STAT Wunderkind Sydney Ramirez uncovers new immune insights

Sydney Ramirez vividly remembers that Wednesday in March. Her future adviser, scientist Shane Crotty, was supposed to be in Italy for a conference. And Ramirez, a physician and immunologist, wasn’t supposed to join Crotty’s lab at the La Jolla Institute for Immunology as a postdoctoral fellow until July.

But it was 2020, and very little was going as planned.

Instead, they were in Crotty’s office, and Covid-19 had just been declared a national emergency; in two days, the institute would shut down. Ramirez, then in the  infectious disease fellowship program at the University of California San Diego, had planned to study the shingles vaccine with Crotty, who researches how the immune system reacts to vaccines. But it was clear that her crucial expertise — she happened to have spent her Ph.D. studying coronavirus virology — might help answer the pressing early questions about SARS-CoV-2. Would people have any immune response to the virus? Who would get the most sick? Would it ever be possible to make a vaccine?

Within 48 hours, Ramirez joined Crotty’s lab and got to work. And within weeks, she and her colleagues would publish a key paper that provided early insight into SARS-CoV-2 immunity in people.

More than five years later, Ramirez, who was recently named a STAT Wunderkind, is both an instructor at the La Jolla Institute for Immunology and an infectious disease physician at UCSD. She’s still studying respiratory viruses, and has helped lead the way in understanding a critical part of the immune system: the upper airway. Containing the nose and throat, it is the part of the body respiratory viruses encounter first, before they reach the lungs — but it has long been overlooked. 

Understanding how the immune system works in the upper airway could help researchers design everything from more effective vaccines to immune-monitoring approaches and personalized vaccination schedules. And Ramirez is just getting started.

An urgent search

When the immune system encounters a virus, it mounts two kinds of immune responses. The first, called innate immunity, is a rapid, nonspecific defense against the pathogen. The second, adaptive immunity, takes longer and builds up a memory of infections. In the initial months of the Covid-19 pandemic, understanding this biological memory — how it formed in response to SARS-CoV-2, whether it was protective or harmful, and the cells involved — was essential for vaccine developers and public health officials.

At LJI, however, acquiring the patient samples to study that memory was proving difficult. By March 2020, Crotty said, “labs at LJI had been working on coronavirus for at least six weeks already, but hadn’t managed to get a single sample into the building from a patient.”

Ramirez turned to colleagues Steven Rawlings and Davey Smith, infectious disease physician-scientists at UCSD. Rawlings and Smith had begun obtaining the approvals and protocols to recruit patients in February, after Smith heard about a new respiratory virus while on vacation in Australia and started planning for its arrival in the U.S. “I remember [it] clear as day,” Smith said. “You can’t contain a respiratory illness.”

Joining onto the framework from Rawlings and Smith, Ramirez began urgently searching around San Diego for Covid-19 patients. She reviewed medical charts and sent out patient portal messages. She talked to patients who were scared but willing to help, sometimes collecting and processing blood samples herself. 

“It’s really hard to be a good clinician, and it’s really hard to be a good scientist, and it’s very hard to do both,” Crotty said. Ramirez “was able to enroll people in these clinical trials when nobody else was able to enroll them because she was able to connect with people.”

Using those samples, a team of researchers across LJI, UCSD, Mount Sinai, and the University of North Carolina at Chapel Hill found that people who’d had Covid-19 showed signs of developing immunological memory; a majority had CD8⁺ “killer” and CD4⁺ “helper” T cells that responded to parts of the SARS-CoV-2 virus. 

In just two months, on May 14, 2020 — Ramirez’s birthday — the study appeared online in Cell. “Everything was moving so fast. I don’t think I’ve ever contributed to a paper where it came out within two months,” she said. “[It took a] huge team effort, lots of long hours, everybody working together.” 

The impact, Crotty said, was immediate: Twitter threads erupted, the paper made international news, Anthony Fauci waved a copy before Congress. As one of the first studies of immune responses to the virus, the paper offered hope that people could develop immunity to SARS-CoV-2 — that a vaccine might be possible. Ramirez and her colleagues savored the recognition, proud to have met the pressure to publish more quickly than ever before without sacrificing scientific rigor. But there was plenty more to uncover.

