Abstract
Nipah virus (NiV), a highly pathogenic zoonotic paramyxovirus, poses a significant public health threat due to its high mortality rate and potential for human-to-human transmission. The attachment (G) and fusion (F) glycoproteins play pivotal roles in viral entry and host-cell fusion, making them prime targets for therapeutic and vaccine development. Recent advances in structural biology have provided high-resolution insights into the molecular architecture and functional dynamics of these glycoproteins, revealing key epitopes and domains essential for neutralizing antibody responses. The G glycoprotein's head domain and the prefusion F ectodomain have emerged as focal points for vaccine design, with multivalent display strategies showing promise in enhancing immunogenicity and breadth of protection. Structural studies have also informed the development of monoclonal antibodies like m102.4, offering potential post-exposure therapies. Additionally, insights from cryo-electron microscopy and X-ray crystallography have facilitated the design of structure-based inhibitors and next-generation vaccines, including nanoparticle and multi-epitope formulations. This review highlights recent structural findings on the NiV G and F glycoproteins, their implications for therapeutic strategies, and the challenges in developing effective and targeted interventions. A deeper understanding of these glycoproteins will be crucial for advancing NiV-specific therapeutics and vaccines, ultimately enhancing global preparedness against future outbreaks.
Introduction
Nipah virus (NiV) belongs to the genus Henipavirus from the Paramyxoviridae family and like other henipaviruses, the NiV genome is a negative-sense, single-stranded ribonucleic acid (RNA) of over 18 kb, substantially longer than that of other paramyxoviruses [1]. NiV, considered one of the deadliest zoonotic viruses in the world with mortality rates reaching up to 90%, is a highly pathogenic, capable of re-emerging paramyxovirus [2]. Initially identified during the 1998–1999 outbreaks in Malaysia, NiV has since been sporadically detected almost annually in some parts of Asia, particularly in Bangladesh and India [3]. The virus is primarily transmitted from Pteropus fruit bats, which act as reservoir to humans, either directly or through intermediate hosts such as pigs and horses. In Bangladesh, consumption of raw date palm sap contaminated by infected bats has been linked to the annual outbreaks in the country [3]. Meanwhile, person-to-person transmission has also been reported, occurring among family members and caregivers of NiV-infected patients, via close contacts with body fluids such as saliva and urine, as well as respiratory secretions [4, 5].
The genome of NiV encodes six major structural proteins, which include the nucleocapsid (N), phosphoprotein (P), matrix protein (M), fusion glycoprotein (F), attachment glycoprotein (G), and large RNA-dependent RNA polymerase (L). Additionally, the P gene produces three non-structural accessory proteins C, V, and W, which play critical roles in host immune evasion. NiV infection begins with viral entry into host cells—particularly respiratory epithelial cells—mediated by two crucial surface glycoproteins: the host-cell attachment glycoprotein (G) and the membrane fusion glycoprotein (F) [6, 7]. The G glycoprotein of NiV interacts with the tyrosine kinases ephrin-B2 and ephrin-B3, which are highly expressed on endothelial and neuronal cells, enabling efficient host cell targeting. The conserved nature of these receptors across mammalian species underlies NiV's broad species tropism. Experimental studies have demonstrated that NiV can infect various animal models, including guinea pigs, hamsters, ferrets, squirrel monkeys, and African green monkeys [8]. After binding on its receptors, the F protein facilitates fusion between the viral envelope and the host cell membrane, releasing the viral RNA genome into the host cytoplasm. Once inside, the viral RNA is transcribed and replicated by the viral RNA-dependent RNA polymerase, leading to the production of new virions. These virions spread through the bloodstream, either freely or in host leukocyte bound form, entering the endothelium of other organs such as the brain, heart, spleen, and kidneys, and triggering systemic endothelial damage, vasculitis, and encephalitis [6, 7].
