It’s just a routine checkup, standard for participants in a clinical trial, but when Alice, a South African shop clerk in her 40s, visits the Be Part Yoluntu Centre for research, she wears her best outfit: trousers, a blouse, and short heels. She wants to be “presentable,” she tells Fortune, because the clinic in Mbekweni, a township northeast of Cape Town, is a special place to her: “What I’ve seen is that your health matters more when you come here.”

For Alice and the other participants in a global clinical trial for a new tuberculosis vaccine, it’s “not just an injection of IV,” explains Dr. Ronald Kapp, a physician and investigator at the center. “It’s also an injection of dignity.”

In this TB hotspot, with its high unemployment rates and poverty, almost everyone has a friend, neighbor, or relative who has been sick or died from the bacterial lung disease. It’s an awful death: Once known as “consumption,” the world’s deadliest infectious disease appears to consume the human body from within, sometimes filling sufferers’ lungs with fluid. Alice (a pseudonym used to protect her identity and the integrity of the clinical trial), a mother of three, says she is proud to participate in the Phase III trial of what could be the first new tuberculosis vaccine in a century—which health researchers hope will eventually eradicate TB worldwide. Efforts like this one, funded by the Gates Foundation in faraway Seattle, alongside Wellcome, are “going to save the world,” Alice tells Fortune.

A preventable disease that nevertheless killed 1.25 million people in 2023 is a tragedy that to the philanthropist Bill Gates is also an opportunity: “It’s amazing how little work has been done on any tools for TB—TB diagnostics, drugs, and vaccines,” the Microsoft founder noted. “TB gets ignored because it’s only in poor countries.” Speaking like the methodical tech pioneer he famously is, Gates explained that the foundation intends to change that, pulling off “breakthroughs in all three of those areas.”

And as Gates told Fortune in an exclusive interview, he is setting a hard deadline to do so. On its 25th anniversary, the foundation has laid out an extraordinarily ambitious global public health agenda for its next 20 years, announcing today that it will double the foundation’s annual spending with a $200 billion commitment over the next two decades—the largest philanthropic commitment in modern history. In that time, it plans to eliminate or drastically reduce deaths from several diseases, including TB; halve the childhood death rate; significantly reduce maternal mortality; and invest in health innovations, including AI, to ease poverty. Then it will end its operations.

Since its beginning in 2000, the Bill & Melinda Gates Foundation, as it was then known, has been the largest private foundation in the world. It has pioneered a model of data-driven, cost-effective interventions so distinctive it’s known in the philanthropy world as “the Gates approach.” It has revolutionized the fight against the world’s deadliest infectious diseases; promoted gender equity; championed contraceptive access for family planning; advanced reforms in education in the U.S.; fought malnutrition; invested in “leapfrog” innovations in medical treatments and delivery; and expanded the philanthropic sector by convincing other wealthy donors that humanitarian causes around the world deserve attention.

In its first quarter century, the foundation spent over $100 billion—about 60% from Gates and his then-wife, Melinda French Gates, and 40% from fellow philanthropist Warren Buffett. The billions per year the foundation spends put it in league with many wealthy countries’ entire aid budgets, and its rallying of governments, corporations, multilateral organizations, and philanthropists around the world makes it arguably the most influential philanthropic organization ever.

It’s no exaggeration to say that the Gates Foundation has dramatically changed, directly and indirectly, the global health landscape: HIV infections have been reduced by 60% since the mid-’90s, and the number of children under five dying from malaria decreased by over 30% between 2000 and 2019. The UN estimates that global efforts to combat TB have saved 79 million lives since the year 2000. The Gates Foundation has played a central role in each of these advances.

Charts show incident cases for four diseases

Now, the Gates Foundation is once again breaking with philanthropic norms: Instead of saving the bulk of its massive endowment to endure for generations—like the Carnegie, Rockefeller, and Ford foundations—the Gates Foundation will spend its last dollar in 2045.

