Less than five years after the outbreak of COVID-19, the world remains vulnerable to another pandemic. Over the past five months, a mutated strain of the H5N1influenza virus detected in dairy cattle poses a potential risk for a pandemic-causing virus. Yet governments and international organizations have done far too little to prepare for such a scenario, despite the lessons they should have learned from the global battle with COVID-19.
After the COVID-19 crisis revealed the shortcomings of the global public health response system, many assumed that governments and international organizations would strive to fix the most obvious problems. Given the catastrophic human and economic costs of the pandemic, countries had a strong incentive to start spending heavily on developing new generations of more protective influenza and coronavirus vaccines, as well as to greatly expand global manufacturing and distribution networks. But this has not happened. At current funding levels, it likely will take a decade or longer to develop more effective and longer-lasting vaccines. Although there are groups at work on new treatments and other antiviral initiatives, on the whole, global society does not appear to be much more prepared for a future coronavirus or influenza pandemic than it was five years ago.
The resurgence of H5N1 influenza in humans and animals has highlighted these failures. Although the virus was identified in the 1990s, over the last 20 years it has continued to mutate, reinventing itself over and over again. Today, it is infecting millions of birds, but it has also become more capable of spilling over into at least 40 species of mammals. It still cannot easily transmit between humans, but infections in dairy cattle, which have influenza receptors for both avian and human influenza viruses in their udders, demonstrate the risk for a new pandemic.
It is impossible to know when a new pandemic will arise, or which specific pathogen will be its cause. H5N1 is just one of the viruses that could mutate into something that will start a pandemic. But eventually, one will happen. It is therefore time to move away from vague recommendations and best practices to a far larger-scale program aimed at producing new and better vaccines, antiviral drugs and other countermeasures, and building the infrastructure at the scale needed to protect entire populations. Although such efforts will be costly, failing to take these steps could be catastrophic.
THE AVIAN THREAT
Although it has never caused a human pandemic, the H5N1 virus has been on the public health radar for decades. It was first identified in late 1996, when a new influenza virus began circulating in avian species in Asia, initially known as high pathogenic avian H5N1. Influenza strains are classified by the characteristics of two proteins, hemagglutinin and neuraminidase, on the virion particle’s surface. The pathogen gained international attention for causing a 1997 outbreak in Hong Kong, killing six of the 18 people infected. To control the spread, Hong Kong was forced to cull millions of poultry from its markets and from the supplying farms.
In December 2003, H5N1 reemerged. For the next three years, wild birds spread the virus to domestic waterfowl and chickens in Asia, Africa, Europe, and the Middle East. It also infected a limited number of mammals, including tigers in Thai zoos, and eventually made its way to 148 humans in five Asian countries. Seventy-nine of those cases—53 percent—proved fatal. As the virus spread, public health officials grew concerned that the world was on the brink of a devastating pandemic. In 2005, at the height of that scare, one of us (Osterholm) wrote a Foreign Affairs article explaining how governments should prepare for such a scenario. The essay noted that the World Health Organization’s (WHO) and various countries’ pandemic response plans were vague and did not offer a realistic blueprint for how to get a population through a potential one-to-three-year pandemic. The article recommended an initiative to provide vaccines for the entire world, with a well-defined schedule to ensure that it would be carried out in a timely way.
Fortunately, H5N1 did not cause a pandemic in 2005. But in late 2019, a different virus did. COVID-19 was a novel coronavirus—so called because of the protein spikes on the virion surface that give it a corona-like appearance—that began infecting thousands of people in Wuhan, China. Soon, it spread across China, then the continent, and then the world. In its first year, COVID-19 infected hundreds of millions of people and killed at least three million.
THE HUMAN MIXING BOWL
Influenza pandemics are not a new phenomenon. From 2009 to 2010, an H1N1 virus—popularly known as swine flu—rapidly spread around the planet, killing an estimated 575,000 people. In United States, the Centers for Disease Control and Prevention (CDC) estimated that 60.8 million people were infected, 273,300 hospitalized, and 12,469 died. This level of morbidity and mortality was tragic, but for a flu pandemic, relatively mild. After all, the 1918 flu pandemic, also H1N1, killed between 50 million and 100 million people worldwide, or at least 2.7 percent of the world’s population.
