A NIAID research team has developed an additional nonhuman primate study model for Crimean-Congo hemorrhagic fever (CCHF), providing an alternative for development of critically needed vaccines and therapeutics. They hope the effort, described in a new study published in npj Vaccines, will lead to a widely available replicating RNA-based vaccine that they are testing against CCHF. In some outbreaks CCHF has had a case fatality rate up to 40%.

Cynomolgus macaques (CM), which typically develop mild to moderate CCHF disease, are the preferred model available to study how the virus causes infection and disease in people. During the COVID-19 pandemic, however, CMs were prioritized for other research, and scientists at NIAID’s Rocky Mountain Laboratories (RML) sought to develop an alternative model using rhesus macaques (RM) to continue promising pre-clinical work on a CCHF vaccine.

CCHF virus primarily is spread by Hyalomma ticks throughout Africa, the Middle East, Asia and parts of Europe. The disease, first described in 1944, infects up to 15,000 people annually, according to the World Health Organization. About 1 in 8 of those who are infected develop severe disease, which leads to about 500 deaths each year. A vaccine developed in 1974 in Bulgaria is available in some places but has not been approved by the U.S. Food and Drug Administration or the European Medicines Agency. The World Health Organization lists CCHF virus as a priority pathogen for development of vaccines.

The RML group in Hamilton, Montana, has worked with University of Washington and HDT Bio collaborators in Seattle for about 6 years on developing and evaluating the replicating RNA vaccine platform for SARS-CoV-2 and CCHFV. A collaboration between NIAID, HDT Bio and the University of Texas Medical Branch was recently awarded more than $80 million dollars in funding by the Department of Defense to advance the replicating RNA vaccine for CCHFV and Nipah virus into human clinical trials.

The researchers decided to try and adapt their CM study model to infect RMs. CMs and RMs are the two most commonly used research animals among the 22 different macaque species. RMs infected with CCHFV developed mild-to-moderate disease, similar to the CM model and consistent with mild-to-moderate disease in humans. 

The scientists then used a prime-boost schedule to show that the experimental vaccine provided six infected RMs with a protective immune response that controlled CCHF virus. The results are consistent with their findings using CMs and support continued advancement of this vaccine into human trials.

Future work with the vaccine is planned to try and pinpoint how it triggers immune responses in the animals and provides protection from CCHF virus infection. They also plan to explore which animal models will most accurately predict how the vaccine might act in people.

References:

D Hawman, et al. A replicating RNA vaccine confers protection in a rhesus macaque model of Crimean-Congo hemorrhagic fever. npj Vaccines DOI: 10.1038/s41541-024-00887-z (2024).

S Leventhal, et al. Replicating RNA vaccination elicits an unexpected immune response that efficiently protects mice against lethal Crimean-Congo hemorrhagic fever virus challenge. eBio Medicine DOI: https://doi.org/10.1016/j.ebiom.2022.104188 (2022).

E Haddock, et al. A cynomolgus macaque model for Crimean–Congo haemorrhagic fever. Nature Microbiology DOI: 10.1038/s41564-018-0141-7 (2018).

NIAID Team Explores Metabolism in Determining Infection Severity

Some pathogens can cause infectious disease by following several different paths into a host, and disease severity can vary depending on the infection route used. This raises research questions about how the route that a pathogen uses influences infection. Francisella tularensis, the bacterium that causes the disease tularemia – also called rabbit fever – can infect a person in many ways:

•    In the lungs by breathing
•    In the skin from a bite or handling infected animals
•    In the eye by airborne exposure
•    In the gut by consuming contaminated food or water

Consistently, the most severe tularemia cases involve lung infections, sometimes leading to death. Fortunately, antibiotics are available to treat tularemia – though early treatment can be challenging because the disease is difficult to diagnose. There are about 200 cases of tularemia reported in people each year in the United States.

Curious to understand why cases of tularemia in the lung – in contrast to those that start in the skin – can be so severe, NIAID scientists compared mice infected with the same F. tularensis dose in the nasal passage (to establish disease in the lung) to mice infected in the skin. They then compared tissue in diseased areas for immune and metabolic responses to find out if the mice were fighting the infection, how, and whether tweaking the responses can influence the outcome.

Their findings, published in the science journal PLOS One, show that the bacterium is “exquisitely adept” at manipulation, delaying the immune response in the lungs to create an environment for greater infection and replication. For mice infected in the skin, symptoms – such as swollen glands – appeared faster, thus triggering timely immune protection.

The research team, at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana, thinks the findings could extend beyond F. tularensis to other pathogens. For example, Yersinia pestis, the bacterium that causes plague, also is transmitted by numerous routes that manifest most severely in the lungs.

“Our hypothesis is that the programmed anti-inflammatory and pro-resolving nature of the lung is exploited by pathogens, resulting in more severe and lethal disease,” study senior investigator Catharine Bosio, Ph.D., explained. “The metabolic environment in the skin is prone to mounting a faster inflammatory response, resulting in better control early in infection.”

By understanding the metabolic role in infection, researchers can better understand and predict which therapeutic approaches could be successful. For example, in the study the team hypothesized that manipulating the lung to be more inflammatory would help control F. tularensis early on.

“However, it had the opposite effect,” Dr. Bosio said. “Now we know that promoting that type of metabolic response may not be a good intervention and may actually harm the host.”

In future studies the group plans to identify how different components of pathogens like F. tularensis affect host metabolic responses and response to infection.

Reference:
F Jessop et al. Route of Francisella tularensis infection informs spatiotemporal metabolic reprogramming and inflammation in mice. PLOS One. DOI: 10.1371/journal.pone.0293450.