NiV interferes with innate immune responses, particularly the JAK-STAT pathway and type I interferon production, facilitating viral spread [9]. The interplay of viral replication and immune evasion mechanisms exacerbates tissue damage, contributing to clinical manifestations such as acute respiratory distress syndrome and febrile encephalitis. While NiV infection may cause mild illness in some mammals, the infection causes severe disease in humans, with symptoms including high-grade fever, mental confusion, headache, and in cases of encephalitis, seizures, which can lead to multi organ dysfunction syndrome and ultimately, mortality [6, 7]. The treatment for NiV infection however, is currently limited to supportive care and syndromic management of acute encephalitis syndromes. Furthermore, the identification of cross-reactive henipavirus antibodies in humans and pteropid bats highlighted the risk of henipavirus spillovers, especially across Africa [10]. NiV spillovers to humans are driven by sporadic local epizootics in pteropid bats, influenced by population turnover, immunity loss, and density-dependent transmission, with broad spatiotemporal viral activity posing a persistent risk wherever human-bat interactions occur [11]. The World Health Organization (WHO) has identified infection by this pathogen as a potential 'Disease X', highlighting its capacity to trigger future outbreaks and pandemics [12]. Despite causing annual outbreaks with high mortality rates, there are currently no approved therapeutics or effective vaccines available for the virus, rendering NiV a major public health. Understanding NiV pathogenesis and host immune responses is essential for developing effective treatments against this emerging threat. This review article provides an in-depth analysis of the structural biology of NiV proteins and their functional roles, highlighting implications for the development of targeted therapeutics and vaccines.
Nipah virus attachment glycoprotein (G)
Structural insights and antibody interactions with the G glycoprotein
The NiV attachment G glycoprotein plays a crucial role in viral entry by mediating attachment to the host cell receptors, ephrin-B2 and ephrin-B3, and is one of the key targets for antiviral therapeutics and vaccine development [13]. High-resolution structures of the G glycoprotein bound to ephrin-B2 and ephrin-B3 have provided us insights into receptor specificity and viral tropism, unraveling the molecular details of NiV pathogenesis and guiding the development of therapeutic and vaccine interventions [13–17]. Nevertheless, the structure of G glycoprotein from NiV is extremely similar to the one from Hendra virus (HeV) – as expected for proteins that share 81% sequence identity, both of which share the same receptors for attachment [16].
A recent cryo-electron microscopy (cryo-EM) data revealed that the NiV G glycoprotein forms a 120-Å-wide and 200-Å-long intertwined homotetrameric structure, with an N-terminal four-helix bundle at the core (the stalk) that is connected to a C-terminal β propeller head domain via an interlaced β sandwich (the neck). The tetramer is stabilized by interprotomer disulfide bonds located in the neck and stalk regions [18]. The structure revealed that it consists of a stalk region for structural stability, a globular β-propeller ectodomain for receptor binding, a transmembrane domain, and an N-terminal cytoplasmic tail involved in viral assembly. The cryo-EM analysis revealed that a single nAH1.3 Fab fragment—previously shown to potently neutralize Malaysia and Bangladesh variants of NiV as well as HeV in vitro—binds to each NiV G head domain, targeting an antigenic site situated on the side of the β-propeller opposite the ephrin-B2 or ephrin-B3 binding site (Fig. 1) [18, 19]. This suggests that nAH1.3 does not interfere with receptor binding, in contrast to the G-specific m102 monoclonal antibodies (mAbs), which interact by mimicking receptor binding [20]. The study further showed that a combination of these two noncompeting mAbs effectively neutralizes both NiV and HeV, working synergistically to reduce the risk of escape mutant development. Using a competition enzyme-linked immunosorbent assay (ELISA), vaccine-elicited antibodies such as nAH1.3 and m102.4 have been shown to target different antigenic sites on the NiV G head domain, demonstrating the diversity of polyclonal antibody responses (Fig. 1). Despite immunization with the full ectodomain tetramer, antibody responses are predominantly focused on the receptor-binding head domain, which is immunodominant and responsible for most serum-neutralizing activity [18].
