CDC's Research Contributions

Overview

Over the past three decades, CDC has contributed to the world's knowledge of malaria, especially the burden of malaria in children and pregnant women and the impact of drug resistance in areas of high malaria transmission. CDC has contributed to the development and evaluation of prevention and control interventions recommended by the World Health Organization and used by programs worldwide to fight malaria: insecticide-treated bed nets (ITNs), intermittent preventive treatment in pregnancy (IPTp), artemisinin-based combination therapies (ACTs), and the RTS,S malaria vaccine.

Having completed the research that has informed the current generation of malaria control interventions, CDC is well-positioned to refine malaria interventions as well as develop new interventions to stay ahead of the curve—and contribute to achieving the ambitious global goals of malaria elimination and ultimately eradication.

In the last decades, CDC has contributed to our knowledge and understanding of these areas:

Understanding the impact of malaria

• CDC work in Malawi and Kenya established the role of malaria in infant and early childhood mortality in high transmission settings and documented the public health importance of severe malaria-related anemia as a major cause of death in such populations.
• CDC studies in Malawi and Kenya determined the risk of malaria-associated low birth weight, one of the adverse effects of malaria infection during pregnancy.
• CDC has also made substantial contributions to efforts to quantify the burden of malaria mortality in African children and the burden of malaria in pregnancy.

Monitoring drug resistance

Beginning in the late 1950s, resistance to the most commonly used antimalarial drug, chloroquine, began to appear almost simultaneously in Southeast Asia and South America.

• Starting in the 1980s, CDC called attention to the impact of antimalarial drug resistance in Africa. CDC and colleagues documented the public health impact of chloroquine resistance and helped countries in sub-Saharan Africa establish malaria drug resistance monitoring networks.
• In the early to mid-1990s, CDC and WHO developed and implemented standard protocols for assessing the therapeutic efficacy of drugs and changing antimalarial drug treatment guidelines. CDC helped develop standard techniques that use molecular techniques for discerning reinfection from recrudescence to assess drug efficacy outcomes in high transmission settings.
• As a result of the findings from CDC-assisted drug efficacy testing, first-line antimalarial drug policy changed from chloroquine to sulfadoxine-pyrimethamine (SP) in Malawi, Zambia, Kenya, Tanzania, and the Democratic Republic of Congo. CDC contributed to economic evaluations of the costs associated with changing antimalarial drug policies.
• CDC continued to contribute to the knowledge of drug resistance by determining the origin and distribution of SP-resistance alleles across Africa. CDC continues to monitor the development of antimalarial drug resistance, now to both SP and artemisinins, and in collaboration with the Rwandan Ministry of Health, documented the first evidence of artemisinin resistance in Africa.
• As part of the U.S. President's Malaria Initiative, CDC supports therapeutic efficacy studies in approximately two dozen sub-Saharan African countries

Gathering evidence to inform malaria control policies

CDC conducted groundbreaking work to develop and evaluate IPTp, to evaluate ITNs in areas of high malaria transmission, and to define how best to manage malaria cases in children. CDC is also working on evaluating new technologies for malaria control.

Intermittent Preventive Treatment for Pregnant Women (IPTp)

• CDC determined that intermittent preventive treatment of malaria during pregnancy (IPTp)—the delivery of curative doses of effective antimalarial drugs as part of routine prenatal care—reduced the risk that malaria-infected pregnant women would have babies with low birth weight, a contributing factor to infant death.
• To benefit from treatment, pregnant women who are HIV-positive need more doses of IPTp with the drug sulfadoxine-pyrimethamine (SP) or, in some cases, a different drug.
• As resistance to sulfadoxine-pyrimethamine (SP) has increased, CDC research has been instrumental in demonstrating the continued impact of intermittent preventive treatment in pregnancy as well as exploring alternative drugs.