It might be tempting to conclude that the 2009 pandemic was less deadly than its 1918 counterpart because of 90 years of intervening medical progress, including improved vaccines. Unfortunately, that conclusion is incorrect. The 2009 virus was simply less virulent than the one that spread in 1918. Moreover, the most vulnerable group—people over 65—already had H1N1 antibodies thanks to previous infections with related viruses. As COVID-19 showed, the world is no better prepared for pandemics today than it was a century ago and, in some ways, worse off. Today, there are three times as many people as in 1918. Hundreds of millions live close to poultry and pigs. Air travel can transport infected carriers anywhere in the world within hours. (There are more than a billion international border crossings annually.) And global supply chains have created far greater international interdependence. Humanity, in other words, has become an extraordinarily efficient biological mixing bowl as well as a highly productive viral mutation factory.
That does not mean an H5N1 pandemic is about to unfold. Both the WHO and the CDC assess the current risk of H5N1 in humans to be low. So far, there is no compelling evidence that the current virus is becoming better at attaching to the receptor sites for influenza in the human respiratory tract, the critical bar H5N1 must clear before it can cause a pandemic. To date, the primary outcome of humans becoming infected with H5N1 in the United States—whether by association with infected poultry flocks or working with infected dairy cows—is conjunctivitis. This is unsurprising since humans have receptor sites in the eye for bird viruses.
But nature can change fast. Viruses are constantly mutating and reassorting. Influenza reassortment can occur when a human, pig, or cow becomes infected simultaneously with two different viruses, presenting the opportunity for the pathogens to swap critical genetic segments and create new strains. Although the vast majority of these alterations either have little significance or make the new form less robust and adaptable, occasionally a mutation or reassortment will make a virus more transmissible, dangerous, or both. H5N1 could experience such a transformation at any point, turning the current consensus on its head. And H5N1 is just one of the influenza strains the epidemiology community is closely monitoring.
Officials should make no mistake: there will be more influenza and coronavirus pandemics, and any one of them could prove far more catastrophic than the COVID-19 pandemic. Whenever it occurs, it will almost certainly be a virus, primarily transmitted from person to person via the airborne route, a “virus with wings,” meaning the viral particles can be suspended in the air for long periods and distances. When such an outbreak transpires, rapid global transmission will happen before anyone realizes the world is in the earliest days of a years-long pandemic. Governments cannot wait to prepare until a virus is already spreading around the world. As the last five years have shown, even a moderately deadly disease can have enormous health, economic, social, and political consequences.
IN SEARCH OF A SILVER BULLET
It is time for all nations to wake up to the danger and prepare for a new pandemic. At the top of the list should be a game-changing improvement in the medical countermeasures that governments put in place to fight influenza viruses and coronaviruses. Specifically, this means vaccines, drug treatments, and diagnostic tests. Improving the design and systems for manufacturing personal protective equipment quickly and in sufficient numbers will also be essential. Governments must begin investing heavily in vaccine research and development, including studies aimed at creating universal influenza and coronavirus vaccines: ones that provide protection against multiple strains of either virus, offer durable protection for extended periods, and can be manufactured quickly and distributed globally.
To be fully effective, improved vaccines must be safe and provide multiyear protection against most possible influenza strains. They must significantly reduce the likelihood of serious illness, hospitalization, and death, as well as prevent infection and transmission. Ideally, they should be produced and routinely administered to the general population before a pandemic virus emerges, and be readily available in low- and middle-income countries. Researchers are still a long way from creating such a vaccine, though current developments in the lab suggest it is possible. But at the current level of support for research and development, it could take a decade or more to achieve these game-changing vaccines. With significantly greater government support, this timeline almost certainly could be shortened.
