A messenger RNA (mRNA) vaccine designed to prevent human cytomegalovirus (CMV) elicited long-lasting CMV-specific responses from several types of immune cells, outperforming a previous vaccine concept in multiple measures in a NIAID-supported laboratory study. The findings were published in the Journal of Infectious Diseases.

CMV has been present in much of the global population for centuries. Most people with CMV experience no symptoms and are unaware that they are living with the virus, but CMV is dangerous for people with compromised immune systems and for babies. It is the most common infectious cause of birth defects in the United States. When babies acquire CMV through birth it is called congenital CMV, and it affects about 1 out of every 200 children. Of babies with CMV, about 1 in 5 will experience long-term health effects, including hearing or vision loss, developmental and motor delays, seizures, or microcephaly (a small head). Infants born before 30 weeks’ gestational age or with low weight for age that have CMV may be susceptible to additional complications.

There is no preventive vaccine for CMV, and treatment options are limited. An effective CMV vaccine could present needless suffering for millions of babies, and research has been progressing for decades. A recent vaccine candidate was designed to use a laboratory-developed protein from CMV’s surface called glycoprotein B (gB)—known to assist CMV in fusing with and entering human cells—to safely teach the immune system how to respond to CMV exposure without causing disease. The vaccine provided about 50% protection from CMV in Phase 2 trials, but that effect was insufficient for the concept to advance to large efficacy studies. 

A different, mRNA-based, vaccine is now in a Phase 3 efficacy study in cisgender women with no existing CMV infection. The vaccine was designed to instruct cells to produce the gB protein while also producing a combination of five other glycoproteins on CMV’s surface, which like gB are involved in human cell entry.

To better understand how the mRNA vaccine might perform in comparison to gB-based vaccine, researchers examined the immune cells present in blood samples provided by people when they participated in previous studies of each vaccine. The study team performed several assays—laboratory tests—and made the following key observations:

• The mRNA vaccine generated higher levels of antibodies to the five glycoproteins unique to the that vaccine in the form of immunoglobulin G (IgG) antibodies, which are associated with long-term immunity.
• The mRNA vaccine generated more potent signals that the immune system was prepared to deploy antibodies to surround and neutralize—destroy—CMV.
• The gB-based vaccine generated higher levels of IgG antibodies to gB.
• Immune responses to both vaccines were greater in study participants with no existing CMV, but the vaccines still amplified immune system activity in people already living with the virus. 

The authors concluded that the mRNA vaccine concept showed promise for better performance than its predecessor in ongoing clinical studies, of which results are expected soon. These results also highlight an opportunity to reformulate the mRNA vaccine to increase the amount of gB proteins it generates, which in tun could improve gB-specific immune responses.

This work was led by Weill Cornell Medicine in collaboration with the Duke Human Vaccine Institute at Duke University Medical Center, Vanderbilt University, Cincinnati Children’s Hospital Medical Center, and Moderna, Inc. in Cambridge, Mass. Moderna co-funded the research with NIAID.

Reference: X Hu, et al. Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine. Journal of Infectious Diseases DOI: 10.1093/infdis/jiad593 (2024). 

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

NIAID-funded researchers working in Peru have signaled concern about the deaths of birds and marine mammals from highly pathogenic avian influenza (HPAI) that has been spreading globally. Historically, South America’s coastal ecosystems and poultry industry have been spared from HPAI outbreaks.

“These viruses are rapidly accruing mutations, including mutations of concern, that warrant further examination and highlight an urgent need for active local surveillance to manage outbreaks and limit spillover into other species, including humans,” the researchers say.

Their study documenting the outbreak was published Sept. 7 in Nature Communications. It was led by Mariana Leguia of Pontificia Universidad Católica del Perú in Peru and EpiCenter for Emerging Infectious Disease Intelligence (Centers for Research in Emerging Infectious Diseases [CREID] Network). Other project collaborators included the National Forest and Wildlife Service of Peru; Wildlife Conservation Society; One Health Institute; and National Center for Biotechnology Information (NCBI) at the U.S. National Institutes of Health (NIH). 

The study identifies flu type A/H5N1 lineage 2.3.4.4b, which in late 2021 spread from Europe to North America and then, in 2022, to South America. Along the way it has devastated wild birds and poultry farms. The scientists say their analyses supports a single introduction of 2.3.4.4b into Peru from North America during October 2022, presumably through the movements of migratory wild birds. The virus then infected local seabirds that share habitats with marine mammals.

