WASHINGTON — Melinda Moree met plenty of naysayers who dismissed the prospects of a malaria vaccine. Then she encountered Bill Gates.

No one had developed a human vaccine against a parasite like malaria before, and the monetary incentives simply did not exist for pharmaceutical companies to develop drugs targeted at poor children. Development would require cooperation among scientists, drug companies, health groups and international governments — an alliance so large it didn't seem possible, she recalled someone telling Gates.

"Of course it is," Gates countered, according to Moree, now director of the PATH Malaria Vaccine Initiative in Seattle, which along with other groups has received nearly $500 million from the Bill & Melinda Gates Foundation to develop, test, manufacture and eventually distribute a malarial vaccine. "There's something about vision and belief that these things are possible," Moree said.

People in the nonprofit world say Gates, 50, could fundamentally alter the methodology of philanthropy with his recent announcement that he will quit his day-to-day role at Microsoft Corp. in two years to spend more time on his foundation. He will take the same energy he once directed toward software technology to global health, education and other intractable issues, they say.

Even as Microsoft is grappling with a changing competitive environment in which the software that Gates championed is losing ground to Internet-based services, the foundation is facing hurdles that observers say only Gates may be able to clear.

The co-founder of Microsoft has given $25.9 billion of his personal wealth to the foundation and has pledged to give billions of dollars more to devote to several dozen specific programs, such as minority scholarships, clean water initiatives, updated computer systems in libraries and the development of a variety of vaccines. (His wife, Melinda Gates, is on the board of The Washington Post Co.)

The foundation has not been able to carry many of its projects through to completion because of the enormous logistical, political and commercial barriers inherent in distributing malarial vaccine to Africa, for example, and developing a vaccine against HIV and AIDS. Finishing those tasks requires political diplomacy, organizational efficiency, and monetary and human resources — challenges that Gates may be uniquely positioned to take on as one of the most successful and driven businessmen of the era.

"A lot of the corporate foundations were born in the corporate style," but few have had someone of Gates' stature get involved personally in the execution of their programs, said Sharon Oster, director of the Program on Social Enterprise at Yale University. Logistics — getting vaccines into places such as Rwanda quickly, for example — will be a large part of what the foundation will need to do, and Gates will likely have to make hard decisions about which causes are more deserving of his money, such as medicines, infrastructure or education, she said.

Decisions about operational controls and investment are not new to Gates, Oster said, adding, "There are also more complicated governmental issues, and certainly Microsoft has dealt with those." But this time Gates' enemy isn't another company — it's disease, mosquitoes, ignorance, political unrest. And vanquishing those requires a different approach to partnership, she said. It will require working with a disparate group of governments, other nonprofit groups and companies that do not answer to him.

Vaccines have to be tested in human populations in large numbers. Collecting that data in the poor, remote villages where many diseases are common requires manpower, organization and funding. Once a drug is ready for production, it has to be mass produced in a way that allows it to withstand transportation, high temperatures and other environmental factors that can be tough on vaccines.

The most frustrating problem with vaccine delivery is the lack of political will and social infrastructure in some countries where people need the medicines, said Adel Mahmoud, incoming chief executive of the Global HIV Vaccine Enterprise, another group sponsored by the Gates Foundation.

The pharmaceutical industry also needs a business case to justify such work. By helping to fund drug development and trials for diseases such as malaria, tuberculosis and acute diarrheal disease, which usually affect poorer populations, the Gates Foundation has essentially created a new market for drug companies.

GlaxoSmithKline PLC conducted malaria vaccine trials on 2,000 children, and "that trial wouldn't have taken place without the Gates Foundation," said Nils Daulaire, president and chief executive of the Global Health Council, a Gates Foundation grantee and a membership group that advocates for worldwide healthcare access from its offices in Vermont and Washington, D.C. "As lead investors, they're almost like a country in themselves, with their own world aid programs."

As an ambassador for projects, Gates is likely to draw more funding and interest from other corporations, Moree, the director of the Malaria Vaccine Initiative, said.

"The Gates Foundation is a quality brand. It's something they want to be associated with," she said. "People want to be associated with success."