Hantavirus infection future investigational therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Basir Gill, M.B.B.S, M.D.[2] Seyedmahdi Pahlavani, M.D. [3]
Overview
There are no FDA-approved antiviral therapies or vaccines for hantavirus infection in Europe or the Americas.[1] Multiple investigational therapies are under active preclinical and early clinical development, including antiviral small molecules, monoclonal antibodies, polyclonal antibody products, host-directed repurposed drugs, RNA interference strategies, and vaccine candidates spanning DNA, mRNA, viral vector, and virus-like particle (VLP) platforms.[2][3] Randomized clinical trials are warranted to evaluate the efficacy of candidate antivirals, neutralizing antibodies, and drugs such as icatibant.[1]
Future and Investigational Therapies
Investigational Antiviral Small Molecules
Favipiravir (T-705): A broad-spectrum antiviral agent that inhibits RNA-dependent RNA polymerase. In vitro, T-705 potently inhibited both Sin Nombre virus (SNV) and Andes virus (ANDV), with an IC90 estimated at ≤5 μg/mL (≤31.8 μM) for both viruses. In the lethal ANDV hamster model, daily oral T-705 at 50 or 100 mg/kg significantly improved survival rates when treatment was initiated prior to the onset of viremia. T-705 also demonstrates potent activity against Hantaan virus (HTNV) in vitro, and combination with ribavirin enhances efficacy. No human clinical trials for hantavirus have been completed. Evaluation of early post-exposure treatment with favipiravir (before viremia) may be considered for close household contacts of ANDV cases, high-risk laboratory exposures, or super-spreader events.[4][5][1]
Icatibant acetate: A bradykinin B2 receptor antagonist (FDA-approved for hereditary angioedema) that has been used in several patients with severe hemorrhagic fever with renal syndrome (HFRS). Randomized clinical trials are warranted to evaluate its efficacy in hantavirus infection.[1]
Vandetanib: A small molecule antagonist of vascular endothelial growth factor receptor 2 (VEGFR-2). ANDV infection causes upregulation of VEGF and downregulation of VE-cadherin, leading to increased vascular permeability. Vandetanib has been evaluated in the Syrian hamster model of hantavirus pulmonary syndrome (HPS).[6]
Lactoferrin: Bovine lactoferrin inhibits hantavirus adsorption to cells in vitro (ED50 of 39 μg/mL with pretreatment). Combined lactoferrin pretreatment and ribavirin post-infection treatment demonstrated synergistic anti-hantaviral effects in vitro. In vivo, double administration of lactoferrin at 160 mg/kg improved survival rates to 94% in suckling mice infected with hantavirus.[7][8]
Repurposed Host-Directed Drugs
Statins (HMG-CoA reductase inhibitors): Cholesterol 25-hydroxylase (CH25H) and its product 25-hydroxycholesterol (25HC) inhibit HTNV infection by lowering HMG-CoA reductase, which inhibits cholesterol biosynthesis. Cholesterol-lowering drugs such as HMGCR-targeting statins have demonstrated potent hantavirus inhibitory effects in vitro, suggesting the possibility of repurposing FDA-approved statins for treating hantavirus infection.[9]
Dihydropyridine calcium channel blockers: Benidipine hydrochloride inhibits the entry of hantaviruses in vitro. An array of calcium channel inhibitors, including cilnidipine, felodipine, amlodipine, manidipine, nicardipine, and nisoldipine, exhibit similar antiviral properties against both HFRS- and HPS-causing hantaviruses using pseudotyped virus systems.[10]
Urolithin B: A host-directed small molecule compound that inhibits ANDV infection and restores cellular metabolism with minimal changes in host transcription, identified through pharmacotranscriptomic screening in human primary lung endothelial cells and stem cell-derived models.[11]
Investigational Monoclonal and Polyclonal Antibodies
SAB-163: A fully human, quadrivalent polyclonal antibody produced from transchromosomic bovines vaccinated with DNA plasmids encoding the major glycoproteins of ANDV, SNV, HTNV, and PUUV. SAB-163 has potent neutralizing antibodies (PRNT50 >200,000) against all four targeted hantaviruses and cross-neutralization against several heterotypic hantaviruses. At a dosage of 10 mg/kg, SAB-163 protected all hamsters from lethal ANDV disease when administered 1 day before or 5 days after exposure. SAB-163 has a half-life of 10–15 days in hamsters and is investigational new drug (IND)-enabled for phase 1 clinical trials.[12]