Another recently published NIAID-funded study documents the evolution of the H5 virus over two decades from Europe to North America, prior to its spread to South America. The study—also in Nature Communications—involves St. Jude Children’s Research Hospital, part of NIAID’s Centers of Excellence for Influenza Research and Response (CEIRR) network.

In November 2022, scientists began documenting animal deaths along the Peruvian coast, including dolphins, sea lions, sanderlings, pelicans, and cormorants. The study—made possible by researchers quickly establishing new partnerships—identified HPAI A/H5N1 virus in the animals and analyzed how it had mutated since moving into South America. 

They singled out one mutation to monitor: “… we are particularly concerned by the presence of PB2 D701N in 2 sea lion samples, and in a human case reported in Chile, as this mutation has been specifically linked to mammalian host adaptation and enhanced transmission.”

The project involved scientists obtaining 69 samples from 28 animals; they identified influenza A in 12 animals: a dolphin, four individual sea lions, one sample pooled from five sea lions, and six sea birds. The researchers then confirmed HPAI A/H5N1 in 11 of the 12 samples (one sample was too deteriorated to determine the specific type of influenza A). The researchers say there is concern of HPAI spreading to endangered species, such as the Andean condor, Humboldt penguin, and marine otter. 

“An even larger concern,” they say, “is the possibility of spillover into human populations.” They say public awareness campaigns are needed to inform people about the presence of HPAI influenza and to avoid contact with animals that appear ill. The study notes that the outbreak in Peru occurred along the Pacific coast and during the summer, when many people go to the beach.

“It is not uncommon,” the study states, “for beachgoers (and their pets) to interact with sick and disoriented animals without any knowledge of the risks, or for free-roaming dogs in rural and semi-rural coastal areas to encounter sick or dead animals as they scavenge for food.”

In particular, they note, workers responsible for cleaning animal carcasses need additional training in the proper use of personal protective equipment and on waste management and disposal. “People in contact with sick and dead animals infected with HPAI A/H5N1 are at risk of infection,” the researchers say, “and human cases could be missed in the absence of active and obvious human-to-human transmission.”

These studies were funded in part by NIAID awards U01AI151814, 75N93021C00014, 75N93021C00016, HHSN272201400006C, and R01AI150745; and by the NIH's National Library of Medicine's Intramural Research Program.

References:

M Leguia, et al. Highly pathogenic avian influenza A (H5N1) in marine mammals and seabirds in Peru. Nature Communications DOI: 10.1038/s41467-023-41182-0 (2023). 

A Kandeil, et al. Rapid evolution of A(H5N1) influenza viruses after intercontinental spread to North America. Nature Communications DOI: 10.1038/s41467-023-38415-7 (2023).

SARS-CoV-2 evolves three times faster in white-tailed deer than in people, making NIAID-funded scientists at The Ohio State University and colleagues ask whether deer are an important reservoir for emerging virus variants—similar to how influenza virus evolves and spreads from pigs.

The Ohio State project, published August 28 in Nature Communications, examined infection rate, persistence, spread and evolution of SARS-CoV-2 in deer throughout Ohio. Scientists collected more than 1,500 deer nasal samples in 83 of the state’s 88 counties and, from antibody results, estimated that 23.5% of the animals had been infected with SARS-CoV-2. Their work also identified more than 30 instances where the virus had spread from people into deer between November 2021 and March 2022. For the next eight months, they then documented the virus further spreading among deer, noting that the alpha and delta virus variants evolved in deer three times faster than in people.

Their study found no concerning evolutionary changes—the virus efficiently transmitted among deer without significant changes. But their study also noted that “SARS-CoV-2 viruses have transmitted in white-tailed deer populations for a relatively short duration, and the risk of future changes may have serious consequences for humans and livestock.”

The work has drawn attention from NIAID viral ecology colleagues at Rocky Mountain Laboratories (RML) in Hamilton, Montana, who approached the Ohio State team to collaborate on new investigations. They are hoping to answer questions about how the virus survives in nature and transmits and evolves among non-human hosts such as deer, mink, cats and dogs. Those answers could help predict future SARS-CoV-2 evolution. The RML scientists plan to expand the Ohio State work by assessing how different SARS-CoV-2 variants respond in deer cells and whether new variants are emerging.

“SARS-CoV-2 is currently not considered an important risk for North American livestock,” the Ohio State study states. “But the continued spread of the virus in white-tailed deer, humans, and other hosts could open new pathways for SARS-CoV-2 evolution that we are only beginning to uncover.”

Reference:

D McBride et al. Accelerated evolution of SARS-CoV-2 in free-ranging white-tailed deer. Nature Communications DOI: 10.1038/s41467-023-40706-y (2023).