Measles, a highly contagious viral infection, continues to pose a significant public health threat worldwide. Despite the availability of effective vaccines, outbreaks persist, particularly in regions with low immunization rates. In 2023, the World Health Organization observed up to a 30-fold increase in measles cases in Europe (1). There are currently no treatment options for measles. Instead, patients must allow the virus to take its course and let the immune system naturally clear the infection. 

Erica Ollmann Saphire, a structural biologist, and her research team at the La Jolla Institute for Immunology uncovered the structure of the measles glycoprotein and engineered a neutralizing antibody against it (2). This therapy could be implemented to manage measles outbreaks worldwide. 

“Measles is a virus that we thought we had eradicated in the US around [the year] 2000,” said Saphire. “We need over 95 percent vaccine coverage for herd immunity. We are below 95 percent, and there are a number of people that cannot be vaccinated with the [measles vaccine] because it's a live attenuated virus.” This includes pregnant people and immunocompromised people such as cancer patients. 

Measles has made a significant resurgence in recent years. This can be attributed to several factors, including declining vaccination rates and the emergence of vaccine-resistant strains. While vaccination remains the most effective preventive measure, a concerning number of individuals, even after receiving the recommended two-dose regimen, fail to develop adequate immunity. Measles infection can impair the immune system, leaving survivors vulnerable to other diseases, a phenomenon known as immune amnesia (3). The potential for severe complications due to the infection, including encephalitis, further demonstrates the gravity of this public health threat.

Saphire and her team needed to learn more about the virus to find a non-vaccine way to prevent measles from infecting people. “We wanted to understand what was the structure of the protein that mediates fusion of the virus into the host cell,” Saphire said.

The researchers first determined the high-resolution structure of the measles fusion glycoprotein using cryogenic electron microscopy (cryo-EM). Saphire and her team identified the glycoprotein’s prefusion, intermediate, and postfusion conformations, which are important for the measles virus’s virulence. Using the cryo-EM structure of the intermediate fusion state, they found that the antibody mAb77 specifically bound to this conformation. 

“This is the first structure of any antibody in complex with measles,” said Saphire. “[With] cryo-electron microscopy, where we take a photograph of all the molecules in the field. We see everything. We were able to capture the fusion protein in the different steps and snapshots of its activity.”

[With] cryo electron microscopy, where we take a photograph of all the molecules in the field. We see everything. We were able to capture the fusion protein in the different steps and snapshots of its activity. 
- Erica Ollmann Saphire, La Jolla Institute for Immunology

When mAb77 binds to the fusion glycoprotein, it locks the measles protein in its intermediate state, preventing its transition to the postfusion state that the virus uses to enter and infect host cells. This finding suggested that mAb77 can act as a way to stabilize the fusion glycoprotein in an inactive state, preventing viral infection. 

To assess the efficacy of mAb77 in vivo, the researchers treated cotton rats with mAb77 before exposing the animals to the measles virus. They saw a significant reduction in viral replication in the lungs of the antibody-treated rats compared to control groups that did not receive mAb77. 

“If you can no longer count on herd immunity, we need some treatment options for patients who cannot take the vaccine,” said Saphire. “Giving a patient an antibody treatment would grant them the immune response required to protect them from the virus, like the rat model we used where even small doses of mAb77 protected the animals from measles infection.”

Alessandro Sette, an immunologist at the University of California, San Diego who was not part of this study, said, “The viral glycoproteins expressed on the surface of the virus or of cells have been notoriously difficult to solve, and this has now been solved and at a very high level of resolution, so that's impressive.”

The structural insights gained from this study will help researchers design and develop other antiviral agents targeting the measles fusion glycoprotein. These therapeutics could offer new tools to combat measles outbreaks by disrupting key steps in the viral life cycle. Saphire’s group is interested in creating vaccines that can give people lifelong immunity to viruses and other infections as well as understanding the physiology of immune memory. 

Saphire added, “[This is] something that's going to protect vulnerable people in the event of an outbreak or [be] a treatment for people who have gotten infected and help us engineer a vaccine for the vulnerable.”

References

1. Gori, M. et al. Increased reports of measles in the Metropolitan City of Milan, northern Italy, September 2023 to March 2024. Euro Surveill  29, 2400201 (2024).
2. Zyla, D.S. et al. A neutralizing antibody prevents postfusion transition of measles virus fusion protein. Science  384, eadm8693 (2024).
3. Cox, R.M. et al. Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets. Nat Commun  15, 1189 (2024).