The Long Road to a Promising Malaria Vaccine Started at NYU

The malaria vaccine reported today to reduce life-threatening cases of the parasitic disease among children in Mozambique is based on the pioneering research of Drs. Ruth and Victor Nussenzweig and their colleagues at NYU School of Medicine.

Ruth Nussenzweig, Doc en Med, PhD, the C.V. Starr Professor of Medical and Molecular Parasitology, and her husband, Victor Nussenzweig, MD, PhD, the Hermann M. Biggs Professor of Preventive Medicine, have devoted decades of research to preventing one of the world's biggest killers. Malaria afflicts hundreds of millions of people, causing up to 3 million deaths every year, mostly in sub-Saharan Africa. Many of its victims are young children.

In a study reported today of more than 2,000 children in Mozambique, the vaccine reduced life-threatening attacks of malaria by 58 percent, and reduced milder forms of the disease by 30 percent. The study was published in the Oct. 16, 2004, issue of The Lancet, a medical journal.

"This is really fantastic news," says Dr. Victor Nussenzweig. "It is the first time that a vaccine has been shown to protect against severe malaria, which is a major cause of death in children in Africa. It is not yet an ideal vaccine because it is expensive, requires three doses, and it isn't known yet how durable the vaccine's protection will be, but it is a very big step forward."

The vaccine, designated RTS.S/AS02A, contains a large portion of a protein called circumsporozoite (CS) protein, which coats malaria parasites that invade the liver. This protein, which the Nussenzweigs first isolated from parasites in 1980, is the basis for some 15 malaria vaccines that now are in clinical trials or in pre-clinical testing.

The vaccine, developed by GlaxoSmithKline in collaboration with the Walter Reed Army Institute of Research, contains a large portion of the CS protein fused with a part of another protein found on the hepatitis B virus, combined with substances that enhance the immune response.

The Nussenzweigs and their NYU colleagues were the first investigators to show that it was possible to generate an immune response against the CS protein, which occurs in all of the various species of the parasite called Plasmodium causing malaria. They found that the CS protein coats the parasite when it is in the salivary glands of the Anopheles mosquito. At that stage it is a crescent-shaped and called sporozoite, a stage in the complex life cycle of the parasite before it invades the human liver and causes devastating illness.

The CS protein has been an important focus of the Nussenzweigs' work ever since Dr. Ruth Nussenzweig first showed in 1967 that it was possible to prevent malaria infection by immunizing mice with irradiated parasites. At the time, scientists didn't think it was possible to prevent malaria by eliciting an immune-based response.

In the early 1980s, the Nussenzweigs showed that the CS protein could generate antibodies against malaria parasites, a hallmark of an immune response. Later work--in collaboration with Elizabeth Nardin, Ph.D., and Fidel Zavala, MD, both professors in medical and molecular parasitology at NYU--led to the development of simple immunological assays that could identify mosquitoes carrying the parasite. This marked an important advance because previously scientists could only identify infected mosquitoes under a microscope, a painstaking process, and the species of Plasmodium could not be ascertained.

In 1983 the Nussenzweigs, in collaboration with Nigel Godson, PhD, DSc, professor of biochemistry, and cloned the gene encoding the CS protein of a monkey malaria parasite, and later they cloned the gene for the human malarial parasite Plasmodium falciparum. Further work in the 1980s led to the discovery that antibodies against CS protein could destroy the ability of malarial sporozoites to invade the liver.

The NYU investigators later found that certain subunits of the CS protein were as effective as the whole in evoking a response. This work provided the experimental basis for clinical trials of the first semi-synthetic malaria vaccine in 1987. This vaccine was developed by the Nussenzweigs in collaboration with scientists at Hoffmann-LaRoche. It was the first vaccine to show that the CS protein could protect humans against malaria.

Source: New York University Medical Center