Three decades of #discovery: An overview of #Hendra virus, the original #Henipavirus

 

Abstract

Hendra virus (HeV) emerged in Australia in 1994, causing a devastating outbreak among horses in Brisbane with spread to humans, resulting in one death. This nonsegmented, negative-stranded RNA virus belongs to the family Paramyxoviridae and represents the first zoonotic paramyxovirus isolated from bats. Flying foxes (genus Pteropus) serve as the natural reservoir, with all four mainland Australian species carrying antibodies with no apparent disease. HeV initiates infection by binding ephrin-B2 receptors on vascular endothelial cells, driving characteristic pathology involving vasculitis, thrombosis, and neurological complications. Horses are amplifying hosts, shedding virus abundantly in respiratory secretions and posing transmission risks to humans during invasive procedures. To date, seven confirmed human infections have been documented, with a 57% fatality rate, presenting as severe respiratory disease or progressive encephalitis. Two genetic variants are now recognized: the original HeV genotype 1 and the emerging HeV genotype 2, identified in limited equine cases. Recent surveillance of bat roosts revealed substantial viral diversity, with peak shedding occurring during winter—coinciding with equine spillover peaks. Prevention integrates multiple strategies: the licensed equine vaccine Equivac which provides One Health protection for both horses and human contacts; biosecurity measures including proper PPE; and habitat restoration to reduce nutritional stress in bat populations. Emerging therapeutics include monoclonal antibodies, with m102.4 showing cross-protective activity against both HeV and the closely related Nipah virus. No licensed human vaccines currently exist, though candidates are in development. Future prevention strategies increasingly recognize the importance of Indigenous-led conservation approaches alongside biomedical interventions. This review will focus on the history of HeV, virus replication and diversity, epidemiology, clinical manifestations, diagnosis, treatment, prevention, as well as ecological and interdisciplinary countermeasures.

Author summary

Hendra virus (HeV) was first detected in 1994, with two outbreaks occurring within 2 months of that year. One was the index outbreak in the Brisbane suburb of Hendra, and the other was retrospectively diagnosed in the following year. This review examines the discoveries that have been made in the 30 years since its discovery.

Source: 

Link: https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014138

____

Functional and #antigenic constraints on the #Nipah virus #fusion protein

 

Abstract

Nipah virus is a highly pathogenic virus in the family Paramyxoviridae that utilizes two distinct surface glycoproteins to infect cells. The receptor-binding protein (RBP) binds host receptors whereas the fusion protein (F) merges viral and host membranes. Here, we use nonreplicative pseudoviruses to safely measure the effects of all F single amino acid residue mutations on its cell entry function and neutralization by monoclonal antibodies. We compare mutational tolerance in F with previous experimental measurements for RBP and show that F is much more functionally constrained than the RBP. We also identify mutationally intolerant sites on the F trimer surface and core that are critical for proper function, and describe mutations that are candidates for stabilizing F in the prefusion conformation for vaccine design. We quantify how F mutations affect neutralization by six monoclonal antibodies, and show that the magnitude of mutational effects on neutralization varies among antibodies. Our measurements of mutational effects on Nipah virus F predict the ability of the antibodies to neutralize the related Hendra virus. Overall, our work defines the functional and antigenic constraints on the F protein from an important zoonotic virus.

Source: 

Link: https://www.pnas.org/doi/abs/10.1073/pnas.2529505123?af=R

____

Integrating #Prevention and #Response at the Crossroads of #Henipavirus #Preparedness, Hendra@30 Conference, 2024

 

Abstract

Diseases caused by henipaviruses, exemplified by Hendra virus and Nipah virus, pose a serious risk to public health because of their epidemic potential and high case-fatality rates and the paucity of medical countermeasures to mitigate them. In December 2024, a group of 150 scientists from 16 countries convened in Geelong, Victoria, Australia, to mark the 30th anniversary of the discovery of Hendra virus. The Hendra@30 conference built upon its predecessor conference held in 2019 in Singapore, Nipah@20, by expanding its program across broader disciplines and integrating sessions on human sociology and disease ecology into the main scientific discussions. We describe key highlights from Hendra@30 and reflect on 4 key elements that have advanced henipavirus research and medical countermeasures research and development. We propose that integrating bat ecology into henipavirus research blueprints will enable development of ecologic countermeasures that prevent spillover and will complement existing preparedness and response efforts with evidence-based prevention strategies.

