HMN 2025: How Influenza A-infected volunteers display different patterns of expelling viruses into environment

Late in the Middle Ages, Italian stargazers gave a name to the annual contagion that rolled around each year like clockwork. It was a name that stuck, and to this day is known as influenza.

Medieval Italians were convinced that the infection was caused by celestial forces—an influence of the stars—that drive patterns of the infection’s annual arrival and departure. The Italians further believed the stars released fluid that rained down to cause sickness and epidemics.

While 21st century scientists are well aware that medieval disease prognosticators were wise to recognize influenza’s periodicity, modern virologists have long been aware that viruses, not celestial fluid, cause the flu.

But now, flu scientists are on the hunt for much subtler patterns regarding the seasonal infection, and these patterns have nothing to do with the influence—or as the Italians would say—the “influentia” of the stars. Researchers are posing tough, provocative new questions about differences in viral shedding from one flu sufferer to the next.

Viral shedding is critical to the infection process and refers to the expulsion of viral particles into the environment by an infected individual. Innocuous acts of daily life can result in an infected person’s shedding of flu viruses—talking, coughing, sneezing, even breathing.

A team of scientists from institutions throughout the United States discovered a variety of patterns associated with viral shedding. In a study that involved volunteers who were purposely infected with influenza A viruses, the team revealed that some individuals never shed after being dosed with live viruses. Others, however, had persistent shedding over multiple days. And, finally, individuals who shed viruses for only a single day were more likely to be female, the study found.

The new analysis, which is expected to influence the development of future generations of vaccines—including nasal ones—is published in the journal Science Translational Medicine.

“Seasonal influenza A virus infections are a substantial medical and economic burden worldwide,” writes Dr. Kathie-Anne Walters, lead author of the flu study, and a researcher at the Institute for Systems Biology in Seattle, Washington.

The World Health Organization considers influenza a serious global health concern. More than 1 billion cases are estimated to occur annually, including three to five million severe cases, and anywhere from 290,000 to 650,000 deaths, depending on the virulence of the prevailing strain.

But as pervasive as influenza is worldwide, little is known about the complexities of preexisting immune histories among people when exposed to influenza A viruses in the midst of flu season.

“The goal of this study was to model annual seasonal influenza vaccination and H1N1 exposure,” Walters explained in the study, adding that researchers also studied volunteers’ immunity and viral shedding.

H1N1 (A/2009) was the strain the drove the 2009 flu pandemic that circled the globe that year. It was the strain chosen to infect volunteers.

Immunity to H1N1 or any flu virus is difficult to study in groups of people, according to the study, because all humans “have complex histories of prior infection and vaccination.”

To answer questions about viral shedding, 74 volunteers, all with their own “complex preexisting immune histories” were exposed to H1N1 influenza virus. Half of the group of volunteers was vaccinated with a licensed quadrivalent flu vaccine; the other half remained unvaccinated. Leaving half the volunteers unvaccinated better modeled what occurs in communities where some, but not all people, are vaccinated during flu season.

These complex immune backgrounds offered a more realistic environment to understand the effects of infection and vaccination, scientists wrote in the study, especially compared with more controlled investigations involving animal models. The duration of viral shedding is a measure of how successfully a virus has replicated in its host, the team of researchers noted in the study.

“Historically, human influenza challenge and vaccine efficacy studies have enrolled and studied responses in participants with little preexisting immunity to the challenge virus strain,” Walters explained.

“Although these studies have provided important insights into the natural history of infection, these populations do not reflect real-world immune complexity and dynamics to influenza infection. This is especially true for mucosal immunity, which represents the first line of defense against infection,” she asserted.

Authors of the study found that individuals who never shed virus after the challenge dose had increased diversity in their B and T cell responses and potent evidence of immune activation in their nasal mucosa. Volunteers who shed virus for two or more days had higher early viral loads. Those who shed virus for one day were three times more likely to be female, the researchers found. Women apparently shed less virus than men, according to the research, theoretically because of the protective effects of estrogen.

Their takeaway finding is that nasal and systemic immune responses correlate with viral shedding after influenza virus exposure—in this case, H1N1—among people with complex preexisting immunity.

Still, Walters and colleagues concluded that more data are needed to draw a more complete picture of various patterns of viral shedding and the potential for influenza infection risk.

“Limitations of the study include the small sample size and young age of participants,” Walters added, noting the average age among the 74 volunteers of the current study was 34 years.

The research also lacked a cohort of volunteers with underlying conditions and comorbidities, which means it’s impossible to draw conclusions, based on current data, for pregnant women, the elderly, or those with serious medical disorders, such as pulmonary disease, cardiovascular problems, immunosuppression and obesity.

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