Monoclonal antibody may prevent malaria

Date:
August 11, 2021
Source:
NIH/National Institute of Allergy and Infectious Diseases
Summary:
One dose of a new monoclonal antibody prevented malaria for
up to nine months in people who were exposed to the malaria
parasite. The small, carefully monitored clinical trial is the
first to demonstrate that a monoclonal antibody can prevent malaria
in people.



FULL STORY ==========================================================================
One dose of a new monoclonal antibody discovered and developed at the
National Institutes of Health safely prevented malaria for up to nine
months in people who were exposed to the malaria parasite. The small,
carefully monitored clinical trial is the first to demonstrate that a monoclonal antibody can prevent malaria in people. The trial was sponsored
and conducted by scientists from the Vaccine Research Center (VRC)
of the National Institute of Allergy and Infectious Diseases (NIAID),
part of NIH, and was funded by NIAID. The findings were published today
in the New England Journal of Medicine.


========================================================================== "Malaria continues to be a major cause of illness and death in many
regions of the world, especially in infants and young children;
therefore, new tools are needed to prevent this deadly disease," said
NIAID Director Anthony S. Fauci, M.D. "The results reported today suggest
that a single infusion of a monoclonal antibody can protect people
from malaria for at least 9 months. Additional research is needed,
however, to confirm and extend this finding." According to the World
Health Organization, an estimated 229 million cases of malaria occurred worldwide in 2019, resulting in an estimated 409,000 deaths, mostly
in children in sub-Saharan Africa. So far, no licensed or experimental
malaria vaccines provide more than 50% protection from the disease over
the course of a year or longer.

Malaria is caused by Plasmodiumparasites, 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 Plasmodiumspecies most likely to result in severe malaria infections, which, if not promptly
treated, may lead to death.

Laboratory and animal studies have demonstrated that antibodies can
prevent malaria by neutralizing the sporozoites of P. falciparum in the
skin and blood before they can infect liver cells. The NIAID trial tested whether a neutralizing monoclonal antibody called CIS43LS could safely
provide a high level of protection from malaria in adults following
careful, voluntary, laboratory-based exposure to infected mosquitos in
the United States.

CIS43LS was derived from a naturally occurring neutralizing antibody
called CIS43. Researchers led by Robert A. Seder, M.D., chief of the
Cellular Immunology Section of the VRC Immunology Laboratory, isolated
CIS43 from the blood of a volunteer who had received an investigational
malaria vaccine. The scientists found that CIS43 binds to a unique site
on a parasite surface protein that is important for facilitating malaria infection and is the same on all variants of P. falciparum sporozoites worldwide. The researchers subsequently modified this antibody to extend
the amount of time it would remain in the bloodstream, creating CIS43LS.



========================================================================== After animal studies of CIS43LS for malaria prevention yielded promising results, VRC investigators launched a Phase 1 clinical trial of the experimental antibody with 40 healthy adults ages 18 to 50 years who had
never had malaria or been vaccinated for the disease. The trial was led
by Martin Gaudinski, M.D., medical director of the VRC Clinical Trials
Program, and was conducted at the NIH Clinical Center in Bethesda,
Maryland, and the Walter Reed Army Institute of Research (WRAIR) in
Silver Spring, Maryland.

During the first half of the trial, the study team gave 21 participants
one dose of CIS43LS by either an intravenous infusion or an injection
under the skin. The infusions ranged from 5 to 40 milligrams per
kilogram (mg/kg) of body weight, and the subcutaneous injections were
5 mg/kg. Investigators followed the participants for 6 months to learn
whether the infusions and subcutaneous injections of the various doses of
the experimental antibody were safe and well tolerated. In addition, they measured the amount of CIS43LS in the blood to determine its durability
over time.

In the second half of the trial, six participants who had received an intravenous infusion during the first half of the trial continued to participate. Four of these participants received a second antibody
infusion while the other two did not. In addition, four new participants
joined the study and received a single intravenous infusion of
CIS43LS. Another seven people joined the study as controls who did not
receive the antibody.

