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Hemagglutinin-Based Universal Flu Vaccine Shows Early Promise

November 25, 2019

By Will Boggs MD

NEW YORK (Reuters Health) - An influenza-vaccine candidate targeting the hemagglutinin (HA) stalk elicits cross-reactive antibodies in healthy human adults, according to interim results of a phase 1 clinical trial.

"This was the first time a rationally designed universal-influenza-vaccine approach targeting the HA stalk was ever tested in humans," said Dr. Florian Krammer of Icahn School of Medicine at Mount Sinai, in New York City.

"The results show that these broadly reactive anti-stalk antibodies can actually be induced by vaccination. The results pave the way for developing anti-stalk universal vaccine candidates further (and not just ours)," he told Reuters Health by email.

Current influenza vaccines target the immunodominant head domain of HA whose antigenic drift necessitates changes in the vaccine each season. The HA stalk, on the other hand, is highly conserved, but there are no clinical data for stalk-based vaccine approaches.

Dr. Krammer and colleagues constructed a chimeric H1 hemagglutinin-based universal-influenza-virus-vaccine candidate and tested its ability to induce broadly cross-reactive antibodies targeting the stalk domain of the group 1 hemagglutinin-expressing influenza viruses in their phase 1 clinical trial of 65 healthy adults with pre-existing immunity to influenza virus HA.

The researchers compared three vaccine regimens: (1) a chimeric H8/1 intranasal live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1 intramuscular inactivated vaccine on day 85; (2) the same regimen, but with the inactivated vaccine adjuvanted with AS03; and (3) an AS03-adjuvanted, chimeric H8/1, intramuscular inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular inactivated vaccine.

All study participants had pre-existing H1 anti-stalk baseline titers. After the first vaccine dose, anti-H1 stalk antibody titers increased seven-fold but only with the third regimen (with both doses adjuvanted).

Moreover, with this regimen, 80% of participants had an increase in titers of four times or higher and 33% had at least a 10-fold increase over baseline, the researchers report in The Lancet Infectious Diseases, October 17.

Anti-H1 stalk antibody titers with the first two regimens (or placebo) remained similar up to study day 85, but in the group given the third regimen, antibody titers declined by half from day 29 to day 85.

At 28 days after the booster vaccination, antibody titers increased 5.6-fold with the second regimen, 2.2-fold with the first regimen, and an additional 1.4-fold with the third regimen.

After the booster vaccination, 20.0% of participants that received the second regimen, 14.3% of those that received the third regimen, and none of those who received the first (non-adjuvanted) regimen had achieved a 10 times or greater increase in anti-H1 antibodies.

Results were similar for the induction of anti-H2 stalk antibodies.

"It is possible to design universal vaccines against influenza," Dr. Krammer said. "It might take a long time until these vaccines are on the market, but they will likely change how we think about influenza and how we vaccinate against it. In the future, influenza vaccines might be given during childhood, maybe 2-3 times like other vaccines and that might be enough for a lifetime."

"Currently, influenza vaccines are mostly used in high-income countries because they need to be given annually, which requires a specific infrastructure, and it is also very costly," he said. "A universal influenza virus vaccine would be available for everybody, also in low- and middle-income countries, just like MMR and other vaccines are."

Dr. Sophie Valkenburg of the University of Hong Kong, who co-authored a linked editorial, told Reuters Health by email, "This report shows that universal influenza vaccines are becoming a reality rather than an unattainable goal, and investment in these vaccines platforms will accelerate their development."

The third regimen - IM adjuvanted inactivated prime followed by IM adjuvanted inactivated boost - "resulted in high levels of HA-stalk antibodies with a range of cross-reactivity," she said. "Therefore, developing HA-stalk antibodies in people with a diverse and high level of existing antibodies is possible."

The Icahn School of Medicine at Mount Sinai (ISMMS) has issued patents and filed patent applications covering the use of chimeric hemagglutinin antigens as vaccines and has granted GlaxoSmithKline (GSK) certain license rights to these patents and patent applications. Four of the authors, including Dr. Krammer, are named as inventors on these patents and applications, and five are employed by GSK.


Lancet Infect Dis 2019.

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