In Mumbai, the most populous city in India, the modern day tale of two cities is unfolding. Glitzy, steel and glass apartment towers are rising adjacent to some of the poorest slums in the world. It’s the wealthiest city in India, yet like other fast developing cities around the globe, Mumbai also suffers from widespread poverty, unemployment and poor public health.

Because of the tropical climate, female anopheles mosquitoes are ubiquitous, and when they bite, they don’t discriminate between the rich and poor. Unlike other metropolitan cities where improvements to public health are strongly associated with economic development, reports of new malaria infections are up 71 percent in Mumbai over the last four years, according to a survey conducted by Mumbai-based Praja Foundation.

A sharp increase in cases of drug-resistant malaria has experts like Drexel Microbiology and Immunology professor Akhil Vaidya especially worried that malaria could be making a comeback in that region.

“I visit Mumbai often, and I’ve seen people who live in apartments who are wealthy get sick and die,” Vaidya says. “It’s a real problem.”

Philadelphia residents were contracting malaria as late as the 1940s, but the disease largely has been eliminated in the United States thanks to better sanitation practices, elimination of standing water and advances in health care. Fewer than 1,400 cases were reported last year, nearly all of which involved people who contracted the disease while traveling abroad.

Malaria disease is caused by parasites that are transmitted to people through the bites of infected mosquitoes. Plasmodium falciparum and Plasmodium vivax are the most common species of parasite affecting humans; Plasmodium falciparum is the most deadly.

The fight against malaria dates to ancient times, yet the disease remains one of the most lethal infectious killers in the world.

As new, drug-resistant strains of the disease emerge and spread across southeast Asia, Vaidya and his colleagues half a world away at the Center for Molecular Parasitology at the College of Medicine are leading groundbreaking efforts to stop it. Vaidya, the center’s director, and professors James Burns, Bill Bergman and Sandhya Kortagere are probing the complex molecular and genetic structure of the parasites that cause malaria, hoping to discover hidden weaknesses that can be exploited with new, targeted medicines and vaccines. Their efforts, in collaboration with research partners around the globe and made possible in part by a new $2 million grant from the National Institutes of Health, could lead to the development of powerful new tools in the prevention and treatment of malaria.

Efforts Increase, Challenges Remain

Malaria is an entirely preventable and treatable disease. Yet ongoing malaria transmission occurs in 106 countries in the world. The World Health Organization estimates there were 219 million cases of malaria in 2010 and 660,000 deaths were attributed to the disease. Those most at risk include young children, non-immune pregnant women and people with HIV/AIDS. Although 80 percent of cases and 91 percent of deaths occur in Africa, half of the world population is at risk of malaria, according to the Roll Back Malaria Partnership.

The last decade has seen many gains in the fight to control, prevent and treat malaria. Malaria mortality rates have fallen by more than 25 percent globally since 2000. This coincides with a steep increase in international investments in malaria control, up from $100 million in 2000 to an estimated $1.84 billion in 2012. The money has been used to distribute many more insecticide-treated bed nets in sub-Saharan Africa, to increase indoor residual spraying, and to buy and distribute drugs that can prevent infection. Seasonal malaria chemoprevention is a “simple and inexpensive intervention that has the potential to prevent more than 75 percent of uncomplicated and severe malaria among children younger than five years of age,” says WHO Director-General Margaret Chan.

Targeting resources to regions hardest hit by malaria has prevented an estimated 274 million more cases and 1.1 million more deaths between 2001 and 2010, according to the WHO’s 2012 annual report on malaria, released in December.

Still, major challenges persist. The worldwide economic downturn has meant a leveling off of government funding for malaria research and control efforts—less than half what is needed is available, the WHO says. Disease surveillance is poor in the hardest hit countries. And diagnostic testing rates are nearly the same today as a decade ago.

Vaidya says eradication of malaria is just as simple—and equally as complex—as eradication of poverty.

“If everyone in the world lived in air-conditioned houses with screen doors, there would be no malaria,” he says.

Economic issues aside, what has Vaidya and his colleagues very concerned is the emergence of parasite resistance to artemisin, the most effective antimalarial currently in use, in four Southeast Asia countries. Resistance to previous generations of therapies in the 1970s and 1980s undermined malaria control efforts. Child survival rates started decreasing. Now scientists are in a race to understand how the parasite has evolved and prevent similar setbacks.

For Vaidya, the race has been more of a marathon, spanning a 35 year Drexel career. While studying the molecular biology of retroviruses in the 1980s at what was then Hahnemann University, he “got pulled in” to a study on malaria. He never looked back.

His lab looks at the mitochondria functions of malaria parasites to understand how they differ and are similar to host cell mitochondria. In 1989, the laboratory found that the mitochondrial genome of malaria parasites consisted of a very unusual DNA molecule. The breakthrough discovery led to a better understanding of the mechanism of action for antimalarial drugs that were especially effective against Plasmodium falciparum parasites, but less so against other varieties. This knowledge helped narrow the choice of which antimalarial drug combinations clinicians should use in patients with a confirmed diagnosis of Plasmodium falciparum malaria. It also helped minimize drug resistance.

“What we are doing is essentially making drugs that work as cyanide for the malaria parasite without working as cyanide for us. We are essentially selectively poisoning mitochondria of the parasite without poisoning human mitochrondria. This is possible because the mitochondria of parasites are so very different from host mitochondria in humans,” Vaidya says.

