force was set up to explore this medical mystery, invited the 28-year-old Osterholm into the room that day. He was at the CDC for another purpose entirely: toxic shock syndrome (TSS). Following an outbreak of TSS in Osterholm’s home state of Wisconsin, he became involved in a different medical detective story—what was causing TSS and how could it be prevented? Curran’s career, like many others working in public health in the early 1980s, went on to be defined by HIV/AIDS. While Osterholm did not work solely on the virus throughout his career, it affected him both professionally and personally. In 1985 his aunt, a nun and teacher in San Francisco, died an agonizing death from PCP after receiving an HIV-tainted blood transfusion following a broken hip.

“AIDS can serve as a dire warning about the possible: a black swan of an infectious disease that seemingly came out of nowhere, unleashing unimagined suffering on an unsuspecting world,” Osterholm and Olshaker say.

Other infectious disease threats are well known, such as influenza. The authors provide a detailed and terrifying description of the death and destruction of pandemic influenza. Some estimates suggest the death toll from the 1918 flu pandemic, often inaccurately referred to as the Spanish flu, was close to 100 million. That is far greater than all the civilian or military deaths due to World War I. “In sheer numbers of human beings killed, the 1918 flu was the deadliest pandemic killer of all time. More people died in a six-month period … than have died from AIDS in the roughly thirty-five years since that virus was identified in the human population,” they write. Yet Osterholm and Olshaker estimate that globally US$35 million to $45 million is spent annually on the research and development of more effective and longer lasting flu vaccines, compared to an annual investment of $1 billion on HIV vaccine research. “Imagine what we could do if research on a game-changing flu vaccine was funded at a similar level to HIV and done in a coordinated and collaborative manner.”

And the worst part is that unlike other pathogens, including Ebola, the severe acute respiratory syndrome (SARS) virus, or the Middle East respiratory syndrome (MERS) virus, which most likely will manifest as regional epidemics, epidemiologists know that pandemic influenza will strike again. “We don’t know which, of all the influenza strains we’re watching, will emerge as a pandemic one, or whether it will be something we haven’t seen before. What we do know is that when it happens, it will spread before we realize what is happening. And unless we are prepared, it would be like trying to contain the wind,” they write. Like I said, terrifying. Even a moderately severe flu outbreak would have dire consequences on global trade and the already taxed healthcare systems of developing countries, similar to but likely much worse than what was seen during the 2014-2015 Ebola outbreak in West Africa.

So why aren’t we more prepared for pandemic flu? Well there are probably a multitude of reasons, both financial and scientific, but Osterholm suggests that the public as a whole isn’t as concerned about it as other viral threats because they are driven largely by emotion, not reason. There was a great deal of panic across continents during the latest Ebola outbreak, and media coverage was saturated with stories about the link between Zika and microcephaly in newborn babies, but there aren’t nearly as many people worried about pandemic flu. “Public health science is based on statistics and probabilities. But we as a population don’t think in those terms,” the authors suggest. “Rather we think emotionally about things like disease and death.” This is what allows us to be afraid of Ebola, but have little concern about antimicrobial resistance that threatens to leave the arsenal of currently available antibiotics largely moot.

In many ways, the world today provides what the authors refer to as a hyper-mixing vessel for pandemic pathogens. Livestock production, which has expanded to support a growing human population, is helping fuel the spread of viruses from animals to humans. As Osterholm pointed out in a recent op-ed article in The New York Times, the earth is now populated by 7.4 billion people, 20 billion chickens, and 400 million pigs. Trade and air travel have made the world more interconnected than ever before. And climate change is also aiding the spread of disease, with more and more places on the globe suffering from mosquito-spread viruses, including Zika and malaria.

The best way, the authors contend, to be ready to face these growing threats is to develop and deploy vaccines against the top pathogens. This of course is the goal of the newly formed Coalition for Epidemic Preparedness Innovations (CEPI; see A Crisis Gives You Wings and An Interview with Richard Hatchett, IAVI Report, Vol. 21, Issue 1). Osterholm points out that the role of CEPI, as well as that played by foundations such as the Bill & Melinda Gates Foundation and The Wellcome Trust, are critically important in helping to fill gaps in vaccine discovery. These gaps exist in part because the business model for vaccine development has changed. In 2014, the authors say that the five top drugs generated more than $49 billion in sales for the pharmaceutical companies that manufacture and market them. By contrast, the top five vaccine manufacturers in the world had combined sales of only $23.4 billion that same year. Vaccines are not the money makers they once were and the cost to develop and manufacture them is high. And Osterholm argues that governments haven’t stepped up as much as they should, leaving some of the burden of vaccine development to public-private partnerships. This is why he suggests a product-development partnership (PDP) akin to the International AIDS Vaccine Initiative (IAVI) be formed to address flu vaccines.