Source: 

Link: https://wwwnc.cdc.gov/eid/article/32/1/25-0979_article

____

Safety and immunogenicity of a #Nipah virus #vaccine (HeV-sG-V) in adults: a single-centre, randomised, observer-blind, placebo-controlled, phase 1 study

 

Summary

Background

First discovered in 1999 in Malaysia, Nipah virus (NiV) causes yearly outbreaks throughout south and southeast Asia with associated mortality rates of 40–75%. Due to the structural and sequence similarities between the NiV and Hendra virus (HeV) attachment G glycoproteins, and the extensive extant evidence of the ability of a recombinant soluble glycoprotein G (HeV-sG) to provide heterologous cross-protective immunity when used as vaccine (HeV-sG-V), this study aimed to evaluate HeV-sG-V for safety, tolerability, and immunogenicity against NiV.

Methods

We conducted a phase 1, single-centre, randomised, observer-blind, placebo-controlled study. Eligible participants were aged 18–49 years, healthy, and not pregnant; participants were ineligible if they were immunocompromised, had received blood products within 6 months of enrolment, had potential exposure to NiV or HeV, or had known allergies to components of the vaccine. Participants were randomly assigned in a 5:1 ratio to receive either one or two doses of the vaccine candidate (at 10 μg for the first cohort; 30 μg at days 1 and either days 8 or 29 for cohort 2; and 100 μg with the same timing for cohort 3) or placebo. The primary endpoints were solicited and unsolicited adverse events, clinically significant laboratory test result abnormalities, medically attended adverse events, and serious adverse events. Secondary endpoints were serum IgG binding via ELISA and neutralising antibody responses against prototypical NiV Bangladesh (NiVB) and NiV Malaysia (NiVM) reporter viruses.

Findings

Between Feb 24, 2020, and Oct 6, 2021, 268 participants were screened, and 192 were enrolled. 173 (90%) participants met the per-protocol criteria. Mild-to-moderate injection site pain was the most commonly reported adverse event. No serious adverse events, hospitalisations, or deaths were reported. The immune response to HeV-sG-V was dose-dependent; a single administration was not sufficiently immunogenic, whereas two administrations were immunogenic, with the highest response rates observed among vaccinees that received two administrations of the 100 μg HeV-sG-V 28 days apart (neutralising antibody geometric mean titres rose dramatically 7 days after the second investigational product dose, reaching 1485·6 (990·5–2228·1) and 2581·9 (147·1–3194·2) for NiVB and NiVM, respectively).

Interpretation

All three doses and regimens of HeV-sG-V had a tolerable risk profile and were able to induce an immune response. The induction of antibodies within 1 month of vaccination, along with the persistence afforded by two dosages, suggests the vaccine candidate has potential for reactive outbreak control and preventive use.

Funding

Coalition for Epidemic Preparedness Innovations (CEPI).

Source: 

Link: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01390-X/abstract?rss=yes

____

Safety and immunogenicity of a #Nipah virus #vaccine (HeV-sG-V) in adults: a single-centre, randomised, observer-blind, placebo-controlled, phase 1 study

 

Summary

Background

First discovered in 1999 in Malaysia, Nipah virus (NiV) causes yearly outbreaks throughout south and southeast Asia with associated mortality rates of 40–75%. Due to the structural and sequence similarities between the NiV and Hendra virus (HeV) attachment G glycoproteins, and the extensive extant evidence of the ability of a recombinant soluble glycoprotein G (HeV-sG) to provide heterologous cross-protective immunity when used as vaccine (HeV-sG-V), this study aimed to evaluate HeV-sG-V for safety, tolerability, and immunogenicity against NiV.

Methods

We conducted a phase 1, single-centre, randomised, observer-blind, placebo-controlled study. Eligible participants were aged 18–49 years, healthy, and not pregnant; participants were ineligible if they were immunocompromised, had received blood products within 6 months of enrolment, had potential exposure to NiV or HeV, or had known allergies to components of the vaccine. Participants were randomly assigned in a 5:1 ratio to receive either one or two doses of the vaccine candidate (at 10 μg for the first cohort; 30 μg at days 1 and either days 8 or 29 for cohort 2; and 100 μg with the same timing for cohort 3) or placebo. The primary endpoints were solicited and unsolicited adverse events, clinically significant laboratory test result abnormalities, medically attended adverse events, and serious adverse events. Secondary endpoints were serum IgG binding via ELISA and neutralising antibody responses against prototypical NiV Bangladesh (NiVB) and NiV Malaysia (NiVM) reporter viruses.