In a series of studies that build on these early findings, Vaidya’s lab is working to develop new antimalarial compounds. One such venture, in collaboration with investigators at Oregon Health Sciences University, aims to disrupt the mitochondrion function of the invasive parasites. The compound has been nominated as a candidate for clinical development in humans.

Last year, the National Institutes of Health awarded Vaidya’s team a $2 million grant for a four-year project to investigate molecular pathways targeted by other promising, new antimalarial compounds identified by his group. He characterizes unpublished data from early lab experiments as “very promising,” and one of the agents is slated for testing in humans beginning this year. Over the last three years, the team’s drug discovery and development work also has been supported with a $1 million grant from Medicines for Malaria Venture, a non-profit organization based in Geneva, Switzerland.

Drexel Takes the Lead

As malaria became a major area of research emphasis in the College of Medicine’s Department of Microbiology and Immunology, three labs came together in 2001 to form the Center for Molecular Parasitology. With seven faculty members, today it is one of the largest academic groups in the country working to understand, treat and prevent malarial disease.

Bergman’s investigations chiefly are concerned with the complex molecular interactions responsible for the disease. A cellular biologist, he is interested in how the parasite manages to invade the host cell, where it lives and reproduces.

“The way the parasite gets into the cell is the same way you get in bed at night. Just as you reach out and grab the covers and pull them over you, the parasite reaches out and grabs the cell it wants to invade and pulls itself using this actin-myosin motor,” he says.

Scientists reason that if they could inhibit the motor from latching on to the host red blood cell, they could prevent disease. But the parasites have many of these actin-myosin motors and they have different functions. In fact, numerous parasite and host cell components play a role in the invasion process.
“I always say, ‘The parasite is smarter than I am,’” Bergman says. “It is a difficult foe, no doubt.”

By laboriously figuring out from a biological point of view what actin-myosin motors do for the parasite, Bergman and Kortagere have potentially identified small molecule inhibitors of the invasion process. The work has led to a collaboration with Kortagere to design small molecule inhibitors that seem to block growth of Plasmodium falciparum in lab cultures. The next step is to solicit support to discover how these molecules work and develop them further as potential new antimalarials.

“The goal of any scientist is that the discovery they would make would somehow be implemented into some sort of treatment, and we continue on that quest. In many cases, this is all through an understanding of the basic biology of the parasite.”

The Search for a Vaccine

Eradication of malaria, though, would require a vaccine capable of completely preventing infection. Vaccines against all stages of the malaria parasite lifecycle are in development, but none have been approved for use in humans. Progress here has lagged the gains realized by those working on drug development.

“The vaccine side of the house, I have to admit, really hasn’t gone as well over the years. Parasites are tough. They have multiple ways of doing things,” says Burns, whose lab designs and tests vaccines.

He and his peers are closely watching the results of a Gates Foundation-sponsored Phase 3 clinical trial in humans across 10 sites in Africa,

“What we are doing is essentially making drugs that work as cyanide for the malaria parasite without working as cyanide for us.”
—Akhil Vaidya, professor of Microbiology and Immunology and director of the Center for Molecular Parasitology

the largest of its kind and “best shot we have going.” Early results showed a promising 50-percent efficacy rate. But the most recent data showed the effectiveness dropping to 30 percent for the youngest age group—those most vulnerable to the disease because they lack any natural built up immunity.
From the glass-half-full perspective, some protection is better than no protection at all, Burns says, adding “I think all along it’s been recognized that this is a first generation vaccine and we’re going to need to improve on it. But we were hoping for better numbers out of the gate.”

Different vaccines act to prevent or delay a malaria attack at different stages. Burns’ main interest is looking at blood-stage parasites, the point after which they reach the bloodstream and invade host red blood cells. A compound he’s developed and tested in rats and rabbits induced strong antibody responses. To predict whether or not it would work well in humans as a vaccine, the team mixed the antibodies that they elicited in animals with blood stage parasites in vitro to see if they could inhibit growth. Parasite growth was notably suppressed.

The next step is an immunization and challenge trial with monkeys, which have been used for decades to test the safety and protective efficacy of potential vaccines and drugs for human use. Burns is collaborating with a researcher at the CDC in Atlanta to immunize Aotus monkeys so they can measure the immune responses that are elicited. The monkeys are then infected with human malaria parasite Plasmodium falciparum to measure the efficacy of the vaccine. If they’re successful, the vaccine could be considered a candidate for human trials.

“It would be another component to a cocktail of antigens. There’s pretty much a consensus in the field that the ultimate vaccine is going to have to have multiple components against each of the targets and across these development stages,” he says.

While the prospects are exciting, Burns says he’s learned over his 30-year research career to temper his expectations.

“If you look at the parasites that are circulating in those endemic areas, you’ll see that with a lot of what we consider the best vaccine targets, there’s a lot of variability from one strain to the next. It can switch amino acids here and there and avoid immune mediated clearance by whatever you may have been inducing by a vaccine effort,” he says. “It’s not the magic bullet that’s going to completely prevent infection the way pre-erythrocytic stage vaccines are designed to do. But it would reduce parasite burdens in these populations and hopefully reduce some of the severe complications of malaria that lead to morbidity and mortality.”

Ultimately, Vaidya says, reducing malaria deaths will require increased investments in mosquito vector control, drug development programs, vaccine research and strengthening health systems.

“If a diagnosis is made in time, drugs are available and people can afford to pay for the drugs, we can take care of malaria,” Vaidya says. “The problem is that many times all these conditions are not met. That’s the reason why we see so many deaths due to malaria.”