Tag Archives: zika

Scent, sweat from human skin attract disease-spreading mosquitoes

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Mosquitoes that spread Zika, dengue and yellow fever are guided toward their victims by a scent from human skin. The exact composition of that scent has not been identified until now.

A UC Riverside-led team discovered that the combination of carbon dioxide plus two chemicals, 2-ketoglutaric and lactic acids, elicits a scent that causes a mosquito to locate and land on its victim. This chemical cocktail also encourages probing, the use of piercing mouthparts to find blood.

This chemical mixture appears to specifically attract female Aedes aegypti mosquitoes, vectors of Zika as well as chikungunya, dengue, and yellow fever viruses. This mosquito originated in Africa, but has spread to tropical and subtropical regions worldwide, including the U.S.

Mosquitoes use a variety of cues to locate their victims, including carbon dioxide, sight, temperature, and humidity. However, Cardé’s recent research shows skin odors are even more important for pinpointing a biting site.

Mosquito

Aedes aegyptii mosquito biting a person./CREDIT CDC

“We demonstrated that mosquitoes land on visually indistinct targets imbued with these two odors, and these targets aren’t associated with heat or moisture,” Cardé said. “That leaves skin odor as the key guiding factor.”

Given the significance of odor in helping mosquitoes successfully feed on humans, Cardé wanted to discover the exact chemicals that make our scent so potent for the insects. Part of the equation, lactic acid, was identified as one chemical element in the odor cocktail as long ago as 1968.

Since then, several studies have identified that carbon dioxide combined with ammonia, and other chemicals produced by humans also attract these mosquitoes. However, Cardé, who has studied mosquitoes for 26 years, felt these other chemicals were not strong attractants.

Methods that chemists typically use to identify these chemicals would not have worked for 2-ketoglutaric acid, Cardé said. Gas chromatography, which separates chemicals by their molecular weight and polarity, would have missed this acid.

“I think that these chemicals may not have been found before because of the complexity of the human odor profile and the minute amounts of these compounds present in sweat,” said chemist Jan Bello, formerly of UCR and now with insect pest control company Provivi.

Searching for mosquito attractors, Cardé turned to Bello, who extracted compounds from the sweat in his own feet. He filled his socks with glass beads and walked around with the beads in his socks for four hours per odor collection.

Malaria

Credit: MINDY TAKAMIYA/KYOTO UNIVERSITY ICEMS

“Wearing the beads felt almost like a massage, like squeezing stress balls full of sand, but with your feet,” said Bello. ‘The most frustrating part of doing it for a long time is that they would get stuck in between your toes, so it would be uncomfortable after a while.”

The inconvenience was worth the investment. Bello isolated chemicals from the sweat deposited on the sock beads and observed the mosquitoes’ response to those chemicals. In this way, the most active combination emerged.

Future studies are planned to determine whether the same compound is effective for any other mosquitoes, and why there is such variation in how individuals are apt to be bitten. “Some are more attractive than others to these mosquitoes, but no one’s yet established why this is so,” Cardé said.

Though this discovery may not lead to insights for the development of new repellants, the research team is hopeful their discovery can be used to attract, trap, and potentially kill disease-spreading mosquitoes.

Antibody protects against Zika and dengue, mouse study shows

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Brazil and other areas hardest hit by the Zika virus – which can cause babies to be born with abnormally small heads – are also home to dengue virus, which is spread by the same mosquito species.

A new study led by researchers at Washington University School of Medicine in St. Louis shows that an antibody that protects against dengue virus is also effective against Zika in mice.

Antibodies remain in the bloodstream for weeks, so one or a few doses of an antibody-based drug given over the course of a woman’s pregnancy potentially could protect her fetus from Zika, with the added benefit of protecting her from both Zika and dengue disease, the researchers said. Dengue causes high fever, severe headaches, and joint and muscle pain in children and adults but does not directly harm fetuses.

“We found that this antibody not only neutralizes the dengue virus but, in mice, protects both adults and fetuses from Zika disease,” said Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and the study’s senior author.

The study is published Sept. 25 in Nature Immunology.

Since dengue and Zika are related viruses, the researchers reasoned that an antibody that prevents dengue disease may do the same for Zika. Diamond and graduate student Estefania Fernandez collaborated with Gavin Screaton, MD, DPhil, of Imperial College London, who had generated a panel of human anti-dengue antibodies years before.

