By now, we’ve had a chance to brush up on the Hanta virus, esp. the Andes variety which caused a mini-epidemic on the arctic cruise ship MV Hondius. Named after Hantaan, the river in South Korea where the disease first emerged, we give credit to Dr. Ho Wang Lee, the researcher who worked on the virus in the 1980s and single-handedly developed a vaccine called Hantavax.
We recognize the different disease presentations of this agent, as HFRS in SEA and Europe and as HPS in the Americas. Most importantly, we learned that the Andes virus is capable of person-to-person spread, a finding of concern as the disease has a high mortality rate (approx. 35%).i
CDC and various expert groups assure us that Hanta/Andes is not a repeat of Covid-19 which – at least in its early days – presented similarly with high mortality and spread on cruise ships. This advice is certainly right for today. How about for tomorrow?
It is good to see that Hanta-related funding and research have picked up considerably in the past years with a boost since the Hondius miniepidemic.
Prevention in the form of vaccines and treatment options are being evaluated. Several excellent articles and online publications provide a status update on vaccine research. [i],[ii],[iii]
There is also a comprehensive review of therapies that are currently under consideration.[iv]
This is a virus that cannot be tackled by industry. Hanta research belongs in BSL-4 facilities which have the capability to do this kind of dangerous research. There are very few facilities like the one at Fort Detrick, USA located in other countries.
A central problem remains: How is one to conduct efficacy trials for a disease as rare as HPS? Studies following the standard staged development paradigm are just not feasible. For anthrax, we can fall back on animal models, but not for Hanta. This will presumably change over time, but for now, this is a major issue. There is a Syrian hamster model, but it remains to be seen if it is predictive.
Hanta is just one of many potentially lethal pathogens that demand attention. We are somewhat familiar with Ebola and Mpox but less so with Hendra, Nipah, Sabia, Marburg and the myriad of viruses that we may have to confront at some point in the future. In the ever expanding Hanta family tree alone there are more species names that none of us have ever heard of (see Table 1 below). We should recognize our deficits in knowledge; there remains a lot work to be done and learned.
This creates a dilemma for which we have no easy solution: Even in endemic areas like Chile and Argentina, symptomatic cases are fairly rare and outbreaks remain small sporadic events. Traditional efficacy trials require large patient numbers and are bound to miss enrollment targets. For example, the aborted trial by Merz et al shows the difficulties; it is still remarkable in several ways:
- Design: This was a prospective, double-blind, placebo-controlled, randomized trial of ribavirin in HPS patients
- Enrollment: 23 patients with documented HPS (10 active, 13 placebo) over 5 years
- Disease: By the time Hanta/Andes was positively identified, patients were just hours away from ARDS and respiratory failure
- Efficacy: There was no improvement with ribavirin therapy
- Safety: Not even the hematologic side effects of ribavirin were clearly evident given the small cohort size
It would make little sense to repeat such a trial now; the case numbers are still too small. Considering the number of drug candidates for testing, we would need a Covid-like surge in cases which no one wishes for.
With Hanta/Andes we would consider at least 3 targets for intervention: the virus, its immune signature, and the capillary leak syndrome which underpins both HPS and HFRS. This makes for a long list now, only to mushroom over time.
A lack of cases is only one problem, another is disease dynamic. HPS patients can become sick very fast developing fulminant ARDS in a matter of hours to a few days. By the time a diagnosis of Hanta infection is made (or suspected), the disease may have run its course, and even the most efficacious antiviral may offer little.
This reminds us of meningococcal disease which can also present with fulminant coagulopathy (Waterhouse-Friderichsen syndrome) and for which efficient therapy is available in the form of Penicillin G. Still, mortality remains very high, unaffected by highly efficient antibacterial treatment. In the later stages of meningococcal disease the damage is done, no longer caused by the infecting bacteria but by the cascade of events they triggered.
What can we do in preparation for the next epidemic? Below a listing of the genus Orthohantavirus, based on recent taxonomy. Importantly, only Orthohanta viruses are known to cause disease.[v] This list is likely to get longer.
Vigilance is good, active surveillance is better. Early identification of these pathogens with modern rapid diagnostics should be feasible; we believe that early diagnosis – even in the absence of specific therapeutics – can only be beneficial.
Quarantine and supportive care is all we have presently. Viruses sometimes spread very fast across the globe. International collaboration is key and should be a given, but human behavior is not always driven by logic. There are the anti-vaxxers and individualists that would rather die than change their minds, arguing against ‘school medicine’ and calling it ‘government overreach’ when restrictions of civil liberties are imposed.
There is often an engrained bias against everything that’s ‘not invented here’, the folks that are ready to blame and engage in finger pointing with 20/20 hindsight. One should not have to mention any of this, but the way we handled Covid was a wake-up call. Researchers working together can find solutions, but dealing with politicized decision processes makes the job only harder.
We need to learn together, work together and share knowledge and data. Too little is known about Hanta/Andes now, and nothing about the virus that might create the next epidemic.
Preparedness is a word that we often hear. However, not even the most basic protective measures were readily available when needed. Early in the Covid epidemic, there was a shortage of face masks. Not N95 masks, mind you, we are talking about standard surgical face masks. Then we did not have enough disinfecting soap solutions. The use of alcohol in dispensers was considered a fire hazard in US hospitals, despite a long proven history of safety elsewhere. We quickly ran out of PPE, the gowns and gloves. Such barrier methods can be stockpiled, they will be needed for any and all viruses that spread via the respiratory route. These items are cheap and don’t have an expiration date. Wide availability avoids distribution issues; all these measures can be organized much better than in the past.