The price tag for such measures will be high, and not all of the investment will pay dividends. But a new pandemic could prove far more deadly or costly than a new war, and governments rarely shy away from spending whatever is deemed necessary on new and better weapons. Biological security is just as important as military security, and the United States needs to accept the idea that it would be going to war against a microbial enemy potentially far more dangerous than any conceivable human foe.
THE WEAPONS WE HAVE
Until these universal or near-universal vaccines are created, policymakers will need to work with currently available influenza and COVID-19 vaccines. These shots are good, but hardly great. For example, they limited illness and deaths caused by the 2009‒10 H1N1 influenza and the COVID-19 pandemics, but the protection they provide against infection varies widely. Even now, the effectiveness of COVID-19 vaccines against symptomatic illness, disease severity, and hospitalization is largely determined by the viral variant then circulating and whether the infected person is immunocompromised. Similarly, the effectiveness of influenza vaccines against illness requiring medical care ranges from less than 20 percent to as high as 60 percent for any given flu season.
COVID-19 and flu vaccines also lack durability. In one recent study, the CDC found that COVID-19 inoculations provided approximately 54 percent protection against the need for medical care at an average of 52 days after vaccination. According to a different study, the vaccine loses almost all of its protective powers after a year. Current flu vaccine protection is even shorter, beginning to wane after only a month or two.
To keep up, health authorities generally recommend booster vaccines every year for influenza and even more often for COVID-19, with the antigenic component changing to match the most recent circulating strain. But when a reassorted or mutated virus with pandemic potential emerges, it is likely to be significantly different, causing vaccines to miss their targets. That, in part, was why H1N1 was able to spark a pandemic in 2009. The United States has tried to get out ahead of H5N1 by stockpiling 4.8 million vaccine doses, which were recently tested and found to be potentially effective against H5N1 by the Food and Drug Administration. But if a new H5N1 variant were to cause a pandemic, the changes to the virus’s makeup could render the present vaccines largely or entirely ineffective.
COVID-19 and flu vaccines lack durability.
Even if the vaccine in the current stockpile does prove effective, there are not enough doses to control an emerging H5N1 pandemic. The United States is home to 333 million people, each of whom would need two shots to be fully immunized, meaning the 4.8 million doses on hand would cover only about seven percent of the population. The government would, of course, try to scale up production quickly, but doing so would be tricky. During the 2009 H1N1 pandemic, the first lot of vaccine was released on October 1, almost six months after the pandemic was declared. Only 11.2 million doses were available before peak incidence.
Other countries are no better equipped. In a 2019 report, the WHO and three academic centers estimated annual worldwide seasonal influenza vaccine production capacity to be 1.48 billion doses, with potential production capacity to be 4.15 billion doses. That means a maximum of two billion people—25 percent of global population—could be vaccinated in the first year of a pandemic.
The WHO’s estimates rely on some optimistic assumptions. In the event of a pandemic, for example, the research assumes that there would be an adequate supply of egg-laying chickens, since fertilized chicken eggs are the vessels in which most influenza vaccines are grown. But since the natural reservoir for all influenza strains is avian, the virus could kill off or otherwise compromise large numbers of chickens. Even if it didn’t, an H5N1 pandemic might erupt when manufacturers are in the middle of their normal, seasonal vaccine production, making it hard for them to rapidly switch. And a pandemic influenza vaccine strain may not grow as well in eggs and cells as do seasonal virus vaccines.
The 2019 WHO study also identified several potential bottlenecks. Manufacturers may not have sufficient facilities to put their vaccine into vials or syringes, and there may not be a sufficient and timely supply of those vials and syringes, or of reagents- the chemicals to produce the vaccines. Shipping and administration of shots will be a significant challenge in many low- and middle-income countries. Manufacturers could lack the workforce protection needed to ensure continuous production. And producers may be short on adjuvants, compounds that enhance immune responses. Without them, twice as much antigen would be needed per dose.