The scientists infected nonpregnant adult mice with Zika virus and then administered one of the anti-dengue antibodies one, three or five days after infection. For comparison, another group of mice was infected with Zika virus and then given a placebo. Within three weeks of infection, more than 80 percent of the untreated mice had died, whereas all of the mice that received the anti-dengue antibody within three days of infection were still alive, and 40 percent of those that received the antibody five days after infection survived.

To find out whether the antibody also could protect fetuses from infection, the researchers infected female mice on the sixth day of their pregnancies with Zika virus and then administered a dose of antibody or a placebo one or three days later.

On the 13th day of gestation, the amount of Zika’s genetic material was 600,000 times lower in the placentas and 4,900 times lower in the fetal heads from the pregnant mice that were treated one day after infection, compared with mice that received the placebo. However, administering the antibody three days after infection was less effective: It reduced the amount of viral genetic material in the fetal heads nineteenfold and in the placentas twenty-threefold.

These findings suggest that for the antibody to effectively protect fetuses from Zika infection, it must be administered soon after infection. Such a goal may be unrealistic clinically because women rarely know when they get infected.

However, giving women the antibody as soon as they know they are pregnant could provide them with a ready-made defense against the virus should they encounter it. Antibody-based drugs have been used for decades to provide temporary protection against infectious diseases such as rabies when there is no time to vaccinate or, as in the case of Zika, when there is no vaccine available.

The key to using this antibody as a preventive drug would be to make sure that antibody levels in a woman’s bloodstream stay high enough to protect her fetus for the duration of her pregnancy.

Diamond and colleagues are working on identifying how much antibody a pregnant woman would need to ensure that her fetus is protected from Zika. They also are exploring ways to extend the antibody’s half-life in the blood, to reduce the number of times it would need to be administered.

Having anti-dengue antibodies circulating in the bloodstream for months on end poses a risk, though, because antibodies that protect against one strain of dengue virus sometimes worsen symptoms if a person is infected by another dengue strain.

To avoid the possibility of accidentally aggravating an already very painful disease, the researchers mutated the antibody in four spots, making it impossible for the antibody to exacerbate dengue disease.

“We mutated the antibody so that it could not cause antibody enhancement of dengue infection, and it was still protective,” said Diamond, who is also a professor of pathology and immunology, and of molecular microbiology. “So now we have a version of the antibody that would be therapeutic against both viruses and safe for use in a dengue-endemic area, because it is unable to worsen disease.”

Scientists develop improved, potentially safer Zika vaccine

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The worldwide Zika threat first emerged in 2015, infecting millions as it swept across the Americas. It struck great fear in pregnant women, as babies born with severe brain birth defects quickly overburdened hospitals and public health care systems.

In response, there has been a flurry of heroic scientific efforts to stop Zika. Whole governments, academic labs and pharmaceutical companies have raced to develop Zika vaccines ever since global health experts first realized the dangers wrought by the mosquito-borne virus.

Now, ASU has taken a major step forward in boosting Zika prevention efforts.

ASU Biodesign Institute scientist Qiang “Shawn” Chen has led his research team to develop the world’s first plant-based Zika vaccine that could be more potent, safer and cheaper to produce than any other efforts to date.

“Our vaccine offers improved safety and potentially lowers the production costs more than any other current alternative, and with equivalent effectiveness,” said Chen, a researcher in the Biodesign Center for IVV and professor in the School of Life Sciences. “We are very excited about these results.”

Rapid response network

Several potential Zika vaccines have had promising results in early animal and human tests. Last year, the Food and Drug Administration approved the first human testing of a Zika vaccine candidate, and this summer, a $100 million U.S. government-led clinical trial is underway.

But currently, there are no licensed vaccines or therapeutics available to combat Zika.

Several dedicated ASU scientists also heeded the call to action, wanting to use their special know-how to find a way to overcome the pandemic crisis.

First, ASU chemist Alexander Green, along with collaborators at Harvard, developed a more rapid and reliable Zika test, an achievement highlighted by Popular Science in its “Best of What’s New” of 2016.

Now, Chen may have come up with a better vaccine candidate based on a key Zika protein. Chen is a viral expert who has worked for the past decade on plant-based therapeutics and vaccines against West Nile virus and Dengue fever, which come from the same Zika family, called flaviviruses.

He honed in on developing a vaccine against a part of a Zika viral protein, called DIII, that plays a key role for the virus to infect people.

“All flaviviruses have the envelope protein on the outside part of the virus. It has three domains. “The domain III has a unique stretch of DNA for the Zika virus, and we exploited this to generate a robust and protective immune response that is unique for Zika,” said Chen.

