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

NIAID Approach Highlighted in New Journal Supplement

A special Oct. 19 supplement to the Journal of Infectious Diseases contains nine articles intended as a summary of a National Institute of Allergy and Infectious Diseases (NIAID)-hosted pandemic preparedness workshop that featured scientific experts on viral families of pandemic concern. Sponsored by NIAID, the supplement features articles on 10 viral families with high pandemic potential known to infect people. Concluding the supplement is a commentary from NIAID staff on the “road ahead.”

Many of the viruses in these 10 families have no vaccines or treatments licensed or in advanced development for use in people. Rather than facing the enormous task of developing medical countermeasures for individual viruses, one strategy is to use the “prototype pathogen” approach – which was shown to be successful with the rapid development of vaccines during the SARS-CoV-2 pandemic. This approach characterizes “representative” viruses within viral families so that knowledge gained, including medical countermeasures strategies, can be quickly adapted to other viruses in the same family.

The NIAID workshop on pandemic preparedness had several goals, including to describe the prototype pathogen approach, select prototype pathogens for future study, and identify knowledge gaps within the selected viral families. Prototype viruses being considered for study within the 10 families of pandemic concern are listed below. The ranges of these prototype viruses span the globe.

• Arenaviridae: These viruses are capable of spillover from animals to people and can lead to severe viral hemorrhagic fevers. Lassa virus and Junín virus were selected as prototypes.
• Bunyavirales, includes the Hantaviridae, Nairoviridae, Peribunyaviridae and Phenuivirdae families, among others. Viruses in this family are spread by several different arthropods (mosquitoes, ticks, midges) or rodents and can cause mild to severe symptoms and death.
  • Phenuivirdae prototypes are Rift Valley fever virus, severe fever with thrombocytopenia syndrome virus (SFTSV), Toscana virus, and Punta Toro virus.
  • Nairoviridae prototypes are Crimean-Congo hemorrhagic fever virus and Hazara virus.
  • Hantaviridae prototypes are Hantaan virus, Sin Nombre virus, and Andes virus.
  • Peribunyaviridae prototypes are La Crosse virus, Oropouche virus, and Cache Valley virus.
• Paramyxoviridae: This family includes highly transmissible viruses that are well known (measles, mumps) and more recently emerged (Nipah virus). Viruses proposed as prototypes are Cedar virus, canine distemper virus, human parainfluenza virus 1/3, and Menangle virus.
• Flaviviridae: These viruses, primarily transmitted by mosquitoes and ticks, are responsible for hundreds of millions of human infections worldwide each year. Viruses proposed as prototypes are West Nile virus, dengue serotype 2 virus, and tick-borne encephalitis virus.
• Togaviridae: Most of these viruses are spread by mosquitoes and cause disease in animals that then can spillover to people. Viruses proposed as prototypes are Chikungunya virus and Venezuelan equine encephalitis virus.
• Picornaviridae: This family includes common human viruses such as polio and hepatitis A, but new technology has led scientists to recently discover more than 300 new viruses. The four selected prototypes are enteroviruses A71 and D68, human rhinovirus C virus, and echovirus 29.
• Filoviridae: Filoviruses can cause severe hemorrhagic fever in people and have been causative agents of recent outbreaks. Ebola virus is the prototype virus.

Experts with careers built on knowledge of each virus family are leading research teams across the U.S., studying how viruses infect cells, which models of disease most closely mimic human disease, and how to use new technology when designing vaccines and treatments. NIAID leaders are anticipating that the prototype approach will create “opportunities for investigators from multiple fields or with specialized technical expertise to collaborate in new ways.”

Reference: Pandemic Preparedness at NIAID: Prototype Pathogen Approach to Accelerate Medical Countermeasures—Vaccines and Monoclonal Antibodies. Journal of Infectious Diseases (2023).

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

Mosquito-borne diseases include some of the most important human diseases worldwide, such as malaria and dengue. With global temperatures increasing because of climate change, mosquitoes and the pathogens they transmit are expanding their range. For example, the Centers for Disease Control and Prevention recently reported a number of malaria and dengue cases transmitted within the United States in Texas and Florida. Therefore, it has become more urgent to understand the interactions between climate, mosquitoes, and the pathogens mosquitoes transmit to humans.

The National Institutes of Health (NIH) Climate Change and Health Initiative is a collaborative effort across NIH Institutes and Centers to reduce the public health impact of climate change. As part of the Initiative’s Scholars Program, NIH brings climate and health scientists from outside the U.S. federal government to work with NIH staff to share knowledge and help build expertise in the scientific domains outlined in the Initiative’s Strategic Framework. 

