New research from the National Institute of Allergy and Infectious Diseases (NIAID) may pave the way toward more effective seasonal influenza vaccines. Traditionally, flu vaccine strains have been evaluated by their ability to induce high levels of one type of antibody. The new study, published this April in the journal mBio, suggests another type of antibody is more predicative of flu protection and should therefore be considered when designing and evaluating future flu vaccines.

The need for better flu vaccines

Though flu seasons vary in severity, on average 5 to 20% of the United States population gets the flu each year. This results in more than 200,000 hospitalizations from flu-related complications, as well as an average of 36,000 deaths per year. Worldwide, the toll is even higher: on average, seasonal influenza causes 250,000 to 500,000 deaths in industrialized countries each year.

The main method of protection against influenza is the yearly flu vaccine. However, the effectiveness of the vaccine can vary from year to year. Typically, the vaccine reduces the risk of flu illness by about 50-60%, but the 2014-2015 flu season had a vaccine effectiveness rating of only 23%. This raises questions about how to design better vaccines.

All about the antibodies

Current seasonal flu vaccines work to induce high levels of antibodies against hemagglutinin (HA), a glycoprotein located on the surface of the influenza virus that allows it to enter and then infect human cells. HA antibody levels guide vaccine strain selection; approved vaccines seek to elicit a hemagglutinin inhibition (HAI) titer of ≥ 1:40. It is this variable that researchers have been using to design, evaluate and select seasonal influenza vaccines.

Because seasonal flu vaccines have underperformed in recent years, the NIAID researchers decided to test the correlation between anti-HA antibody levels and influenza protection, as well as explore what other variables beyond HA antibodies might influence immune response to the influenza virus.

A human challenge study

The NIAID researchers conducted a human challenge study – a type of clinical trial in which healthy volunteers are exposed to a disease under carefully controlled conditions. One group of participants had high levels of anti-HA antibodies; the other group had low levels of the antibodies. Each volunteer was exposed to a dose of the 2009 H1N1 influenza virus, after which they remained in the study unit for nine days. Then, after completing two days of negative flu tests, the participants were discharged. Finally, four follow up visits were conducted over a period of eight weeks.

The researchers found that participants with high levels of anti-HA antibodies did experience a lower incidence of mild-to-moderate influenza, as well as a reduction in disease duration compared to participants with lower levels of the antibodies. However, both groups of volunteers were just as likely to experience some flu symptoms.

Surprising, the study showed that higher levels of antibody against another influenza protein — neuraminidase (NA) — were better correlated with protection against the flu and its side effects. NA is also found on the surface of influenza viruses; it enables the virus to be released from its host cell and is required for viral replication. The team found that participants with high anti-NA antibody levels did better than participants with high anti-HA antibody levels in three ways: they experienced less severe disease, a shorter duration of viral shedding and symptoms, and fewer and less severe symptoms.

According to the study authors, this represents the first time NA inhibition (NAI) titer has been clearly identified in a controlled human challenge trial as an independent predictor of reducing all aspects of an influenza infection. They concluded that NA antibodies are a stronger factor than HA antibodies in determining disease severity, meaning anti-NA antibody levels should be considered in the development and evaluation of future flu vaccines. Going forward, the most effective way to predict whether someone will develop influenza – and how severe their symptoms will be – could be looking at both HA and NA antibody levels together.

As NIAID Director Anthony S. Fauci, M.D. said in a press release, “This new study provides some interesting clues about how we might improve the level of protection that flu vaccines provide.”

Do you work in this area of research? Check out our available influenza antibodies from laboratories at the Icahn School of Medicine at Mount Sinai as well as the University of Manitoba. The selection includes antibodies against both hemagglutinin and neuraminidase, as well as several other influenza proteins.