New sacrifices amid the pandemic

By 2020, Ramirez was used to long hours. The daughter of two pediatricians, she’d chosen an M.D.-Ph.D. program at the University of Texas with no illusions about its workload. Then, after her second year of medical school in 2010, she gave birth to her daughter Aliya. Finishing her degrees now meant juggling maternity leave with graduate classes and trips to the lab with daycare pickups and drop-offs. Ramirez’s dad rented a house down the street to help with child care, and Aliya was independent from the start — she grew up insisting on carrying her own lunchbox to school. Still, there were the holidays Ramirez spent in the lab running T cell assays, the cell incubations she couldn’t cut short. She found herself apologizing for not being home.

The pandemic demanded new sacrifices. By now a clinical and research fellow in infectious disease at UCSD, Ramirez knew she could not stop working. To keep her family safe, Ramirez sent Aliya, then 9, to live with her mother in Sacramento, Calif. At night, on the weekends, and in the mornings before clinic, Ramirez gathered data, often driving across town to collect samples. When she had time, she drove to parts of San Diego she hadn’t seen before, where the beaches were full of birds and other wildlife. “It was so peaceful and quiet,” she remembered. “It was just a really good mental break from everything.”

Ramirez had gravitated toward biology as an undergrad for its variability, the way two genetically identical mice didn’t behave the same way in the lab. Now, she wondered why some people got sicker than others. She’d seen 90-year-old patients with Covid-19 who’d never developed symptoms.

Understanding why meant studying patients with a range of disease severity, as soon after infection as possible. This time, the team studied all three arms of the adaptive immune response: killer and helper T cells, plus antibody-producing B cells. Patients with a coordinated response — from antibodies and both kinds of T cells, rather than from just one or two of these groups — fared better than those with a poorly coordinated one. People who were 65 and older were also more likely to have less coordinated responses and severe disease, in many cases potentially because they had fewer T cells that could respond to new viruses.

Searching for missing pieces

The outlines of the human immune response were emerging, but Ramirez still felt that pieces were missing. As a respiratory virus, SARS-CoV-2 infected the upper airway first. It would make sense if the body could clear the upper airway to prevent the virus from descending into the lungs and causing more severe disease. But Ramirez couldn’t find studies on immune cells in the upper airway, and most “atlases” of the immune system left out anything above the neck.

To fill that gap, there were technical challenges. Could she get enough immune cells from the back of the throat? Many medical schools taught that the adenoids — immune tissue behind the nose — disappeared after childhood.

At first, when Ramirez’s deep-nasal swabs picked up what looked like immune cells from the adenoids, Crotty was skeptical. But when they used an endoscopy camera to follow the swab during collection, the results were incontrovertible. They were sampling adenoid tissue.

From more than 300 patient swabs over a one-year period, Ramirez and her colleagues wrote in a 2024 paper that both T and B cells with memory of the virus stayed in the nasal passages for at least six months. To Ramirez and Crotty, that was exciting. A population of immune cells that lived in the upper airway for months or even years would be powerful — primed and ready to eliminate viruses more quickly than cells from the bloodstream. Understanding those cells could help researchers design more effective intranasal vaccines and better understand patient responses to vaccines that already exist.

“There’s a lot we just don’t understand about mucosal immunity, because people weren’t really looking before,” Ramirez said. “This is a time where we have the technology, we have the resources, we have the understanding that we can actually start asking these questions.”

To start, Ramirez wants to know just how long those T and B cells stick around, and whether that changes with new viral exposures. She and her collaborators are studying the responses of these cells to newer SARS-CoV-2 variants and vaccinations. Other researchers want to study the role of airway immune cells in other conditions such as autoimmune diseases, respiratory-related allergies, and cancer. Understanding how these cell populations change — and what baseline levels are — could be useful in the clinic, to diagnose disease or monitor how well a patient is responding to treatment.

Ramirez hopes that doctors could one day use their sampling techniques to monitor a patient’s immune memory and personalize their vaccination schedule. High-risk patients would receive booster shots, for example, while patients with immune memory could wait.

“We have general guidelines, but it’d be nice to actually be able to tell someone their immune status or immune protection status,” she said. “That might take more than five years to figure out.” But, she said, “it would be great to know more about our bodies.”

‘That’s all I could have asked of myself’

Already, Ramirez’s work studying Covid-19 and the upper airway has earned her the marks of academic success: a Burroughs Wellcome Fund award, other competitive grants, her name on highly cited papers. But forging her own path as a physician-scientist — particularly as a single mom — continues to be hard. “There are definitely days where I feel like I’m doing one ‘job’ better than the other,” Ramirez said.

On those days, she tries to put aside her feelings of guilt, of not being good enough, and focuses on making the best use of the samples patients have entrusted to her.

“[I] tell myself, if, at the end of the day I did the best I could do — that’s all I could have asked of myself,” she said.