Findings

Between Feb 24, 2020, and Oct 6, 2021, 268 participants were screened, and 192 were enrolled. 173 (90%) participants met the per-protocol criteria. Mild-to-moderate injection site pain was the most commonly reported adverse event. No serious adverse events, hospitalisations, or deaths were reported. The immune response to HeV-sG-V was dose-dependent; a single administration was not sufficiently immunogenic, whereas two administrations were immunogenic, with the highest response rates observed among vaccinees that received two administrations of the 100 μg HeV-sG-V 28 days apart (neutralising antibody geometric mean titres rose dramatically 7 days after the second investigational product dose, reaching 1485·6 (990·5–2228·1) and 2581·9 (147·1–3194·2) for NiVB and NiVM, respectively).

Interpretation

All three doses and regimens of HeV-sG-V had a tolerable risk profile and were able to induce an immune response. The induction of antibodies within 1 month of vaccination, along with the persistence afforded by two dosages, suggests the vaccine candidate has potential for reactive outbreak control and preventive use.

Funding

Coalition for Epidemic Preparedness Innovations (CEPI).

Source: The Lancet, https://www.sciencedirect.com/science/article/abs/pii/S014067362501390X?dgcid=rss_sd_all

____

The intracellular #virus-host #interface of #henipaviruses

ABSTRACT

The Henipavirus genus comprises five viral species, of which the prototype members, Hendra virus (HeV) and Nipah virus (NiV), are reported to infect humans. In humans and other spill-over hosts, HeV/NiV can cause severe respiratory and/or encephalitic disease, with mortality rates exceeding 50%; currently, there are no approved human vaccines and only limited therapeutic options. As members of the family Paramyxoviridae, henipaviruses have six “core” structural proteins and typically three additional accessory proteins that are expressed from the P gene. Several of these proteins are multifunctional, with roles in forming intracellular interfaces with the host (in particular, M, P, V, W, and C proteins), to modulate processes including antiviral responses, supporting viral replication. Understanding the molecular basis of these interfaces and their functions is critical to delineate the mechanisms of pathogenesis and may inform new strategies to combat infection and disease. Recent research has significantly advanced the understanding of the functions and interactions of multifunctional intracellular henipavirus proteins, including revealing novel roles in subverting the nucleolar DNA damage response (DDR) and modulating the functions of 14-3-3 proteins. This review will discuss the intracellular virus-host interface, focusing on the M, P, V, W, and C proteins of HeV/NiV, with a focus on recently identified functions and interactions.

Source: Journal of Virology, https://journals.asm.org/doi/full/10.1128/jvi.00770-25?af=R

____

Laboratory #Diagnosis of #Hendra and #Nipah: Two Emerging Zoonotic Diseases with One Health Significance

Abstract

Hendra virus (HeV) and Nipah virus (NiV) are two highly pathogenic RNA viruses with zoonotic potential, which can cause severe diseases with high mortality rates (50–100%) in humans and animals. Given this context, these viruses are classified as Biosafety Level 4 (BSL-4) pathogens, thus limiting research studies. Despite the high case fatalities, there are currently no human vaccines available for either virus, owing in part to the limitations in research and hesitancy in funding. In the absence of widespread vaccination, diagnostic tests are crucial for the rapid identification of cases and disease surveillance. This review synthesizes current knowledge on the epidemiology, transmission dynamics, and pathogenesis of NiV and HeV to contextualize a detailed assessment of the available diagnostic tools. We examined molecular and serological assays, including RT-PCR, ELISA, and LAMP, highlighting sample sources, detection windows, and performance. Diagnostic considerations across human and animal hosts are discussed, with emphasis on outbreak applicability and field-readiness, given the need for diagnostic assays that are suitable for use in low-income areas. Further development of diagnostic assays, including isothermal amplification tests and other next-generation approaches, is recommended to fill the gap in rapid, point-of-care diagnostics.

