Researchers at Seattle’s Fred Hutchinson Cancer Center have discovered a potent antibody that appears to block all four strains of the mosquito-borne virus that causes dengue fever, a disease that sickens 100 million people every year.
Piggybacking on a warming global climate, dengue virus is extending its range. The disease is nicknamed breakbone fever for the joint and muscle pain it causes. Dengue is moving in concert with the spread of the Aedes aegypti mosquito, which transmits the virus and thrives in tropical and sub-tropical zones that are expanding.
The same mosquito also spreads a related virus, Zika, which during a 2016 global outbreak was shown to cause severe birth defects. The newly found antibody can block Zika, as well.
Fred Hutch researcher Leslie Goo, PhD, MPH, is an expert in flaviviruses, a family of pathogens that include Zika, dengue, West Nile, yellow fever and Japanese encephalitis viruses. She leads a team of scientists that used an advanced laboratory technique, called single-cell RNA sequencing, to study blood drawn from patients in Colombia who had experienced multiple exposures to both dengue and Zika.
“Zika and dengue virus are very closely related,” Goo said. “Half the world is now at risk for infection with the four types of dengue and Zika, because they are transmitted by the same mosquito species.”
The Fred Hutch researcher grew up in Indonesia, where dengue virus is endemic. Although she has never been sickened by it, her mother was hospitalized with a severe case, as was a cousin. An uncle died of it — among the estimated 21,000 worldwide who succumb to dengue each year.
“It’s important to me personally to study dengue because it’s always hugely affecting people in my home country and in many countries in tropical and subtropical regions,” she said.
The goal of her team’s experiment was to find natural immune proteins called broadly neutralizing antibodies, so named because they are both potent and can block many strains of the virus. The Colombian cohort was an ideal group in which to search for these rare antibodies. Because of the repeated assaults from dengue virus, and more recently by Zika, the immune systems of people in this group were a perfect environment for evolving broadly neutralizing antibodies, or bNabs.
In the end, Goo and her colleagues landed on results from just four of those patients that together yielded 23 new bNabs. Several of those antibodies appear better than the handful that have been previously identified by dengue researchers using more conventional laboratory techniques.
And one of the Goo team’s newly discovered antibodies, designated F25.S02, stood out from all the rest.
Found in a sample of blood from one patient, it was a highly potent, broadly neutralizing antibody that blocked infection by all four dengue strains and also neutralized Zika. In short, it was the top-performing antibody from that group of patients.
Crucially, its structure places it among a different family, or isotype, of antibody that had never before been shown to block multiple types of flaviviruses.
That result, posted April 11 on bioRxiv, was entirely unexpected and marks the first time a member of family of antibodies know as immunoglobulin A, or IgA, has been shown to inhibit multiple flaviviruses. As detailed below, the work hints that vaccines that generate antibodies from that family might not only be more effective at blocking dengue and Zika, but also be safer to use. Because bioRxiv is a site for “preprints,” advance publication of research that has yet to undergo the rigorous process of peer review, the findings are considered preliminary.
Goo also stresses that the antibodies in her experiment have only been tested in one kind of blood cell, tailored for laboratory research. It needs to be tested against dengue and Zika infection in samples of donated human blood to fully gauge its potential. Then, if work holds up, it could open a new avenue of research for scientists searching for more effective vaccines and treatments for flaviviruses.
Human antibodies are lumped, based on their structure and function, into five different families. For simplicity, we can call them immune families A, D, E, G and M. Until now, all the attention for flavivirus bNabs focused on IgG, or antibodies of the G family. However, the Fred Hutch experiment points to a previously unsuspected role for the A family antibodies.
IgA antibodies tend to populate immune-rich fluids such a mucus, milk and the lining of the intestines — unlikely places to look for an immune response to dengue viruses, which are best known to attack blood and liver cells. The most severe cases are marked by hemorrhagic fevers, bleeding gums and liver failure.
The surprise discovery of F25.S02 is a product of the technology Goo’s team used, single-cell RNA sequencing. By collecting bits of RNA left like a pile of receipts when a cell makes a protein, the method tracks and counts the genetic activity of immune cells. Those receipts — called RNA transcripts — yield an enormous amount of data. Computers search that data for patterns. They can pinpoint precisely which antibody-making cells, like the makers of F25.S02, were responding most vigorously to dengue.
Goo notes that the more conventional approach is extremely sophisticated as well. It requires robots to fill hundreds of tiny test tubes with individual immune cells. Then researchers drop in key pieces of the virus, which serve as bait to attract antibody-making cells drawn only to those viral parts. It is a powerful way to fish up rare antibodies; but works best if you know exactly what you are looking for and choose the right bait. Unfortunately, that can skew the search toward what you already think is out there.
Single-cell RNA sequencing is better at scanning for the unexpected, looking for patterns of antibody-making genetic activity to see what stands out.
“It enables us to look at the antibody repertoire in a more unbiased way,” Goo said.
In other words, perhaps a strong IgA antibody response to dengue had not been found before, because researchers were not looking for it. Traditional methods in fact have been focused heavily on fishing up immune proteins only from cells that make G family antibodies.
Goo credits her colleague Duncan Ralph, PhD, a scientist in the Fred Hutch lab of computational biologist Erick Matsen, PhD, for his complex computer analysis of the sequencing data. Goo lab members Jay Lubow, PhD and research technician Lisa Levoir are lead authors of the study.
As a result of their discovery, Goo and her team may have brought to the field an important clue for those working to develop a better dengue vaccine.
While there is already is an approved dengue vaccine made by Sanofi-Pasteur, Goo notes it is only moderately effective, provides uneven protection against the four dengue strains, and it has a serious drawback, rooted in the biology of dengue.
Researchers have long known that the first infection by dengue tends to be mild, and those infected — usually as children — develop strong neutralizing antibodies to whichever of the four strains was carried by the mosquito that bit them. But that first mild infection puts them at risk for severe disease in their next infection, if that mosquito is carrying one of the three other strains. It is a phenomenon called antibody-dependent enhancement, or ADE.
The same problem can occur with vaccines, which after all are designed to mimic an actual exposure. If the current vaccine is given to a child who has never been exposed to dengue, it can trigger the same effect as a first, natural exposure to the dengue virus — and it can set the stage for a severe infection as antibody protection wanes and a second exposure takes place.
As a strategy to combat that, the World Health Organization requires that before a child can receive the protective Sanofi Pasteur dengue vaccine, they must pass a blood test that shows they have already experienced, naturally, their first mild dengue infection. For these children, the vaccine can then provide cross-protection against all four strains.
Goo notes that current vaccines and vaccine candidates stir up all types of antibody families, but studies of dengue virus neutralization and the antibody-dependent enhancement phenomenon have so far only focused on the G family. In fact, her team’s preliminary result suggest that the A-family antibodies might, in fact, protect against ADE.
“Before our study, there were other examples of potent bNabs, but they were all IgG, which is the isotype that has been associated with ADE. The potential advantage of IgA is that it can have broadly neutralizing activity without the capacity to enhance infection,” Goo said. “The reason we think this is exciting is because IgA antibodies are not only capable of neutralizing Zika and dengue virus, but they might also be inherently safer than IgG antibodies.”
Time — and a flurry of additional research — will tell whether Goo and her team’s unexpected discovery will bring the field of flavivirus research an important step closer to a better vaccine. Such a vaccine is needed to make life safer in what seems to be to be an increasingly warmer and more dangerous world.
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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