Osterholm, who is involved in CEPI, sees that model as the best chance for creating a “viable and dependable” pipeline of vaccines for emerging pathogens with pandemic potential. “We should all pay close attention to CEPI’s progress,” he writes. “Our lives could one day depend on it.”

I spoke with Osterholm in May about his book. An edited version of our conversation follows.

In the beginning of the book, you describe what it was like to attend a meeting at the CDC to discuss a new infection occurring among small pockets of gay men, which of course was later identified as HIV. How did that experience shape your career?

You have to put meetings like this into two buckets of perspective. One is what I was thinking about at that time in my career. And second of all, how do you look at it years later in terms of what was happening? You know that some events are history-defining as soon as they happen, like the morning of 9/11. You only really come to understand the importance and significance of other events in history with time.

That first meeting was very significant for me as it came early in my career, and as I said in the book, I felt kind of like I was beamed up to the “mother ship” of public health. But it was only with time that I understood the significance of having been able to participate in that, and what a special opportunity it was for me to be there. Of course the close relationships that I developed over the years with the CDC professionals working on HIV were also incredibly valuable. Most notably was my relationship with Jim [Curran], who, as I said in the book, was one of the real heroes of the work with HIV, in my opinion. He really did so much to help define the epidemiology in the early days of HIV.

Did you ever consider making HIV/AIDS the focal point of your career?

If you ever worked on HIV in the early days you never did stop working on it, no matter what else you did. In a sense it created a type of presence in your public health soul that you just never lost.

I have remained involved with HIV because even today we have issues with what you would call gay bathhouses reopening in the Twin Cities right now. And so I still find myself, even after all these years, involved with the virus. I also worked for many years to normalize HIV testing so that we could, in fact, effectively address care and treatment in ways that we needed to. For so long there was so much stigma associated with HIV/AIDS.

Back in those early days—1983 to 1985—I worked to make HIV reportable in Minnesota; in fact we were the first government body in the world to make it reportable. It was not about some kind of punishment, it was to help inform some individuals that they were potentially exposed. And when treatment became available, we quickly made certain that we would get these people into the appropriate settings for the latest antiretroviral treatment. And as we all know, the success of antiretroviral therapy in the United States has been nothing short of a miracle. It’s been remarkable what has happened.

In a few places in the book, you describe the now-infamous statement made by US Health and Human Services Secretary Margaret Heckler at an April 1984 press conference when she said that an AIDS vaccine would hopefully be ready for testing within two years. You called this “wildly unrealistic.” Curran agreed, saying, “The honest question would be, not when there would be a vaccine, but if there would be a vaccine.” You have said you didn’t believe we would see an effective HIV vaccine in your lifetime. Do you still feel that way or has your thinking changed?

I think that at the time there were two reasons I felt that way. The most important reason was that I did not want us to take our eye off the ball on prevention. What I was really concerned about was that people would say, “We have a vaccine coming shortly; we don’t need to worry about primary prevention,” which in the end still has been for all these years our most important weapon, in a sense, against this virus. Therapy truly has played a key role in prevention too. That was really the thrust of it. It was not to project some dire kind of crisis mindset, but it was more to make sure that we didn’t let people think they didn’t need to worry about all this because a vaccine is coming.

The second reason for saying that was just the science. I was sitting there trying to honestly and objectively understand the biology of how we were going to intercept this retrovirus from introduction into the body before it actually creates an ongoing infection. And for me, that was kind of, “Beam me up, Scotty”-type science.

Now, I’m the first to say that with technologic advances this could all change. Maybe today we are doing things that we wouldn’t have even considered 30 years ago. I’m still very open to that and that’s why I emphasize the need to continue to invest in HIV vaccine research. I would not for a moment suggest retrenching on any of that. We need to continue but I think we just have to be honest about the unique challenges that HIV poses, which the science world has recognized. It’s not an inconsistent message to say we have to continue to invest in this even if we don’t know if it is possible because a safe and effective vaccine for HIV would be, in a sense, a public health miracle. We can’t lose sight of that. We just can’t hold off on all of our other efforts with the idea that a vaccine is forthcoming.

