Promising Steps Toward a Universal Influenza Vaccine

Using a unique approach of targeting the stalk of the hemagglutinin, investigators are taking steps toward developing a universal influenza vaccine candidate.

The influenza virus is among the most daunting global health challenges, with current seasonal vaccines requiring close calibration to strains circulating in the population. But now, new progress has been made in the development of a universal influenza vaccine candidate, using a novel approach called chimeric hemagglutinin.

A phase 1 study, led by investigators from the Icahn School of Medicine at Mount Sinai, deployed the unique approach and according to interim results, published in The Lancet Infectious Diseases, the method shows promise.

Interim results indicate that this is the first human trial able to generate antibodies which will target a different area of the hemagglutinin protein, which binds the influenza virus to target cells, than traditional influenza vaccines.

One of the study’s lead investigators, Florian Krammer, PhD, professor of microbiology at the Icahn School of Medicine at Mount Sinai, compares the hemagglutinin to a mushroom: there’s a cap and a stalk. Regular vaccines target the “cap,” but, according to Krammer, the cap is not an ideal target for a vaccine to protect across seasons and strains because it has a lot of variability between seasonal influenza and pandemic strains.

On the other hand, Krammer pointed out that the stalk is a much more consistent target, with content “cross-conserved from an H1 strain, which is the seasonal influenza virus strain, and the H5 strain which is a highly pathogenic avian influenza.” A universal vaccine functioning on this basis, if successful, would carry over between strains and not require an annual seasonal vaccine

Krammer also told Contagion® that a universal influenza vaccine would have substantial ramifications for global health and said, “Flu vaccines are not used in most low- and middle-income countries, they’re typically used in the United States and in Europe. One of the main reasons for that is you need an infrastructure to roll out the vaccine every year and you have to pay for it again and again. If you have a vaccine that you only give 2 or 3 times, for example to children, you can give them at the same time a measles vaccine or diphtheria vaccine… that would actually make the vaccine globally available.”

The study enrolled 65 participants between October 10, 2017, and November 27, 2017. At enrollment the participants were randomized into 1 of 3 study groups or 1 of 2 placebo groups. One study group received a chimeric H8/1 hemagglutinin based live attenuated intranasal vaccine followed by an intramuscular boost with a non-adjuvanted chimeric H5/1 hemagglutinin based inactivated vaccine (IIV). Another group received the same regimen but with the IIV intramuscularly with an adjuvant called AS03. The third group received an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine, followed by an AS03-adjuvanted, chimeric H5/1, intramuscular inactivated boost.

The adjuvanted inactivated vaccine induced a substantial immunoglobulin G (IgG) antibody response after the prime immunization, with a 7-time increase in anti-H1 stalk titers on day 29. All 3 regimens induced a detectable H1 stalk antibody, cross-reactive serum IgG, and peripheral blood plasmablast response after receiving boosts.

Unsolicited adverse events were reported in 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 of 25 (48%) participants following prime vaccination with intramuscular study vaccine or placebo, 12 of 36 (33%) patients following prime intranasal product or placebo, and in 18 of 56 (32%) following booster doses. Solicited systemic adverse events were also reported in 14 of (56%) 25 participants following prime immunization with intramuscular vaccine or placebo, in 22 of (61%) 36 participants after immunization with intranasal product or placebo, and in 21 (38%) of 56 participants following booster doses.

According to the investigators these were significant findings, though Krammer cautioned that the study is still in a relatively early stage. “With a phase 1 study you cannot look at protection. We’re missing a lot of the immunological readouts that we’ll get with the full study report. But it’s already a good sign that the concept works, and we could induce these antibodies…it’s really the first time that anybody has done that.”

Additional results from the study will be available upon completion of the research at the conclusion of 2019.