Gates has pledged the foundation will spend another $200 billion—including its $77 billion current endowment, assumed returns on investments, and most of Gates’ remaining fortune, which currently stands at over $100 billion. The influx of funding won’t change the foundation’s approach but rather the organization will double down on the strategies that have worked: collaboration; data-driven innovation; and a relentless focus on vaccination.

“We’ll be able to spend at a pretty high rate, and that’ll give us a chance to make a great deal of progress, we think, on the key issues,” Gates told Fortune. “Spending the money sooner than later allows us to be very ambitious.” By 2045, the hope is the foundation will have played a major role in eradicating both polio and malaria, and in reducing TB and AIDS death rates by 90%. Gates also said the world will “certainly” see another halving of childhood deaths to below 2.5 million by 2045. (Today, 5 million children die globally before their fifth birthday—half the rate of 2000, but still a horrifying number.) It’s an unprecedented move for a philanthropic entity of this size.

And it comes at an unprecedented moment. The poor world’s public health infrastructure, and the fragile progress of the past few decades, is taking a smashing blow from U.S. President Donald Trump’s dramatic dismantling of international aid, with other countries following suit. In an interview in late April, Gates called the moment “an abrupt and negative situation”—then shifted to blunter language to describe the dire situation caused by the aid pullback: “We will cut kids off from vaccines,” he told Fortune, “and kids will die.” Historically, Gates said, we’re at a crossroads. As he wrote in a 2024 letter: “Will we look back on this period as the end of a golden era?” he asked. “Or is it just a brief intermission before another global health boom begins?”

Indeed, the tethers holding the vast network of key global health stakeholders together—a network Gates and his foundation helped assemble—appear to be fraying. TB has come roaring back; AIDS programs that provide PrEP and drug therapies to keep HIV at bay are running out of lifesaving medicine for children and adults. The mosquito is still the world’s most deadly creature, and cutting malaria-assistance programs could lead to an estimated 15 million additional cases after a year, according to an early 2025 memo from USAID.

So, can Gates, with his foundation’s $200 billion commitment, save the day in a moment when rich governments are reducing their support for the world’s poor and sick? Or will the turning of the tide in international aid leave the Gates Foundation high and dry, powerless to achieve its lofty goals of eradicating preventable deaths, without the broader collective effort?

Gates himself is the first to admit that he doesn’t know the answer to this question. “That uncertainty means that how much we’ll achieve in the next 20 years—that’s probably the biggest unknown,” he said. “Do our fellow travelers stay generous, or do they tune out these millions of deaths and turn inward?”

That second scenario, Melinda French Gates told Fortune, would be both “devastating” and “wasteful.” “We have infrastructure out there, so we’re going to pull back and let all of that crumble?” she asked. “You can never fill the gap if the public sector pulls back. You just can’t … What’s keeping me up at night is that the strings of our institutions, the threads, are being pulled out.”

French Gates, who parted with the foundation three years after her divorce from Bill Gates (its name was changed to the Gates Foundation last year), said while she was not involved in the decision, she knew that spending down Gates’ massive fortune had always been the plan. “It is fantastic that there’s now a public pledge to that,” French Gates told Fortune in February. “I think it’s a fantastic decision.”

Even with the Gates Foundation’s massive planned outflow over the next two decades, this may be a tough pill to swallow for the many organizations around the world who have relied upon its largesse. Now the nonprofit world is digesting the news that it must prepare for the planned obsolescence of the Gates Foundation—and it’s unclear who can or will fill the Gateses’ big shoes when the 20-year clock runs out.

Gates Foundation CEO Mark Suzman says the two decades will consist of “thoughtful and responsible planning” for the foundation’s successors. “We certainly hope and believe there will be a new generation of hopefully even more generous philanthropists that are willing to step in and see these causes as causes that they can take on for the next generation,” he said.

