New way of predicting dominant seasonal flu strain

Mathematical method requires no animal tests, better predicts flu-vaccine targets

Rice News staff

Rice University scientists have found a way to predict rapidly whether a new strain of the influenza virus should be included in the annual seasonal flu vaccine. While it sometimes takes new flu strains up to three years to become dominant worldwide, the new method can predict whether they will become dominant as little as two weeks after the sequence first appears in the GenBank database, the National Institutes of Health’s collection of all publicly available DNA sequences.

“We studied a new strain of the virus that evolved in British Columbia in the middle of March 2009,” said Michael Deem, co-author of a new study featured on the cover of the Dec. 12 issue of Protein Engineering Design and Selection. “By the end of March, just about two weeks after it came out, we could detect that it would become the dominant strain of H3N2 in 2009. By contrast, it wasn’t detectable as a novel strain by the standard methods that the World Health Organization uses until July or the middle of August.”

It takes several months to produce the millions of doses of flu vaccine needed each year, and officials at the World Health Organization (WHO) use a combination of statistical methods and animal tests to choose the following year’s formula.

He’s on a hot streak

Grad student Jiankui He scores 3 major papers on cusp of earning doctorate

Rice News staff

Jiankui He has had quite a semester. As if three published papers of tremendous significance weren’t enough, the Rice graduate student defended his dissertation in mid-November after only three-and-a-half years of study with Rice Professor Michael Deem.

Soon he will be Dr. He.

His specialty is the theoretical modeling and computer simulation of biological systems. And he has been on a remarkable run this year, capped off by his lead authorship on the cover paper in the Dec. 12 issue of the journal Protein Engineering Design and Selection.

In that paper (already published online), He and Deem present a mathematical model that reliably predicts which variant of a particular strain of flu will become dominant in a given season. That’s important because the World Health Organization has to decide which variants are likely to dominate months in advance of flu season, in time to make enough vaccine.

If the WHO is wrong, it may inoculate entire populations against a flu that does not present a threat at the expense of one that does.

Using public genetic sequencing data, statistical analysis by He and Deem correctly predicted the dominant form of H3N2 of flu for almost all of the past 15 years. In several cases, their analysis succeeded where the WHO failed.

The new study followed one in October, published in Physical Review Letters, that applied statistical techniques from evolutionary biology to United Nations trade data to show that the world economy, due to the increased globalization of trade, is more sensitive to recessionary shocks and recovers more slowly than it did from recessions 40 years ago. That study gained attention in the Wall Street Journal.

In a September paper, also in Physical Review Letters, He and Deem created a computational model to determine how natural selection and evolution influence the way bacteria acquire immunity from diseases. The latter two papers were the basis of his graduate thesis.

It’s remarkable that He, the son of rice farmers in Hunan Province in China, was accepted by only one of the three or four graduate schools he applied to. He arrived at Rice before the fall semester in 2007 to meet with potential advisers and hit it off immediately with Deem, Rice’s John W. Cox Professor in Biochemical and Genetic Engineering and a professor of physics and astronomy.

“Jiankui is a very high-impact student,” Deem said. “He has done a fantastic job here at Rice, and I am sure he will be highly successful in his career.”

He appreciates the freedom Deem gave him to follow his own research path. “Although trained as a physics student, I did not restrict my work to conventional physics,” he said. “Instead, I applied the techniques and methods in physics to the study of biology and the economy.”

He is grateful to Rice for financial support and to Deem for allowing him to attend frequent conferences around the country. A meeting at one landed He a postdoctoral position at Stanford University, where he’ll join the lab of noted bioengineer Stephen Quake. Quake found fame earlier this year for sequencing his own genome with a technology he invented, finding in the process his own elevated risk for heart disease.

The Rice graduate looks forward to making the move from theoretical work in Deem’s lab to experimental work in immunology and single-molecule sequencing with Quake. Eventually, He wants to work in the new area of synthetic biology, building bacteria from the bottom up for biofuel or to treat disease.

Graduate students are often depicted as people who rarely see the light of day, but He covered a lot of ground during his time at Rice. As president of Rice Chinese Students and Scholars Association, he helped organize a steady stream of events for a community of more than 400.

“Rice is a place where you can really enjoy graduate school,” he said. “Outside of the lab, there’s a lot to do. There’s Valhalla, of course, and I love to play soccer. Oh, my God, Rice has six soccer fields! That’s awesome.”

Just a month before the British Columbia strain was first recorded in GenBank, the
WHO had made its recommendations for the annual 2009-2010 vaccine. While the biggest flu story of 2009 was the H1N1 pandemic that began in Mexico and spread rapidly worldwide, the British Columbia strain went on to become the dominant variant of H3N2 the following year.

Because it was significantly different from the H3N2 strain that had been included in the seasonal vaccine for that year, the vaccine’s efficacy against British Columbia was estimated at about 20 percent.

“It’s not that we could have predicted that British Columbia would have emerged out of thin air, but once it had emerged,
our method could detect the signature of its eventual dominance with a very limited amount of sequence data,” said Deem, the John W. Cox Professor in Biochemical and Genetic Engineering and professor of physics and astronomy at Rice.

Deem and study co-author Jiankui He, a graduate student in physics and astronomy, developed a mathematical method that used freely
available genetic profiles of new flu strains to predict whether a strain will become dominant. Using the method, they examined the H3N2 flu strain for the past 14 years and made their own predictions based on the available data in GenBank, where public health
officials post all the latest genetic sequences of new flu strains.

Deem and He compared their predictions with the WHO’s predictions from 1996 to 2010. They found their new method correctly predicted
the dominant strain of H3N2 for most years, including three years — 2002, 2003 and 2009 — when the WHO vaccine was formulated with an H3N2 strain that turned out not to be the dominant strain that year.

The new method involves a statistical technique called multidimensional
that is used to create graphical plots of complex data in fields as diverse as marketing and physics. In their study, He and Deem used multidimensional scaling to create a graphical plot of amino acid sequence data for all strains of H3N2. They limited their study to a 329-amino-acid region of the virus that mutates regularly to avoid detection by the immune system.

“Using multidimensional scaling, we project from those 329 dimensions to the two dimensions that contain the most information,” Deem said. “We just plot all of the points as a function of two variables instead of listing all 329, which is too much information to work with. With the two-dimensional scaling, we have a workable problem and we still have enough information to see clusters of new strains that will eventually become dominant.”

Deem said the results of the study suggests that public health officials could benefit by using the new method, which is both fast and
inexpensive, in addition to the well-accepted methods that are currently used to formulate vaccine strain recommendations.

The research was supported by the Defense Advanced Research Projects Agency’s FunBio program.

About Mike Williams

Mike Williams is a senior media relations specialist in Rice University's Office of Public Affairs.