Genetically Attenuated Parasite Boosts Malaria Immunity

This is an Anopheles stephensi mosquito infected by Plasmodium berghei. [Institut Pasteur]

Malaria vaccines that consist of genetically attenuated parasites (GAPs) continue to evolve, with new genetic modifications leading to vaccine prototypes showing different capabilities. To date, most GAP vaccines have been engineered with mutations in housekeeping genes important for parasite development in red blood cells. A new GAP vaccine, however, takes a different approach, omitting a gene that expresses histamine-releasing factor (HRF). This new GAP vaccine, report its creators, is the first of its kind to impact the host’s immune response directly.

HRF-mutant parasites conferred mice with protection from any potential reintroduction of Plasmodium, the parasite responsible for malaria. This protection was long lasting, as it was maintained for more than a year, suggesting that a long-term immunological memory had been established.

Protection was effective not only against strains of different virulence strains, it was also effective against all stages of the parasite’s life cycle. Finally, unlike the standard wild-type Plasmodium berghei strain, which does not induce a cellular or humoral response, this vaccine strain not only induced a cellular response (CD4 and CD8 T cells), it also triggered high levels of specific antibodies that recognized parasite antigens known to be vaccine targets.

Details about the new GAP vaccine appeared July 18 in the Journal of Experimental Medicine, in an article entitled, “Protection against Malaria in Mice Is Induced by Blood Stage–Arresting Histamine-Releasing Factor (HRF)–Deficient Parasites.”

“Lack of HRF causes an IL-6 [interleukin-6] increase, which boosts T and B cell responses to resolve infection and leave a cross-stage, cross-species, and lasting immunity,” wrote the article’s authors. “Mutant-induced protection involves a combination of antiparasite IgG2c antibodies and FcγR⁺ CD11b⁺ cell phagocytes, especially neutrophils, which are sufficient to confer protection.”

The article’s authors concluded that their immune-boosting GAP highlights an important role of opsonized parasite-mediated phagocytosis, which may be central to protection induced by all self-resolving blood-stage GAP infections.

“In recent years, the vaccine strategy of choice using live, genetically attenuated parasites to combat malaria has received renewed interest,” note the study’s senior author, Salaheddine Mécheri, a researcher at the Institut Pasteur. “The HRF mutant is a promising prototype in this respect, offering a rapid, long-lasting, and wide-ranging protective effect.”