Over the past several months, Fortune has examined the implications of Gates’ decision, interviewing both Gateses and over 30 foundation leaders, researchers, grantees, and outside experts, and visiting programs funded by the Gates Foundation in South Africa.

The No. 1 way to save lives

In the heady days of 2000, at the dawn of the age of globalism and the tech boom, Bill and Melinda French Gates were the parents of young children and flush with a previously inconceivable fortune, after Microsoft had become a $595 billion powerhouse and the world’s most valuable company. They joined with Bill’s father, Bill Gates Sr., and began looking for big problems they could solve.

French Gates recalled sitting in an office above Big Time Pizza in Redmond, Wash., with the foundation’s first two employees to pore over data showing how infectious diseases were devastating the world’s poorest countries. In that era, about 1,500 children under the age of 5 were dying from malaria every day. In 2000, 3.5 million people died from tuberculosis. Some parents in sub-Saharan Africa and parts of Asia would forgo naming their children during measles season, for fear of losing them.

The situation was bleak, but the early 2000s were a moment rife with optimism in global health. It was a time when there was a bipartisan agenda to fight the world’s deadliest diseases, as shown by Congress’s support of programs like the President’s Emergency Plan for AIDS Relief (PEPFAR), established under President George W. Bush in 2003, and the United Nations’ Millennium Development Goals, ratified by all 189 member nations in 2000 to reduce maternal mortality, poverty, and deadly diseases across the globe.

Speaking earlier this year at her offices in Kirkland, Wash., French Gates mused, “It’s kind of unbelievable to think about the progress that has been made.” Vaccines were the key to this progress. The Gates Foundation ramped up funding for the development and delivery of vaccines for rotavirus, pneumonia, and other deadly diseases to reach the millions of children globally who were unvaccinated, clustered in the world’s poorest countries. And it funded the development of new formulations, including the first malaria vaccine and a new oral polio vaccine, and innovative combinations to target multiple diseases in one shot for children in low- and middle-income countries. More recently, it provided funding for a trial that showed one dose, instead of two or three, of the HPV vaccine successfully protected women and girls.

Previously, “childhood immunization was the place ambition sort of withered on the vine,” recalled Gargee Ghosh, the foundation’s president of global policy and advocacy. “There was no innovation happening in the sector, not in the science side, not in the delivery side. And then all of a sudden, here comes this businessman out of Seattle asking questions like, ‘What could you do with a billion dollars?’ … It was this freedom to be ambitious, to think differently about the sector.”

The Gateses had other pointed questions, too, questions few others were asking: Why were millions of children in poor countries dying of diseases that killed almost no one in rich countries? Answer: Because kids in rich countries got vaccines that prevented those diseases. Why didn’t kids in poor countries get those vaccines? Because the poor countries couldn’t afford them. Why were they so expensive?

Bill Gates looks on as a health worker vaccinates a child in Ghana in 2013.

The problem was that vaccine manufacturers didn’t see a market in poor countries. The Gateses saw a solution, but it would require a new worldwide institution bringing together rich-country and poor-country governments, philanthropic foundations, pharmaceutical companies, and other organizations. Those players would have to strike complicated deals to get the vaccines in bulk to those who desperately needed them, involving a promise to the pharmas of guaranteed long-term, high-volume purchases, in exchange for lower prices. The foundations and wealthier countries would pick up the bill.

No one was organizing such an institution, so the Gateses took the lead in bringing it together. It became the Global Alliance for Vaccines and Immunization, now known as Gavi. Gavi also came to life in 2000, starting with six vaccines—using glass syringes instead of the now widely used auto-disable retractable syringes. Since then, Gavi says, it has enabled the vaccinations of more than 1.1 billion children in 78 poor countries, helped significantly by the Gates Foundation, which has invested more money in Gavi—$6.1 billion—than any other program.

