Finding Factors That Protect Against Flu

Each year, thousands of people in the United States die from seasonal influenza and its complications. Annual flu vaccines are the most effective way to protect against the disease. However, data from the past decade show that vaccine protection can be inconsistent.

Influenza viruses have 2 types of surface proteins: hemagglutinin (HA) and neuraminidase (NA). Seasonal flu vaccines are currently developed and evaluated in part based on the ability to induce production of antibodies against HA. This standard, however, is based on research dating back to the 1970s. A research team led by Dr. Matthew J. Memoli at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) set out to revisit this standard by carefully examining the body’s response to influenza virus.

The scientists tested 65 healthy volunteers, ages 18 to 50, in a human challenge study—a trial in which people are exposed to disease-causing pathogens under carefully controlled conditions. The team first measured levels of existing anti-HA and anti-NA antibodies to the virus in the participants’ blood. The volunteers were then placed into 2 groups: those with high levels of anti-HA antibodies (25 participants) and those with low levels of anti-HA antibodies (40 participants).

The volunteers received an intranasal dose of the 2009 H1N1 influenza virus in the clinical studies unit at the NIH Clinical Center in Bethesda, Maryland. This unit has stringent isolation and infection control features. The volunteers stayed in the study unit for a minimum of 9 days, where they were monitored by medical staff 24 hours a day. Participants were discharged after 2 days of negative flu tests. They then had 4 follow-up visits over 8 weeks. The results appeared in mBio on April 19, 2016.

As expected, participants who had high levels of anti-HA antibodies when enrolled had a significantly lower incidence of influenza disease than those with low HA antibody levels (24% vs. 72%). Those with high levels of anti-HA antibodies were much less likely to shed virus, which enables the spread of virus to others. However, there was no significant difference in either the number or severity of symptoms between groups. In fact, most participants in both groups experienced symptoms (80% high vs. 88% low). These results suggest that anti-HA antibody levels may be useful for predicting protection against and spread of the disease, but may not predict who will experience flu symptoms.

Participants with a high baseline level of anti-NA antibodies were similarly less likely to develop disease than those with a low level (44% vs. 100%). However, those with high levels of anti-NA antibodies also had less severe disease, a shorter duration of viral shedding and symptoms, and fewer, milder symptoms than those with low levels.

“The idea behind this study was to re-evaluate the bar that was previously established for evaluating a person’s immune response to influenza vaccines,” Memoli says. If these findings reflect naturally occurring flu infections, NA antibodies are the stronger factor for determining disease severity. HA and NA antibody levels together could provide better predictions than either factor alone. The team will continue to analyze the study samples to gain further insights.