Structures of the henipavirus G glycoprotein complex with ephrin-B2, m102, and nAH1.3. a) Ephrin-B2 (orange) binds to the NiV G glycoprotein (gray) mainly via its G-H loop (residues 107–125) that is inserted into a central depression in the upper surface of the G glycoprotein β-propeller. F120 of ephrin-B2 is deeply buried within a pocket and interacts with Q559, E579, I580, Y581, and I588 of the G glycoprotein, and is crucial for binding. Similarly, L124 and W125 of ephrin-B2 are essential for NiV-G binding, engaging with a highly hydrophobic surface of NiV-G that includes W504, F458, and L305 (PDB ID: 2VSM) [16]. b) m102.3 Fab binds to the hydrophobic central cavity of the HeV G glycoprotein (gray) via its complementarity determining region (CDR)-3 of the heavy chain (green) in a similar angle and from the same direction as the G-H loop of ephrin-B2. Among the eight residues at the tip of CDR-H3 of m102.3, L105 is surrounded by Q559, A532, N557, Y581, I580, I588, and E579 of HeV-G; P107 interacts with T530, A532, P488, T507, and Q490 of HeV-G; P109 is in proximity to E505, W504, and Y458 of HeV-G; S110 is surrounded by L305 and W504 of HeV-G; and Y122 is enclosed by T241, C240, T218, S239, and E579 of HeV-G (PDB ID: 6CMG) [20]. c) Unlike the ephrin-B2 binding, nAH1.3 binds to a discontinuous epitope at the opposite side of the β-propeller. The interacting nAH1.3 heavy and light chains CDRs (CDRH and CDRL) rendered in green and cyan, respectively (PDB ID: 7TXZ) [18]. The structural visualization was generated using PyMOL (Schrödinger, New York, USA)
Citation: European Journal of Microbiology and Immunology 2025; 10.1556/1886.2025.00017
The m102 mAbs, initially developed against HeV G glycoprotein, have been shown to elicit stronger neutralizing activity against NiV compared to HeV. In a phase 1 clinical trial evaluating the safety, tolerability, pharmacokinetics, and immunogenicity of m102.4, the results demonstrated that m102.4 was well-tolerated and safe, with no severe adverse events or deaths reported. Most importantly, no anti-m102.4 antibodies were detected throughout the study, indicating an absence of an immunogenic response [21]. Structural and binding studies revealed that m102.3 and m102.4 exhibit higher affinity for G glycoprotein from NiV than HeV, likely due to enhanced hydrophobic interactions, owing to the substitution of T507 and Y458 in HeV with the hydrophobic residues valine and phenylalanine in NiV [20]. Nonetheless, given the structural similarity between the two glycoproteins from NiV and HeV, the m102 mAbs bind to the head domain of the glycoproteins in a similar fashion. Interestingly, this binding mode is also similar with ephrin-B2 binding, in which the complementarity determining region (CDR)-3 of the heavy chain of the antibody fragment has been shown to interact with the hydrophobic central cavity of the glycoprotein in a similar angle and direction as the G-H loop of ephrin-B2 (Fig. 1). However, the m102 mAbs binding did not induce apparent conformational changes in the head domain of the glycoprotein, unlike the nAH1.3 mAb, which is conformation-dependent and binds to a discontinuous epitope [18, 20]. This suggests that the m102 mAbs recognize and bind to a relatively stable or rigid epitope within the head domain, likely influencing their neutralization mechanisms or effectiveness. Similarly, neutralizing antibodies (nAbs) targeting the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been shown to prevent viral attachment to the angiotensin-converting enzyme 2 (ACE2) receptor, a mechanism critical for neutralization [22]. Both demonstrate that targeting the primary receptor-binding interface either in NiV or other viral infections is a highly effective strategy for viral neutralization. However, RBD-targeting nAbs may face challenges like viral escape mutations, highlighting the importance of designing broadly neutralizing antibodies or combination therapies [22].
Recent studies revealed that potent henipavirus cross-neutralizing antibodies against HeV and NiV present significant progress in the development of nAbs, addressing the importance of therapeutics against these highly pathogenic pathogens. Several potent cross-neutralizing antibodies, including 1E5, NiV41, and NiV42, have been shown to effectively target key viral proteins [23, 24]. The 1E5 nAb, a Macaca-derived G-specific antibody, binds to the G glycoprotein with receptor-like patterns, demonstrating robust protective efficacy against NiV in female hamsters. Crystallographic analysis revealed that 1E5 has a similar binding pattern to the ephrin-B2/B3 receptor, in which 1E5 binds to the central cavity of the G head domain at an angle almost perpendicular to the plane of the six β-propeller blades, with its CDRs exhibiting high shape complementarity to the central cavity. This precise fit enables extensive residue-level interactions between 1E5 and the G head domain [24]. Furthermore, cryo-EM analysis showed that 1E5 binds to the upper or lower heads, resulting in two distinct dynamic structures of G-tetramer. Nevertheless, it binds preferentially to the upper heads of the G-tetramer due to steric hindrance limiting access to the lower heads near the membrane [24]. This selective binding aligns with its potent neutralizing capacity, as it blocks the RBD most effectively, preventing viral attachment to host cells. Moreover, 1E5 induces dynamic structural changes in the G-tetramer, suggesting that antibody or receptor binding to the upper head may trigger conformational shifts in the lower heads, exposing otherwise inaccessible trigger sites necessary for F-protein activation. Similarly, the NiV41 nAb and its mature form, 41-6, also exhibits cross-reactivity against both HeV and NiV by blocking the receptor-binding interface of the RBD, providing protective efficacy against a lethal NiV challenge in hamsters [23]. Cryo-EM analysis have shown that the 41-6 nAb primarily interacts with the NiV RBD through its heavy chain variable region, particularly the CDRs, forming key interactions such as three hydrogen bonds with S239, I237, and R242 of the RBD, mimicking the natural receptor in its binding strategy, allowing it to effectively block viral attachment to host cells [23]. Its reliance on a conserved epitope highlights the antibody's potential as a broad-spectrum therapeutic candidate for henipavirus infections. Collectively, these findings provide valuable structural insights, paving the way for novel antiviral strategies and offering a promising foundation for future intervention development.
