Country-led genetic analysis of samples collected through the Republic of Congo (RoC) epidemiologic surveillance system in early 2024 showed that mpox was affecting people in parts of the country where it has not been historically reported, and point to increases in human-to-human transmission across the border with the neighboring Democratic Republic of the Congo (DRC), where a large outbreak was declared a public health emergency of international concern in August of the same year. The analysis was conducted by the RoC Laboratoire National de Santé Publique (LNSP) in Brazzaville with support and scientific partnership from NIAID and was published in The Lancet. 

There are two known types or “clades” of monkeypox virus (MPXV), which causes mpox clinical disease. Clade I is endemic in Central Africa and can cause severe illness. Clade II, endemic in West Africa, caused the global mpox outbreak that began in 2022 and tends to result in milder illness. Each clade has two known subtypes referred to as “a” and “b.” Clade Ia has been identified in RoC and DRC intermittently for decades and Clade Ib was first identified during the active DRC outbreak. Mpox is a zoonotic disease, meaning it can be spread between animals and people. MPXV has been detected in rodents that live in areas historically affected by mpox. 

Genetic sequencing of MPXV can help determine the transmission dynamics and guide the public health response to mpox, but until recently most sequencing of MPXV was done outside of affected countries like RoC, requiring costly sample transport and delaying decision-making by local health authorities. 

To better understand whether mpox in RoC was driven by spillover from local animal hosts or cross-border human-to-human transmission from DRC, a team led by the RoC LNSP analyzed 31 samples of laboratory-confirmed MPXV collected through the country’s routine epidemiologic surveillance system between January and April of 2024. Using new in-country sequencing technology, the team determined that there were diverse circulating strains of MPXV in the country, all of the Clade Ia subtype, and some showed up to 99.9% genetic similarity to MPXV sequenced from the DRC. Moreover, MPXV samples came from provinces without historical reports of mpox. 

According to the authors, the diversity of identified stains suggest MPXV has been introduced to the human population in RoC through multiple distinct events, which could be a combination of direct zoonotic transmission from local animals as well as human-to-human transmission within and across the country’s borders. They state that current epidemiological data are insufficient to definitively confirm the directionality of MPXV transmission and that further epidemiological research is needed to understand local transmission patterns and inform the public health response in RoC. Finally, they highlight that while only 31 samples met criteria for analysis in the study, it is likely these cases represent only a fraction of the RoC mpox burden at the time of collection.

This research informed the RoC’s decision to declare a national mpox epidemic in April 2024. It is part of a longstanding scientific collaboration between NIAID’s Rocky Mountain Laboratories and the Congolese government. The U.S. Embassy in RoC, the U.S. Agency for International Development, the U.S. Centers for Disease Control and Prevention, and the World Health Organization also provided technical and laboratory support for this study. 

Learn more about NIAID’s mpox research priorities. Play a video of NIAID Director Jeanne Marrazzo discussing these priorities. 

Reference:

CK Yinda, et al. Genetic sequencing analysis of monkeypox virus clade I in Republic of the Congo: a cross-sectional, descriptive study. The Lancet DOI: 10.1016/S0140-6736(24)02188-3 (2024)

NIAID-developed Test Could Be Used to Find Hot Spots for Disease-spreading Mosquitoes

Not all mosquitoes are the same. Some carry pathogens that cause diseases in the people they bite. Scientists at NIAID developed a new tool to help identify geographic hot spots for Aedes mosquitoes, a type of mosquito that can spread diseases such as dengue, Zika and chikungunya. The tool uses a marker from blood serum to identify people bitten by Aedes mosquitoes. Monitoring for this marker in blood samples could help find sites where disease-carrying mosquitoes live, allowing for targeted interventions against dengue and other diseases.

Nearly half of the world’s population lives in areas affected by dengue, a viral disease spread by Aedes mosquitoes, primarily of the species Aedes aegypti and Aedes albopictus. The disease symptoms include fever, head and body aches, nausea and rash, and severe cases of dengue can be fatal. Each year, between 100 and 400 million people develop the disease, resulting in approximately 40,000 deaths. In places where dengue is common, it is often a major cause of illness. However, vaccines against dengue are not widely available throughout the world. For these reasons, mosquito control is an important strategy for preventing the disease in these regions.

