Scientists elicit rare affinity-matured human antibodies protective against malaria

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Scientists from the German Cancer Research Center (Heidelberg, Germany) have unveiled the molecular details of antibody binding to two distinct protective epitopes within a four amino acid repeat region of circumsporozoite protein (CSP) termed NANP.

Earlier attempts to induce antibodies against the NANP repeat of CSP, the major surface antigen of Plasmodium falciparum sporozoites, have been successful in animals but have proved difficult in humans.

This study, recently published in the journal Immunity examined, for the first time, at single-cell level whether a lasting immune memory is formed, providing the groundwork for the next generation of malaria vaccine.

“Ideally, a vaccine should elicit an antibody response against the so-called sporozoites, the parasite stage that the mosquito transfers to humans,” explained Hedda Wardemann from the German Cancer Research Center. “If the immune system is able to destroy the infectious agent at this stage, before it reaches the liver, then the infection is stifled from the start.”

Wardemann and colleagues collected blood samples from individuals living in a high-risk malaria setting and isolated memory B cells that were directed against malaria sporozoites.

The researchers proved their hypothesis that only very few CSP-specific memory cells are generated per individual, due to the small quantities of sporozoites released into the blood per mosquito bite and their rapid migration to the liver. As a result “the quantity is simply too small to stimulate the immune system sufficiently,” Wardemann confirmed.

Initially the team demonstrated that the small quantities of affinity-matured antibodies raised by these memory B cells could protect mice from infection by sporozoites. They next went on to analyze the exact amino acid sequences of CSP that are targeted by these protective antibodies.

“An effective vaccine must cause the memory cells to generate an extremely powerful response – before the sporozoites disappear out of reach into the liver. To make this happen, we must know the targets of a protective immune response as exactly as possible. In our current study, we have achieved this: the sporozoite amino acid sequences against which the protective antibodies are directed can serve as a basis for a new vaccine.” Wardemann concluded.

Sources: Triller G, Scally SW, Costa G, et al. Protective human anti-malarial antibodies induced by natural parasite exposureImmunity. doi: 10.1016/j.immuni.2017.11.007 (2017); www.dkfz.de/en/presse/pressemitteilungen/2017/dkfz-pm-17-58-Malaria-Protective-antibodies-following-natural-infection.php

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