The team of researchers from Leiden University Medical Center and Radboud University Medical Center in the Netherlands showed in a small clinical trial that a late liver-stage attenuated malaria parasite vaccine has promising safety and efficacy.
Immunization with a genetically modified Plasmodium falciparum (Pf) parasite, GA2, resulted in a favorable immune response and conferred protective efficacy against malaria infection, according to the study. To this date, malaria is a serious medical condition around the world. Malaria disproportionately affects young children and pregnant women, and urgent improvement in the effectiveness and durability of vaccination strategies is necessary.
Efforts to eradicate malaria have stalled, necessitating innovative strategies. Almost all vaccines in advance for malaria provide minimal short-term protection. An alternative approach that might enhance immunity through exposure of the immune system to a broader array of antigens is whole-sporozoite vaccination with live attenuated parasites.
Researchers studied the safety and efficacy of immunization with a genetically modified P. falciparum parasite (GA2) in a double-blind, controlled clinical trial assessed as a safety and side effect profile as well as for efficacy in the study “Safety and Efficacy of Immunization with a Late-Liver Stage Attenuated Malaria Parasite,” published in The New England Journal of Medicine.
The parasite detaches itself using GA2 and can develop further inside liver cells, exposing more parasite antigens to the host’s still-developing immune system. It is postulated that this prolonged exposure improves the immune system’s ability to recognize and battle the parasite more completely.
Healthy adult volunteers without prior malaria exposure were randomly assigned to receive immunization with either the GA2 parasite, the GA1 parasite, or a placebo consisting of uninfected mosquito bites.
All 25 participants were randomly divided into three groups: 10 received GA2, 10 received GA1, and 5 received the placebo. Participants received 3 immunization sessions with 28-day intervals, one involving 50 mosquitoes infected with the individual parasites or 50 uninfected mosquitoes for those in the placebo group. Two weeks after the last immunization, participants were exposed to a controlled human malaria infection, to assess protective efficacy.
The primary endpoints were the number and severity of adverse events, as well as the occurrence of blood-stage parasitemia (presence of more than 100 P. falciparum parasites per milliliter). All groups experienced similar adverse events, mostly mild local reactions such as erythema and pruritus at the mosquito bite sites.
These results were that eight of nine participants (89%) in the GA2 group showed protective efficacy and 1 of 8 participants (13%) in the GA1 group as well as none in the placebo group. There were no breakthrough infections reported after exposure to GA2, which has a very strong safety profile. For the placebo group, this gave a median time to parasitemia of 12 days, whereas the GA1 group was in parasitemia in a median of 11 days.
Immunological analyses revealed that GA2 recipients had a higher frequency of P. falciparum-specific CD4 polyfunctional cells than GA1 recipients. These cells produced a strong pro-inflammatory response, including Interferon γ, tumor necrosis factor α, and interleukin 2.
Both GA2 and GA1 elicited antibody titers against the P. falciparum circumsporozoite protein similar to levels elicited by O inoculation, consistent with protection due to GA2 being mediated by cellular immune responses rather than mere antibody level.
The study concludes that GA2 testing resulted in favorable immune profiles and demonstrated sufficient protective efficacy against malaria infection, warranting further evaluation in larger and more diverse populations.
Reference: Lamers OAC, Franke-Fayard BMD, Koopman JPR, et al. Safety and Efficacy of Immunization with a Late-Liver-Stage Attenuated Malaria Parasite. N Engl J Med. 2024;391(20):1913-1923. doi:10.1056/NEJMoa2313892‌