Source: Viruses, https://www.mdpi.com/1999-4915/17/7/1003

____

A #nanobody-based #therapeutic targeting #Nipah virus limits viral escape

Abstract

Nipah virus (NiV) and Hendra virus (HeV) are highly pathogenic henipaviruses without approved human vaccines or therapies. Here, we report on a highly potent bispecific therapeutic that combines an anti-fusion glycoprotein nanobody with an anti-receptor-binding glycoprotein (RBP) antibody to deliver a dual-targeting biologic that is resistant to viral escape. We show that the nanobody, DS90, engages a unique, conserved site within the fusion glycoprotein of NiV and HeV and provides neutralization and complete protection from NiV disease. Bispecific engineering of DS90 with the anti-RBP monoclonal antibody m102.4 results in neutralization, elimination of viral escape and superior protection from NiV disease compared to leading monovalent approaches. These findings carry implications for the development of cross-neutralizing immunotherapies that limit the emergence of henipaviral escape mutants.

Source: Nature Structural and Molecular Biology, https://www.nature.com/articles/s41594-025-01598-2

____

Infectome analysis of #bat #kidneys from #Yunnan province, #China, reveals novel #henipaviruses related to #Hendra and #Nipah viruses and prevalent bacterial and eukaryotic microbes

Abstract

Bats are natural reservoirs for a wide range of microorganisms, including many notable zoonotic pathogens. However, the composition of the infectome (i.e., the collection of viral, bacterial and eukaryotic microorganisms) within bat kidneys remains poorly understood. To address this gap, we performed meta-transcriptomic sequencing on kidney tissues from 142 bats, spanning ten species sampled at five locations in Yunnan province, China. This analysis identified 22 viral species, including 20 novel viruses, two of which represented newly discovered henipaviruses closely related to the highly pathogenic Hendra and Nipah viruses. These henipaviruses were found in the kidneys of bats inhabiting an orchard near villages, raising concerns about potential fruit contamination via bat urine and transmission risks to livestock or humans. Additionally, we identified a novel protozoan parasite, tentatively named Klossiella yunnanensis, along with two highly abundant bacterial species, one of which is a newly discovered species—Flavobacterium yunnanensis. These findings broaden our understanding of the bat kidney infectome, underscore critical zoonotic threats, and highlight the need for comprehensive, full-spectrum microbial analyses of previously understudied organs to better assess spillover risks from bat populations.

Author summary

Although extensive investigations have been conducted on the bat virome, most studies have focused on fecal samples, leaving other tissues, such as the kidney, largely unexplored. However, the kidney can harbor important zoonotic pathogens, including the highly pathogenic Hendra and Nipah viruses, and genomic evidence of henipaviruses in bats from China has remained undocumented. In this study, we report the first detection of two novel henipavirus genomes from bat kidneys in China, one of which is the closest known relative of pathogenic henipaviruses identified to date. Beyond virome analysis, our study also examined highly prevalent bacteria and eukaryotic microbes, identifying those potentially relevant to bat infections. Overall, these findings provide valuable insights into the infectome of the bat kidney, highlighting the need for broader microbial surveillance beyond the gastrointestinal tract.

Source: PLoS Pathogens, https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1013235

____

Genetic Diversity and #Geographic #Spread of #Henipaviruses

Abstract

Henipaviruses, such as Hendra and Nipah viruses, are major zoonotic pathogens that cause encephalitis and respiratory infections in humans and animals. The recent emergence of Langya virus in China highlights the need to understand henipavirus host diversity and geographic spread to prevent future outbreaks. Our analysis of the National Center for Biotechnology Information Virus and VIRION databases revealed ≈1,117 henipavirus sequences and 142 complete genomes. Bats (64.7%) and shrews (11.7%) dominated the host species record, and the genera Pteropus and Crocidura contained key henipavirus hosts in Asia, Australia, and Africa. Henipaviruses found in the Eidolon bat genus exhibited the highest within-host genetic distance. Phylogenetic analysis revealed batborne and rodent- or shrew-derived henipaviruses diverged ≈11,000 years ago and the first known lineage originating in Eidolon genus bats ≈9,900 years ago. Pathogenic henipaviruses diverged from their ancestors 2,800–1,200 years ago. Including atypical hosts and regions in future investigations is necessary to control future outbreaks.

Source: US Centers for Disease Control and Prevention, https://wwwnc.cdc.gov/eid/article/31/3/24-1134_article

____