When a person or animal is bitten by a mosquito, saliva from the mosquito is injected into the skin. The saliva is what causes the bite to itch—and it can also contain pathogens such as viruses and parasites that cause disease. The immune system reacts to a mosquito bite, producing antibodies against the proteins contained in mosquito saliva. People who have been bitten by Aedes mosquitoes carry antibodies against these proteins in their blood. Although a mixture of mosquito salivary gland proteins can be used in the lab to test whether a person has been bitten by Aedes mosquitoes, the test can be expensive, time-consuming, and difficult to standardize among different labs.

A team of researchers led by Dr. Fabiano Oliveira in NIAID’s Laboratory of Malaria and Vector Research aimed to develop a test suitable for large-scale monitoring of Aedes mosquito exposure in people. The researchers tested blood serum from children in Cambodia who had enrolled in a study conducted by the NIAID International Center for Excellence in Research, Cambodia. The researchers compared the levels of several mosquito saliva proteins in the blood of children who had and had not developed dengue. They found that most of the children who had developed the mosquito-borne disease had higher levels of antibodies against two proteins, AeD7L1 and AeD7L2, which are from the saliva of the Ae. aegypti mosquito. Based on these findings, the scientists developed a test that uses lab-produced versions of the proteins. They found that the test could detect antibodies produced by Aedes mosquito bites without detecting exposure to other types of mosquitoes, such as some Culex and Anopheles species.

The researchers note that the new test could be a valuable tool for public health programs, such as for identifying where mosquito control measures could have the greatest effect in areas with limited access to resources. However, they say that additional development is needed to ensure that the test produces consistent results in different populations, including adults. They note that the test uses reagents that are inexpensive, could be standardized among different labs, and would need only a drop of blood for analysis, making it a promising means to help prevent the spread of dengue and other mosquito-borne diseases.

Reference: 

S. Chea and L. Willen, et al., “Antibodies to Aedes aegypti D7L salivary proteins as a new serological tool to estimate human exposure to Aedes mosquitoes.” Frontiers in Immunology, May 1, 2024. [DOI: 10.3389/fimmu.2024.1368066]

World Neglected Tropical Diseases (NTD) Day offers an opportunity to reflect on recent strides in tropical disease research and the work that remains. NIAID conducts and supports work on a wide variety of diseases—some of which rarely make headlines but cause immense suffering. An example of this is leishmaniasis, a parasitic disease that sickens hundreds of thousands of people each year, mostly in equatorial regions of the globe. In recent years, NIAID has made significant efforts to study the parasite that causes the disease and find new ways to battle it.

The single-celled Leishmania parasite, which is spread by the bites of infected sand flies, can cause a wide array of symptoms. Cutaneous leishmaniasis, the most common form of the disease, is a skin infection.  It manifests as skin ulcers, which may lead to lifelong scarring. The World Health Organization estimates that between 600,000 and 1 million people get cutaneous leishmaniasis each year. A rarer form, mucosal leishmaniasis, attacks the membranes in the nose and mouth and results in painful ulcers, nosebleeds, and related symptoms.

The most severe form is visceral leishmaniasis (also known as kala-azar), in which the Leishmania parasites attack the patient’s internal organs, such as the spleen, liver and bone marrow. This leads to organ dysfunction that is usually fatal if left untreated. Sick patients with visceral leishmaniasis often have fevers, anemia, weight loss and severe fatigue. While a wide array of therapeutics can be used to treat leishmaniasis, not all therapeutics work equally well for different forms of Leishmania parasites.

This diversity of treatment options poses a serious problem for healthcare providers because there are at least 20 species of Leishmania. Studying each individual strain and how they differ from one another will be key in developing therapeutics and preventive measures. NIAID supports a Tropical Medicine Research Center (TMRC) in Sri Lanka, which has conducted epidemiological and molecular studies on locally occurring types of Leishmania, comparing it with strains from India.

Unfortunately, recent research has suggested that different strains of Leishmania are capable of hybridizing with each other, potentially creating offspring resistant to multiple kinds of drugs. How this occurs is largely a mystery, given that Leishmania are single-celled protozoa, and when observed in the lab setting, largely reproduce by cloning themselves. A recent paper from researchers at NIAID explores how their hybridization works. By analyzing the whole genomes of Leishmania parasites, the researchers identified several genes which could allow the parasites to perform meiosis-like gene recombination. In other words, they have the necessary genes to perform a genetic recombination and exchange process similar to sexual reproduction in animals and plants. Understanding how these hybrids arise could be key to understanding how the different strains evolve and change in the future.

