Malaria Team Publishes New Findings In New England Journal of Medicine

A new study published this month in the New England Journal of Medicine by researchers from the University of California San Francisco (UCSF), Dominican University of California, Brown University, and the Infectious Disease Research Collaboration (Kampala, Uganda) shows that resistance to antimalarial drugs is growing in Africa. 

The paper, titled “Evolution of Partial Resistance to Artemisinins in Malaria Parasites in Uganda,” was led by Dr. Melissa Conrad from UCSF and Victor Asua in Uganda.

The results from the study highlight the urgent need for new antimalarials and continued
country-wide surveillance, said co-author Dr. Roland Cooper, professor of biology in Dominican’s Department of Natural Sciences and Mathematics in the School of Health and Natural Sciences.

Malaria, a parasitic blood infection transmitted by Anopheles mosquitoes, has worsened in Africa over the last several years, with deaths in young children around 600,000-700,000 annually. Resurgence is due to mosquito resistance to insecticides used to spray homes and treat bed nets, lack of an effective vaccine, and loss of resources for malaria control to other problems such as Covid-19. 

Treatment of malaria with drugs, which relies on the artemisinin-combination therapies (ACTs), remains mostly effective in Africa, but cracks are beginning to appear. Parasite resistance to the artemisinin component of the treatment is already widespread in Asia. Resistance is known to be associated with mutations in a parasite protein known as Kelch13. Resistant parasites are cleared from the human body more slowly, extending the normal three-day regimen to five days, which causes problems in terms of cost and patient compliance.

The research team studied malaria parasite samples from around 5,000 patients at 16 surveillance locations spread around the country, collected from 2016-2022. The goal was to genetically characterize the parasites to determine the spread of mutations in the resistance over time.

“What we found was that the prevalence of key genetic mutations in the parasite Kelch13 gene
was increasing. This is very worrisome for the control efforts by the Ugandan Ministry of Health,” Dr. Cooper says.

Dr. Cooper and his former Dominican student, Frida Ceja ’17, analyzed parasites from 100 malaria patients in Tororo, Uganda, in summer 2021. Their data, published last year in Nature Communications, demonstrated that parasites had reduced susceptibility to the artemisinin component of ACTs, and were associated with the Kelch13 mutations and other genetic factors. 

“We are certain that the genotyping data in the NEJM study reflects the spread of resistance,” Dr. Cooper notes. 

Additionally, Dr. Cooper’s team showed that the main partner drug contained in the ACT, lumefantrine, is also losing potency against the parasite.

The reasons for the spread of resistance are unclear but may be due to the misuse of the drug by private health clinics, as well as loss of natural immunity in local populations. If malaria is controlled over several years to reduce infections, the downside is that natural immunity wanes, especially in children. If control interventions stop, then the malaria quickly returns, and children are left with less immunity to deal with the infection, placing more pressure on the drug to fully clear the parasites from the blood.

The research team is involved in new clinical trials in the north of Uganda, where severe malaria is common, as well as the presence of Kelch13 resistance mutations in the parasite. 

“We want to assess how children with life threatening malaria are responding to the artemisinin drugs, and if a change in therapeutic approach is warranted,” Dr. Cooper says. “This would likely involve switching to another ACT formulation until new drugs arrive on the scene.” 

Dr. Conrad and the team will continue active surveillance around Uganda for several years. The researchers recently received a shared $3.8 million dollar grant from National Institutes of Health to continue their studies of drug-resistant malaria in Uganda. 

“This is a very exciting time for malaria research in Africa, with all eyes on the efficacy of the current therapies that are responsible for saving millions of lives,” Dr. Cooper says. 

Photo: A timeout for a hike with the Ugandan researchers during an April 2023 visit to the Kalong District Hospital, in the north of the country. Left to right: Dr. Roland Cooper, Peter Olwoch, Daniel Ayo, Yoweri Taremwa, Dr. Michael Ferdig (University of Notre Dame) and Martin Okitwi.