Safety and Immunogenicity of an Andes Virus DNA Vaccine by Needle-Free Injection: A Randomized, Controlled Phase 1 Study.

BACKGROUND: Andes virus (ANDV), a rodent-borne hantavirus, causes hantavirus pulmonary syndrome (HPS). The safety and immunogenicity of a novel ANDV DNA vaccine was evaluated. METHODS: Phase 1, double-blind, dose-escalation trial randomly assigned 48 healthy adults to placebo or ANDV DNA vaccine delivered via needle-free jet injection. Cohorts 1 and 2 received 2 mg of DNA or placebo in a 3-dose (days 1, 29, 169) or 4-dose (days 1, 29, 57, 169) schedule, respectively. Cohorts 3 and 4 received 4 mg of DNA or placebo in the 3-dose and 4-dose schedule, respectively. Subjects were monitored for safety and neutralizing antibodies by pseudovirion neutralization assay (PsVNA50) and plaque reduction neutralization test (PRNT50). RESULTS: While 98% and 65% of subjects had at least 1 local or systemic solicited adverse event (AE), respectively, most AEs were mild or moderate; no related serious AEs were detected. Cohorts 2, 3, and 4 had higher seroconversion rates than cohort 1 and seropositivity of at least 80% by day 197, sustained through day 337. PsVNA50 geometric mean titers were highest for cohort 4 on and after day 197. CONCLUSIONS: This first-in-human candidate HPS vaccine trial demonstrated that an ANDV DNA vaccine was safe and induced a robust, durable immune response. Clinical Trials Registration. NCT03682107.

Orthohantaviruses in Misiones Province, Northeastern Argentina.

Few cases of hantavirus pulmonary syndrome have been reported in northeastern Argentina. However, neighboring areas show a higher incidence, suggesting underreporting. We evaluated the presence of antibodies against orthohantavirus in small rodents throughout Misiones province. Infected Akodon affinis montensis and Oligoryzomys nigripes native rodents were found in protected areas of Misiones.

Protocadherin-1 is essential for cell entry by New World hantaviruses.

The zoonotic transmission of hantaviruses from their rodent hosts to humans in North and South America is associated with a severe and frequently fatal respiratory disease, hantavirus pulmonary syndrome (HPS)1,2. No specific antiviral treatments for HPS are available, and no molecular determinants of in vivo susceptibility to hantavirus infection and HPS are known. Here we identify the human asthma-associated gene protocadherin-1 (PCDH1)3-6 as an essential determinant of entry and infection in pulmonary endothelial cells by two hantaviruses that cause HPS, Andes virus (ANDV) and Sin Nombre virus (SNV). In vitro, we show that the surface glycoproteins of ANDV and SNV directly recognize the outermost extracellular repeat domain of PCDH1-a member of the cadherin superfamily7,8-to exploit PCDH1 for entry. In vivo, genetic ablation of PCDH1 renders Syrian golden hamsters highly resistant to a usually lethal ANDV challenge. Targeting PCDH1 could provide strategies to reduce infection and disease caused by New World hantaviruses.

"Super-Spreaders" and Person-to-Person Transmission of Andes Virus in Argentina.

BACKGROUND: From November 2018 through February 2019, person-to-person transmission of Andes virus (ANDV) hantavirus pulmonary syndrome occurred in Chubut Province, Argentina, and resulted in 34 confirmed infections and 11 deaths. Understanding the genomic, epidemiologic, and clinical characteristics of person-to-person transmission of ANDV is crucial to designing effective interventions. METHODS: Clinical and epidemiologic information was obtained by means of patient report and from public health centers. Serologic testing, contact-tracing, and next-generation sequencing were used to identify ANDV infection as the cause of this outbreak of hantavirus pulmonary syndrome and to reconstruct person-to-person transmission events. RESULTS: After a single introduction of ANDV from a rodent reservoir into the human population, transmission was driven by 3 symptomatic persons who attended crowded social events. After 18 cases were confirmed, public health officials enforced isolation of persons with confirmed cases and self-quarantine of possible contacts; these measures most likely curtailed further spread. The median reproductive number (the number of secondary cases caused by an infected person during the infectious period) was 2.12 before the control measures were enforced and decreased to 0.96 after the measures were implemented. Full genome sequencing of the ANDV strain involved in this outbreak was performed with specimens from 27 patients and showed that the strain that was present (Epuyén/18-19) was similar to the causative strain (Epilink/96) in the first known person-to-person transmission of hantavirus pulmonary syndrome caused by ANDV, which occurred in El Bolsón, Argentina, in 1996. Clinical investigations involving patients with ANDV hantavirus pulmonary syndrome in this outbreak revealed that patients with a high viral load and liver injury were more likely than other patients to spread infection. Disease severity, genomic diversity, age, and time spent in the hospital had no clear association with secondary transmission. CONCLUSIONS: Among patients with ANDV hantavirus pulmonary syndrome, high viral titers in combination with attendance at massive social gatherings or extensive contact among persons were associated with a higher likelihood of transmission. (Funded by the Ministerio de Salud y Desarrollo Social de la Nación Argentina and others.).