To better prepare for these changes, other NIAID-supported researchers are investigating new therapeutics for leishmaniasis and finding better uses for existing therapeutics. In 2021, a team investigating oral antifungal agents for leishmaniasis found that a miltefosine/posaconazole combination worked well together ex vivo, and could be very effective against the most common Leishmania species in Colombia. This year, a different group of scientists found a new therapeutic agent that seems to harm several different species of Leishmania parasites during the part of their life cycle when they are infecting human cells. This agent could be, in theory, both easy and cheap to produce, making it an appealing prospect as a treatment if proven safe and effective in later studies. A third group with NIAID support has been doing early work to optimize a series of imidazopyridine drugs, which pharmacokinetic surveys hint might be effective against visceral Leishmania species. This process attempts to increase the agent’s potency against Leishmania while also making it more tolerable for mammalian cells.  

As with many neglected tropical diseases, researching the parasite’s vector is also key to understanding this disease. The sand flies that carry the Leishmania parasite are tiny—smaller than mosquitoes—and transmit the parasites when they bite people and take a blood meal. Another NIAID TMRC, based in East Africa, conducts research on the ecology and behavior of sand flies, in the hopes of finding ways to control the disease by controlling the flies. In the United States, NIAID supports the Sand Fly Repository at the Walter Reed Army Institute of Research, the largest sand fly repository in the world. Through the repository, researchers can access flies from 15 different colonies for use in their own work.

Leishmaniasis remains challenging to prevent and treat—and like all neglected tropical diseases, its impact on people in affected areas is significant. NIAID’s efforts to study Leishmania and its hosts will continue in the years to come in the hopes of finding new and improved ways to combat this disease

Following a peak in the summer of 2022, new infections in the mpox clade IIb outbreak have decreased, due in part to the rapid availability and uptake of vaccines and other preventive measures. However, mpox remains a health threat, and no treatment has been proven safe and effective for people experiencing mpox disease.

The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, launched the STOMP trial to determine whether the antiviral drug tecovirimat can safely and effectively treat mpox. Tecovirimat, also known as TPOXX, was initially developed and approved by the Food and Drug Administration to treat smallpox—a species of virus closely related to mpox—but the drug’s safety and efficacy as an mpox treatment has not been established. The STOMP trial is a phase 3 study that aims to enroll about 500 people—a process that may require considerable time while mpox burden is low in study countries. NIAID continues to prioritize this study even while case counts are low.

VIDEO: Cyrus Javan of NIAID’s Division of AIDS explains the importance of the STOMP trial (audio description version here):

The STOMP trial was designed to be as inclusive as possible to ensure study results provide information on how tecovirimat works in the diverse populations affected by mpox. The trial is enrolling adults and children of all races and sexes, people with HIV, and pregnant and lactating people across 60 sites in the United States and Mexico, with an option for remote enrollment from other U.S. locations. More sites are expected to open in East Asia and South America.

The mpox virus has been endemic—occurring regularly—in west, central and east Africa since the first case of human mpox disease was identified in 1970. Mpox can cause flu-like symptoms and painful blisters or sores on the skin. People who acquire mpox tend to clear the infection on their own, but the virus can cause serious disease in children, pregnant people, and other people with compromised immune systems, including individuals with advanced HIV disease. Rare but serious complications of mpox include dehydration, bacterial infections, pneumonia, brain inflammation, sepsis, eye infections and death.

Completing the STOMP trial is essential, not only to evaluate a therapeutic option for the current mpox outbreak, but also to guide preparation for future outbreaks and provide evidence that could inform medical practice in historically endemic countries. The STOMP trial is sponsored by NIAID and led by the NIAID-funded Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG).

Beyond STOMP, NIAID is co-sponsoring the PALM007 trial of tecovirimat as treatment for clade I mpox in the Democratic Republic of the Congo (DRC) with the DRC’s National Institute of Biomedical Research. PALM007 is actively enrolling. In addition, NIAID is sponsoring an immunogenicity study of the JYNNEOS preventive vaccine, which has completed enrollment and is expected to report initial results in 2024. More information about these studies, including enrollment in STOMP and PALM007, is available here:

STOMP tecovirimat treatment study 
PALM007 tecovirimat treatment study
JYNNEOS vaccine study