Virus World

Scientists identified a new class of antibodies in human blood that are able to target multiple strains of influenza A virus in the lab. A newly discovered class of antibodies in human blood can neutralize different types of the flu virus and could be key to the development of broadly protective vaccines against the seasonal viruses, scientists say.  Circulating flu viruses constantly mutate, so "we need annual influenza virus vaccines to keep pace with continuing viral evolution," the researchers behind the discovery said in a statement. "Our work suggests that the barriers to eliciting more broadly protective immunity may be surprisingly low," they said.  There are four types of flu virus, known as influenza A, B, C and D, with A and B being responsible for the seasonal flu epidemics in the U.S. every year. Influenza A comes in many subtypes whose differences lie in two proteins that the virus uses to infect our cells: hemagglutinin (H) and neuraminidase (N). For example, H1N1 and H3N2 are subtypes of influenza A that routinely infect people. Within each subtype are different "strains" that constantly tweak their genetic code. For example, a strain of H1N1 is currently the dominant virus causing flu in the U.S. Influenza B, meanwhile, is divided into two lineages — Yamagata and Victoria — and is typically responsible for a much smaller proportion of flu cases.

Making effective flu shots relies on harnessing the protective power of antibodies — immune proteins that attack invading pathogens — but the virus' ability to quickly mutate makes this challenging. Flu vaccines prime the immune system to produce specific antibodies that latch onto a flu virus and prevent it from infecting cells after it invades the body. However, these vaccines are formulated to target specific strains, and because those strains mutate year over year, people then need a new flu shot each year to keep up. In the new study, published Thursday (Dec. 21) in the journal PLOS Biology, scientists described a newfound class of antibodies in human blood samples that target multiple forms of the influenza A virus.  The research was conducted only in the lab, so the scientists aren't sure exactly how these antibodies contribute to the body's flu shot response. However, one day, these antibodies could be used to develop vaccines that are more effective at protecting people from multiple strains of flu at the same time.  To guard against influenza A, conventional flu vaccines usually prompt the immune system to produce antibodies against the H protein on the surface of the virus. Antibodies have previously been discovered that target two main types of hemagglutinin, called H1 and H3, at the same time. However, they can only do this if there is a specific mutation in H1, namely the insertion of an amino acid in the outer edge of the protein that binds to a receptor on the outside of our cells. This consequently limits the antibodies' efficacy against different flavors of flu virus. 

Through lab experiments, the study authors identified antibodies that are abundant in human blood and can bind to certain H1 and H3 strains of influenza A, whether or not this hemagglutinin mutation is present. This means that they'd theoretically be able to provide broad protection against both subtypes of virus, potentially even as circulating strains mutate over time.  The authors also looked at how well these antibodies targeted strains of H1 and H3 that have circulated in the past. The antibodies reacted with H3 strains from the late 1980s to late 1990s and H1 strains from the early 2000s through to 2015.  This suggests the patients whose blood was sampled originally made the antibodies in response to H3 strains of the virus. Then, after a later exposure to H1 strains at a later date through either infection or vaccination, the antibodies became primed to target H1 as well. These findings may have important applications for future vaccine design.  "Given the right series of influenza virus exposures/vaccinations, it is possible for humans to mount robust antibody responses that neutralize divergent H1N1 and H3N2 viruses, opening new avenues to design improved vaccines," the authors said in the statement.  In other words, there may be a way to ensure vaccines trigger the production of these broad-acting antibodies, to ensure the shots guard against both subtypes of the virus equally well.

The scourge of the influenza virus devastates health and claims many lives worldwide each year. It is especially daunting because vaccines are only protective when they are well matched to the strains circulating in the population. But now, a team led by researchers at the Icahn School of Medicine at Mount Sinai is getting closer to a universal flu vaccine using a novel approach they've developed called chimeric hemagglutinin (cHA).

A protein on the surface of influenza viruses, hemagglutinin, shepherds the virus into host cells. Hemagglutinin is comprised of a 'head' (variable) and a 'stalk' (varies less from strain to strain). Thus, Icahn School of Medicine researchers, led by Peter Palese, Ph.D., Professor and Chair of Microbiology and Florian Krammer, Ph.D., Professor of have focused their efforts on developing a vaccine against the stalk portion of this protein. Their study, undertaken in collaboration with PATH, an international nonprofit, the Cincinnati Children's Hospital Medical Center, the Duke Early Phase Clinical Research Unit, and the University of Chicago, involved testing of several cHA-based vaccination regimens to see if they would induce antibodies that provide broad protection against influenza virus infections. The results were published this month in The Lancet Infectious Diseases.

The diverse research team including Adolfo García-Sastre, Ph.D., Professor of Microbiology and Director of the Global Health and Emerging Pathogens Institute at Icahn; Bruce Innis, M.D., Leader, Respiratory Infections and Maternal Immunizations at PATH; and Patrick Wilson, Ph.D., Professor of Medicine at the University of Chicago, have investigated whether several potential cHA-based vaccines might induce antibodies that would target the stalk of group 1 hemagglutinin-expressing influenza viruses. An adjuvant, an ingredient that boosts the effectiveness of vaccines, was also part of the testing process. Vaccine regimens examined included: 1) a group receiving a chimeric H8/1 hemagglutinin-based live attenuated vaccine followed by a boost with a non-adjuvanted chimeric H5/1 hemagglutinin-based inactivated vaccine (IIV), and 2) the same regimen but with the IIV having an adjuvant called AS03, and 3) a prime-boost regimen including an adjuvanted cH8/1 IIV prime followed by an adjuvanted cH5/1 IIV boost.

The researchers found that the IIV, but not the live attenuated vaccine, induced a significant antibody response after the prime, with a strong increase in anti-H1 stalk titers. All vaccine regimens induced detectable H1 stalk antibody responses after receiving boosts. "The vaccine induced a broad antibody response which was not only cross-reactive for currently circulating human influenza virus but also to avian and bat influenza virus subtypes," said Florian Krammer. "It was surprising to find that the inactivated formulation with adjuvant induced a very strong anti-stalk response already after the prime suggesting that one vaccination might be enough to induce protection against pandemic influenza viruses yet to arise. The results indicate that we are moving towards a universal influenza virus vaccine, but these are still interim results. Additional results will be available upon completion of the study at the end of 2019."...

Published in the Lancet Infectious Diseases (Open Access):

https://doi.org/10.1016/S1473-3099(19)30393-7