NEJM: Monoclonal antibodies prevent malaria infection in African adults

A clinical trial by the National Institutes of Health found that a dose of antibody drugs could safely protect healthy non-pregnant women from malaria infection
during the six-month malaria peak season in Mali, Africa.
The antibody was as effective as 88.
2% in preventing infection over 24 weeks, demonstrating for the first time that monoclonal antibodies could prevent malaria infection
in malaria-endemic areas.
The findings were published today in the New England Journal of Medicine and presented at
the 2022 annual meeting of the American Society for Tropical Medicine and Hygiene in Seattle.

Anthony S.
Fauci, M.
D.
, director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, said, "We need to expand the arsenal of available interventions to prevent malaria infection and accelerate efforts to
eliminate the disease.
" "These findings suggest that monoclonal antibodies may complement other measures to protect travelers and vulnerable groups, such as infants, children and pregnant women, from seasonal malaria and to help eliminate malaria
in specific geographic areas.
"

NIAID sponsored and funded the trial, which was led
by Peter D.
Crompton, M.
D.
, M.
P.
H.
, and Kassoum Kayentao, M.
P.
H.
, M.
D.
, M.
D.
Dr.
Crompton is the director of the Department of Malaria Infection Biology and Immunology at NIAID's Immunogenetics Laboratory, while Dr.
Kayentao is a professor
at the University of Science, Technology and Technology (USTTB) in Bamako, Mali.

According to the World Health Organization (WHO), an estimated 241 million cases of malaria occurred globally in 2020, resulting in an estimated 627,000 deaths, mostly children
in sub-Saharan Africa.
These cases include more than 11 million pregnant women in Africa, resulting in an estimated 819,000 newborns with low birth weight, increasing the risk of
morbidity and death.

The only malaria vaccine currently recommended by WHO, called RTS,S (Mosquirix), provides partial protection
against clinical malaria early in life by giving it to children aged 5 to 17 months in four doses over a 20-month period.
Infants and young children, as well as travelers, also have access to other medicines
consisting of small compounds that are effective in preventing malaria infection.
However, the requirement for frequent dosing may limit drug adherence, and the emergence of resistance may also limit its effectiveness
.
Therefore, new, rapid-acting, low-dose interventions are urgently needed to provide strong protection
against malaria infection in a safe manner.

Malaria is transmitted to humans by the malaria parasite, which is transmitted to humans
through the bite of an infected mosquito.
Mosquitoes inject a parasite called a spore into the skin and bloodstream
.
These cells reach the liver, where they mature and multiply
.
The mature parasite then spreads through the bloodstream throughout the body to cause disease
.
Plasmodium falciparum is the species most likely to cause severe malaria infection and can lead to death
if left untreated.

The NIAID-USTTB Phase 2 trial evaluated the safety and efficacy
of a one-time intravenous infusion of a monoclonal antibody called CIS43LS.
This antibody is previously shown to make.
.
.
The spores neutralize Plasmodium falciparum in the skin and blood before infecting liver cells by Robert A.
, MD.
The Seder-led researchers isolated a naturally occurring antibody from the blood of a volunteer who was studied with a malaria vaccine and then modified to extend its stay in
the bloodstream.
Dr.
Seder is the Acting Chief Medical Officer and Acting Deputy Director of the NIAID Vaccine Research Center (VRC) and Director
of VRC's Division of Cellular Immunology.

The team from the second phase of the trial recruited 369 healthy, non-pregnant adults aged 18 to 55 years in rural communities in Califabgou and Torodo, Mali, where transmission of Plasmodium falciparum usually occurs from
July to December each year.

The first part of the trial evaluated the safety of three different doses of CIS43LS – 5 mg, 10 mg/kg and 40 mg/kg of body weight – intravenously to 18 study participants at each dose level of six participants
.
The team followed these participants for 24 weeks and found that the antibody infusion was safe and well
tolerated.

The second part of the trial evaluated two different doses of CIS43LS versus placebo
.
330 participants were randomly assigned to intravenous 10 mg/kg antibody, 40 mg/kg antibody, or placebo
.
Until the end of the trial, no one knew who was put into which group
.
The team followed these individuals for 24 weeks, testing their blood for Plasmodium falciparum once a week for the first 28 days and every two weeks thereafter
.
Any participant who developed symptomatic malaria during the trial received standard treatment
from the study team.

The researchers analyzed the efficacy
of CIS43LS in two ways.
According to the time to the first Plasmodium falciparum during the 24-week study period, CIS43LS was 88.
2% effective in preventing infection at high doses (40 mg/kg) and 75%
effective at low doses (10 mg/kg).
Analysis of infection ratios Plasmodium falciparum at any time during the 24-week study period found that high-dose infection prevention was 76.
7% effective and low-dose effective 54.
2%.

"These first-of-its-kind field results demonstrate that a monoclonal antibody safely provides a high level of protection against strong malaria transmission in healthy adults, paving the way for further research to determine whether this intervention can prevent malaria infection
in infants, children and pregnant women," said Dr Seder.
"We hope that monoclonal antibodies will change malaria prevention
in malaria-endemic areas.
"

Dr.
Seder and his colleagues developed a second antimalarial monoclonal antibody, L9LS, which is much stronger than CIS43LS and can therefore be administered
in smaller doses by subcutaneous (subcutaneous) injection rather than intravenous drip.
Early trials of L9LS by NIAID in the United States found the antibody to be safe, and 15 of the 17 healthy adults exposed to the antibody were prevented from malaria infection for 21 days with Plasmodium falciparum in a carefully controlled environment
.
Two larger Phase II trials sponsored by NIAID to evaluate the safety and efficacy of L9LS in infants, children, and adults are underway in Mali and Kenya.

More information about the CIS43LS Phase 2 clinical trial can be found in the ClinicalTrials.
gov, Study Identifier NCT04329104
.