A Shot in the Arm

Vaccines are underfunded, understudied, and underappreciated as a vital tool in public health. Could COVID-19 be the start of a vaccine renaissance?

Goudsmit, a bespectacled MD-PhD who hails from the Netherlands, is one of eight scientists who are part of the COVAX Independent Product Group, an effort spearheaded by Gavi, the international public-private partnership focused on vaccines, and the World Health Organization to steer billions of doses of a COVID-19 vaccine to low- and middle-income countries. To stay on top of the immense scientific progress being made, he starts every morning around 6:00 by logging on to medRxiv and bioRxiv, digital repositories where preprints of studies pertaining to COVID-19 are uploaded daily to expedite research efforts. He then prints out all the new studies he’s interested in and starts reading. Goudsmit’s primary focus with HII is on immunity and vaccine response among elderly populations, an issue that is poorly understood but of critical importance in the presence of an airborne virus that’s disproportionally killing people ages 65 and over. The volume of science being published on COVID-19 and the speed at which it’s moving are unprecedented, Goudsmit says. So are the challenges ahead, from supply-chain struggles to ensuring equitable distribution to fine-tuning our understanding of the immune response the vaccines generate.

this is a watershed moment for vaccines and a great victory for public health,” says jaap goudsmit, chief scientific officer of the human immunomics initiative, a recently launched joint project between the harvard t.h. chan school of public health and the human vaccines project.

The COVID-19 pandemic has sparked a wholesale reassessment of public health and illuminated barriers to vaccine research and development (R&D). It has cast a light on the risk-averse, profit-oriented agendas of drug makers that have led to a drop-off in traditional vaccine R&D investment, and it has exposed the dangerous tendency of governments around the world to remain reactive rather than proactive in the face of emerging health threats.

While vaccines are among the most potent tools of public health, in the last two decades they have been one of the most maligned frontiers in medicine. The fate of a COVD-19 vaccine could rectify that imbalance and shape public opinion and influence industry and government research priorities for years to come. The scientific, economic, and sociopolitical obstacles to overcome are huge. But so are the opportunities. “This is a watershed moment for vaccines and a great victory for public health,” Goudsmit says. “We may have entered an era where adult and elderly vaccination becomes as much an established public health measure as childhood vaccinations. We’ve never seen anything like this.”

An insider’s view

Over the last 35 years, Goudsmit has published more than 500 papers and has worked on developing vaccines and monoclonal antibodies for rabies, HIV, West Nile virus, and influenza, among other diseases. He was the founding chair of the Scientific Advisory Committee to the International AIDS Vaccine Initiative and co-founder of the European AIDS Vaccine Initiative. His career spans private industry, the nonprofit sector, and academia, and each professional perch he’s alighted on has provided new insights into the multilayered complexities of vaccine development—challenges that have only been amplified in the 21st century.

In 2003, Goudsmit became chief scientific officer at Crucell, a Dutch biotech firm that specialized in vaccines. That same year, the virus that causes severe acute respiratory syndrome (SARS) jumped across 26 countries, infected 8,000 people, and killed 800. The world was on edge, and “we felt an enormous sense of urgency,” Goudsmit recalls.

He and his team got to work and in two years successfully developed two antibodies that neutralized the virus when tested in vitro. The problem was, nobody needed a SARS vaccine by that point. The virus had been contained and stamped out, and in the absence of a market, the company shelved the program. The antibodies were relegated to journal articles and intellectual property filings, a sort of scientific purgatory that’s home to hundreds of other vaccine candidates that have shown promise in the laboratory against myriad diseases, including pneumonia and malaria, but have never been put through the long and expensive process of clinical testing.

At Crucell, Goudsmit worked on dozens of other projects, including one with Dan Barouch of Harvard Medical School to develop a platform that’s been used to develop and produce an Ebola vaccine, is in advanced testing against HIV, and underpins a COVID-19 vaccine candidate from Janssen Pharmaceutical Companies of Johnson & Johnson.