THE MILITARY MODEL
Public health experts and government health officials are aware of the threat of another pandemic and have launched a variety of initiatives to mitigate it. The Coalition for Epidemic Preparedness Innovations—focused on developing vaccines and treatments for infectious diseases—has outlined a plan for delivering “pandemic-beating vaccines” within 100 days of a WHO declaration. CEPI has laid out five areas of innovation needed to make this a reality: creating a library of prototype vaccines for pathogens across multiple virus families, having clinical trials networks at the ready, speeding up identification of immune response markers, building global vaccine manufacturing capacity, and strengthening disease surveillance and global early-warning systems. These innovations, if realized, would greatly improve the world’s pandemic readiness. But with current funding levels, the project’s 100-day target is hugely ambitious and unlikely to be realized over the next decade for either influenzas or coronaviruses. And as public health experts and governments rightly focus on shortening the time from the beginning of the pandemic until the first vaccine doses are available, just as important is how long it takes until everyone is vaccinated.
Nonetheless, some important steps forward have been made since the 2019 report. Improvements in mRNA technology, first used to make the most successful COVID-19 vaccines, could help speed up influenza vaccine production. Three Phase 3 trials are underway to evaluate the effectiveness of mRNA influenza vaccines. But no such vaccines are yet ready, and it is unclear when they will be.
In response to all these shortcomings, beginning in 2019, the Center for Infectious Disease Research and Policy at the University of Minnesota, which one of the current authors (Osterholm) directs, has led an effort to coordinate research and development of new seasonal and universal influenza vaccines. Using a team of 147 multidisciplinary experts, CIDRAP launched the Influenza Vaccines Research and Development Roadmap to advance the scientific and policy knowledge needed to produce better vaccines and track progress. So far, the initiative has identified more than 420 projects that address at least one of these strategic goals, totaling over $1.4 billion, with U.S. government agencies funding approximately 85 percent of these research studies. This is a start toward more effective vaccines, but only a start. Recently the Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) provided $176 million to Moderna to develop an mRNA-based pandemic influenza vaccine aimed at multiple strains of the virus. This effort should improve the speed with which a vaccine can be made available in an emerging influenza pandemic, but it is not expected to improve on the effectiveness of the current generation of mRNA vaccines.
Hope is not a strategy.
BARDA has recently launched an initiative to develop better coronavirus vaccines and antiviral drugs, called Project NextGen. While it is to be hoped that this effort leads to better and quicker results, the $5 billion government investment—a tiny fraction of what the United States devotes to weapon systems procurement—is only a minimal down payment on the research and development needed to accomplish this important goal. There is nothing currently in the legislative pipeline to suggest that Project NextGen will continue receiving vital government support.
Given these shortfalls, it will likely be a long time before scientists develop game-changing vaccines. In the interim, governments will have to dramatically increase the capacity to produce at pandemic scale the vaccines the world already has. This will mean high-income nations subsidizing their own pharmaceutical manufacturing capacity and helping middle- and low-income countries establish facilities and train workers to staff them.
At first glance, the costs may seem prohibitively high. But consider the stakes. If H5N1, or any other airborne virus that begins to spread in the human population, sparks a pandemic with a fatality rate even three to five percent higher than COVID, the world will be going to war against a terrifying microbial enemy. It would be far more deadly than any pandemic in living memory or any military conflict since World War II. Viewed from that perspective, adopting a military model of planning, procurement, and development is not just rational but essential. Yes, some of the pandemic preparedness projects the government funds may not pan out. Others may never go into use. But governments, and the people that vote them into power, have long accepted that aircraft carriers, fighter jets, and other weapon systems come with enormous price tags and take many years to finance, design, build, test, and commission. And they also accept that some of these arms may sit in storage until they are obsolete. Nations invest anyway, because in war, such weapons become indispensable. It is urgent that governments begin to think the same way about pandemic preparedness.
Of course, it is still possible that such a pandemic may never arise—or that it doesn’t occur for many years. But hope is not a strategy. The United States and the rest of the high- and middle-income world need to start devoting the necessary resources to developing better vaccines, treatments, and other countermeasures immediately. Humanity will not get ahead of a pandemic-causing virus without such commitment.
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