You mention in your book how underfunded the efforts are to develop a broader and more effective influenza vaccine, which as you say is the one infectious disease that we can be certain will once again reach pandemic proportions. Do you think HIV vaccine R&D, by contrast, is well funded?

I don’t look at it as well funded; I look at it as an appropriately funded effort. I think people want to compare one funding effort versus another, and if you say well funded that tends to allow you to say, “Well, maybe we should move some of the funding over here.” When you talk about appropriately funded—in other words, what we must do or should do—then instead of moving funding around, you recognize that we should be increasing funding for the other infectious disease threats. I think people sometimes feel like I’m saying that HIV vaccine research is getting way too much money, but that’s not it at all. It just goes to show how underfunded we are for all these other programs. I think that for HIV vaccine research, it’s not clear you could really use much more money effectively, but you sure wouldn’t want to have less funding than you have right now.

You outline several factors that are blocking or impeding the development of an improved or as you call it “game-changing” flu vaccine, including the lack of pharmaceutical interest and the failure of governments to really put the money behind this. But yet you quote several people who say this should be a huge priority. Why isn’t it?

This is the classic example of what kills us, versus what hurts us, versus what concerns us, versus what scares us. And they all may be very different.

We have had 27 new cases of H7N9 over the last seven days in China. We have had 20-some cases every week over the last month. And normally at this time of year, the seasonal occurrence of H7N9 infection would be waning. It’s really concerning. But just like antimicrobial resistance, a vaccine to prevent pandemic influenza is majorly underfunded because both of these are not a crisis that we can yet see or feel. I think that’s the mindset we have to get away from. It would be like trying to secure all of your military equipment and all your troops the week after the war is declared. It would never happen like that in the military, yet that’s what we do with infectious disease preparedness.

One of the challenges we have is trying to allocate resources in a way that says, “It’s not a crisis yet, but this is one that you can’t wait until it happens to try to respond.” When the next influenza pandemic strain emerges it’s going to be way too late to do anything to try to stop its global spread. And our current influenza vaccines will fall so short of what we need in terms of effectiveness and availability. What we’re going to go forward with is what we have at that point. If we don’t have it by then, we’re not going to have it.

And you suggest that with the appropriate level of funding, development of a vaccine to prevent pandemic flu is absolutely possible.

It is. I think there are still many challenges to realizing an effective influenza vaccine because of the science. But I am quite optimistic, based on all we have and what we’ve done in our own work looking at game-changing flu vaccines, that there are truly those parts of the virus which we can, in fact, use as antigens that could very well produce broad spectrum protection against multiple strains for an extended duration of time.

Imagine taking pandemic flu or for that matter even a lot of seasonal flu off the table as a potential public health crisis.

Are there any shared lessons from research into broadly neutralizing antibodies for HIV that are applicable to the work on flu vaccines?

One of the things that has happened with HIV vaccine research, which I don’t think is fully appreciated, is the extent to which it has touched so many areas of immunology and infectious disease research. The basic science research has been absolutely phenomenal. There is no doubt that HIV vaccine research has had a tremendous impact on our understanding and application of human immunology as it pertains to medicine and infectious diseases. So, absolutely, the flu vaccine work has benefitted immensely from that investment in HIV vaccine research.

What do you think is needed to accelerate flu vaccine research?

I believe that the IAVI model should be the primary model for influenza. I think we need that kind of coordinated, collaborative effort—that’s as close as we get, in a sense, to a vaccine Manhattan Project. That really is important. I’m a very big fan of the IAVI model. The fact that we don’t have an effective HIV vaccine is not a function of a bad model; it’s just a function of the tough biologic challenges.

I think the CEPI model, which is really trying to advance vaccine candidates into Phase IIa trials, is really addressing more of a market issue. And even though I’m very involved with CEPI, I’ve been somewhat critical in that I don’t think it’s going fast enough. We don’t have five more years to get a MERS vaccine. We just had four new MERS cases this morning reported out of Saudi Arabia and they just keep happening and happening. If that virus shows up in East Africa and affects the camel population there, we could need that human vaccine right now.

CEPI is providing a new avenue of funding and it’s surely bringing people into the research space that wouldn’t otherwise be there, but I see the problem with flu vaccine development as more of a major coordinating issue and that’s why I favor the IAVI model. In many ways we are not any better prepared to handle pandemic influenza today, medically, than we were largely in 1918.

