Researchers may be one step closer to creating a universal influenza vaccine after successfully testing a new sequential chimeric hemagglutinin (cHA) vaccination strategy in humans.

The immunodominant head domain of the viral hemagglutinin protein, which is targeted by typical flu vaccines, is variable and constantly changes as a result of antigenic drift. By administering two cHA constructs, spaced months apart, that shared the same hemagglutinin stalk but had divergent head domains, the research team was able to redirect the immune response from the head to the stalk.

Vaccination with these constructs, especially with adjuvanted inactivated chimeric hemagglutinin vaccines, induced a broad, strong, durable and functional immune response targeting the conserved, usually immunosubdominant, stalk domain of the hemagglutinin, Dr. Florian Krammer of the Icahn School of Medicine at Mount Sinai, in New York City, and colleagues report.

“The results suggest that chimeric hemagglutinins have the potential to be developed as universal influenza virus vaccines that protect broadly against influenza viruses,” they write in Nature Medicine.

In a press release, Dr. Krammer said the new vaccine candidate “is a major advance over conventional vaccines which are often mismatched to the circulating strains of virus, impacting their effectiveness. In addition, revaccinating individuals annually is a huge and expensive undertaking.”

He and his colleagues tested a regimen of two immunizations, the first with a cH8/1 construct followed 84 days later by a second with a cH5/1 construct, against saline placebos. They also tested different vaccination platforms (live-attenuated influenza vaccine, or LAIV, followed by an intramuscular booster of inactivated influenza virus vaccine, or IIV, vs. IIV both times) as well as the effect of GlaxoSmithKline’s AS03 adjuvant.

The researchers randomly assigned 65 young and healthy volunteers at multiple research sites to one of five experimental groups. The main immunological readout for the study was the level of anti-HA stalk antibodies as measured by enzyme-linked immunosorbent assays (ELISA) with a chimeric 6/1 HA (cH6/1) protein as the substrate.

“This substrate should be recognized by anti-H1 stalk antibodies, but since humans are naive to the H6 head domain, few anti-head antibodies will be detected,” the researchers explain, adding that this readout has been found to be an independent correlate of protection from H1N1 infection.

A single LAIV vaccination did not increase serum IgG titers against the stalk, but when LAIV-primed participants were boosted with IIV5/AS03, they induced a robust anti-stalk response. When the booster dose was given without the adjuvant, a lower induction of anti-HA stalk antibodies was observed and vaccinees had a more heterogeneous response.