Why it’s hard to develop immunity against malaria


Axel Kallies, PhD, and

Diana Hansen, PhD

Photo courtesy of the Walter

and Eliza Hall Institute

Results of preclinical research appear to explain how the malaria parasite Plasmodium falciparum causes an inflammatory reaction that sabotages the body’s ability to protect itself from malaria.

Researchers found evidence to suggest that the same inflammatory molecules that drive the immune response in clinical and severe malaria also prevent the body from developing protective antibodies against the parasite.

They said this discovery opens up the possibility of improving new or existing malaria vaccines by boosting immune cells needed for long-lasting immunity.

Diana Hansen, PhD, of the Walter and Eliza Hall Institute of Medical Research in Parkville, Victoria, Australia, and her colleagues described this work in Cell Reports.

Dr Hansen said this is the first time scientists have pinpointed why the immune system fails to develop immunity during malaria infection.

“With many infections, a single exposure to the pathogen is enough to induce production of antibodies that will protect you for the rest of your life,” she explained. “However, with malaria, it can take up to 20 years for someone to build up sufficient immunity to be protected.”

The fact that the body is not good at developing long-lasting immunity to the parasite has hampered vaccine development, Dr Hansen added.

“This was complicated by the fact that we didn’t know whether it was the malaria parasite itself or the inflammatory reaction to malaria that was actually inhibiting the ability to develop protective immunity,” she said.

“We have now shown that it was a double-edged sword. The strong inflammatory reaction that accompanies and, in fact, drives severe clinical malaria is also responsible for silencing the key immune cells needed for long-term protection against the parasite.”

Dr Hansen and her colleagues conducted experiments in mouse models of malaria and found that inflammatory molecules released by the body to fight the infection were preventing protective antibodies from being made.

“Specialized immune cells called helper T cells join forces with B cells to generate these protective antibodies,” said Axel Kallies, PhD, of the Walter and Eliza Hall Institute of Medical Research.

“However, we showed that, during malaria infection, critical inflammatory molecules actually arrest development of helper T cells, and, therefore, the B cells don’t get the necessary instructions to make antibodies.”

Specifically, the researchers found that severe malaria infection inhibited the establishment of germinal centers in the spleens of the mice. And malaria infection induced high frequencies of T-follicular-helper cell precursors but resulted in impaired T-follicular-helper cell differentiation.

Precursor T-follicular-helper cells induced during infection had low levels of PD-1 and CXCR5 and co-expressed Th1-associated molecules such as T-bet and CXCR3.

However, when the researchers blocked the inflammatory cytokines TNF and IFN-γ or deleted T-bet, they were able to restore T-follicular-helper cell differentiation and germinal center responses to infection.

Dr Hansen said these findings could lead to new avenues in the search for effective malaria vaccines.

“This research opens the door to therapeutic approaches to accelerate development of protective immunity to malaria and improve efficacy of malaria vaccines,” she said.

“Until now, malaria vaccines have had disappointing results. We can now see a way of improving these responses by tailoring or augmenting the vaccine to boost development of helper T cells that will enable the body to make protective antibodies that target the malaria parasites.”

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