G glycoprotein as a vaccine target
The current absence of effective antiviral therapies highlights the critical importance of developing vaccines against NiV, with immunogen design playing a pivotal role in their success. Several studies have identified the G glycoprotein as a promising vaccine candidate due to its role in viral attachment and entry into host cells, with recent findings showing that this attachment glycoprotein elicits strong neutralizing antibody responses, making it a key target for vaccine development [25–27]. Furthermore, animal studies have shown that vaccines based on the G glycoprotein provide protective immunity, further supporting its potential as an effective immunogen. Three recombinant replication-defective type 5 adenovirus vector vaccines expressing different forms of the NiV G glycoprotein: full-length (Ad5-NiVG), ectodomain (Ad5-NiVGe), and head domain (Ad5-NiVGs) have recently been developed [25]. All three candidates elicited G-specific humoral and cellular immune responses against both NiV and HeV in mice, with Ad5-NiVGe demonstrating the strongest immunogenicity after a single dose. Booster immunization with the Ad5-NiVGe vaccine demonstrated a 7.9-fold increase in G-specific antibody levels, achieving a mean log10 titer of 5.51. Furthermore, the ephrin-B2 receptor competition inhibition assay against the NiV G glycoprotein demonstrated that the half-maximal inhibitory concentration (IC50) titer of Ad5-NiVGe was significantly higher compared to those of Ad5-NiVGs and Ad5-NiVG groups, indicating enhanced nAbs production [25]. Another study using a chimpanzee adenovirus-based vaccine (AdC68-G) carrying recombinant G glycoprotein demonstrated that the AdC68-G vaccine elicited the production of long-lasting nAbs and robust T-cell responses targeting the G protein in mice, achieving the strongest humoral and cellular immune responses after two-dose immunization. The vaccine also provided robust protection against lethal NiV infections in Syrian golden hamsters, in which high levels of G-specific IgG and nAbs were detected even after a single dose, completely neutralizing several NiV strains [27].
A ferritin-based self-assembling nanoparticle displaying the NiV G head domain (NiV G-ferritin) has recently been reported, conferring complete protection against lethal NiV challenge in Syrian golden hamsters, with no detectable viral RNA. Notably, NiV G-ferritin induced significantly faster, broader, and higher serum nAb responses against both NiV and HeV compared to the soluble NiV G head domain [26]. Moreover, a competition binding assay using Bio-Layer Interferometry revealed that the mAbs isolated from mice immunized with NiV G-ferritin targeted four distinct epitopes on the NiV G head domain: the ephrin-B2 receptor binding site (epitope similar to m102), an epitope distal from the receptor binding site (epitope similar to nAH1.3) and two new epitopes [18, 20, 26].
Nucleic acid vaccines offer several advantages, such as rapid development with low-cost manufacture and large-scale deployment, straightforward design, stability at lower temperatures, and cost-effectiveness – key factors for deployment in outbreak-prone regions [28]. A deoxyribonucleic acid (DNA) vaccine expressing the codon-optimized full-length G glycoprotein of NiV has recently been developed [27]. When used as a prime for the AdC68-G vaccine, this combination provided a robust immunization strategy, conferring complete protection against a lethal NiV challenge in hamsters through heterologous immunization approach. Notably, after two doses, the DNA-G prime/AdC68-G boost vaccine group exhibited the highest level of IFN-γ produced by T cells and induced the highest G-specific IgG antibody titers among all tested regimens [27]. These findings highlight the potential of prime-boost vaccination strategies to enhance protective immunity against NiV. Additionally, mRNA vaccines have emerged as promising alternatives to conventional vaccines, particularly in combating SARS-CoV-2. However, their efficacy in providing long-lasting adaptive protection may be limited, as newly emerging variants of SARS-CoV-2 can reduce the effectiveness of currently deployed vaccines [28]. A previous study demonstrated that a single dose of a lipid nanoparticle-based, nucleoside-modified mRNA vaccine encoding the soluble HeV glycoprotein provided protection to up to 70% of Syrian hamsters against a lethal NiV challenge [29]. Notably, the geometric mean copy numbers of NiV N gene RNA were markedly lower in surviving hamsters compared to their non-surviving counterparts, and all survivors were tested positive for anti-NiV IgG and nAbs. These findings underscore the potential of G glycoprotein-based immunogens in inducing strong and sustained immune responses, highlighting their promise as candidates for effective vaccine development against NiV.