Longtimers at the foundation call Gavi “our oldest, largest, and best investment.” “The scale of what happened just became unimaginable,” said Trevor Mundel, the foundation’s president of global health. “Gavi triggered something that became viable and sustainable on the vaccine side.”

From then until now, vaccines have been the foundation’s No. 1 means of saving lives—and a proof of concept for Gates’ data-driven drive to find the cheapest way to do the most good. “It was like, wow,” Gates said, recalling this epiphany. “You could save lives for very limited amounts of money per life saved.”

Like any multibillion-dollar venture, the Gates Foundation has not gone without criticism—from the left as well as the right. Linsey McGoey, a professor of sociology at the University of Essex and author of No Such Thing as a Free Gift: The Gates Foundation and the Price of Philanthropy, argues that a wealthy elite wielding this much power over public health creates a dangerous precedent. “They’ve got a lot of discretion to put money wherever they want without significant democratic oversight,” she says of the Gates Foundation. As foreign aid is being diminished globally, she said, she hopes to see philanthropic ventures like the Gates Foundation “trying to use some of their clout and their money to give voice to people who will be and are being marginalized in the current climate.”

Meanwhile, despite a Mar-a-Lago dinner this past winter at which President Trump and Bill Gates were reportedly cordial and friendly, many top officials in the current administration have derided Gates as motivated by progressive ideology. Vice President JD Vance called the Gates Foundation and other philanthropies “cancers on American society” in 2021 while running for U.S. Senate, questioning their tax-exempt status. (This criticism, however, pales in comparison to the demonization that Bill Gates and his foundation have come in for in some far-right circles—where bizarre rumors and misinformation have spread about the foundation’s work.)

The ‘final mile’

A gigantic world map is spread across the wall of Chris Elias’s corner office at the Gates Foundation’s Seattle headquarters, overlooking the Space Needle.

The foundation’s president of global development showed Fortune a handful of pushpins tracking the last few dozen cases of active polio, clustered on the Pakistan and Afghanistan border, a hard-to-reach area where health workers have sometimes been attacked.

The Global Polio Eradication Initiative was launched in 1988, when polio was active in more than 125 countries and was paralyzing 1,000 children every day. As a result of massive immunization programs, a multilateral effort in which the Gates Foundation played a large role, the prevalence of polio has decreased by 99%, and the last case of wild polio in Africa was detected in 2016 in Northern Nigeria.

How do you find the kids who’ve never seen a vaccine?
Chris Elias, president of global development, The Gates Foundation

Since the eradication of smallpox in 1980, polio is the infectious disease that has come closest to eradication, with only 10 new cases of wild polio reported this year and with the virus endemic to only two countries: Pakistan and Afghanistan. Last year, the foundation funded 40% of the Global Polio Eradication Initiative, having committed over $6.2 billion to date. The end of this devastating nervous system disease, which affects the brain and spinal cord and can lead to paralysis, is in sight. “The top of my to-do list is to help steward this final mile in polio eradication,” said Elias, who also chairs the initiative’s polio oversight board. “We’re in the final sprint.”

But as any runner knows, the final sprint is often the hardest part of the race: With polio, that final mile means finding the handful of cases still active in remote parts of the world. “The challenge is the fifth kid’s not standing next to the other four,” Elias explains. “If he was, it’d be easy. But that fifth kid is in a slum. The government doesn’t even know they exist. They’re in some migrant populations, some informal settlements. They’re in a war zone … How do you find the kids who’ve never seen a vaccine?”

With infectious disease, there’s a huge gulf between “almost eradicated” and “eradicated”; even the last 1% of infections can propel a disease to come roaring back. It’s essential to not let your guard down, Bill Gates told Fortune. “If you back off, then it can go back up because [polio] spreads very easily,” he explained. “Zero is very much a magic number in eradication.”