While they won’t stop the spread of a highly contagious respiratory pathogen, they can slow it down.
We hope that ‘gain-of-function’ research for Hanta/Andes is not on the NIH priority list…
List of OrthoHanta Viruses
| SPECIES | VIRUS NAME | ABBREVIATION |
|---|---|---|
| Orthohantavirus andesense | Andes virus | ANDV |
| Orthohantavirus andesense | Castelo dos Sonhos virus | CASV |
| Orthohantavirus andesense | Lechiguanas virus | LECV; LECHV |
| Orthohantavirus andesense | Orán virus | ORNV |
| Orthohantavirus artybashense | Artybash virus | ARTV |
| Orthohantavirus asamaense | Asama virus | ASAV |
| Orthohantavirus asikkalaense | Asikkala virus | ASIV |
| Orthohantavirus bayoui | Bayou virus | BAYV |
| Orthohantavirus bayoui | Catacamus virus | CATV |
| Orthohantavirus boweense | Bowé virus | BOWV |
| Orthohantavirus brugesense | Bruges virus | BRGV |
| Orthohantavirus caobangense | Cao Bằng virus | CBNV |
| Orthohantavirus caobangense | Liánghé virus | LHEV |
| Orthohantavirus carrizalense | Carrizal virus | CARV |
| Orthohantavirus carrizalense | Huitzilac virus | HUIV |
| Orthohantavirus chocloense | Choclo virus | CHOV |
| Orthohantavirus dabieshanense | Dàbiéshān virus | DBSV |
| Orthohantavirus delgaditoense | Caño Delgadito virus | CADV |
| Orthohantavirus dobravaense | Dobrava virus | DOBV |
| Orthohantavirus dobravaense | Kurkino virus | KURV |
| Orthohantavirus dobravaense | Saaremaa virus | SAAV |
| Orthohantavirus dobravaense | Sochi virus | SOCV |
| Orthohantavirus fugongense | Fúgòng virus | FUGV |
| Orthohantavirus hantanense | Hantaan virus | HTNV |
| Orthohantavirus hantanense | Amur virus | AMRV |
| Orthohantavirus hantanense | Soochong virus | SOOV |
| Orthohantavirus jejuense | Jeju virus | JJUV |
| Orthohantavirus kenkemeense | Kenkeme virus | KKMV |
| Orthohantavirus khabarovskense | Khabarovsk virus | KHAV |
| Orthohantavirus khabarovskense | Topografov virus | TOPV |
| Orthohantavirus lankaense | Lanka virus | LNKV |
| Orthohantavirus luxiense | Lúxī virus | LUXV |
| Orthohantavirus mamorense | Rio Mamoré virus | RIOMV |
| Orthohantavirus mamorense | Laguna Negra virus | LANV |
| Orthohantavirus mamorense | Maripa virus | MARV |
| Orthohantavirus maporalense | Maporal virus | MAPV |
| Orthohantavirus montanoense | Montaño virus | MTNV |
| Orthohantavirus nigrorivense | Black Creek Canal virus | BCCV |
| Orthohantavirus ozarkense | Ozark virus | OZAV |
| Orthohantavirus prospectense | Prospect Hill virus | PHV |
| Orthohantavirus puumalaense | Puumala virus | PUUV |
| Orthohantavirus puumalaense | Hokkaido virus | HOKV |
| Orthohantavirus puumalaense | Muju virus | MUJV |
| Orthohantavirus puumalaense | Puumala virus | PUUV |
| Orthohantavirus rockportense | Rockport virus | RKPV |
| Orthohantavirus sagercreekense | Sager Creek virus | SACRV |
| Orthohantavirus sangassouense | Sangassou virus | SANGV |
| Orthohantavirus seoulense | Seoul virus | SEOV |
| Orthohantavirus seoulense | gōu virus | GOUV |
| Orthohantavirus seoulense | Seoul virus | SEOV |
| Orthohantavirus sinnombreense | Sin Nombre virus | SNV |
| Orthohantavirus sinnombreense | New York virus | NYV |
| Orthohantavirus tatenalense | Tatenale virus | TATV |
| Orthohantavirus thailandense | Anjozorobe virus | ANJZV |
| Orthohantavirus thailandense | Serang virus | SERV |
| Orthohantavirus thailandense | Thailand virus | THAIV |
| Orthohantavirus tulaense | Adler virus | ADLV |
Modified from Ref. V
ABBREVIATIONS
ARDS adult respiratory distress syndrome
BSL biosafety level
HFRS Hemorrhagic fever with renal syndrrome
HPS Hanta pulmonary syndrome
PPE personal protective equipment
REFERENCES
[i] Merz G. Placebo-Controlled, Double-Blind Trial of Intravenous Ribavirin for the Treatment of Hantavirus Cardiopulmonary Syndrome in North America. Clin Infect Dis 39, Issue 9, 2004: 1307
[ii] Hantavirus Vaccine 2026: Clinical Trials, Candidates, and Development Status · PredictHanta
[iii] Brocado R. Progress on the Prevention and Treatment of Hantavirus Disease. Viruses 2019, 11, 610
[iv] Afzal S. Hantavirus: an overview and advancements in therapeutic approaches for infection. Front. Microbiol. 14:1233433
[v] https://ictv.global/report/chapter/hantaviridae/hantaviridae