ADI-42898: A human monoclonal antibody recognizing a quaternary Gn/Gc epitope on the hantavirus glycoprotein spike. ADI-42898 blocked cell entry of seven HCPS- and HFRS-associated hantaviruses and protected Syrian hamsters and bank voles against lethal ANDV and PUUV challenge with a single dose. An optimized variant with improved potency against Andes virus has been engineered.[13][14]
MIB22 and JL16: Two recombinant human monoclonal antibodies isolated from an HCPS-recovered individual. Both potently neutralized ANDV and protected 100% of Syrian hamsters from lethal ANDV challenge when administered as monotherapy or in combination post-exposure.[15]
SNV-42: A highly neutralizing human monoclonal antibody derived from a memory B cell of an SNV-recovered individual. SNV-42 targets the Gn subcomponent of the tetrameric (Gn-Gc) glycoprotein assembly and interferes with both receptor recognition and membrane fusion during host-cell entry. Crystallographic analysis at 1.8 Å resolution revealed high conservation with germline-encoded gene segments, suggesting that germline-encoded antibodies can inhibit SNV.[16]
AH100: A human-origin monoclonal antibody with specific neutralization against HTNV. Crystallographic analysis revealed that AH100 targets epitopes on domain A and the b-ribbon and E3-like domain of the HTNV Gn head, representing a unique epitope site distinct from previously reported monoclonal antibodies. Sequence analysis of all reported natural isolates indicated the absence of mutations in epitope residues.[17]
RNA Interference (RNAi)
Small interfering RNA (siRNA) targeting specific gene segments (S, M, or L) of hantavirus has demonstrated efficacy in enhancing viral RNA clearance through the RNA interference process in Vero E6 cells and human lung microvascular endothelial cells. However, the use of siRNAs faces challenges due to their low biological stability and limited in vivo targeting ability.[2]
Investigational Vaccines
Currently Licensed (Asia Only)
Inactivated HTNV vaccine (Hantavax) has been used since 1990 in South Korea
Bivalent inactivated HTNV/SEOV vaccines have been used in China for more than 10 years
These vaccines elicit neutralizing antibody titers that may last 2–3 years with three-dose schedules, but clear evidence of vaccine efficacy is absent; a 10-year retrospective cohort study failed to demonstrate the protective effect of Hantavax in Korea[1][3][18]
DNA Vaccines (Clinical Trials)
HTNV/PUUV bivalent DNA vaccine: In a phase 2a randomized, double-blind trial (n=120), a combined HTNV/PUUV DNA vaccine delivered by intramuscular electroporation was safe and immunogenic. Detectable neutralizing antibody titers were achieved in approximately 78% of volunteers using a three-dose scheme with 4-week intervals.[19][18]
ANDV DNA vaccine: In a phase 1, double-blind, dose-escalation trial (NCT03682107, n=48), an ANDV DNA vaccine delivered via needle-free jet injection was safe and induced a robust, durable immune response. Cohorts receiving 4 mg doses or 4-dose schedules achieved seropositivity of at least 80% by day 197, sustained through day 337. This was the first-in-human candidate HPS vaccine trial.[20]
Pan-hantavirus DNA vaccine: Rabbits immunized with a plasmid mix targeting SNV, ANDV, PUUV, and HTNV developed neutralizing antibodies against all four viruses, demonstrating feasibility of a pan-hantavirus vaccine approach.[21]
mRNA and Next-Generation Nucleic Acid Vaccines
A prefusion-stabilized HTNV glycoprotein mRNA-LNP vaccine elicited robust neutralizing antibodies by strongly activating germinal centers and protected mice against high-dose HTNV challenge. When used as a booster in mice primed with inactivated vaccine, only the prefusion-stabilized glycoprotein mRNA-LNP vaccine raised titers to the level achieved by its own full primary vaccination course, demonstrating superiority in recalling memory B cells induced by suboptimal inactivated vaccines.[22]
Viral Vector Vaccines
Vesicular stomatitis virus (VSV) pseudotypes expressing hantavirus glycoproteins have been explored for both HFRS and HCPS. A single dose of rVSVΔG/ANDVGPC provided sterilizing immunity when administered 28 days before lethal ANDV challenge in the Syrian hamster model, with cross-reactive antibody responses observed against both ANDV and SNV.[18]
