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OBITUARY

The malaria vaccine pioneer

Ruth Nussenzweig died in New York City at 89 from a pulmonary embolism

Léo Ramos Chaves Ruth, during a visit to São Paulo in 2012Léo Ramos Chaves

The Brazilian immunologist Ruth Nussenzweig didn’t get the chance to see the real-life performance of a malaria vaccine produced from studies she and her husband Victor Nussenzweig (also an immunologist) conducted in recent decades. The vaccine, produced by a multinational pharmaceutical company through fusing a protein from the surface of the parasite that causes malaria (Plasmodium falciparum) with another from the surface of the hepatitis B virus, will be administered to 360,000 infants in areas with a high incidence of malaria in Ghana, Malawi, and Kenya starting this year. Ruth Nussenzweig was a pioneer in the study of different immunizing agents against malaria; on the night of April 1 she died after a pulmonary embolism in New York, where the couple had resided since the mid-1960s after leaving Brazil during the military regime. She was 89 years old and had been in poor health for a few years after suffering a serious fracture in a fall.

The daughter of two Jewish physicians, Eugenia and Baruch Sonntag, Nussenzweig was born in Austria on June 20, 1928, and emigrated with her parents to Brazil shortly after the country was annexed by Nazi Germany in 1938. She received a degree in medicine from the University of São Paulo (USP), where she met Victor, her husband and lifelong companion. While they were in university, they both began careers as researchers in the same laboratory, studying Chagas disease. After an internship in France, Ruth and Victor returned to São Paulo, and left again in 1963 for further study abroad, this time in New York. Ruth worked with the Hungarian immunologist Zoltán Óváry and Victor worked with the Venezuelan immunologist Baruj Benacerraf, both at New York University (NYU). The couple attempted to return to Brazil after the 1964 military coup, but when faced with the unfavorable environment at the USP School of Medicine returned to NYU. There, Benacerraf obtained a position for both scientists as assistant professors.

It was at NYU (which they almost never left) that the couple produced their most important scientific contributions to the development of compounds to be used in the vaccine against malaria. In an article published in Nature in 1967, Ruth Nussenzweig broke ground by demonstrating that it was possible to obtain immunity against the protozoan that causes malaria. She applied X-rays to the protozoan Plasmodium berghei, which infects rodents, and then injected them into mice, which became immune to the weakened parasites. Subsequent tests on a small number of healthy people indicated that this strategy could be used to produce a vaccine against the most lethal form of malaria caused by Plasmodium falciparum, which is common in Africa. Decades later, this work would lead the researcher Stephen Hoffman to create the biotechnology company Sanaria, which produces attenuated parasites to be used as immunizing agents. Studies published in recent years, however, suggest that the protection generated by this strategy is still low.

In the decades to follow, Ruth and Victor were able to identify circumsporozoite, the protozoan protein which activated the mammalian defense system. They cloned its gene and produced it in the laboratory, using bacteria as biofactories. This work was published in Science in 1984, and would lead to the development of another line of vaccine-candidate compounds including RTS,S, which will be tested in babies in Africa, produced from one plasmodium protein and another from the hepatitis B virus. “The RTS,S structure would not have been possible without the gene structure of the circumsporozoite,” says immunologist Silvia Boscardin, a professor at the USP Institute of Biomedical Sciences who worked with Michel Nussenzweig, an immunologist himself and the son of Ruth and Victor. “Ruth was an extremely persistent person who believed strongly in the vaccine.”

At NYU, Ruth and Victor trained a legion of immunologists who today work around the world. Ruth missed Brazil and always expressed her desire to return. “My friends are here,” she said in an interview with Pesquisa FAPESP in 2004, given together with her husband (see Pesquisa FAPESP issue no. 106). There were even some attempts to return to Brazil, but none was lasting.

Nussenzweig Family Archives Ruth and Victor Nussenzweig (left) married in the library of the USP School of MedicineNussenzweig Family Archives

A short return
After 2010, Ruth and Victor began to visit Brazil a few times each year to work on a project with an old research partner, the immunologist Maurício Martins Rodrigues, a professor at the Federal University of São Paulo (UNIFESP) who carried out postdoctoral work under Ruth’s supervision in the 1990s. “Ruth and Victor were convinced that it was necessary to try to develop a vaccine against Plasmodium vivax, which causes most cases of malaria in the Americas,” said immunologist Irene Soares; she is a professor at the USP School of Pharmaceutical Sciences and the widow of Rodrigues, who died in 2015 at age 53 from complications after a kidney transplant. This collaboration led to the precursor of a vaccine that Soares and her collaborators are testing today—the most recent results were published in Scientific Reports in January, in an article which was also authored by Ruth.

In 2012, Victor and Ruth obtained funding from FAPESP in the São Paulo Excellence Chairs (SPEC) modality to coordinate the definition of enzymes essential to the development of the plasmodium and to look for inhibitors with malaria-fighting potential at UNIFESP. “We thought that Ruth could win the Nobel Prize for her studies showing that it is possible to produce immunizing agents against malaria,” says Soares.

“Ruth was always a leader who believed in people and created a prestigious Department of Parasitology at NYU, which she ran until a few years ago,” says parasitologist Sergio Schenkman, a professor at UNIFESP who interned under the guidance of Victor Nussenzweig in the 1980s. “She was a compelling person who could convince researchers, corporate directors, and politicians that they had to try to develop a vaccine to fight malaria.”

In their careers, Ruth and Victor accumulated awards and honors. In 2013, she was the first Brazilian researcher elected a member of the Academy of Sciences of the United States. In 2015, she, Victor, and the Chinese pharmacologist Tu Youyou received the Warren Alpert Foundation Prize for researchers who contribute to the prevention, treatment, or cure of human diseases. Ruth leaves her husband and children Michel, André, and Sonia, all of whom are researchers.

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