Asymptomatic malaria infections do not reduce the risk of severe disease, as widely believed, but suppress the immune system and prevent it from getting rid of parasites that persist in the bloodstream, research suggests.
In 2020, there were an estimated 241 million cases of malaria worldwide with 627,000 of them turning fatal, according to the World Health Organization. The disease is caused by Plasmodium parasites transmitted by the bite of the female Anopheles mosquito.
Some people develop immunity to the malaria parasite Plasmodium falciparum after many years of repeated infections, but they host a small number of parasites that continue to live in the bloodstream without causing the typical fever-like symptoms, says Diana Hansen, associate professor at the Walter and Eliza Hall Institute of Medical Research, in Melbourne, Australia.
"These infections have historically been viewed as beneficial because they were thought to offer protection against symptomatic disease," says Hansen, who was part of a team that published the results of their research in Molecular Systems Biology.
"Based on this assumption, asymptomatic malaria is often left untreated in countries where malaria is endemic, despite our poor understanding of the real impact that these persistent infections have on people."
Hansen emphasizes that asymptomatic malaria infections are common in endemic areas, "with recent surveys estimating their prevalence to be up to five times higher than symptomatic infections".
A central issue in the malaria eradication agenda is the challenge that asymptomatic infection poses to elimination efforts, as this clinically silent parasite reservoir, has been shown to be contributing to maintain transmission. The progress towards the 2030 malaria elimination goal set by the WHO has stalled in many endemic countries since 2015."
Diana Hansen, Associate Professor, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
The researchers analyzed white blood cells of patients carrying asymptomatic and symptomatic infections in an endemic area of Indonesia. They found that patients with chronic, asymptomatic malaria infections suppressed the immune system, making more proteins to help the parasites survive.
Hansen says that because the immune system is suppressed and cannot work at full capacity, the body cannot take control of the parasites and clear them from the bloodstream."In an immunosuppressed individual carrying an asymptomatic malaria infection, the effectiveness of the malaria vaccine is reduced as the immune system does not have the capacity to be trained appropriately," she explains.
"If we were to treat individuals with asymptomatic malaria infections, we would also reduce the invisible parasite reservoir that perpetuates transmission and deters efforts of malaria elimination campaigns," she says, adding that the research provides a framework to consider new policies supporting screening and treatment of asymptomatic malaria in endemic areas around the world.
"Individuals living in malaria endemic areas only develop what we call clinical immunity after many years of repeated infections. Clinical immunity does not completely clear the infection but prevents symptomatic episodes by substantially reducing parasite numbers in the blood, with adults often experiencing non-febrile asymptomatic malaria."
She adds that since non-febrile infected individuals do not actively seek treatment, asymptomatic infections last longer than symptomatic episodes, becoming chronic in nature. "The full impact of persistent asymptomatic malaria for the host was unclear, and that is why we decided to embark on this research."
Hansen said that the complete lack of information on the real impact of chronic infections discouraged strategies such as mass drug administration. "Our research provides evidence that asymptomatic malaria is not benign or innocuous. This information is critical in providing a framework for new policies supporting screening and treatment of non-febrile malaria in pre-elimination areas of South-East Asia."
Epidemiologists have, in recent times, been using molecular (PCR-based) methods, establishing that asymptomatic malaria is more prevalent relative to symptomatic cases as transmission declines and may represent as much as 80 per cent of all malaria cases, Alyssa Barry, professor of systems epidemiology of infection at Deakin University and principal research fellow at Burnet Institute, Australia, tells SciDev.Net.
"With malaria transmission dropping dramatically over the last two decades, these hidden cases have been increasingly recognized for their key role in sustaining malaria transmission and preventing the disease being eliminated. One key aspect that has not been studied until now is the impact of asymptomatic malaria on human health," says Barry.
"The researchers hypothesize that the suppressed immune response of asymptomatic cases may also prevent appropriate immunity developing following vaccination, and may, in part, explain why so many malaria vaccines successful in clinical trials in unexposed volunteers have failed when tested in malaria endemic areas,' she says.
Barry believes one solution may be to provide malaria treatment to remove the infection, prior to vaccination.
"These results are extremely important for malaria immunity and represent a major paradigm shift from the widely held belief that asymptomatic cases are benign. They also provide new opportunities to further explore the biological mechanisms involved," Barry says.
Studniberg, S.I., et al. (2022) Molecular profiling reveals features of clinical immunity and immunosuppression in asymptomatic P. falciparum malaria. Molecular Systems Biology. doi.org/10.15252/msb.202110824.