番茄社区

SEATTLE -- A monoclonal antibody delivered intravenously was effective in protecting against Plasmodium falciparum infection over a 6-month malaria season in Mali, a phase II placebo-controlled trial showed.

Among 330 healthy adults, P. falciparum infection was detected in 35.5% who received a single dose of CIS43LS 10 mg/kg, 18.2% who received a 40-mg/kg dose, and 78.2% who received placebo, reported Kassoum Kayentao, MD, PhD, of the Malaria Research and Training Center in Bamako, Mali, at the American Society of Tropical Medicine & Hygiene annual meeting.

At 6 months, efficacy of the 40-mg/kg dose was 88.2% (adjusted 95% CI 79.3-93.3, P<0.001) compared with placebo, and efficacy of the 10-mg/kg dose was 75% versus placebo (adjusted 95% CI 61.0-84.0, P<0.001).

Findings from the study were published simultaneously in the .

"Most breakthrough infections occurred in the latter half of the study and occurred earlier in the low-dose group, which is consistent with what we know about monoclonal antibodies -- that their levels in blood gradually decrease with time," co-investigator Peter Crompton, MD, MPH, of the Malaria Infection Biology and Immunity Section at the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, told 番茄社区.

"Ongoing and future studies over the next few years involving children and pregnant women, the populations that suffer most from malaria, will determine how monoclonal antibodies can complement other interventions to save lives," he added.

CIS43LS is a monoclonal antibody that targets the P. falciparum circumsporozoite protein expressed on the surface of sporozoites, the parasite stage transmitted by mosquitoes to humans. Targeting sporozoites to block human infection can prevent malaria and transmission of the parasite, the authors noted.

Since P. falciparum infection is endemic in Mali, and a large proportion of the population has already been infected, Crompton and team tested participants for evidence of the parasite in their blood at enrollment, finding that 7% to 14% across the three groups had prior infection. They were cleared with artemether-lumefantrine before starting the trial treatment.

To increase the potency of the monoclonal antibodies, the researchers altered CIS43 to CIS43LS to increase its half-life from 21 days to about 80 days. "The LS change limits degradation of the antibody," co-investigator Robert Seder, MD, of the Vaccine Research Center at NIAID, told 番茄社区 in an email. Over time, blood concentration goes down, and protection wanes, he added.

At 12-week follow-up, efficacy of the 40-mg/kg dose was 92.3% (95% CI 78.4-97.2), and the efficacy of the 10-mg/kg dose was 84.5% (95% CI 67.1-92.7).

In previous trials, CIS43LS and L9LS showed protection in malaria-naive adults challenged with controlled human malaria infection, Seder said. "Thus, a major advantage of using monoclonal antibodies is that they may provide protection against all ages and would not be influenced by the immune status of the host ... we are not depending on the host to generate an immune response, which is what vaccines do."

For people who will be exposed to malaria regions for a short time, this treatment might be a good option, Seder suggested. "Since the monoclonal antibody still has a high level of efficacy at 3 months (>90%), it would be useful for travelers and for outbreak situations and military deployment."

Intravenous Administration Too Cumbersome

For an intravenous infusion that takes 30 minutes, and needs repeating, the length of protection with this treatment is concerning, noted Umberto D'Alessandro, MD, PhD, of the London School of Hygiene and Tropical Medicine in Banjul, Gambia, in an .

"Several issues should be resolved before monoclonal antibodies are included in the antimalarial arsenal," he wrote.

Intravenous administration is a major issue, he said. "It is difficult to conceive the large-scale implementation of an intervention administered as a single intravenous infusion of 100 mL over a period of 30 minutes."

Subcutaneous administration would be easier to implement, he added, "but the volume that can be injected is limited."

D'Alessandro noted that it would have been helpful to have more data on the incidence of clinical malaria in the population being studied. Two phase II trials being conducted in Mali () and Kenya () looking at subcutaneous treatment with the second-generation L9LS monoclonal antibody in children are expected to report the incidence of clinical malaria as part of their secondary endpoints.

D'Alessandro also said it is unclear what the cost of monoclonal antibodies would be, "although an estimate of $50 per gram has been mentioned," he wrote.

Crompton told 番茄社区 that "the cost of producing monoclonal antibodies for malaria prevention in Africa would be a challenge, but we are optimistic that recent advances in production will bring down the cost, especially when the monoclonal antibody is produced at scale to protect large populations in Africa from a common disease like malaria."

Study Details

This study was divided into two parts. Part A previously showed safety of the monoclonal antibody in 18 participants. In Part B, 330 adults ages 18 to 50 were randomly assigned to receive intravenous infusion of one of the two doses of CIS43LS or placebo.

Across the three groups, median age was 34-35, and 54-60% were men. More than 80% of each group had hemoglobin genotype AA.

Participants and staff were blinded to treatment. Only the pharmacists who prepared the solutions knew which participants received the active drug.

Participants were followed at visits at 1, 3, 7, 14, 21, and 28 days after infusion, then once every 2 weeks for 24 weeks.

At 7-day follow-up, participants across the three groups had similar mild to moderate adverse events. The risk of moderate headache was 3.3 times higher in the 40-mg/kg CIS43LS group versus the placebo group.

At 24-week follow-up, participants across the three groups reported 1,235 unsolicited adverse events -- 342 were grade 1, 880 were grade 2, 12 were grade 3, and one was grade 5.

A death occurred 165 days after treatment in the 10-mg/kg group, in a participant with hemoglobin SC disease, a type of sickle cell disease. The death was determined to be not associated with treatment.