As of 2023, only ~40% of women receive the recommended three doses of IPTp during the course of pregnancy. CDC has assessed community delivery of IPTp and the group antenatal care model to see if these strategies can improve uptake of IPTp.

Insecticide-treated bed nets (ITNs)

• CDC and the Kenya Medical Research Institute (KEMRI) completed one of the first studies to demonstrate that ITNs could reduce malaria-related illness and death in an area of very intense, year-round malaria transmission. Prior to these findings, all of the evidence of bed net efficacy in Africa had been collected in settings where transmission was only moderate or exclusively seasonal.
• This study also broke ground by showing that if enough people in a malaria-endemic community were protected with ITNs, the absolute numbers of mosquitoes would be reduced and even individuals in neighboring households without ITNs could be protected from infection (the "community effect").
• CDC studies also allayed concerns that continued use of bed nets would simply cause children at risk of malaria-related death to die at slightly older ages. Use of regularly maintained ITNs for an additional 2 – 4 years showed that continued protection for infants did not shift mortality to older children.

Pregnant women also were shown to benefit from ITNs. When pregnant women slept under ITNs, malaria infections and the malaria-associated ill effects in pregnancy were reduced. In addition, severe malarial anemia was reduced by 47% and the delivery of low-birth-weight infants decreased by 28%.

Use of Both ITNs and Indoor Residual Spraying (IRS)

• In a 2008–2009 study in Rachuonyo District, Kenya, CDC determined that the use of both ITNs and IRS reduced malaria infections by 62% (and by 67% among those 6 months to 4 years, the most vulnerable) compared with use of ITNs alone. IRS also reduced the numbers of anopheline mosquitoes. These data suggest for the first time that by using both interventions together, people living in areas that receive both interventions benefit considerably.

Case management

• Most of the deaths caused by malaria are in young children under 5 years of age. CDC helped establish the clinical basis for the Integrated Management of Childhood Illnesses (IMCI) strategy and assessed components of its implementation. IMCI is an approach developed by WHO and the United Nations Children's Fund (UNICEF) that promotes accurate identification of childhood illnesses in outpatient settings, ensures appropriate combined treatment of all major illnesses, strengthens caretaker counseling, and speeds referral of severely ill children.
• After resistance developed to sulfadoxine-pyrimethamine, which had replaced chloroquine for first-line treatment, artemesinin-containing combination therapies (ACTs) were widely adopted; CDC contributed to establishing valid techniques for measuring adherence to ACTs.
• CDC has led a number of recent studies assessing how to expand access to case management services and the impact of doing so. These include assessments of age-expanded community case management in Madagascar and Malawi and a trial of proactive community case management in Zambia.

Intermittent Preventive Treatment of Infants (IPTi)

• CDC contributed to understanding the role of intermittent preventive treatment of infants (IPTi) in reducing malaria illness. Similar to IPTp, IPTi consists of treatment doses of sulfadoxine-pyrimethamine (SP), delivered to children regardless of malaria infection or symptoms at their first 3 routine vaccinations. Studies have demonstrated that IPTi can reduce the incidence of clinical malaria by a little more than 30%.

Malaria vaccines

RTS,S

CDC has been engaged in the trials supporting the use of the RTS,S vaccine since 2009, as part of the original phase 3 trial conducted from 2009– 2011, in children ages 6 – 12 weeks and 5 – 17 months at 11 sites in seven African countries. CDC, in collaboration with the Kenya Medical Research Institute, led the trial at one site in western Kenya. The trial's final results, made available in 2015, were a promising advance in development of a malaria vaccine for African children. The RTS,S vaccine reduced clinical and severe cases of malaria by about one-third in 5–17-month-old children over four years who received the three-dose vaccine series plus a booster dose. The vaccine was less effective in children in the young infant group. The vaccine was generally found to be safe, but there were a few safety signals that warranted further study, including febrile convulsions, meningitis, and cerebral malaria.

