Malaria and Monogamy

The Nussenzweigs’ son, Dr. Michel Nussenzweig, a researcher at The Rockefeller University in New York City, thinks that his parents’ attitudes complement each other in the lab. “My mother’s strength is in trying to produce the vaccine,” he says. “My father’s strength is probably more in the area of just trying to understand how things work.”

Getting things to work meant finding the best way to get a stronger immune response using the CS protein. Researchers around the world spent a lot of time looking at substances known as adjuvants that are added to vaccines to stimulate an even greater immune response.

“At that particular time we tried many different adjuvants and so on; nothing really worked very well,” Sanaria’s Hoffman remembers. As the 1980s gave way to the ‘90s, excitement turned to frustration.

Unlike the partnership between Walter Reed and GlaxoSmithKline, the Nussenzweigs could not convince the pharmaceutical company Hoffmann-La Roche to stay the course when things got tough.

“They gave up working on malaria altogether,” Ruth says with regret. “They had a [malaria] drug that was reasonably good. And they got out.” Occasionally Victor would do some research on T. cruzi , but neither Nussenzweig ever considered abandoning malaria.

The Payoff

GlaxoSmithKline soldiered on and is now seeing the reward. After more than 20 years of research, the work that began with the Nussenzweigs’ research has produced a viable vaccine, known as RTS,S.

In October 2007, the results of the RTS,S vaccine trial in infants, in which the Nussenzweigs were not involved, showed that it was safe and reasonably effective. This was the first trial of any malaria vaccine to protect children under five, who represent nearly all the deaths from this disease.

RTS,S is widely hailed as the most successful malaria vaccine so far. The Nussenzweigs laid some of the groundwork early on, but the vaccine was fully developed over the years by GlaxoSmithKline, the Malaria Vaccine Initiative, Walter Reed, the Barcelona Centre for International Health Research and the Ministry of Health of Mozambique.

The malaria antibodies are delivered within the Hepatitis B vaccine. GlaxoSmithKline has invested more than $300 million into this vaccine. Three shots gave infants a 65 percent reduced risk of infection and a 35 percent reduced risk of disease for the six months following the first dose. For most of the infants, it only delayed malaria infection or lessened the severity.

“They have shown it’s possible to immunize babies,” Victor says. Ruth cuts in to put this achievement into perspective, “There is no vaccine against any parasitic organism.” If approved, this would be the first vaccine to protect against a protozoan.

The Search Continues

The Nussenzweigs understand that, even after 40 years of work, there is still basic research that needs to be done. But the Bill and Melinda Gates Foundation has invested more than $100 million into the RTS,S vaccine trials. “They have their idea that things are ready to apply,” Ruth says, “but they are not.”

They laud the Gates Foundation for its commitment to malaria, but worry that the complexity of their favorite protozoan means that the philanthropists are not getting the desired return on their investment—a cure for malaria.

Victor says that a more protective vaccine will still need better adjuvants to stimulate the immune system, or possibly another delivery system altogether.

In 2002, Steven Hoffman founded Sanaria, which is partially funded by the Gates Foundation, to return to the first delivery system developed by Ruth Nussenzweig and Vanderberg—the weakened sporozoite.

After about two years of research and development, Hoffman developed a more efficient system to grow mosquitoes in the lab. The mosquitoes feed on blood infected with malaria, and then the entire mosquito is irradiated.

Sanaria has also designed a method to take the sporozoites out of the glands—without all of the “crap,” as Victor calls it—and cryogenically preserve them. Hoffman points out that using weakened sporozoites is similar to other successful vaccines. Thirteen of the 25 approved vaccines in the U.S. use weakened, live viruses, which usually get a stronger immune response than subunit vaccines.

Hoffman is looking for a vaccine with protection of at least 95 percent. He hopes to begin clinical trials with his weakened sporozoites by the end of 2008.

Some people say it will never happen, but the Nussenzweigs attended the grand opening of Hoffman’s lab, and they are intrigued. “It’s beautiful, because this is a resurgence in vaccine development,” Victor says. While there are still challenges ahead, he admits that the work is “impressive.”

The Nussenzweigs, along with others at New York University, are also researching new approaches. They are working to combine malaria with a yellow fever vaccine, one of the most successful vaccines. A single shot confers immunity for 30 years or more. Their results in mice showed that just one dose of the combined vaccine, followed by a booster of irradiated sporozoites, offers more than 90 percent protection.

Despite all the advancements that have been made in understanding the malaria parasite, Victor is most impressed by his marriage of more than 50 years. “It’s more amazing than making a vaccine,” he beams. Ruth smiles from her chair. But conversation does not dwell on marital bliss for long. Victor guesses there will be a viable malaria vaccine on the market within a decade. “That’s what I was going to say,” says Ruth, who seems to want Victor to come up with his own answer. He hedges his guess. “You can quote me on that,” he says, “but hopefully no one will remember if I am wrong.” Ruth hopes he is right.

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