Last month, the public health community marked one of the most significant biomedical milestones in the fight against malaria in nearly half a century: European regulators authorized the world’s most advanced malaria vaccine candidate — more than three decades in the making — and paved the way for subsequent review by the World Health Organization. Now, as this historic vaccine, known as RTS,S/AS01 (RTS,S), prepares for its next major step, critical new insights into how it fends off malaria are coming to light.
In a technological tour de force, an international research team has harnessed sophisticated molecular tools and analysis methods to probe the underlying biology of RTS,S, helping to explain how it protects against a disease that kills roughly half a million people each year, mostly infants and young children in Africa. The work, led by the Harvard T. H. Chan School of Public Health, the Broad Institute, the Fred Hutchinson Cancer Research Center, the University of Washington, and other leading institutions, was published online October 21, 2015 in the The New England Journal of Medicine. Read the article.
“Through this broad, multinational collaboration, we have brought the power of genomic tools to bear on a disease that poses one of the most significant threats to global public health,” said senior author Dyann Wirth, the Richard Pearson Strong Professor of Infectious Diseases and chair of the Department of Immunology and Infectious Diseases at the Harvard T. H. Chan School of Public Health. Wirth led the NEJM study together with Peter Gilbert of the Fred Hutchinson Cancer Research Center.
Malaria is caused by the Plasmodium parasite, a single-celled organism that is transmitted to humans by mosquitoes. The disease is prevalent in tropical and sub-tropical areas, especially countries in sub-Saharan Africa, and jeopardizes the health of more than half of the world’s population. Efforts to control and hopefully eradicate this global health threat require multiple defensive measures, including effective anti-malaria drugs, insecticide-treated bed nets and other efforts aimed at insect vector control. Another key component is a robust vaccine, which can provide long-term protection against the disease.
Recognizing this need, scientists at GlaxoSmithKline (GSK) embarked on the design of RTS,S in the late 1980’s. Following its early development, GSK and PATH, an international non-profit focused on global health innovation, launched a public-private partnership to further develop the vaccine. Roughly four years ago, as RTS,S progressed through clinical testing, the data revealed a sobering reality: The vaccine was effective in young children, but its protection was not absolute — it offered only partial protection against malaria, and that protection waned over time.
Wirth and her colleagues set out to understand the basis of this partial efficacy. They knew the vaccine was engineered to target a specific protein that sits on the surface of the parasite, called CS (short for circumsporozoite), and that CS was highly variable among parasites. They wondered if the effectiveness of RTS,S might vary according to the genetic makeup of CS, similar to the way the seasonal flu vaccine works. For example, some flu vaccines are better at fighting disease because they are more closely matched to the genes of the influenza viruses that predominate in a given year. (Unlike the flu vaccine, however, the composition of RTS,S is stable, and does not shift from year to year.)
To explore this question, the team harnessed advanced genomic technologies and statistical methods to understand how genetic variation in CS influences the vaccine’s ability to ward off malaria in young children. The work, made possible by a scientific collaboration spanning more than 15 countries and over 25 institutions, was conducted as part of a phase 3 trial of RTS,S/AS01 that ran from 2009 to 2013. The trial included 11 study sites in Africa and involved over 15,000 children.
The research team was given special access, through a collaboration with the vaccine division of the healthcare company GlaxoSmithKline, to blood samples from over 5,000 trial participants. By isolating and sequencing parasite DNA from these samples (which include samples from both vaccinated and unvaccinated children), the team was able to determine whether certain versions (or “alleles”) of CS are linked with better vaccine protection. Earlier efforts, which involved fewer patient samples and cruder methods, failed to detect such an association.
“This uniquely valuable data set posed some challenges to data analysis. The statistical team extended methods previously developed for HIV to provide interpretable answers about differential vaccine efficacy by malaria genetics,” said Peter Gilbert, director of the statistical center for the HIV Vaccine Trials Network at the Fred Hutchinson Cancer Research Center.
Through their deep survey of genetic variability in CS, the researchers made a crucial discovery: The vaccine is significantly more effective at preventing malaria in children infected with parasites that match the vaccine’s version of CS (so-called “matched” alleles) than in those who harbor mismatched parasite alleles. In the case of matched alleles, vaccine efficacy is 50% (measured over one year); with mismatched alleles, it is 33%. (The same effect was not noted in infants.) Moreover, Wirth and her colleagues found that the vaccine was most effective shortly after the final dose.
“This is the first study that was big enough and used a methodology that was sufficiently sensitive to detect this phenomenon. Now that we know that it exists, it contributes to our understanding of how RTS,S confers protection and informs future vaccine development efforts,” said Dan Neafsey, associate director of the Genomic Center for Infectious Diseases at the Broad Institute and co-first author of the NEJM paper.
The researchers’ findings also uncover fundamental aspects of the anti-malaria immunity conferred by RTS,S. These include a non-specific component that offers protection regardless of the parasite strain and a second, strain-specific component that provides additional protection if there is an identical match between the parasite’s CS and the one used in the vaccine.
“Expanding scientific knowledge and innovation is of paramount importance in global efforts to control malaria,” said Pedro Alonso, Director of the WHO Global Malaria Program. “The results of this new genomic study will give us a better understanding of how the RTS,S malaria vaccine works and how it might be improved. This, in turn, could have long-term implications for future vaccine development.”
While the NEJM study offers important insights into the RTS,S vaccine and suggests a path forward for its deployment, it also offers a model for tackling other major infectious diseases that involve highly variable vaccine targets. The approach is already being applied in HIV vaccine trials, and Wirth and her colleagues plan to apply it to future malaria vaccine trials.
Moreover, the work underscores how a full and comprehensive catalogue of the genetic diversity of key pathogens could inform the design of robust, effective vaccines. Indeed, the development of RTS,S began more than thirty years ago — when the scientific tools for probing microbial genomes where just in their infancy. Now the biomedical arsenal has advanced considerably, transformed by the growth of modern, genome-scale tools.
“The tools and methods needed to fully characterize the genomes of major pathogens are now well within our grasp,” said Wirth. “We have an unprecedented opportunity — and an obligation — to apply them in novel ways that will benefit public health across the globe.”
— Nicole Davis
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