Non-replicating adenovirus (Ad) vaccines encoding Gn, Gc, or nucleoprotein (NP) individually or in combination confer protection in the Syrian hamster model for ANDV infection, with some constructs providing sterile immunity despite a lack of neutralizing antibodies.[18]
Summary of Investigational Therapies
| Agent | Class | Target Virus(es) | Development Stage | Key Findings |
|---|---|---|---|---|
| Favipiravir (T-705) | Small molecule antiviral (RdRp inhibitor) | ANDV, SNV, HTNV | Preclinical (animal models) | IC90 ≤5 μg/mL; protective pre-viremia in hamsters; synergistic with ribavirin against HTNV |
| Icatibant | Bradykinin B2 receptor antagonist | HFRS-causing hantaviruses | Case reports; RCTs warranted | Used in severe HFRS patients; FDA-approved for HAE |
| Vandetanib | VEGFR-2 antagonist | ANDV | Preclinical (hamster model) | Targets VEGF-mediated vascular permeability |
| Lactoferrin | Natural glycoprotein (entry inhibitor) | SEOV, HTNV | Preclinical (in vitro/in vivo) | Synergistic with ribavirin; 94% survival in mice at 160 mg/kg |
| Statins | HMG-CoA reductase inhibitors | HTNV | In vitro | Inhibit hantavirus via cholesterol metabolism reprogramming |
| Calcium channel blockers (benidipine) | Dihydropyridine CCBs (entry inhibitors) | HFRS- and HPS-causing hantaviruses | In vitro (pseudotyped virus) | Multiple FDA-approved CCBs show antiviral properties |
| Urolithin B | Host-directed small molecule | ANDV | In vitro (human primary cells) | Inhibits ANDV; restores cellular metabolism |
| SAB-163 | Fully human quadrivalent polyclonal Ab | ANDV, SNV, HTNV, PUUV (pan-hantavirus) | IND-enabled; phase 1 pending | PRNT50 >200,000; 100% protection in hamsters; t1/2 10–15 days |
| ADI-42898 | Human monoclonal Ab (Gn/Gc quaternary epitope) | 7 HCPS/HFRS hantaviruses (pan-hantavirus) | Preclinical; optimized variant engineered | Single-dose protection in hamsters and bank voles |
| MIB22 / JL16 | Recombinant human monoclonal Abs | ANDV | Preclinical (hamster model) | 100% protection as monotherapy or combination post-exposure |
| SNV-42 | Human monoclonal Ab (Gn targeting) | SNV | Preclinical (structural characterization) | Blocks receptor recognition and fusion; germline-encoded |
| AH100 | Human monoclonal Ab (Gn domain A) | HTNV | Preclinical (structural characterization) | Unique epitope; conserved across all natural isolates |
| ANDV DNA vaccine | DNA vaccine (M segment, needle-free jet injection) | ANDV | Phase 1 clinical trial (NCT03682107) | Safe; ≥80% seropositivity by day 197; durable through day 337 |
| HTNV/PUUV DNA vaccine | DNA vaccine (M segment, IM electroporation) | HTNV, PUUV | Phase 2a clinical trial | ~78% seroconversion; safe and immunogenic |
| Prefusion-stabilized HTNV mRNA-LNP | mRNA vaccine | HTNV | Preclinical (mouse model) | Robust nAbs via germinal center activation; superior as booster |
| rVSVΔG/ANDVGPC | Viral vector vaccine (VSV) | ANDV, SNV | Preclinical (hamster model) | Sterilizing immunity with single dose; cross-reactive responses |
| siRNA (S, M, L segments) | RNA interference | HTNV | In vitro | Effective viral RNA clearance; limited by low biological stability |
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Vial PA, Ferrés M, Vial C, Rabagliati R, Castillo C, Ossa G, Mertz GJ, Enria D, López R, Padula P, Pini N, Ramírez E, Godoy P, Calvo M, Valdivieso F (2023). "Hantavirus in humans: a review of clinical aspects and management". Lancet Infect Dis. 23 (9): e371–e382. doi:10.1016/S1473-3099(23)00128-7. PMID 37105214 Check
|pmid=value (help). - ↑ 2.0 2.1 Afzal S, Ali L, Batool A, Afzal M, Kanwal S, Aslam F, Kamal MA, Rabbani I, Waseem M (2023). "Hantavirus: an overview and advancements in therapeutic approaches for infection". Front Microbiol. 14: 1233433. doi:10.3389/fmicb.2023.1233433. PMID 37901807 Check
|pmid=value (help). - ↑ 3.0 3.1 Chai S, Wang L, Du H, Jiang H (2025). "Achievement and challenges in orthohantavirus vaccines". Vaccines. 13 (2): 198. doi:10.3390/vaccines13020198. PMID 40006744 Check
|pmid=value (help). - ↑ Safronetz D, Falzarano D, Scott DP, Furuta Y, Feldmann H, Gowen BB (2013). "Antiviral efficacy of favipiravir against two prominent etiological agents of hantavirus pulmonary syndrome". Antimicrob Agents Chemother. 57 (10): 4673–80. doi:10.1128/AAC.00886-13. PMID 23856782.
