One dose of an
antibody drug safely protected healthy, non-pregnant adults from malaria
infection during an intense six-month malaria season in Mali, Africa, a
National Institutes of Health clinical trial has found. The antibody was up to
88.2% effective at preventing infection over a 24-week period, demonstrating
for the first time that a monoclonal antibody can prevent malaria infection in
an endemic region. These findings were published in The New
England Journal of Medicine and
presented at the American Society of Tropical Medicine & Hygiene 2022
Annual Meeting in Seattle.
“We need to expand the arsenal of
available interventions to prevent malaria infection and accelerate efforts to
eliminate the disease,” said Anthony S. Fauci, M.D., director of the National
Institute of Allergy and Infectious Diseases (NIAID), part of NIH. “These study
results suggest that a monoclonal antibody could potentially complement other
measures to protect travelers and vulnerable groups such as infants, children,
and pregnant women from seasonal malaria and help eliminate malaria from defined
geographical areas.”
NIAID sponsored and funded the trial,
which was led by Peter D. Crompton, M.D., M.P.H., and Kassoum Kayentao, M.D.,
M.P.H., Ph.D. Dr. Crompton is chief of the Malaria Infection Biology and
Immunity Section in the NIAID Laboratory of Immunogenetics, and Dr. Kayentao is
a professor at the University of Sciences, Techniques and Technologies (USTTB)
of Bamako, Mali.
An estimated 241 million cases of
malaria occurred worldwide in 2020, according to the World Health Organization (WHO), resulting in an estimated 627,000 deaths, mostly in
children in sub-Saharan Africa. These cases included more than 11 million
pregnant women in Africa, resulting in an estimated 819,000 newborns with low
birthweight and thus at increased risk for illness and death.
The only malaria vaccine currently recommended
by WHO, called RTS,S (Mosquirix), provides partial protection against clinical
malaria during the early years of life when given to children aged 5 to 17
months in four doses over a 20-month period. Other drugs consisting of small
chemical compounds that effectively prevent malaria infection are also
available for infants and young children as well as travelers. The requirement
for frequent dosing of these drugs can limit adherence, however, and the
emergence of drug resistance may also limit their usefulness. Thus, there is an
urgent need for new, fast-acting, infrequently dosed interventions that safely
provide strong protection against malaria infection.
Malaria is caused by Plasmodium parasites, which are transmitted to people
through the bite of an infected mosquito. The mosquito injects the parasites in
a form called sporozoites into the skin and bloodstream. These travel to the
liver, where they mature and multiply. Then the mature parasite spreads
throughout the body via the bloodstream to cause illness. P.
falciparum is the Plasmodium species most likely to result in severe malaria
infections, which, if not promptly treated, may lead to death.
The Phase 2 NIAID-USTTB trial evaluated
the safety and efficacy of a one-time, intravenous infusion of a monoclonal
antibody called CIS43LS. This antibody was previously shown to neutralize the sporozoites of P. falciparum in the skin and blood before they could infect liver cells.
Researchers led by Robert A. Seder, M.D., isolated a naturally occurring form
of this antibody from the blood of a volunteer who had received an
investigational malaria vaccine, and then modified the antibody to extend the
length of time it would remain in the bloodstream. Dr. Seder is the acting
chief medical officer and acting associate director of the NIAID Vaccine
Research Center (VRC) and chief of the VRC’s Cellular Immunology Section.
The study team for the Phase 2 trial
enrolled 369 healthy, non-pregnant adults aged 18 to 55 years in the rural
communities of Kalifabougou and Torodo in Mali, where intense P.
falciparum transmission
typically occurs from July through December each year.
The first part of the trial assessed the
safety of three different doses of CIS43LS—5 milligrams per kilogram of body
weight, 10 mg/kg and 40 mg/kg—administered by intravenous infusion in 18 study
participants, with six participants per dose level. The study team followed
these participants for 24 weeks and found the antibody infusions were safe and
well-tolerated.
The second part of the trial assessed
the efficacy of two different doses of CIS43LS compared to a placebo. Three
hundred and thirty participants were assigned at random to receive either 10
mg/kg of the antibody, 40 mg/kg, or a placebo by intravenous infusion. No one
knew who was assigned to which group until the end of the trial. The study team
followed these individuals for 24 weeks, testing their blood for P.
falciparum weekly 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 investigators analyzed the efficacy
of CIS43LS two ways. Based on the time to first P.
falciparum infection over the
24-week study period, the high dose (40 mg/kg) of CIS43LS was 88.2% effective
at preventing infection and the lower dose (10 mg/kg) was 75% effective. An
analysis of the proportion of participants infected with P.
falciparum at any time over the
24-week study period found the high dose was 76.7% at preventing infection and
the lower dose was 54.2% effective.
“These first field results demonstrating
that a monoclonal antibody safely provides high-level protection against
intense malaria transmission in healthy adults pave the way for further studies
to determine if such an intervention can prevent malaria infection in infants,
children, and pregnant women,” Dr. Seder said. “We hope monoclonal antibodies
will transform malaria prevention in endemic regions.”
Dr. Seder and colleagues have developed
a second antimalarial monoclonal antibody, L9LS, that is much more potent than
CIS43LS and therefore can be administered in a smaller dose as an injection
under the skin (subcutaneously), rather than by intravenous infusion. An
early-phase NIAID trial of L9LS in the United States found that
the antibody was safe and prevented malaria infection for 21 days in 15 out of
17 healthy adults exposed to P. falciparum in a carefully controlled setting. Two larger, NIAID-sponsored
Phase 2 trials assessing the safety and efficacy of L9LS in infants, children
and adults are underway in Mali and Kenya.
Additional information about the Phase 2 trial of CIS43LS is available at ClinicalTrials.gov under study identifier NCT04329104.
Source: https://www.niaid.nih.gov/news-events/monoclonal-antibody-prevents-malaria-infection-african-adults
Journal article: https://www.nejm.org/doi/10.1056/NEJMoa2206966
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