What about the Ebola vaccine? The advancement of vaccine candidates during the latest outbreak was lauded as a successful public-private collaboration but is it reproducible?

I think that this public-private partnership is somewhat broken. If we were really looking to prevent Ebola, we would have an African-prepared environment for Ebola. Every healthcare worker in any area of Africa that might experience a spillover would be vaccinated or offered a vaccine—emergency responders, healthcare workers, burial team members, and so on. That’s an Ebola-prepared community. We’re not there. When Ebola ended in West Africa there was a sigh of relief and it was no longer a priority. Then for two years, nothing much was happening.

These companies have invested hundreds of millions of dollars, with surely some government support and philanthropic support, but they still have put a great deal out there. GSK just walked away from the Ebola vaccine issue because the only pot that they had at the end of the rainbow was a $5 million purchase order for a yet unlicensed vaccine and they had invested hundreds of millions of dollars.

So should there be a PDP for every infectious disease to ensure development of a vaccine?

Yes, in a sense. But the other part of it is that we have to have the push and the pull. Countries need to see that these vaccines are every bit as valuable as any aircraft carrier or missile. And again, we don’t wait to purchase ships and missiles until after a war breaks out.

I wrote an op-ed piece in The New York Times about a month and a half ago talking about how infectious diseases really are a strategic investment. Our fight against infectious diseases is a national security threat. Imagine if we could take Ebola off the table in Africa, which we’re really close to being able to do today. There is Merck’s monovalent vaccine and other vaccines out there that look like they could be even much better in terms of likely effective multivalent vaccines.

We all acknowledge that in the past we’ve stopped Ebola outbreaks without a vaccine, and that’s great. But now we know what happens if one of these outbreaks gets out of control, particularly in an urbanized area. We must overwhelm an emerging Ebola outbreak every time we can and a vaccine would be the way to do it. If we had a vaccine then we wouldn’t be worried about healthcare workers or burial team members or emergency responders suddenly dying from Ebola, and we’d be much better prepared. This isn’t rocket science. It just requires the commitment to doing it.

To accomplish the nine priorities you lay out in the final chapter of your book, what you call the “Battle Plan for Survival,” you suggest there should be a major overhaul of the World Health Organization (WHO). Why is this necessary?

The real challenge with the WHO is that it is a system that was put in place at a very different time in world history. It was not made for today’s world of public health. There are some really dedicated, wonderful people at the WHO who do work that is just hard to imagine they can do given the constraints they have. If any other organization in the world was led by a board of directors of 194 individuals, there would be chaos. Anybody who took that kind of a scenario into a business class or an MBA program would be laughed out of the room. So part of the challenge is the kind of governance structure that is there. And the financing. The WHO is basically funded on pennies so they have no ability to fund large efforts like something on pandemic influenza. Imagine where we’d be today if the Bill & Melinda Gates Foundation and Wellcome Trust didn’t exist. We’d really be in trouble because the world governments haven’t stepped up either.

It’s not a political issue. It shouldn’t even be an economic issue, because you look at the cost savings of investing in these vaccines and it is so clear and compelling. From an economics standpoint, the return on investment is huge.

We all acknowledge, whether it’s flu or Ebola or any other disease, that it’s not a matter of if it’s going to return; it’s when, where, and how bad. So it’s kind of like preparing for hurricanes. Eventually a hurricane is going to hit us in many of the locations that we routinely have hurricanes, so maybe it happens every 25 years or 50 years, but it is going to happen again. And that’s what we have to see with infectious diseases, we need to have that very same kind of mindset and make the same kind of investment.

So the challenge is much greater than the WHO in and of itself. It’s about the world’s understanding of what it is going to take to provide effective public health in the 21st century. The WHO, as it’s now configured and funded, is not it. I’m not being critical of the WHO, they’re stuck like this. If I were director general of the WHO, I couldn’t do any better than Margaret or anybody else because of the tools that aren’t there that are needed.

The world is going to have to figure that out. The UN [United Nations] has to figure it out. And this is where governments like the United States and the EU and Russia and China and everybody else have to come together. There’s an old line from a commercial some years ago: “You can pay me now or you’ll pay me later.” We’re not willing to pay now, so we always end up paying later and that’s a lot more expensive, and it’s unfortunately, a lot more deadly.