- ↑ Mayor J, Engler O, Rothenberger S (2021). "Antiviral efficacy of ribavirin and favipiravir against Hantaan virus". Microorganisms. 9 (6): 1306. doi:10.3390/microorganisms9061306. PMID 34203936 Check
|pmid=value (help). - ↑ Bird BH, Shrivastava-Ranjan P, Dodd KA, Erickson BR, Spiropoulou CF (2016). "Effect of vandetanib on Andes virus survival in the hamster model of hantavirus pulmonary syndrome". Antiviral Res. 132: 66–9. doi:10.1016/j.antiviral.2016.05.014. PMID 27233645.
- ↑ Murphy ME, Kariwa H, Mizutani T, Yoshimatsu K, Arikawa J, Takashima I (2000). "In vitro antiviral activity of lactoferrin and ribavirin upon hantavirus". Arch Virol. 145 (8): 1571–82. doi:10.1007/s007050070077. PMID 11003470.
- ↑ Murphy ME, Kariwa H, Mizutani T, Yoshimatsu K, Arikawa J, Takashima I (2001). "Characterization of in vitro and in vivo antiviral activity of lactoferrin and ribavirin upon hantavirus". J Vet Med Sci. 63 (6): 637–45. doi:10.1292/jvms.63.637. PMID 11459009.
- ↑ Dang Y, Wang Y, Wei J, Liu G, Zhang L, Zhang Y (2024). "25-Hydroxycholesterol inhibits hantavirus infection by reprogramming cholesterol metabolism". Free Radic Biol Med. 224: 232–245. doi:10.1016/j.freeradbiomed.2024.08.029. PMID 39209137 Check
|pmid=value (help). - ↑ Wang B, Pei J, Zhang H, Yang G, Tong Z, Fan Q, Zhong J (2022). "Dihydropyridine-derived calcium channel blocker as a promising anti-hantavirus entry inhibitor". Front Pharmacol. 13: 940178. doi:10.3389/fphar.2022.940178. PMID 36105208 Check
|pmid=value (help). - ↑ Jeyachandran AV, Irudayam JI, Dubey S, Cario E, Günther S, Oestereich L, Kaderali L, Spiropoulou CF, Chatterjee S (2025). "Differential tropisms of Old and New World hantaviruses influence virulence and developing host-directed antiviral candidates". PLoS Pathog. 21 (8): e1013401. doi:10.1371/journal.ppat.1013401. PMID 40857262 Check
|pmid=value (help). - ↑ Brocato RL, Wu H, Kwilas SA, Principe LM, Josleyn MD, Jangra RK, Chandran K, Hooper JW (2024). "Preclinical evaluation of a fully human, quadrivalent-hantavirus polyclonal antibody derived from a non-human source". mBio: e0160024. doi:10.1128/mbio.01600-24. PMID 39258903 Check
|pmid=value (help). - ↑ Mittler E, Wec AZ, Tynell J, Guardado-Calvo P, Wiber SC, Engdahl TB, Keeffe JR, Bornholdt ZA, Bakken RR, Brocato RL, Hooper JW, Crowe JE Jr, Rey FA, Chandran K, Stass R (2022). "Human antibody recognizing a quaternary epitope in the Puumala virus glycoprotein provides broad protection against orthohantaviruses". Sci Transl Med. 14 (636): eabl5399. doi:10.1126/scitranslmed.abl5399. PMID 35294259 Check
|pmid=value (help). - ↑ Mittler E, Serris A, Esterman ES, Tynell J, Guardado-Calvo P, Stass R, Bakken RR, Brocato RL, Hooper JW, Keeffe JR, Crowe JE Jr, Rey FA, Chandran K (2023). "Structural and mechanistic basis of neutralization by a pan-hantavirus protective antibody". Sci Transl Med. 15 (700): eadg1855. doi:10.1126/scitranslmed.adg1855. PMID 37315110 Check