All participants in the second half of the trial provided informed consent
to be exposed to the malaria parasite in what is known as a controlled
human malaria infection (CHMI). In this procedure, volunteers are exposed
to P.

falciparum through bites of infected mosquitos in a carefully controlled setting, then are closely monitored by medical staff for several weeks
and promptly treated if they develop malaria. CHMI has been used for
decades to generate information about the safety and protective effect
of malaria vaccine candidates and potential antimalarial drugs.

Nine participants who had received CIS43LS and six participants who
served as controls voluntarily underwent CHMI and were closely monitored
for 21 days.

Within that period, none of the nine participants who had received CIS43LS developed malaria, but five of the six controls did. The participants
with malaria received standard therapy to eliminate the infection.



========================================================================== Among the nine participants who received CIS43LS and were protected,
seven underwent CHMI approximately 4 weeks after their infusion. The
other two participants had received their sole infusion during the first
half of the study and were infected approximately 9 months later. These
results indicate that just one dose of the experimental antibody can
prevent malaria for 1 to 9 months after infusion. Collectively, these
data provide the first evidence that administration of an anti-malaria monoclonal antibody is safe and can prevent malaria infection in humans.

To build on this finding, a larger Phase 2 clinical trial is underway
in Mali to evaluate the safety and efficacy of CIS43LS at preventing
malaria infection in adults during a six-month malaria season. The trial
is being led by Peter D.

Crompton, M.D., M.P.H., chief of the Malaria Infection Biology and
Immunity Section in the NIAID Laboratory of Immunogenetics, and Kassoum Kayentao, M.D., M.P.H., Ph.D., a professor at the University of Sciences, Techniques and Technologies of Bamako, Mali. NIAID is sponsoring and
funding the trial.

Results are expected in early 2022.

In addition, VRC scientists are conducting further research on CIS43LS
in the United States to determine the lowest dose that protects people
from malaria infection.

"Monoclonal antibodies may represent a new approach for preventing
malaria in travelers, military personnel and health care workers
traveling to malaria- endemic regions," said Dr. Seder. "Further
research will determine whether monoclonal antibodies can also be
used for the seasonal control of malaria in Africa and ultimately
for malaria-elimination campaigns." For more information about the
completed Phase 1 trial, please go to ClinicalTrials.gov and search
under study identifier NCT04206332. For information about the ongoing
Phase 2 trial in Mali, please go to ClinicalTrials.gov and search under
study identifier NCT04329104.

Reference: MR Gaudinski et al. A monoclonal antibody for malaria
prevention.

New England Journal of Medicine DOI: 10.1056/NEJMoa2034031 (2021).

========================================================================== Story Source: Materials provided by NIH/National_Institute_of_Allergy_and_Infectious Diseases. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Martin R. Gaudinski, Nina M. Berkowitz, Azza H. Idris, Emily
E. Coates,
LaSonji A. Holman, Floreliz Mendoza, Ingelise J. Gordon, Sarah H.

Plummer, Olga Trofymenko, Zonghui Hu, Andrezza Campos Chagas,
Sarah O'Connell, Manjula Basappa, Naomi Douek, Sandeep R. Narpala,
Christopher R. Barry, Alicia T. Widge, Renunda Hicks, Seemal
F. Awan, Richard L. Wu, Somia Hickman, Diane Wycuff, Judy A. Stein,
Christopher Case, Brian P.

Evans, Kevin Carlton, Jason G. Gall, Sandra Vazquez, Britta Flach,
Grace L. Chen, Joseph R. Francica, Barbara J. Flynn, Neville
K. Kisalu, Edmund V. Capparelli, Adrian McDermott, John R. Mascola,
Julie E. Ledgerwood, Robert A. Seder. A Monoclonal Antibody for
Malaria Prevention. New England Journal of Medicine, 2021; DOI:
10.1056/NEJMoa2034031 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210811175215.htm

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