Still, in a wry tone, Goudsmit points out that the only vaccine of his to be licensed during his tenure at Crucell was a West Nile virus vaccine administered to geese (emphasis his) on commercial foie gras farms in Israel. It’s his way of saying that the road to any vaccine is littered with scientific potholes and the perilous detours of market forces.

In the face of these challenges, Goudsmit says, the progress the world has made toward a COVID-19 vaccine is astonishing. The genetic sequence of SARS-CoV-2, the virus that causes COVID-19, was published in early January 2020, and a mere two months later, the first vaccine was being tested in humans. As of mid-November, more than 130 vaccine candidates had been identified and were in various stages of testing, including 11 in large-scale Phase 3 trials that are typically the final step before regulatory approval. Drug companies Pfizer and Moderna reported early Phase 3 data indicating that their experimental vaccines are more than 90 percent effective. Maurice Hilleman’s record for fastest vaccine development was toppled by years.

At the same time, there have been damning missteps and periods of myopia in recent decades that have left the U.S.—and the world—flat-footed in the face of the most significant public health threat of our time. We need a safe, effective vaccine for COVID-19. But we also need to learn from our history so that we can fully leverage the powers of vaccines to improve global health and ensure that we’re not left playing catch-up when the next pandemic arrives.

“There has been so much rapid innovation as a result of COVID-19,” Goudsmit says, “but innovation alone doesn’t guarantee that we will get the results that we want or that we need.”

Two scientists prepare to place tray of tubes into measuring instrument
© Bearwalk Cinema

Industry withdrawals

Vaccines are one of the greatest success stories in the history of public health. They have saved tens of millions of lives, prevented untold human suffering, and protected entire communities by fostering herd immunity to pathogens when a large enough proportion of people are resistant to contagion.

The health benefits of vaccines are also linked to massive economic benefits. One recent study in Pediatrics, for example, modeled the potential health and economic impact of routine vaccines in the U.S. The study, which analyzed a hypothetical birth cohort of 4.2 million infants and followed them through their hypothetical death, estimated the vaccines prevented 42,000 early deaths and 20 million cases of disease, resulting in a net savings of $68.8 billion in total societal costs, including loss of productivity from premature death and costs that parents incur for missing work to care for their sick children.

the list of known and emerging benefits of vaccines is long and getting longer. And yet, the story of commercial vaccine development in the 21st century is a story of contraction and abandonment.

There are other benefits of vaccines that we’re only starting to explore. A recent series of articles in Proceedings of the National Academy of Sciences (PNAS) highlighted how vaccines could slow the surge of antimicrobial resistance by preventing the transmission of drug-resistant infections, which are estimated to kill about 700,000 people a year. Vaccines likewise reduce the use of antibiotics and other anti-infectives, which eases the evolutionary pressure on microbes to forge resistance in the first place.

In that same PNAS series, papers co-authored by Marc Lipsitch, professor of epidemiology and director of the Center for Communicable Disease Dynamics, and Christine Tedijanto, PhD ’21, who works closely with Lipsitch, indicate that vaccines help protect the microbial diversity of the microbiome, which mounting evidence suggests improves immune-system function.

All this is to say that the list of known and emerging benefits of vaccines is long and getting longer. And yet, the story of commercial vaccine development in the 21st century is a story of contraction and abandonment. In the heyday of giants like Jonas Salk, developer of the polio vaccine, and Maurice Hilleman, public and private investment poured into vaccines.

Most vaccine research over the latter half of the 1900s focused on infectious diseases and fit within the model of vaccinating millions of healthy kids to protect them against childhood diseases that have historically killed and harmed millions of children.

“Research in that space has definitely contracted, with a few disease-specific exceptions,” says Sarah Fortune, John LaPorte Given Professor of Immunology and Infectious Diseases and chair of the Department of Immunology and Infectious Diseases. “And it’s contracted because there have been some really big failures. All the low-hanging fruit, so to speak, was covered by early vaccine development.”