Nipah virus fusion glycoprotein (F)
Structural insights of the F glycoprotein and its targeting antibodies
The fusion F glycoprotein from NiV facilitates membrane fusion following the attachment G glycoprotein binding to the ephrin-B2/B3 receptors, enabling the viral RNA to enter the host cell for replication. The F glycoprotein also mediates cell-to-cell membrane fusion via G/F interactions and subsequent F-triggering, leading to syncytium formation, which promotes viral spread while evading immune detection and neutralization [30]. This eventually contributes to the virus's hallmark of vascular damage – vasculitis, and neuronal infection, resulting in severe disease manifestation such as encephalitis. As a key player in NiV pathogenesis, the F glycoprotein is a vital target for therapeutic and vaccine strategies, including mAbs, designed to neutralize its prefusion conformation. High-resolution structures of the F glycoprotein in its prefusion and postfusion states have shed light on the viral pathogenesis [31], thus guiding us in the development of therapeutic and vaccine interventions.
Crystal structure of the prefusion NiV F glycoprotein ectodomain revealed an intricate tree-like hexamer-of-trimers assembly, arranged around a central axis. The hexameric assembly is important in stabilizing the prefusion F conformation before cell-to-cell and virus-to-cell membrane fusion and viral entry, wherein β-sheet S1–S6 is buried in the hexameric interface and, hence, the prefusion F conformation is stabilized [31]. Interestingly, this assembly highly resembles the prefusion structure of the parainfluenza virus 5 (PIV5) F glycoprotein, even though with only 29% sequence identity, suggesting a similar pre- to post-fusion transition among the two viruses [32]. Each F-trimer contains three priming sites—two buried within the hexamer interfaces and one exposed for interaction with the NiV G-ephrin complex (Fig. 2). This interaction triggers conformational changes that disrupt the β-sheet, facilitating the release of fusion peptide and enabling an energetically favorable transition to the post-fusion conformation. This structural shift lowers the energy barrier for F protein activation, ensuring an efficient fusion process [31]. A recent study showed that the F glycoprotein from Langya virus (LayV), a recently emerging henipavirus, shares common structural features with the F glycoprotein from NiV and HeV, despite with low overall sequence identity. Furthermore, the prefusion NiV F glycroprotein elicits stronger nAb responses than its postfusion form, making it a promising target for vaccine development [33]. Stabilizing this prefusion state through specific mutations such as L104C/I114C, L172F, and S191P that are located near the fusion peptide helps preserve its immunogenic structure and prevents premature conformational changes, which may guide in henipavirus vaccine antigen design [33, 34]. Interestingly, a similar trimerization motif was also used to stabilize the prefusion F glycoprotein of PIV5 [32, 35].