These efforts continue even as misinformation campaigns about the safety and efficacy of vaccines are leading to outbreaks of measles and TB in the U.S. and other wealthy countries—but that’s not the main concern of the Gates Foundation at this point. “There’s some people who have been hesitant or refuse vaccines, but that’s small compared to most of the unimmunized kids who are unimmunized because no one ever got to them, either because they didn’t know they were there, or they didn’t know how to reach there, or they lived in a conflict zone, or some failed state where there was no system outside of humanitarian relief,” says Elias.

That experimental tuberculosis vaccine, the one that Alice is helping to test by participating in its Phase III trial, is the kind of innovation that may draw little notice in the West, but will change the lives of millions in sub-Saharan Africa and elsewhere if it’s approved. In those countries, relying on the existing 1921-approved Bacille Calmette-Guérin vaccine is a far from perfect solution because it only protects children from severe illness and it weakens over time. Those with active TB still rely on a painfully slow treatment that involves six months of antibiotics, and no new treatments have been developed in the past 75 years, mainly because there’s no marketplace in wealthier countries for them.

The new vaccine being tested, a two-dose regimen using the M72 molecule, is the first one to show promise in reducing the development of active TB in adults. It is licensed by the biopharma company GSK, which provided a key ingredient for and is a partner on the trial. The Gates Medical Research Institute is leading the final phases of the clinical development of M72 and sponsoring the trial. It has the potential to eliminate a disease that has stalked humans for most of our recorded history.

‘It’s safe to be optimistic’

“We’ve always been about trying to address today’s problems, not tomorrow’s,” CEO Mark Suzman said as he walked Fortune through the Gates Foundation’s two-winged headquarters in Seattle in February. He pointed out a framed T-shirt from the late South African Archbishop Desmond Tutu, the anti-apartheid and human rights icon and champion of the fight to defeat the AIDS epidemic.

Gates’ decision to set a hard deadline of 20 years, and work at warp speed to finish the jobs the foundation started 25 years ago, came from this mindset, Suzman said: “We need to make sure that we are driving through these opportunities that we see right now.”

Gates Foundation CEO Mark Suzman at the organization’s Seattle headquarters.

The job ahead remains a daunting one. Tuberculosis is already playing out as a cautionary tale of how infectious disease can come roaring back from the brink of extinction: Last year, the U.S. logged more cases of TB than it has in any year since the CDC began keeping count in the 1950s, and two people have died. The average untreated case of active tuberculosis will spread the infection to 10 to 15 people a year. In early March, a USAID official estimated that cases of tuberculosis will rise by about 30% globally in one year if aid assistance is not restored. “To see us taking these huge steps backwards is just devastating,” said John Green, the author of Everything Is Tuberculosis, “because we could live in a world without tuberculosis, or at least in a world where tuberculosis is not a public health threat.”

This crisis is the direct result of U.S. government policy, Green noted. “We have chosen not to allocate resources to tuberculosis, and as a result, many millions of people are going to die in the next decade,” he said. “It will continue to grow as long as we underinvest in public health in the United States and underinvest in tuberculosis care globally.” Green (who was not aware at the time of the interview of the Gates Foundation’s plans for the next two decades) said he could not see philanthropy making up for the pullback of government funding: “I don’t think any foundation, even a very well-funded one, can do what governments do.”

A slew of novel challenges is also emerging: The foundation’s modeling estimates that 40 million more children will suffer from hunger by 2050 owing to climate change. And as the climate warms, malaria-carrying mosquitoes can thrive at higher altitudes. “These mosquitoes are learning to live in cities now, so that’s very concerning,” Gates said. “Climate works against you.”

But these challenges shouldn’t paralyze action, Suzman argued. Part of what advocates for a robust global health agenda are up against, he said, is a shift in the prevailing mindset—“a loss of belief that progress is possible.” Restoring that belief, he said, is part of the work ahead: to “signal that it’s safe to be optimistic about what can be done, that there are incredible opportunities to actually accelerate progress and bend that curve—and that we want to both be part of that, a catalyst for that, and demonstrate what it can look like.”