In 1967, the year Hilleman’s mumps vaccine was approved, there were 26 companies making vaccines. By 2000, only nine large companies were developing and manufacturing vaccines, and that number had dropped to just four as of 2019, according to a Nature article co-authored by David Bloom, Clarence James Gamble Professor of Economics and Demography.

That same article noted that there are approximately 240 vaccine candidates in the development pipeline for diseases that affect middle- and low-income countries. Many of these candidates are likely to remain stuck in Phase 1 testing because companies don’t anticipate profit margins big enough to justify the huge investments in money and time necessary to take the candidates into the “formidably challenging” second phase of research.

“Many of the diseases that remain have turned out to be very biologically complicated,” says Fortune, “and for these diseases, it’s been really hard to make vaccines that are effective and will not do any harm to the healthy people, often children, receiving them.”

Among the most prominent failures Fortune mentions was a vaccine developed by the pharmaceutical company Wyeth to fend off rotavirus, which causes days of vomiting and diarrhea in infants and young kids and is estimated to kill approximately 200,000 children annually, most of whom are in low- and middle-income countries. The vaccine passed through Phase 1, 2, and 3 clinical trials before being licensed by the FDA for use in infants in August 1998 and recommended by the American Academy of Pediatrics. Not long after it was rolled out in the U.S., however, several cases of intussusception—a serious condition in which the bowel telescopes in on itself—were reported through the Vaccine Adverse Event Reporting System (VAERS).

In the weeks and months after, reports of intussusception ticked up, and by October 1999, 101 presumed and confirmed cases had been logged in the VAERS. Of those, at least 52 patients required surgery, nine required bowel resection, and one died. Importantly, preapproval data of the vaccine from clinical trials in the U.S., Finland, and Venezuela showed no statistically significant difference between vaccinees and placebo recipients in the rate of intussusception. In October 1999, the Advisory Committee on Immunization Practices withdrew its recommendation of the vaccine, and Wyeth pulled it from the market.

It was a lose-lose situation for patients, industry, and science. The prospect of investing tens of millions of dollars to take a vaccine from a lab bench to market only to have to pull it eight months later in light of newfound risks had a chilling effect on pharmaceutical investment. The reputational, legal, and financial risks of being the company whose vaccine harmed young children were too great, and R&D investment dwindled, shortchanging global health and infectious-disease research.

The pivot to platforms

With industry backing away from childhood vaccines against infectious diseases, some companies instead steered their resources into a nascent revolution in cancer immunotherapy, according to Fortune. Rapid advances in genomics, systems biology, and gene-sequencing technology opened up a world of possibilities and sparked a flurry of activity in the biotech sector. The risks in developing a therapeutic vaccine to be used in sick adults were much more palatable than the risks in developing a preventive vaccine used in healthy children. So were the underlying economics. In short, the money to be made from, say, a therapeutic pancreatic cancer vaccine for adults in wealthy nations would far eclipse the profit margins of a vaccine for a diarrheal disease that primarily afflicts children in low-income countries.

Up until the 2000s, scientists relied on a handful of approaches to develop and manufacture a vaccine. The most popular methods included using whole but inactivated strains of the virus or using live but weakened versions of the virus to induce immunity. These approaches were effective and undergirded some of history’s most successful vaccines, including one that was essential to eradicating smallpox.

But as companies embraced the potential of immunotherapies, attention shifted away from developing target-specific vaccines and toward building vaccine platforms. Rather than culture the virus in their crosshairs, vaccine platforms rely on the genetic sequence of the virus to identify the likely antigens the immune system will need to beat it. Different platforms use different types of synthetic biology and recombinant DNA, but nearly all of them aim to deliver genetic material that instructs the immune system to make a disease-specific antigen. One of the key advantages, in theory, is that platforms are a much faster means to a vaccine because scientists don’t need to start from scratch every time. The proverbial assembly line is already in place, and it’s just a matter of adjusting the process based on the virus’s genetic sequence.

