Algae, mosquitoes and herd immunity

UCSD School of Medicine researchers discover malaria vaccine candidate, but funding sources dry up

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SAN DIEGO—Dedicated for nearly 20 years to finding a cure for malaria, Dr. Joseph Vinetz, professor of medicine, and his research team at the University of California, San Diego (UCSD) School of Medicine, have trekked through the Peruvian Amazon to witness firsthand how the mosquito-borne disease can ravage a village. But, according to the Feb. 17 journal Infection and Immunology, it appears the team has discovered the key to a puzzle that has stumped so many scientists in the past.
“Most malaria vaccine approaches are aimed at preventing humans from becoming infected when bitten by mosquitoes that carry the parasite,” said Vinetz, senior author of the study. “Our approach is to prevent transmission of the malaria parasite from infected humans to mosquitoes. This approach is similar to that of the current measles vaccine, which is such a hot topic of discussion these days, because the goal is to generate herd immunity in a population. We think that this approach is key to global malaria elimination, too.”
To do this, Vinetz and team wanted to produce a large quantity of properly folded Pfs25, a protein found on the surface of the malaria parasite’s reproductive cells, which are only present within the mosquito’s gut after it feeds on a malaria-infected blood meal, according to Vinetz. Since antibodies against Pfs25 can halt the parasite’s lifecycle in the mosquito, they might also block transmission of the parasite to the next host.
However, properly folded Pfs25 that induces transmission-blocking antibodies has been difficult to produce in the lab. To overcome this problem, the researchers turned to an algae better known for its ability to produce sustainable biofuels. They introduced the Pfs25 gene into the algae by shooting the DNA into the plant cell’s nucleus. Then, after they let the algae do the work of replicating, building and folding the protein, the team was able to purify enough functional Pfs25 for laboratory testing.
Besides its effectiveness as a protein producer, “algae is an advantageous tool for developing vaccines because it’s cheap, easy and environmentally friendly,” Vinetz said. “The only requirement is simple chemical nutrients to feed the algae, which can be grown in plastic bags and easily scaled up to produce large quantities of desired proteins.”
Vinetz and collaborators at the Infectious Disease Research Institute in Seattle also tested several new adjuvants, molecules that help stimulate the immune system’s response to Pfs25, he said. The best Pfs25/adjuvant combination elicited a uniquely robust antibody response in mice with high affinity and avidity—antibodies that specifically and strongly reacted with the malaria parasite’s reproductive cells.
Mosquitoes were fed malaria parasites in the presence of control serum or immune serum collected from mice vaccinated with algae-produced Pfs25 in the presence of the new adjuvant, Vinetz said. Eight days later, the researchers examined the mosquitoes’ guts for the presence of the malaria parasite.
“The results were dramatic,” Vinetz said. “Only one of 24 mosquitos (4.2 percent) that consumed the Pfs25/adjuvant-treated mouse serum was positive for the malaria parasite. That’s compared to the 28 infected mosquitoes out of the 40 in the control group (70 percent).”
In the larger context of malaria vaccine development, “a strategy to develop, validate and deploy a vaccine aimed at preventing endemic transmission of malaria, continues to be important yet neglected,” Vinetz stated in the journal article.
Study co-author Stephen P. Mayfield, professor of biological sciences and director of the California Center for Algae Biotechnology at UCSD, stated: “We are really excited to see that Pfs25 produced by algae can effectively prevent malaria parasites from developing within the mosquito. With the low cost of algal production, this may be the only system that can make an economic malaria vaccine. Now we’re looking forward to comparing algae-produced Pfs25 and adjuvant head-to-head against other approaches to malaria vaccine production and administration.”
Vinetz and his colleagues are looking for about $10 million to get their candidate vaccine ready for a human clinical trial in less than a year, if the money is available by then.
“I’m frustrated and exhausted,” Vinetz tells DDNews. “I’ve tried several times to get more funding, but at my last request to the National Institutes of Health (NIH), I was turned down. The NIH simply has no money for discovery. If the funding came through, researchers could promote the necessary clinical studies. Or we need an angel investor who would be happy to invest in a therapy to help save the world.”
Malaria is the leading cause of death and disease in many developing countries, the NIH reports. In 2012, there were approximately 207 million cases of malaria infection worldwide. Young children and pregnant women are most affected by the disease.
Caused by related species of microbial parasites spread by mosquitoes, malaria is one of the most intractable infectious diseases. Of the nearly 200 million malaria cases in 2013, there were about 584,000 deaths, according to the World Health Organization. Treatment can be difficult, and to date, no successful vaccine has been developed.
Vinetz says the algae technology isn’t new; Mayfield, an algae specialist, discovered how to engineer complex protein production in algae, and in December 2012, Mayfield and colleagues published a study demonstrating they could make a complicated biotech drug in algae.
Vinetz is principal investigator of the Peruvian/Brazilian Amazon Center of Excellence in Malaria Research, one of 10 such centers funded by the NIH. He also works in Lima, Peru, with local researchers in addition to Santa Emilia, a remote part of the Peruvian Amazon.
“We have shown that as many as one-third to half of the people living in such remotes areas have malaria parasites in their blood, but do not have symptoms of malaria,” Vinetz said. “Since they are not treated, they continue to infect the vector mosquitoes, Anopheles darlingi, which maintains malaria endemicity in the region.”
Vinetz first became interested in malaria as a medical student at UCSD and took a year off to carry out research at the NIH where he found his mentor, researcher Louis Miller.
In 1998, Vinetz started working on tropical diseases, focusing on malaria. He has received NIH research and training grants, and other foundation grants, including awards from the Doris Duke Charitable Foundation and the Gates Foundation from 2000 to the present.
He is hoping someone comes forward so the work on malaria can be completed.
“[Public health departments] took an interest in funding vaccines for measles and rubella, and because of this, many lives were saved,” Vinetz said. “The potential malaria vaccine is no different. If funding this project is not financially profitable, it is morally profitable.”

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