They first grew the envelope protein in bacteria, then switched to prepare the DIII protein domain in tobacco plants.

After developing enough material for the new vaccine candidate, Chen’s team performed immunization experiments in mice, which induced antibody and cellular immune responses that have been shown to confer 100 percent protection against multiple Zika virus strains in a mouse challenge.

Producing plant-based vaccines, especially in tobacco plants, is old hat for ASU researchers like Chen. For more than a decade, they’ve been producing low-cost vaccines in plants to fight devastating infectious diseases in the developing world.

It’s the same approach ASU plant research pioneer Charles Arntzen used when he played a key role in developing ZMapp, the experimental treatment used during the Ebola outbreak.

Artntzen’s Biodesign colleagues, including Chen, Hugh Mason and Tsafrir Mor, have continued to pursue plant-based vaccines and therapeutics to combat West Nile virus, dengue fever, nerve agents and even cancer.

Effective but not foolproof

While Chen has been cheering on Zika vaccine progress from other researchers, in each case, there can be side effects.

To date, other scientists have tested several kinds of vaccines on mice –including one made from DNA and another from an inactivated form of the virus. With just one dose, both vaccines prompted the creation of antibodies that shielded the animals from becoming infected when they were exposed to the virus.

Any heat-killed vaccine runs the risk of accidentally injecting a live version of the virus if there is an error made in the vaccine production protocol. This tragic scenario happened occasionally with the polio vaccine.

For the second research group, they used the complete Zika envelope protein for their vaccine. Since envelope protein domains I and II are similar to West Nile and dengue viruses, this can cause a dangerous cross-reactive immune response.

“When you make the full native envelope protein as the basis for a vaccine, it will induce antibodies against DI, DII and the DIII domains of the protein,” explained Chen. “Those who have been prior exposed to DI and DII of other members of the Zika virus family may be prone to developing very bad symptoms, or in some cases, fatalities for dengue.”

In fact, animal experiments have shown that prior exposure to dengue or West Nile virus makes the Zika infection and symptoms much worse, suggesting a similar risk for people who had prior exposure to dengue (especially in South America, where it is more common).

“If you have prior exposure to dengue, and then have Zika exposure, the Zika infection may be much worse, and for men, may increase the likelihood of sexual transmission,” said Chen.

Chen’s protein-based vaccine uses the smallest and most unique part of the Zika virus that can still elicit a potent and robust immune response.

“In our approach, we make what we call a pseudovirus. It’s a fake virus. The pseudovirus displays only the DIII part of the envelope protein on the surface. This is at least as potent as previous vaccine versions.”

And he is very confident that his DIII-based protein vaccine will be safer.

“We did a test to make sure that the vaccine produces a potent protective immune response, but also, that it does not produce antibodies that may be cross reactive for dengue, West Nile, yellow fever or others,” said Chen.

Fast track to the clinic

During the height of the Zika pandemic, whole countries of women were told not to become pregnant, due to babies born with a severe brain defect called microcephaly, in which the head and brain don’t develop properly.

There have also been vision and hearing defects and learning disabilities associated with less severe infections.

To make matters worse, in adults, a debilitating nervous system condition called Gullian-Barre syndrome has also been shown to be caused by Zika.

While the most severe wave of the Zika pandemic has ebbed, it won’t go away anytime soon, and a vaccine still offers the best hope.

Tens of millions more could still be infected in the Americas in the coming years (see WHO fact sheet).

The ASU scientists were able to mobilize quickly from idea to proof-of-concept because they could leverage funds from an NIAID grant and seed funds from the Biodesign Institute.

These are all made possible by generous federal, state and public support, including sales tax generated from the long-time Arizona innovation booster, voter-approved Proposition 301.

“This is a great example of the brightest minds quickly coming together, with public support, to take on one of the most significant public health challenges of our time,” said Josh LaBaer, executive director of the Biodesign Institute.

“That’s the essence of Biodesign at its best, and we hope this important proof-of-principal of a Zika vaccine can be translated quickly into the clinic.”

With the successful proof-of-principle, Chen hopes to partner with the medical community to begin the first phase of a human clinical trial in the next two years.

“Above all, we have to ensure the utmost safety with any Zika vaccine, especially because the people who will need it most, pregnant women, have the most worries about their own health, and the health of the fetus,” said Chen. “This has to be 100 percent safe and effective.”

Along with Chen, the research team included Ming Yang, Huafang “Lily” Lai and Haiyan Sun.

The research was published in the online version of Scientific Reports.