Upside to H1N1: informatics clues to multiple vaccine

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  • Published: Jan 15, 2011
  • Author: David Bradley
  • Channels: Chemometrics & Informatics
thumbnail image: Upside to H1N1: informatics clues to multiple vaccine

Flu relief

The 2009 H1N1 influenza pandemic infected an estimated 60 million people and hospitalized more than 250,000 in the USA. But, it brought with it informatics clues about how to make a vaccine that could protect against multiple strains of influenza.

Influenza type A (H1N1) virus is a strain of influenza that emerged widely in a pandemic during 2009 spreading from Mexico across the globe. Some strains of H1N1 are endemic in humans and cause a third or so of all influenza-like illness, including being involved in previous pandemics. But the 2009 outbreak of H1N1, dubbed "swine flu" by the tabloid media because of its lineage had led to 17,000 deaths by the start of 2010. By August 2010, the World Health Organization had declared the H1N1 influenza pandemic over, saying worldwide flu activity had returned to typical seasonal patterns. At the beginning of 2011, this H1N1 strain while now vaccinated against had killed several more. New clues as to how to protect people with some kind of generic vaccine against the ever-increasing strains of influenza is urgently needed.

Immune analysis

Writing in the January issue of Journal of Experimental Medicine, researchers from the University of Chicago and Emory University report on the recovery of people infected with pandemic H1N1. Their analysis of the data shows that those people had an extraordinary immune response that generated antibodies protective not only against pandemic H1N1, but against a variety of flu strains.

The team points out that the 2009 H1N1 virus coincides with typical seasonal influenza strains primarily in those viral components that are critical to the pathogen's survival and replication. H1N1 apparently induced an immune response to those components that overlapped with prior influenza exposures in the strong survivors. By focusing on those overlapping defences, the researchers believe it might be possible to make a more "generic" flu vaccine that would ultimately preclude the annual scramble to predict coming seasonal strains of influenza and so allow rapid production of a vaccine that would protect against all flu viruses and avoid the issue of the kind of vaccine supply shortages that faced health authorities in the UK and elsewhere at the beginning of 2011.

"Our research demonstrates how to make a single vaccine that could potentially provide immunity to all influenza," says team member Patrick Wilson of the University of Chicago. "The surprise was that such a very different influenza strain, as opposed to the most common strains, could lead us to something so widely applicable."

Surprisingly generic

"Our data show that infection with the 2009 pandemic influenza strain could induce broadly protective antibodies that are only very rarely seen after seasonal flu infections or flu shots," adds co-author Jens Wrammert of Emory University School of Medicine and the Emory Vaccine Center. "These findings show that these types of antibodies can be induced in humans, if the immune system has the right stimulation."

When the researchers began their investigation, there was no vaccine for the pandemic 2009 H1N1 strain of influenza. They initially hoped to use the antibodies from patients who recovered simply as therapy for those who were severely ill with this emerging virus. However, when they began analyzing antibody responses from nine patients aged 21 to 45 years old, recruited through the Hope Clinic, the clinical division of the Emory Vaccine Center, they quickly saw that the same virus could cause a wide range of illness, from mild to life-threatening disease. They studied the B cell response in the nine patients but subsequently only made antibodies from four of these.

They soon identified white blood cells from the patients whose immune systems produced antibodies against the virus, then isolated the antibody genes from individual cells. They used the genes to produce antibodies in the laboratory - a total of 86 varieties - and tested which of these antibodies reacted against which flu strains. Antibodies isolated by the team could bind all the seasonal H1N1 flu strains from the last decade, the devastating "Spanish flu" strain from 1918, plus a potentially lethal H5N1 avian flu strain. This indicated that "while the flu changes from year to year, some core elements have been consistent for nearly a century," adds Wilson.

The team explains that the antibodies, which they refer to as cross-reactive are generated by highly mutated antibody genes. They appear to be produced by white blood cells that have previously been exposed to influenza virus. The antibody genes have a way to evolve to adapt to the new emerging strain to which they have been exposed, continuing to mutate and increasing their affinity for certain key targets present on both strains with each generation of cell.

Half of the cross-reactive antibodies the team identified attached to the virus's "stalk" region, a sort of biochemical drill-bit the virus uses to enter cells. Because this part of the virus doesn?t change as much as other regions, scientists have proposed to make it the basis for a vaccine that could provide broader protection.

Broad protection

"Previously, this type of broadly protective, stalk-reactive antibody was thought to be very rare," Wrammert explains. "In contrast, in the patients we studied, these stalk-reactive antibodies were surprisingly abundant."

Tests in mice of a vaccine derived from this discovery have so far proven positive. Although relatively few patients could be analyzed in detail at the antibody level, the authors conclude that "with the proper immunogen, the long-sought development of a pan-influenza vaccine might be possible."

At the time of writing, additional information about H1N1 was due to be published in BioEssays. The new research by Hans Dieter Klenk from Philipps-Universitaet Marburg, Germany, reveals how the 2009 H1N1 pandemic challenges the conventional wisdom regarding the emergence of this virus from an existing influenza subtype. "H1N1 emerged in February 2009 in Mexico and swept around the globe within 6 months," explains Klenk. "The conventional ideal is that pandemics are fuelled by new strands which emerge in the human population, yet it was because H1N1 did not conform to this ideal that its spread was so unexpected." It was previously thought that a pandemic occurs when a virus with a new HA, or a new HA and a new NA that are not recognised by the human immune system emerges and spreads throughout the population, the so-called antigenic shift. In the 2009 outbreak, a strain of H1N1 containing new HA and NA lineages caused a pandemic even though H1N1 had already circulated through the human population, thus revealing an antigenic shift from within the same subtype.

"This means future research should not simply monitor one or a few viruses and that plans to deal with pandemics must be flexible enough to handle the unexpected," adds Klenk. The finding makes all the more important efforts to develop a generic vaccine against influenza viruses of all strains.

The 2009 H1N1 influenza pandemic infected an estimated 60 million people and hospitalized more than 250,000 in the USA. But, it brought with it informatics clues about how to make a vaccine that could protect against multiple strains of influenza.

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