COVID-19 Respiratory Treatment Effective in Encephalitis Study

Molnupiravir Reduced Viral Brain Disease in Mice

NIAID research into finding broad uses for existing drug treatments has a potential new success story: Molnupiravir, a relatively new antiviral developed to treat respiratory diseases – such as COVID-19 – reduced brain swelling in study mice infected with a pathogen dangerous to children, La Crosse virus (LACV).

The new study, from NIAID scientists and colleagues at the University of North Carolina and Emory University, is published in PLOS Pathogens. LACV, which is spread by mosquitos, can cause brain inflammation in children. LACV was first isolated in the early 1960s near La Crosse, Wisconsin. Since then, LACV encephalitis cases have been found in more than 20 states, mostly in the basins of the Mississippi and Ohio rivers and throughout the Appalachian Mountains.

Most LACV infections in people are mild, but the virus sometimes – particularly in children – enters the brain, infects neurons and causes disease that can result in learning and memory difficulties, paralysis, seizures and death. Between 30 and 90 cases of severe LACV – those that affect the central nervous system (CNS) – are reported each year, though the Centers for Disease Control and Prevention believes many mild cases occur but are not diagnosed.

The study used a new strategy to test three antiviral drugs – N4-Hydroxycytidine (NHC, the active metabolite of the prodrug molnupiravir), ribavirin and favipiravir– for treatment against LACV infection. The scientists chose LACV because it broadly represents several RNA viruses that cause disease in the CNS, including Jamestown Canyon and Cache Valley viruses – which also were part of the study – and rabies, polio, West Nile, Nipah and several other viruses not part of the study.

The three antiviral drugs were tested in a cell culture system to examine an antiviral strategy called lethal mutagenesis. This approach increases the number of errors in the viral genome that RNA viruses make when they replicate, weakening the resulting viruses. By incorporating the drug, more errors are induced in the viral genome and more weakened viruses emerge, providing the host an opportunity to recover.

Ribavirin and favipiravir used in cell treatment studies did not produce potent enough results to justify testing in mice. The NHC prodrug molnupiravir, however, was used in two different mouse study models. Oral treatment with molnupiravir reduced brain disease in mice by 32% when LACV infection was started by an injection in the abdomen, and by 23% when the infection was started in the nose, offering easy access to the brain.

Also noteworthy: The researchers tested NHC against LACV and found it effective in the cell and mouse models, as well as in cell models using Jamestown Canyon and Cache Valley viruses. This showed that the drug treatment strategy could be successful against viruses related to LACV and supports the idea that this strategy could be used against a broader group of encephalitic RNA viruses.

The researchers say more study is needed to see how these drugs counter RNA viruses, particularly to determine whether injecting the drug directly into cerebrospinal fluid would provide better results and possibly reduce adverse side effects.

Reference:

D Ojha et al. N⁴-Hydroxycytidine/Molnupiravir Inhibits RNA Virus-Induced Encephalitis by Producing Less Fit Mutated Viruses. PLOS Pathogens DOI: 10.1371/journal.ppat.1012574 (2024).

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).

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.                     

NIAID scientists and colleagues are one step closer to developing a safe and effective therapy against alphaviruses with the identification of SKT05, a monoclonal antibody (mAb) derived from macaques vaccinated with virus-like particles (VLPs) representing three encephalitic alphaviruses.

Spread by mosquitos, alphaviruses primarily affect people in one of two ways: causing severe neurological impairment such as encephalitis (brain swelling) or crippling muscle pain similar to arthritis. Western, eastern and Venezuelan equine encephalitis viruses (EEV) are examples of the former, while chikungunya and Ross River viruses are examples of the latter.

Building on studies from the past decade, scientists in NIAID’s Vaccine Research Center and colleagues knew that macaques produce dozens of different protective antibodies when experimentally vaccinated against the EEVs. In a new study published in Cell, the research team identified 109 mAbs in macaques immunized with the experimental western, eastern, and Venezuelan EEV VLP vaccine. All antibodies were individually tested for binding and neutralization against the three EEVs, with the best ones also assessed against arthritogenic alphaviruses not included in the vaccine. Collaborators included scientists from NIAID’s Laboratory of Viral Diseases, USAMRIID’s Virology Division, and Columbia University.

Their work identified SKT05 as the most broadly reactive antibody – remarkably, it also provided protection against both types of alphaviruses, those that cause encephalitis and those that cause arthritic-like disease. High-resolution structural studies further revealed that the way SKT05 binds to alphaviruses could make it resistant to surface changes that can occur in viruses – which means the mAb is likely to have lasting effectiveness.

Further studies are planned to investigate potential clinical development of SKT05. They aim to better define how SKT05 interacts with viruses and whether it can confer protective benefits against additional alphaviruses.

References:
M Sutton et al. Vaccine elicitation and structural basis for antibody protection against alphaviruses. Cell DOI: https://doi.org/10.1016/j.cell.2023.05.019 (2023).

EE Coates, et al. Safety and immunogenicity of a trivalent virus-like particle vaccine against western, eastern, and Venezuelan equine encephalitis viruses: a phase 1, open-label, dose-escalation, randomised clinical trial. Lancet Infectious Diseases (2022).

SY Ko, et al. A virus-like particle vaccine prevents equine encephalitis virus infection in nonhuman primates. Science Translational Medicine (2019).