Structures of the NiV F glycoprotein in its prefusion state and complex with mAb66. a) The prefusion F glycoprotein adopts a tree-like shape with three copies of the glycoprotein arranged around a central axis. The fusion peptide (residues 110–122), within the N-terminal segment, is colored in magenta, with the cathepsin-L cleavage site (R109–L110), which is easily accessible for cleavage, is labelled (PDB ID: 5EVM) [31]. b) Crystal structure of the NiV F glycoprotein (gray) complex with mAb66. The heavy and light chains are shown in green and cyan, respectively. The structure shows that each mAb66 molecule binds to an epitope near the apex of a single prefusion F protomer in the trimer. The interaction is predominantly mediated by CDR L3 of mAb66 that targets the epitope within domain III of the NiV F glycoprotein, primarily interacting with residues K60–K80 (shown in yellow). I95A on CDR L3, the most buried residue in the complex, is shown. Other interacting residues are Y92, Y93, and Y95C (PDB ID: 6T3F) [36]. The structural visualization was generated using PyMOL (Schrödinger, New York, USA)
Citation: European Journal of Microbiology and Immunology 2025; 10.1556/1886.2025.00017
Structural biology has revealed a conserved epitope at the membrane-distal portion—a region that undergoes substantial refolding during host-cell entry—of the prefusion trimeric NiV F glycoprotein, suggesting a potential target for therapeutic as well as vaccine development. This epitope is the key target for mAb66, a NiV F-specific mAb as well as mAb36, a HeV F-specific mAb, suggesting the membrane-distal region of the prefusion NiV F glycoprotein as a site of vulnerability on the NiV surface [36]. Crystallographic analysis demonstrated that the NiV F glycoprotein, when bound to mAb66, retains an uncleaved, prefusion conformation. This structure closely resembles the native prefusion state of the F glycoprotein, with a root-mean-square deviation (RMSD) of 0.7 Å [36]. The minimal structural deviation suggests that mAb66 binding does not induce significant conformational changes, highlighting its potential mechanism of action in neutralizing while stabilizing the prefusion form. This structural conservation is crucial, as prefusion F glycoproteins are often key targets for neutralization and vaccine design, emphasizing the importance of mAb66 in therapeutic and prophylactic strategies against NiV. mAb66 targets the epitope within domain III (DIII) of the NiV F glycoprotein, primarily interacting with residues K60–K80 (Fig. 2). The binding interface is dominated by its light chain, with CDR L3 playing a key role by extending a 13-amino acid loop into a shallow depression on the NiV F glycoprotein surface. Key interactions include several hydrogen bonds and hydrophobic interactions formed with the NiV F glycoprotein residues N64, V65, S66, N67, S69, Q70, E77, and K80 [36]. These structural insights highlight mAb66's precise epitope recognition and further support its potential as a therapeutic against NiV. Similarly, a more recent cryo-EM analysis of the vaccination-derived neutralizing mAb92 reveals a similar binding to the DIII domain at the membrane-distal apex of the NiV F glycoprotein, a well-established site of vulnerability [36, 37]. Prophylactic administration of mAb92 in hamsters has been shown to provide complete protection against NiV infection, demonstrating its strong in vivo efficacy [37]. Furthermore, cross-reactive antibodies such as 1F5, 12B2, and 5B3 that neutralize both NiV and HeV have been shown to recognize distinct, prefusion-specific epitope on DIII, hence locking F glycoprotein in its prefusion state [38, 39].
Targeting F glycoprotein for vaccine development
Several studies have highlighted the crucial role of the prefusion NiV F glycoprotein in the vaccine development. Using the prefusion NiV ectodomain F glycoprotein as a model, multiple stabilizing mutations including 46 disulfide bonds, 16 cavity-filling mutations, 16 helix-disrupting mutations, and various structural modifications were engineered in the NiV Malaysia fusion protein sequence. These optimizations led to the development of a stabilized pre-F/G protein (prefusion F trimer covalently linked to three G monomers), which elicited the strongest neutralizing responses and targeted diverse antigenic sites [33]. Notably, this design was also effective for other henipaviruses, supporting a prototype pathogen approach for pandemic preparedness. Interestingly, the post-F trimer immunogen did not elicit neutralizing activity, highlighting the importance of prefusion structural stabilization in designing effective subunit vaccines. Prefusion-stabilized F proteins often expose key neutralizing epitopes that are lost or altered in the postfusion state, as seen in other viral vaccine developments like respiratory syncytial virus (RSV) and SARS-CoV-2 [40–43]. Consequently, a chimeric F and G glycoprotein antigen, delivered by mRNA has been developed as a candidate for NiV vaccine [44]. Mice immunized with pre-F or pre-F/G mRNA generated strong F-specific antibody responses, independent of mRNA dose [44]. This aligns with the findings from the previous protein-based immunization study [33], reinforcing that mRNA constructs incorporating prefusion-stabilized F glycoprotein are more effective at inducing F-specific antibodies than those expressing postfusion F glycoprotein, further highlighting the critical role of stabilizing the prefusion conformation.