|pmid=value (help). - ↑ Garrido JL, Prescott J, Calvo M, Bravo F, Alvarez R, Vial C, Riquelme R, Rioseco ML, Williamson BN, Haddock E, Feldmann H, Vial PA (2018). "Two recombinant human monoclonal antibodies that protect against lethal Andes hantavirus infection in vivo". Sci Transl Med. 10 (468): eaat6420. doi:10.1126/scitranslmed.aat6420. PMID 30463919.
- ↑ Stass R, Engdahl TB, Chapman NS, Wolters RM, Handal LS, Diaz SM, Crowe JE Jr, Bhella D (2023). "Mechanistic basis for potent neutralization of Sin Nombre hantavirus by a human monoclonal antibody". Nat Microbiol. 8 (7): 1293–1303. doi:10.1038/s41564-023-01413-y. PMID 37322112 Check
|pmid=value (help). - ↑ Wang F, Liu T, Liao L, Qi X, Lv M, Jiang D, Li Y, Xu Z, Hou W (2024). "Molecular insight into the neutralization mechanism of human-origin monoclonal antibody AH100 against Hantaan virus". J Virol. 98 (8): e0088324. doi:10.1128/jvi.00883-24. PMID 39078157 Check
|pmid=value (help). - ↑ 18.0 18.1 18.2 18.3 Saavedra F, Díaz FE, Retamal-Díaz A, Covián C, González PA, Kalergis AM (2021). "Immune response during hantavirus diseases: implications for immunotherapies and vaccine design". Immunology. 163 (3): 262–277. doi:10.1111/imm.13322. PMID 33462643 Check
|pmid=value (help). - ↑ Hooper J, Paolino KM, Mills K, Jiang J, Kwilas SA, Josleyn M, Ballantyne J, Brocato R (2020). "A phase 2a randomized, double-blind, dose-optimizing study to evaluate the immunogenicity and safety of a bivalent DNA vaccine for hemorrhagic fever with renal syndrome delivered by intramuscular electroporation". Vaccines. 8 (3): E377. doi:10.3390/vaccines8030377. PMID 32664486 Check
|pmid=value (help). - ↑ Paulsen GC, Frenck R, Tomashek KM, Kwilas SA, Josleyn MD, Brocato RL, Hooper JW, Beasley D, Cardenas-de la Garza JA, Boonnak K, Creech CB, Munoz FM, Keitel WA (2024). "Safety and immunogenicity of an Andes virus DNA vaccine by needle-free injection: a randomized, controlled phase 1 study". J Infect Dis. 229 (1): 30–38. doi:10.1093/infdis/jiad235. PMID 37380156 Check
|pmid=value (help). Vancouver style error: initials (help) - ↑ Hooper JW, Josleyn M, Ballantyne J, Brocato R (2013). "A novel Sin Nombre virus DNA vaccine and its inclusion in a candidate pan-hantavirus vaccine against hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS)". Vaccine. 31 (40): 4314–21. doi:10.1016/j.vaccine.2013.07.025. PMID 23892100.
- ↑ Ye W, Dang Y, Wang Y, Wei J, Zhang L, Zhang Y (2026). "Prefusion-stabilized Hantaan virus glycoprotein nucleic acid vaccine elicits potent neutralizing antibody responses via germinal center activation". Nat Commun. 17 (1): 3972. doi:10.1038/s41467-026-70285-7. PMID 41832144 Check
|pmid=value (help).