Luis Chaves, Ph.D., is a 2023 Scholar working with NIAID. Dr. Chaves is an associate professor in the Department of Environmental and Occupational Health in the School of Public Health-Bloomington, Indiana University, and was previously an associate scientist at the Instituto Gorgas in Panama. His research focuses on understanding the impacts of environmental change on the ecology of insect vectors and the diseases they transmit. Over the last 20 years, he has combined field studies and modeling approaches, both statistical and mathematical, to address how insect vectors respond to changes in the environment and how these changes impact the transmission of diseases, such as malaria and dengue. NIAID spoke with Dr. Chaves about his work. 

Note: responses to the questions have been edited for clarity and brevity.

In what ways have you seen climate changes impact vectors and disease transmission?
There is very strong evidence that climate change has affected vector-borne diseases. This includes mosquito-borne diseases, like malaria and dengue, but also other diseases like leishmaniasis, which is transmitted by sandflies. Changes in temperature and rainfall affect the spread of disease vectors and impact their breeding behavior. For example, there is evidence of the impact of El Niño weather events on malaria transmission. Higher temperatures and more rainfall make a more suitable habitat for mosquito breeding, causing an increase in disease transmission. In other areas, El Niño weather patterns are associated with droughts, which may reduce disease transmission but cause food shortages. These weather patterns have been known and studied before, but climate change has generated more extreme conditions resulting in more extreme weather events. So, we can see that there is robust evidence that climate change is having a massive impact on human health and wellbeing.

What sparked your interest in examining how socio-economic conditions impact vector-borne disease transmission and control? 
I remember the first encounter I had with Chagas disease was visiting an uncle who lived in a rural setting. I was told not to visit a neighbor’s house because they had Chagas disease. There were lots of discussions about how his neighbor got Chagas because his home was made from mud, which is why kissing bugs, the vectors of Chagas disease, got inside. That was the first time I observed an increased prevalence of diseases in places with social exclusion and poverty. More generally, infectious diseases cannot be put out of the social and economic context where they emerge and are transmitted. If you have people with substandard housing, is that a choice, or a constraint because of the underlying socio-economic inequities? It is impossible to learn about the ecology of disease transmission without understanding that the ecology of transmission is not only ecological and environmental but also social. 

What are the advantages of using mathematical modeling to study vector-borne diseases?
Mathematical and quantitative modeling have been incredibly useful to expand the ways in which the relations shaping disease patterns can be studied This ability to understand interactions advances our capacity to engage in more relational science, where factors aren’t understood as fixed and independent forces, but as dynamic and interdependent. Relations between variables can’t be described by a fixed constant proportion, but by nonlinearities that can be easily grasped by machine learning algorithms and other data science tools.  Computers have made it easier to collect, process and analyze larger datasets. The automation of data assimilation using pipelines that integrate different data sources and algorithms can lead to robust “boosted” predictions about where and when to expect the transmission of some vector-borne diseases. Mathematical models also show how the stability of natural systems can collapse following small changes in the environment, and that has clear implications about why we need to worry as climate change continues its current course.   

What limitations do you see in the use of data science?
Data science poses ethical dilemmas, because not everyone mining freely available data is likely to do so with altruistic aims, nor is it clear how communities and individuals could benefit from the data they generated when someone profits from that or how communities, and even individuals, are protected from potential misuse.  I also think there is a need to always consider the context in which data are generated, as this approximation allows us to see what else is out there. The more nuanced our knowledge is, the more likely we can generate actionable knowledge that improves human health and wellbeing. That’s why it’s so important to include information on how data is collected (metadata) and how to use it.  The nuances don’t come from just looking at the data. They require experience, observation, and immersion in nature to create a clearer picture of vector-borne disease transmission. 

How has your work influenced vector control and prevention activities?
My research at the Costa Rican Institute for Research and Training in Nutrition and Health’s (INCIENSA) and the Costa Rican Vector Control Program was centered around developing insect vector maps and training people working in vector control about the impacts of climate change. This also involved evaluating past policies and their impact on parasitic and neglected tropical diseases. For example, comparing how different public health strategies like Mass Drug Administration versus vector control might impact malaria transmission and elimination. These activities increased the awareness about the importance of climate change, particularly among vector control inspectors, with whom I interacted closely on their work.  My research has also supported a focus on Mass Drug Administration as a major tool to eliminate malaria in Costa Rica.

What impact do you hope your research will have?
I’ll be happy if my research can serve, at least, the communities where the research is being done. As long as my research can lead to diminishing transmission of infectious pathogens or reducing the populations of vectors, then I will be happy. If that eventually leads to the elimination of those diseases, I’ll be even happier. I want to be able to provide resources for the local communities, so they can understand health problems or health threats within their local environment. For example, one of the nicest experiences I have had as a researcher was in Panama, where at least three or four studies on leishmaniasis have been done in the same community. In that community, we have seen how people come up with their own solutions, partly based on what they learn from when you did research in that location. You see how they modify their houses and look for changes in incidence of new cases. When they tell you that cases of leishmaniasis have gone down, that newborns and children aren´t getting the disease, that is very fulfilling.