Furthermore, efforts to develop NiV vaccines have explored various structural and antigenic optimizations of the F and G glycoproteins, incorporating both glycoproteins in different vaccine platforms. A recent study evaluated eight structure-based mammalian-expressed recombinant NiV F and G glycoproteins in different structural forms, including monomeric, multimeric, and chimeric subunit vaccines. Multimeric structures, administered as bivalent and trivalent formulations elicited the strongest nAb responses, particularly potent when combined with the oil-in-water nano-emulsion adjuvant AddaS03 [45]. Previously, AS03-adjuvanted DNA vaccines have been shown to induce robust humoral and cellular immune response against SARS-CoV-2 [46]. Using the attenuated rabies virus strain SRV9, two recombinant viruses, rSRV9-NiV-F and rSRV9-NiV-G, which displayed the NiV F and G glycoproteins, respectively were constructed and following three immunizations in mice, the ISA 201 VG-adjuvanted recombinant vaccines, either administered alone or in combination, were shown to induce the antigen-specific cellular and Th1/Th2-biased humoral immune responses such as TNF-α, IL-4, IL-6, and IL-10. In addition, the results further showed that the specific serum IgG titers in the immunized group were higher at 14 days post-immunization than in the control group with the ratio of IgG2a/IgG1 produced after the final immunization was greater than 1 [47]. In a different study, live-attenuated vaccine vectors based on recombinant vesicular stomatitis viruses (rVSV) expressing NiV G or F glycoproteins have been shown to induce strong humoral immune responses with neutralizing activities in Syrian hamsters, even with a single dose [48], highlighting the potential of rSRV9- and rVSV-based live-attenuated vaccines in eliciting strong immune responses for NiV outbreak control and vaccination strategies.
Similarly, another study evaluated recombinant F and G glycoproteins in a different structural form, incorporating both F and G glycoproteins from NiV and RSV [49]. Given that both viruses rely on F and G glycoproteins for cellular entry, vaccine development has predominantly targeted both glycoproteins. In a mouse model, the NiV combinatorial vaccine elicited a strong immune response capable of neutralizing both pseudotyped NiV and an escape mutant (E77K and K80T) resistant to two known F-specific antibodies, mAb66 and 5B3 [36, 39, 49]. Interestingly, while the RSV combinatorial vaccine induced nAb responses to both F and G glycoproteins, its neutralization capacity was inferior than the vaccine designed with F glycoprotein alone, likely due to about 30% lower F glycoprotein content [49]. This is expected, as most of the recent vaccine development against RSV utilized F glycoprotein as the main immunodominant target [41, 50, 51]. Together, these studies highlight the importance of incorporating both F and G glycoproteins into NiV vaccine strategies. Whether through recombinant subunits, multimeric formulations, or cross-virus designs, optimizing antigen conformation and immune targeting may enhance vaccine efficacy and extend protection.
Challenges and future directions
The development of a NiV vaccine is associated with scientific, logistical, and economic challenges, due to its unique epidemiology, pathogenesis, and zoonotic nature, despite the urgent need to address this high-mortality pathogen. One of the primary scientific challenges is the incomplete understanding of the pathogenesis of NiV and its associated immune evasion strategies. For instance, the virus's ability to infect a wide range of host cells, including endothelial, epithelial, and neuronal cells with broad species tropism [8], complicates the identification of effective therapeutics and vaccine targets. Many recent studies have highlighted the role of the NiV G and F glycoproteins in viral attachment and host cell entry, emphasizing their potential as vaccine targets. However, mutations in these proteins as well as their host cell receptors [13, 52, 53] and the virus's ability to evade host immune responses through non-structural proteins C, V, and W [54, 55] pose significant challenges for vaccine design.
Furthermore, the sporadic and unpredictable nature of NiV outbreaks, primarily occurring in South and Southeast Asia—such as the 2014 outbreak in the Philippines, multiple outbreaks in Bangladesh between 2001 and 2015, and multiple outbreaks in Kerala, India since 2018 [3]—pose a challenge for conducting large-scale clinical trials and obtaining sufficient data on vaccine efficacy. For instance, during the Kerala outbreaks, the swift response by health authorities contained the virus before a vaccine trial could even be initiated [56]. This unpredictability, coupled with the relatively limited market for a NiV vaccine, discourages pharmaceutical companies from investing in its development. Unlike globally prevalent diseases such as the recent COVID-19 pandemic, NiV lacks the commercial incentive necessary for large-scale vaccine production. Despite being a WHO priority pathogen, NiV remains a serious epidemic threat due to its high mortality rate, potential for human-to-human transmission, and the widespread presence of Pteropus bats. However, there has been no systematic effort to improve patient care for NiV infection, leading to consistently poor clinical outcomes and sometimes death. Current management relies solely on supportive care, with treatment options limited to the compassionate use of unapproved antiviral drugs such as ribavirin and remdesivir [57].
