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Serology Test That Provides Data on Timing of Infection Developed by Australian Team

NEW YORK – A team led by researchers at Australia's Walter and Eliza Hall Institute of Medical Research has devised a serology testing approach that provides information not only on if a person has been infected by a disease but also when.

Detailed in a study published this month in Nature Medicine, the approach was originally developed as a tool for fighting malaria but it could prove useful for a variety of infectious diseases, including SARS-CoV-2, said Ivo Mueller, an epidemiologist at the Walter and Eliza Hall Institute and senior author on the paper.

As opposed to antigen testing where an assay directly detects the presence of an infectious agent, serology testing looks at the host's immune reaction, measuring antibodies generated in response to infection to determine whether or not a person has been exposed to the disease.

Typically, this is done by selecting a protein or peptide from the pathogen of interest and using it to bind to antibodies in a person's blood that were produced in response to exposure to that protein or peptide during infection.

In their work, Mueller and his team aimed to add a temporal component to their measurements. To achieve this, they measured antibodies against a number of different proteins from the pathogen of interest. Because the host produced antibodies to the different proteins at different time points during infection, and because these different antibodies lasted for different amounts of time in the host's blood, the researchers could use these measurements to determine not only if a person had been infected but also roughly when.

The researchers developed the approach for use in malaria elimination efforts, malaria caused by Plasmodium vivax, in particular. The biology of P. vivax presents a challenge in that it can live within individuals in a dormant state as liver hypnozoites, which are undetectable. It can then reactivate weeks or months after the initial infection leading to illness and to transmission of the disease.

The fact that P. vivax can exist in this undetectable dormant state leads to a diagnostic dilemma, Mueller said. Doctors can treat only patients with active infections, in which case he estimated they would miss between 50 percent to 60 percent of infected individuals. Or they could treat the entire population, in which case they would be giving drugs, which can have toxic side effects in some individuals, that are unnecessary for around 90 percent to 95 percent of the population.

However, patients with P. vivax hypnozoites commonly suffer an initial relapse within nine months of their initial infection. This, Mueller and his colleagues realized, meant that if they could identify patients who had had an active P. vivax infection within the previous nine months, they could target them for treatment.

To develop a serology test capable of identifying individuals with an active infection within that nine-month window, the researchers measured the IgG response to 342 P. vivax in longitudinal plasma samples collected from infected patients over a nine-month period. This allowed them to identify both the immunogenicity of the different proteins and their half-lives in patient blood. From this analysis they selected 142 proteins as potential components of a serology panel.

They then built and tested panels composed of subsets of these 142 proteins using plasma samples from a 2,511-subject cohort with known history of malaria infection to determine what group of proteins would best enable them to identify individuals with an active infection in the previous nine months. Ultimately, they arrived at a set of eight proteins that was able to identify such individuals with a sensitivity and specificity of 80 percent.

While this performance is not especially high, it could substantially improve targeting of anti-malaria treatment in regions where P. vivax is a problem, the authors noted. An approach that simply treated everyone would give unnecessary drugs to more than 80 percent of the population, while an approach that treated only active infections would miss between 60 percent and 80 percent of carriers. Using the temporal serology test, which Mueller and his team dubbed seroTAT, clinicians would be able to treat at least 80 percent of carriers while giving unnecessary treatment to less than 20 percent of the population.

Mueller said his team is working with Australian diagnostics company Axxin to develop a point-of-care version of the test for use in countries where P. vivax is endemic. He said the company was developing a new POC device for running the test, though he declined to provide additional details.

He said that the researchers had developed the test on a Luminex bead array platform but that while this system was available in research institutes and core facilities in many developing and middle-income countries, there were not easily deployable in the more remote regions they hoped to reach.

"It's not a system you can take out into a village and screen 500 people and then decide on the same day who needs treatment and who doesn't," he said.

In addition to the P. vivax test, the researchers are also developing a seroTAT assay for SARS-CoV-2, which Mueller said could be useful in developing countries without well-established disease surveillance systems.

In such countries "you are maybe getting data [on infection rates] from the capital, and even there, the data is quite sparse because their molecular testing capacity is very limited," he said. "You can do a serology surveillance survey, and that will give you information on what the attack rate is in the population, but it will give you no information on whether that attack rate is still rising and these are people who have been very recently infected, or if the peak passed three months ago or six months ago or nine months ago."

A test with a temporal component could tell you, for instance, that "you've had 20 percent of the population exposed, but most of these exposures are three months old or older," Mueller said. "And that will give you some idea of what the dynamic of the [outbreak] is."

He said he hoped to be able to offer the SARS-CoV-2 test along with the P. vivax, which he said would allow countries to most efficiently use their resources by piggybacking coronavirus testing on top of existing malaria testing infrastructure.

"It is not necessarily easy for a lower income country to conduct these mass surveys," he said. "So it gives them the added value of being able to say we are doing coronavirus but we can use our whole malaria [surveillance] infrastructure and get the malaria data at the same time."