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U Maryland Researchers, Vaccine Maker Sanaria Collaborate on Plasmodium Sequencing Study

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NEW YORK (GenomeWeb) – Effective vaccination against malaria could saves hundreds of thousands of lives each year, particularly among children in sub-Saharan Africa. An existing malaria vaccine does not provide full protection, but a research team at the University of Maryland hopes to change that.

In collaboration with vaccine developer Sanaria, the team will conduct a sequencing-based genome-wide study on samples from vaccine trials to discover loci yielding protection against the deadly disease.

The study is being led by Joana Silva, a microbiology researcher affiliated with the University of Maryland, Baltimore, Institute for Genome Sciences. She is also an associate member of the Center for Vaccine Development at the university, or UMB-CVD, an institute with nearly 50 years of malaria vaccine research experience. The project was recently awarded a five-year grant from the National Institute of Allergy and Infectious Disease, with a 2019 allotment totaling $762,829.

Malaria is typically caused when a person contracts Plasmodium falciparum parasites from the bite of an infected mosquito. The parasites in turn infect the host's red blood cells, and have evolved a multitude of ways to evade the host immune system as well as the drugs designed to kill them.

The vaccine is made from live Plasmodium parasites. While purposely injecting live parasites into the bloodstream seems perhaps like a bad idea, when Plasmodium falciparum are in a particular life cycle stage called sporozoites — that, importantly, have been attenuated by irradiation — yield metabolically active live organisms dubbed PfSPZ which have been found to produce immunity to subsequent infections with few side effects.

The PfSPZ vaccine was initially developed by Sanaria, a Rockville, Maryland firm. In the early days, the live vaccine was actually administered by exposing people to infected mosquitoes, but thankfully technology to cryopreserve the live sporozoites has since enabled using a syringe instead of a mosquito.

Although there are still no approved malaria vaccines commercially available, live-attenuated or otherwise, according to the US Centers for Disease Control and Prevention, there are a number of experimental vaccines in trials, particularly in malaria endemic areas. Indeed, as of August last year, Sanaria has conducted more than 30 clinical trials of its live-attenuated vaccines, including in seven countries in Africa.

The Sanaria vaccine is quite powerful, but it is still not effective in about half of all cases in the field, or in 15 percent of cases when patients are challenged with the same exact genotype as the vaccine. This incomplete efficacy is thought to be due to a vaccinated person getting subsequently infected with parasites that are just not antigenically similar enough to the Plasmodium isolate in the vaccine, Silva said in a recent interview.

Despite the years of vaccine development efforts, however, the specific antigen proteins in the Plasmodium vaccine that produce immunity and protection — as well as the genes that encode the proteins —are not yet known.

Silva and her team plan to sequence the parasite genome in samples obtained from people who were given live-attenuated vaccine, as well as people given control saline injection in the vaccine trial, to find the loci that are producing an immune response as well as loci producing protection.

"In order to improve the PfSPZ vaccine, we would like to, for example, be able to add another strain that gives it additional representatives at each of the protein variants in the genome," she said. But in order to know which strain to add, "we kind of need to know which loci are important," she added.

The research team will collaborate closely with Sanaria. Whole venous blood from both vaccinated people and controls are collected in the field during the vaccine trials. The blood is leukocyte-depleted in the field to remove as much human DNA as possible, and then infected red blood cells are shipped frozen to U Maryland, Silva said.

The P. falciparum will be sequenced using Illumina sequencing, she said, and initial analysis is likely to begin this year for samples from a vaccine field trial in Kenya that has already been completed. "We already have the samples in hand," she said. Samples from a field trial in Gabon will be used next, and are likely to be ready in a year or two. Results from these two studies will be validated with samples from a third vaccine trial site in Equatorial Guinea.

Interestingly, the particular isolate of Plasmodium that the Sanaria vaccine uses — called NF54 — has always been somewhat of a mystery.

Malaria is a tropical disease carried by strains of mosquitoes that live in temperate environments, but NF54 was first isolated in Europe — from a farmer in the Netherlands who had never left the country but just happened to live near an airport, as described in 2016 Vaccine review by scientists at Sanaria.

The NF54 isolate was subsequently shown by whole-genome sequencing to have originated in West Africa, essentially meaning a mosquito carrying the parasites must have itself traveled on a plane, Silva explained.

For each of the 5,600 or so genes in the Plasmodium falciparum genome, and their respective proteins, each parasite in the population will most likely encode an orthologous gene, expressed from exactly the same region in the genome but with variations, Silva said.

Currently, it is not known which of the immunogenic proteins in PfSPZ NF54 also induces a protective response, and how many of the P. falciparum variants circulating in the population they protect against

"People who get infected with parasites that look a lot like NF54 in that particular region of the genome might be protected, but people who are re-infected with P. falciparum isolates that are very different in that particular region of the genome from the vaccine strain might have a breakthrough infection," Silva said.

Thus, the team will develop new Plasmodium falciparum genome reference assemblies from the recently collected strains to increase the quality and quantity of sequence variants, including SNPs and indels. They will then use genome-wide genotype calls to compare infections in PfSPZ NF54 vaccines and controls to identify parasite antigens that produce protective immunity, assuming that allele frequency distributions will differ in malaria infections in the two trial arms.

Further aims of the new grant also include conducting high-throughput immunologic validation with peptide arrays of targets of PfSPZ vaccine-induced protection, and, ultimately choosing new strains to create a multivalent live-attenuated vaccine.

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