The University of Pennsylvania Health System, the largest private employer in Philadelphia, on Wednesday announced that all employees and clinic staff will be required to be vaccinated against COVID-19 by Sept. 1.

Debates — and a few unsettled lawsuits — have swirled around the legality and ethics of vaccine mandates, even as evidence mounts that the three vaccines used in the United States and globally are spectacularly effective and safe. COVID-19 cases and deaths are falling in many regions, including Southeastern Pennsylvania, as vaccination rates grow.

Penn Health officials decided the only issue that really matters is protecting people.

“We recognize that not everyone will agree with this decision,” said a Wednesday memo to UPHS employees. “As an industry grounded in the science and art of healthcare, we believe it is imperative for the UPHS to take the lead in requiring vaccinations to protect our patients and to set an example for those who remain hesitant both within our institution and in the broader community. The safety of our patients and staff are our highest priorities. The threat of further harm and the possibility of more dangerous viral mutants emerging before we reach herd immunity compels us to take this step.”

Health-care systems across the country are debating vaccine mandates, but so far few have taken the plunge. Houston Methodist, a system with eight hospitals and 26,000 employees, announced its mandatory vaccination policy March 31, with workers required to comply by June 7 or face termination. One nurse has sued the system; other employees are asking the Texas legislature to ban vaccine mandates. Several states have passed such laws.

Asked about their own policies, a wide range of the Philadelphia region’s largest and most prominent employers — Campbell Soup Co., Cooper University Health Care, Independence Blue Cross, Rivers Casino, Temple University Health System, Vanguard Group, Wawa, and Wells Fargo — said Wednesday they are encouraging but not requiring employees to be vaccinated. Only Jefferson Health said it is actively considering whether to require vaccination.

» READ MORE: Penn hopes vaccine requirements will set an example for other Philadelphia employers

New UPHS hires will have to provide proof of vaccination, or be fully immunized two weeks before starting work. Religious or medical exemptions may be granted, just as with the seasonal flu shot policy in place for more than a decade. But non-exempted workers who remain unvaccinated will be subject to disciplinary actions, including firing, the memo said.

In a statement, UPHS said all employees and clinicians have been offered the vaccine, and more than 33,000 — nearly 70% of the 47,000-member workforce — are now fully immunized.

“Ultimately, people do have a choice,” Patrick J. Brennan, chief medical officer and senior vice president of UPHS, said in an interview. “But there is evidence that unvaccinated workers are still getting sick and spreading it in nursing homes and other health-care settings. And staff members are getting sick and dying. So it’s a double-edged sword. No one is forced to be vaccinated, but it is a choice that affects employment” at UPHS.

Ezekiel J. Emanuel, a Penn professor of medical ethics and health policy, echoed that sentiment in a recent pro-mandate opinion piece in the New York Times: “Health care workers are professionals whose primary obligation is to their patients’ health and well-being.”

Kaiser Family Foundation polls show that vaccine “hesitancy” has steadily declined since the winter debut of vaccines by Pfizer, Moderna, and Johnson & Johnson. But Kaiser found that 13% of those surveyed said they would “definitely not” get vaccinated, with Republicans and white evangelical Christians being the most likely to take that unequivocal position. In March, nearly half of frontline health-care workers had not yet rolled up their sleeves.

UPHS is in a stronger position to require vaccines than many health systems because it has virtually no labor unions. Two lawsuits against mandates have been filed by unionized workers: a corrections officer in New Mexico, and employees of the Los Angeles Unified School District.

Both lawsuits argue that the three COVID-19 vaccines used in the United States are “experimental” because they were granted emergency authorization, not full approval. By federal law, people must be told they can refuse or accept such a provisionally approved vaccine.

Some legal experts dismiss that argument as a red herring. And even if it is valid, the Pfizer-BioNTech vaccine, which this month applied for full Food and Drug Administration approval, is expected to get it soon.

A growing number of colleges and universities — including the University of Pennsylvania — have followed Rutgers University’s lead in requiring students to be fully vaccinated to return to campus. (Penn is still weighing a mandate for faculty and staff.)

The coronavirus has so far killed 3.4 million people globally, with the U.S. toll nearing 600,000. The Pfizer and Moderna vaccines both use mRNA technology, which was pioneered at Penn but had not previously yielded a successful product.

“The transformational mRNA technology discoveries at Penn which laid a foundation for the first COVID-19 vaccines are a tremendous point of pride which further buoys our confidence in the science that is now being deployed to save lives across the globe,” the UPHS statement said.

Staff writer Harold Brubaker contributed to this article.