Dozens of different platforms—RNA, DNA, proteins delivered by nanoparticles—have sprung up in recent years. While cancer immunotherapies were a driving force behind many of these advances, so was national security, says Barry Bloom, Joan L. and Julius H. Jacobson Research Professor of Public Health.

the efforts being made to boost vaccine production and distribution in the u.s. shouldn’t be jettisoned when a covid-19 vaccine comes along. they should be the basis for a new foundation for public health, pandemic preparedness, and vaccines in america.

In the aftermath of the September 11, 2001, terrorist attacks and the subsequent anthrax mailings, the National Academy of Sciences appointed Bloom co-chair of a committee set up to analyze America’s biosecurity. The committee’s overarching conclusion, says Bloom: “We were incredibly vulnerable and totally unprepared for a biological attack, natural infection or otherwise.”

In response, the country built up stockpiles of vaccines for anthrax and smallpox, two of the most urgent threats, and the Biomedical Advanced Research and Development Authority (BARDA)—an entity of the Department of Health and Human Services—turned its attention to improving vaccine development, knowing the importance vaccines would play in a pandemic. According to Bloom, senior officials at BARDA recognized early the potential recombinant DNA had in redefining how vaccines are made, and the agency put out a call for research proposals to create quick and nimble vaccine platforms. It was, Bloom says, largely a success.

“That funding helped lead to the development of adenovirus platforms, mRNA [messenger RNA] platforms, the protein-production-in-insect-cells platform, as well as the development of adjuvants that help boost immune responses,” Bloom says, noting that all these technologies are now being tested against COVID-19.

A defining trait of the race for a COVID-19 vaccine is the wide range of platforms being tested. Still, the vast majority of them were not built with a focus on coronavirus.

“Look at the Moderna vaccine,” Fortune says, referencing the Cambridge, Massachusetts–based biotech company whose COVID-19 vaccine candidate is based on an mRNA platform. “The Moderna platform and business model was not primarily developed for infectious diseases,” she says. “It was developed with cancer in mind.”

The ascent of platform technology is promising, but most of the approaches being tested on COVID-19 have never yielded a licensed vaccine. And many questions hang over how these vaccines will perform in a real-world setting, including how long the immunity they generate will last. As Fortune explains, it’s not uncommon for companies to build a platform and then go looking for the disease for which their technology is best suited. And in the case of COVID-19, just about every company with a platform wants to take a crack.

“All these companies are basically just taking a shot on goal, wondering if their platform will work for COVID-19,” Fortune says. “And it remains to be seen how biologically complicated the virus that causes COVID-19 is.”

I dont think theres a single reasonable person who would say, if we had to do it again, lets just do it like we did in 2020,’” says amitabh chandra, ethel zimmerman wiener professor of public policy and director of health policy research at the harvard kennedy school and henry and allison mccance professor of business administration at harvard business school.

A foundation for the future

Pharmaceutical and biotech companies are not hospitals, public health agencies, or government entities. They’re not beholden to patients’ needs, nor are they responsible for crafting public health policies and safeguarding populations from emerging threats. By and large, they respond to signals from the market and seek to maximize value for shareholders.

Nurse administers vaccine to patient
Sandra Lindsay, left, a nurse at Long Island Jewish Medical Center, is inoculated with the Pfizer-BioNTech COVID-19 vaccine by Dr. Michelle Chester, Monday, December 14, 2020, in the Queens borough of New York. (AP Photo/Mark Lennihan, Pool)

“When COVID-19 was in China and when it was ravaging Lombardy, Italy, we didn’t see a lot of companies jumping into the vaccine race,” says Amitabh Chandra, Ethel Zimmerman Wiener Professor of Public Policy and director of health policy research at the Harvard Kennedy School and Henry and Allison McCance Professor of Business Administration at Harvard Business School. “It was only when it became clear it was going to be a worldwide pandemic and there was going to be a strong market that a bunch of companies jumped in.”

