Breakthroughs against Plasmodium falciparum pave way for latest advancement

When the highly-influential European Medicines Agency announced its recommendation to approve what could be the world's first licensed vaccine against malaria in infants and children, there was much celebrating in the research community at NYU Langone Medical Center.

For it was, in many respects, the culmination of the life's work of Ruth Nussenzweig and Victor Nussenzweig, the husband and wife team whose research over the past half-century against malaria has brought them international acclaim - and which contributed greatly to this latest breakthrough.

The key component of the recently-endorsed vaccine is the circumsporoziote protein (CSP) of Plasmodium falciparum, the most deadly form of malaria in humans and responsible for 80 percent of the estimated 500 million annual infections and 90 percent of malaria-related deaths worldwide. In particular, most deaths from malaria occur in children, the target group for the new vaccine. According to the World Health Organization (WHO), in 2013, 627,000 deaths from malaria were reported, of which almost 90 percent occurred in Sub-Saharan Africa in children under the age of five.

It was the Nussenzweigs' work from the mid-1960s through the 1990s on the biology of CSP and malaria sporoziotes that paved the way for the development of the new vaccine - and other vaccines being tested for human-borne malaria.

Specifically, the latest clinical trial for the new vaccine showed that following three doses, the number of malaria cases reduced by almost half in children ages 5-17 months, and by 27 percent in children 6-12 weeks after only one dose. At the study's end, four doses of the vaccine reduced malaria cases by almost 40 percent. WHO will provide its recommendation on the vaccine in November.

"Without the work of Ruth and Victor Nussenzweig, we probably would not be at the precipice of a first-ever approved vaccine to prevent malaria," says Jeffrey N. Weiser, MD, chair of the Department of Microbiology at NYU Langone. "Malaria is one of the 'ancient plagues of mankind,' affecting regions throughout the world. The Nussenzweigs' commitment to fighting this disease has earned them a rightful place among the leaders in the fields of parasitology and vaccinology. And it is wonderful that they have seen this historic announcement in their lifetime."

CSP has been the critical focus of the Nussenzweigs' work ever since Ruth first showed in the mid-1960s 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.

Moving into the early 1980s, the Nussenzweigs, now working in tandem, showed that CSP could generate antibodies against malaria parasites, a hallmark of immune response. Later work in collaboration with other researchers at NYU Langone led to the development of simple immunological assays that identified mosquitoes carrying the parasite. In 1983, the Nussenzweigs led efforts that cloned the gene encoding CSP of a monkey parasite, and later they cloned the gene for the human malarial parasite Plasmodium falciparum.

They later found that certain subunits of CSP 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.

Dr. Weiser points to the Nussenzweigs' success against malaria as an important link in NYU Langone's long and illustrious history in immunological research. Among others he points to are Saul Krugman, whose work led to the hepatitis B vaccine, and Colin McLeod, whose team demonstrated the efficacy of the first polysaccharide-based vaccine. In addition, NYU School of Medicine alumni and trainees were responsible for licensed vaccines for polio (Jonas Salk and Albert Sabin), pneumococcus (Robert Austrian), meningococcus (Emil Gotschlich), and the development of protein- conjugates to make polysaccharides immunogenic for young children (J. B. Robbins).

"Many breakthroughs against some of the great health scourges have occurred through research at NYU Langone," he says. "Ruth and Victor carry on the finest traditions of important scientific work that is rooted here."

Now both in their 80s, the Nussenzweigs remain active pursuing their deadly nemesis. Having done much of the work that led to the breakthroughs against Plasmodium falciparum, they essentially are starting over -- leading the charge against the second great malaria strain, Plasmodium vivax. This has personal meaning to them; it is the form of malaria that most affects the Amazon basin and hotter regions of South America. The Nussenzweigs escaped Brazil in 1964 during a military coup, and are now working closely with Brazilian colleagues on this latest endeavor.

Reflecting recently on their lifelong battle against Plasmodium falciparum, their dogged determination still shines through. "We are now trying to develop drugs that will inhibit that which controls the latent stage of the parasite," Victor says.


NYU Langone Medical Center


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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