The innovative universal influenza vaccine is promising in the first clinical trials.Science

For epidemiologists, the COVID-19 pandemic greatly strengthened their long-standing nightmare about another virus: the emergence of a new and deadly strain of influenza. A universal influenza vaccine that is effective against any strain of influenza virus that can infect humans can protect us from this danger, but progress is slow. This new concept of universal influenza vaccine is currently passing the first tests in small clinical trials. Developer reports today To Nature Medicine.

“This is an important paper,” says Aubrey Gordon, an epidemiologist at the University of Michigan’s School of Public Health, who studies influenza infections and vaccines.

Influenza viruses rapidly accumulate mutations, easily “reclassifying” or exchanging genes between strains, creating mutants that allow people to dodge past immunity that they have acquired naturally or from vaccines. Therefore, it is necessary to develop a new influenza vaccine every year.

Existing influenza vaccines include a weakened or inactivated influenza virus mixed with a surface-studded protein, hemagglutinin (HA). These vaccines are primarily intended to provoke an antibody response to the upper or head of HA. Genetic changes in the influenza virus rarely change most of the head. However, because only a small part of the head reassembles or mutates frequently, new virus strains dodge immunological memory and influenza vaccine makers need to update HA and prepare new formulations each year.

The bottom of HA, the stem, is resistant to change, and epidemiological studies have shown that those exposed to the flu strain and who have developed antibodies to the stem can ward off a variety of other strains. As a result, a handful of new universal influenza vaccine candidates under development bring HA stalks to the fore. The study shows for the first time that “a vaccine strategy that produces stalk-reactive antibodies in humans can be developed,” said Florian Krammer, a virologist at Mount Sinai School of Medicine, who co-leads the multicenter universal influenza vaccine. .. A consortium funded by the National Institute of Allergy and Infectious Diseases to support the development of candidates tested in new trials. Other clinical trials testing stalk-based universal influenza vaccine candidates have not yet reported data.

Targeting the stem is more difficult than expected because the immune memory cells accumulated throughout the life of the influenza infection react so strongly to the conserved region of the HA head that this reaction nullifies the production of antibodies to the stem. is. Some researchers have tried to make an influenza vaccine that contains only HA stems, but this fragment is very unstable. To avoid this problem, Krammer et al. Created a so-called chimeric HA that links protein-conserved stems to an abnormal head that is completely new to the human immune system and does not cause human immune memory. .. Only low levels of head antibodies are produced, predominantly a strong new immune response to the stem. In essence, the chimeric head is only there to stabilize the stem.

Influenza vaccines include 3-4 strains of the virus that fall into Group A, which falls into the other two categories, and Group B strains. Researchers have developed a vaccine made from an attenuated version of the influenza virus or an inactivated virus with a chimeric HA that represents only one division of Group A. In the study, 51 participants received various vaccines and compared their antibodies to the 15 antibodies that received placebo. Researchers report that a single shot of the vaccine with the chimeric HA inactivated virus “induced significantly higher anti-stem antibody titers.”

This study was only a phase I study to establish safety and measure the immune response. That is, they have not tested the vaccine’s ability to protect people from the flu. Nevertheless, when researchers transferred human antibodies caused by the vaccine to mice and “challenged” rodents with the influenza virus, the mice lost much less weight than untreated mice, which were also infected, and the antibodies Suggested that they were protected. The study is a “serious effort” and an “important first step” to test the stem antibody hypothesis, said James Crow, an immunologist who runs a vaccine center at Vanderbilt University. I am.

According to Kramer, it will take at least two years to develop a chimeric HA that represents enough other strains from influenza groups A and B and combine it with the universal vaccine. The mixture is then tested in a large multi-year study designed to show that vaccine candidates work better than seasonal vaccines. Chimeric HA works quite well in the year when its HA closely matches the circulating mutant, so chimeric HA works only in one of the rare years when there is a mismatch.

Kramer believes this “long development path” is the main reason his team lost their first corporate partner, GlaxoSmithKline. GlaxoSmithKline is vaccinated with another universal flu vaccine in clinical trials. “It’s hard to get a lot of attention to something like this,” says Krammer.