Despite these challenges, recent advancements in vaccine technology provide renewed optimism for NiV prevention. The success of mRNA vaccines during the COVID-19 pandemic has paved the way for their application in emerging infectious diseases, including NiV [44]. The company Moderna, for instance, has incorporated NiV into its mRNA vaccine pipeline (mRNA-1215), capitalizing on the platform's adaptability and rapid development capabilities [58]. Beyond the well-known mRNA technology, innovative approaches such as nanoparticle-based vaccines and multi-epitope formulations are also showing promise. A recent study demonstrated the efficacy of a novel nanoparticle vaccine designed to protect against both NiV and HeV, highlighting the potential for a broad-spectrum henipavirus vaccine [26, 29]. The identification of the NiV and HeV G head domain as the primary target of nAbs highlights the importance of focusing antibody responses on this vulnerable domain [18]. By presenting the G head antigen in an ordered, multivalent array to enhance immunogenicity, a mosaic vaccine displaying multiple henipavirus head domains can be created, which potentially induce broad and potent nAb responses. Furthermore, viral vector-based vaccines are being evaluated for their ability to elicit strong and durable immune responses against NiV [59, 60]. These advancements underscore the growing momentum in NiV vaccine research, despite the logistical and commercial challenges.
Looking ahead, NiV vaccine development must focus on exploring universal vaccine strategies that elicit broad protective immune responses to ensure cross-protection, given that NiV has multiple strains with genetic variations between outbreaks. For example, NiV-Malaysia and NiV-Bangladesh strains exhibit differences in pathogenicity and transmissibility, which could influence vaccine efficacy. Future research should focus on developing broadly protective vaccines that target conserved regions of NiV proteins so that cross-protection between strains could be achieved, while passive immunization with mAbs like m102.4 could provide interim protection during outbreaks [18, 21]. Advances in structural biology, including X-ray crystallography and cryo-EM, as well as artificial intelligence- and machine learning-driven vaccine design are accelerating the development of more effective vaccine candidates by providing detailed insights into the molecular structure of NiV proteins. Finally, coordinated global efforts, including funding for NiV research, strengthening surveillance systems, and enhancing international collaborations, are crucial. International partnerships, such as those facilitated by the Coalition for Epidemic Preparedness Innovations (CEPI), are critical for funding and coordinating vaccine development efforts [61]. While the path to an effective vaccine remains complex, sustained investment, technological innovation, and a commitment to global health security offer hope for preventing future outbreaks of this deadly zoonotic virus.
Conclusion
The structural biology of the NiV G and F glycoproteins has provided critical insights into the mechanisms of viral entry, host-cell fusion, and immune evasion, offering a foundation for the development of targeted therapeutics and vaccines. High-resolution structural studies have elucidated the conformational dynamics of these glycoproteins, revealing key epitopes and domains, such as the G head domain, that are central to nAb responses. These discoveries have guided the design of novel vaccine candidates, which aim to enhance immunogenicity and induce broad-spectrum protection against NiV and related henipaviruses. Furthermore, the identification of vulnerable sites on the G and F glycoproteins has opened pathways for the development of mAbs such as m102.4, providing promising strategies for post-exposure therapies. Advances in protein engineering, such as improving the stability and scalability of antigen production, have further accelerated progress toward viable vaccine candidates. As the threat of zoonotic spillover events continues to grow, the integration of structural biology with innovative vaccine technologies and therapeutic approaches will be essential in combating emerging pathogens, especially NiV with broad species tropism. Continued and coordinated global research efforts into the structures and functions of NiV glycoproteins will not only deepen our understanding of the biology of henipavirus but also pave the way for effective interventions to prevent future outbreaks and protect global health.
Funding
This work was supported by the Kementerian Pendidikan Tinggi Malaysia, Fundamental Research Grant Scheme (Project No: FRGS/1/2024/SKK12/USM/03/1) and Universiti Sains Malaysia, Short-Term Grant (Project No: R501-LR-RND002-0000000996-0000).
Institutional review board statement
Not applicable.
Informed consent statement
Not applicable.
Data availability statement
All data relevant to this review is included in the text and references.
Conflicts of Interest
The author has no Conflicts of Interest.
Acknowledgements
Not applicable.
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