Notably, the vaccine provided this protection in settings with ongoing use of other effective malaria prevention and treatment interventions: bed nets, antimalarial drugs for disease treatment, indoor residual insecticide spraying to prevent mosquito-borne transmission, and drugs to protect pregnant women and their newborns from malaria's adverse effects.

In July 2015, the European Medicines Agency (EMA) gave a positive regulatory assessment of the RTS,S/AS01 vaccine for 5 – 17-month-olds, but WHO recommended in October 2015 that the vaccine be further evaluated in large-scale pilot studies before recommending it. Large-scale pilots of the vaccine began in Ghana, Kenya, and Malawi in 2019, including several hundreds of thousands of infants. CDC, in collaboration with KEMRI and several other organizations, is led the evaluation of the large-scale RTS,S/AS01 pilot in western Kenya (Malaria Vaccine Pilot Evaluation, or MVPE). The pilot evaluation assessed the feasibility of delivering the three-dose vaccine series plus booster through routine health systems, carefully examine the relationship of the vaccine to specific adverse events (febrile seizures, meningitis, cerebral malaria), and evaluated its impact on all-cause mortality.

Whole sporozoite vaccines

Whole sporozoite vaccines consist of the sexual form of the parasite extracted from mosquito salivary glands, which have either been made non-infectious through irradiation or are administered along with chemoprophylaxis. The irradiated whole sporozoite PfSPZ Vaccine made by Sanaria® is safe and well tolerated; IV administration to adults has resulted in moderate levels of protection. A collaborative CDC and KEMRI trial in western Kenya demonstrated that the PfSPZ Vaccine is safe and well tolerated in infants and young children. Unfortunately, the vaccine did not provide significant protection against P. falciparum infection at 6 months, precluding further evaluation in this age group, although other studies are currently evaluating the efficacy of the PfSPZ Vaccine in different populations in Mali, Gabon, Tanzania, and Equatorial Guinea. This study provided important information on the immune response to the vaccine which will aid researchers in developing a more effective vaccine for young children.

Antimalarial drug use, diagnosis, and non-falciparum malarias

Antimalarial drug issues

In many countries substandard and counterfeit drugs present a problem.

• CDC-developed a colorimetric test for counterfeit artesunates, a key component of ACTs. The test can be used by workers in the field to determine whether the packaged drug contains the antimalarial drugs.
• CDC and Ifakara Health Institute completed the only study of malaria infection among clients at retail shops and contributed to the first nationally representative study of antimalarial drug quality in the retail sector.
• CDC contributed to testing new drug candidates and vaccine components in nonhuman primates.

Diagnosis

• CDC collaborated with local research institutions in Kenya and Tanzania to learn more about how best to use recently available rapid diagnostic tests (RDTs) for malaria, which can provide diagnosis in as little as 15 minutes.
  • CDC supported research in Tanzania demonstrated that health workers at rural health facilities can successfully use RDTs to improve patient care when supported by appropriate supervision and RDT quality control, leading to scaling up of RDT use by community health workers. Better diagnostics and appropriate treatment will result in fewer malaria-related complications and deaths and provide a more accurate way of measuring the impact of malaria control.

• CDC helped demonstrate that many malaria parasites in South America do not produce a specific protein product, which will preclude the use of many RDTs for malaria in endemic regions on this continent and contributed to the push for the development of newer RDTs which assess multiple proteins.

Non-falciparum malarias

• CDC contributed to the understanding that P. vivax, long thought to be much less lethal than P. falciparum, could be quite virulent.
• CDC helped document that a 5th malaria parasite, P. knowlesi, which was recently recognized as a cause of human malaria disease, had been imported into North America by a traveler.

Malaria in travelers

• CDC's contributions to research of malaria in travelers include examining trends in imported malaria in the U.S. and monitoring for drug resistance and adverse reactions to antimalarials. Previous activities have included collaborations with the Peace Corps, the Department of Defense, and academic institutions.