Under the new regime, the foundation plans to spend nearly $9 billion for 2025 and about $10 billion annually thereafter. (In 2020, the foundation spent about $5 billion.) Speaking in February, Suzman said he has hope that polio and malaria “will no longer be with us” when the foundation spends its final dollar. In a follow-up conversation in late April, after weeks of watching the Trump administration dismantle the U.S.’s global aid infrastructure, the CEO said he remains confident.

But his boss told Fortune he had to “temper my polio statements a tiny bit”: Gates now says he’s not as certain that polio will be eradicated in the next 20 years. “If we don’t get the U.S. government back engaged in that, then there’s no way that can succeed,” he said. He added, however, that he’s reasonably confident that some of the funding cuts will be restored. “We’ll see,” he said. “You know, that could prove to be naive. It’s been cut very dramatically—and you know, very differently than what I expected.”

As for TB and HIV, full eradication by 2045 is likely not feasible, but Suzman said the foundation will create powerful tools to fight those diseases—like the TB vaccine being tested—then hand the last mile of the job off to Gates’ philanthropic successors: “Hopefully, the hard job of creating—of really, what are the tools that will allow you to eradicate the diseases—we will have done it.”

And Gates said he remains confident about the donors of the future. “At the end of 20 years, there will be many other rich people,” he said. “They’ll be more up to date about what governments are doing, what science is doing, how things are going in the poor parts of Asia or Africa, and they can step in, using their skills and their resources, and carry on whatever we’re not able to finish.”

As for French Gates, she plans to continue making the case that the wealthy have a responsibility to give back. “If you’re a billionaire in the United States, you benefited from this country,” she said. “You benefited from good roads. You probably benefited somewhere along the way from the health sector. You probably benefited because maybe it was a good business climate, and you could start your business … People in other places don’t have those things, and so yes, we owe something back to society.”

‘You can’t just walk away’

The same week in January that President Trump issued an executive order to start the process of dismantling USAID, it was a 90-degree day in the southern hemisphere’s summer, in Mbekweni.

For Dr. Lize Hellström, one of the TB vaccine trial’s lead investigators, the topic of American aid brought back memories. She recalled, in the 1990s and early 2000s, working with AIDS patients just before antiretroviral drugs became available in South Africa. “We literally had to stop these people from dying because we said to them, ‘The medication is coming! You need to just keep going,’ ” Hellstrӧm recalled, adding that the medications arrived in 2004 largely thanks to American aid.

Over two decades later, Hellstrӧm feels a similar mixture of hope, fear, and urgency about the TB vaccine she’s trialing. The stakes—human lives—are just as high, and the potential for progress is tantalizing: The trial is going well, and recently announced that the global recruitment of 20,000 participants was completed earlier than expected. Despite weakening foreign assistance, Hellstrӧm still clings to the same hope that guided her through the darkest days of the AIDS crisis.

Giving up that hope isn’t an option, she said. Unlike those overseas who are cutting aid budgets, she is personally connected to the plight of her patients. “You can’t work in a community and close your eyes to the problems that exist, the poverty,” she said. “You can’t just walk away.”

Researchers are optimistic about a new TB vaccine in Phase III trials.

Gates, who has visited many similar clinics, clearly agrees. “It’s hard because most people don’t get to see this work as humans,” he mused during the April interview. “If you go and see a malaria ward with kids dying, you would be very affected. If you see mothers bleeding to death, you’d be very affected.”

“We have to up our game,” he said, seemingly as much to himself as to Fortune. “Because the value involved—helping other human beings—I don’t think that’s changed. And I do think we will resume forward progress. The cause is too valuable. The innovation is too strong. So I just have to do better advocacy and engage more philanthropists as partners. It’s a challenging time—but hey, all important causes go through this.”

Geoff Colvin contributed to this story

The Gates Foundation will end in 2045. What will the world look like without it?