That fact isn’t surprising, but it represents a long-term problem that is deeply concerning, Chandra says. The market failures of vaccines for infectious diseases are well documented, yet little has been done to improve the situation. “We’ve known for years that we need nonmarket entities to step up,” he says, “and yet the only nonmarket entity to step up again and again and again is the Bill and Melinda Gates Foundation, which does great work. But what if it didn’t exist? What a crazy way to do public health.”

the pattern of funding epidemics in general is that when they hit, we’re unprepared, and the science has been underfunded in most cases for extended periods of time, says barry bloom, joan l. and julius h. jacobson research professor of public health. then the money flows too late, and the moment the epidemic is under some sort of control, the faucet of funding is shut off.

One obvious (and obviously complex) solution is for the federal government to significantly increase investments in vaccines and pandemic preparedness. To that end, one of the more promising, albeit temporary, steps the U.S. government took in recent months was the launch of Operation Warp Speed, a program supported by the National Institutes of Health (NIH) with the goal of producing and delivering 300 million doses of safe and effective COVID-19 vaccines starting as early as January 2021.

The project has steered billions of dollars to companies including Johnson & Johnson, Moderna, and AstraZeneca to accelerate their research, and it marks a sharp pivot in how NIH funding is typically allocated. In most cases, NIH funding is incremental, limited to a single or a select few awardees, and is done in sequence—solve step one before applying for funding to work on step two.

Operation Warp Speed, by contrast, has freed up resources so that COVID-19 vaccine research can run in parallel across many different companies and institutions and their various platforms. Importantly, the money isn’t just focused on speeding up discovery; it’s also supporting efforts to kick-start vaccine manufacturing and set up the infrastructure needed to rapidly deploy vaccines when they become available.

The trick now is to build on this momentum and not suffer from collective amnesia three or five or 10 years down the line. “The pattern of funding epidemics in general is that when they hit, we’re unprepared, and the science has been underfunded in most cases for extended periods of time,” Bloom says. “Then the money flows too late, and the moment the epidemic is under some sort of control, the faucet of funding is shut off.”

Unlike SARS or Middle East respiratory syndrome, COVID-19 isn’t going anywhere. This time around, the need for a vaccine hasn’t diminished; it has only intensified, as the U.S. death toll climbs higher every day—more than 400,000 and counting.

The sickness and death wrought by this pandemic is also inflicting massive economic damage, the effects of which will be felt for years to come. A recent viewpoint in JAMA estimated that the cumulative financial costs of COVID-19 will be $16 trillion, or nearly an entire year of the U.S. gross domestic product. In light of the financial toll, will policymakers, biotech and pharma companies, and the public reassess their willingness to support long-term investments in vaccines and pandemic preparedness?

“I don’t think there’s a single reasonable person who would say, ‘If we had to do it again, let’s just do it like we did in 2020,’” Chandra, the health economist, says. The efforts being made to boost production and vaccine distribution in the U.S. shouldn’t be jettisoned when a COVID-19 vaccine comes along. They should be the basis for a new foundation for public health, pandemic preparedness, and vaccines in America. And companies, governments, and research institutions should support ambitious scientific endeavors to decode the many mysteries of the immune system long after the threat of COVID-19 fades.

Chandra contends that there is a strong case to be made that the government should invest several billion dollars annually in pandemic-preparedness efforts and vaccine research if it will help prevent another $16 trillion catastrophe. “Think of it as an insurance policy against SARS-CoV-3 or whatever virus hits next time,” he says. “And by the way, the next time could be three months from now or three years from now.”

Chris Sweeney is a senior science writer at Harvard T.H. Chan School of Public Health.