Modeling potential risk areas of Orthohantavirus transmission in Northwestern Argentina using an ecological niche approach.

BACKGROUND: Hantavirus Pulmonary Syndrome (HPS) is a rodent-borne zoonosis in the Americas, with up to 50% mortality rates. In Argentina, the Northwestern endemic area presents half of the annually notified HPS cases in the country, transmitted by at least three rodent species recognized as reservoirs of Orthohantavirus. The potential distribution of reservoir species based on ecological niche models (ENM) can be a useful tool to establish risk areas for zoonotic diseases. Our main aim was to generate an Orthohantavirus risk transmission map based on ENM of the reservoir species in northwest Argentina (NWA), to compare this map with the distribution of HPS cases; and to explore the possible effect of climatic and environmental variables on the spatial variation of the infection risk. METHODS: Using the reservoir geographic occurrence data, climatic/environmental variables, and the maximum entropy method, we created models of potential geographic distribution for each reservoir in NWA. We explored the overlap of the HPS cases with the reservoir-based risk map and a deforestation map. Then, we calculated the human population at risk using a census radius layer and a comparison of the environmental variables' latitudinal variation with the distribution of HPS risk. RESULTS: We obtained a single best model for each reservoir. The temperature, rainfall, and vegetation cover contributed the most to the models. In total, 945 HPS cases were recorded, of which 97,85% were in the highest risk areas. We estimated that 18% of the NWA population was at risk and 78% of the cases occurred less than 10 km from deforestation. The highest niche overlap was between Calomys fecundus and Oligoryzomys chacoensis. CONCLUSIONS: This study identifies potential risk areas for HPS transmission based on climatic and environmental factors that determine the distribution of the reservoirs and Orthohantavirus transmission in NWA. This can be used by public health authorities as a tool to generate preventive and control measures for HPS in NWA.

Management of Hantavirus Cardiopulmonary Syndrome in Critical Care Transport: A Review.

In 1993, the Southwest found itself staring down a disease then known as "unexplained adult respiratory syndrome." During the outbreak, 12 of 23 known patients died. What we now recognize as hantavirus cardiopulmonary syndrome still remains a rare and deadly disease. Although no cure exists, modern supportive techniques such as extracorporeal membrane oxygenation have increased survival among these patients. Early diagnosis has become the primary factor in patient survival. The initial presentation of hantavirus is similar to acute respiratory distress syndrome, necessitating a high index of suspicion to afford the patient the best chance of survival. Diagnosis is further complicated by prolonged and nonspecific incubation periods making it difficult to pinpoint an exposure. Familiarizing oneself with common clinical presentations, diagnostic strategies, and testing is the best way to increase patient survival. Because hantavirus has a predilection for rural areas, transport to a tertiary facility is paramount to provide the resources necessary to care for these complex patients. Rapid sequence intubation, although common in airway-compromised patients, could prove fatal in the setting of the severe hemodynamic instability found in hantavirus cardiopulmonary syndrome. Anticipation of significant pressor use and fluid administration could likely mean the difference in patient mortality during transport.

Experimental Infection of Peromyscus Species Rodents with Sin Nombre Virus.

We demonstrate that 6 distinct Peromyscus rodent species are permissive to experimental infection with Sin Nombre orthohantavirus (SNV). Viral RNA and SNV antibodies were detected in members of all 6 species. P. leucopus mice demonstrated markedly higher viral and antibody titers than P. maniculatus mice, the established primary hosts for SNV.

Hantavirus Pulmonary Syndrome in a COVID-19 Patient, Argentina, 2020.

We describe a patient in Argentina with severe acute respiratory syndrome coronavirus 2 infection and hantavirus pulmonary syndrome (HPS). Although both coronavirus disease and HPS can be fatal when not diagnosed and treated promptly, HPS is much more lethal. This case report may contribute to improved detection of co-infections in HPS-endemic regions.

Tracing Transmission of Sin Nombre Virus and Discovery of Infection in Multiple Rodent Species.

Sin Nombre orthohantavirus (SNV), a negative-sense, single-stranded RNA virus that is carried and transmitted by the North American deer mouse Peromyscus maniculatus, can cause infection in humans through inhalation of aerosolized excreta from infected rodents. This infection can lead to hantavirus cardiopulmonary syndrome (HCPS), which has an ∼36% case-fatality rate. We used reverse transcriptase quantitative PCR (RT-qPCR) to confirm SNV infection in a patient and identified SNV in lung tissues in wild-caught rodents from potential sites of exposure. Using viral whole-genome sequencing (WGS), we identified the likely site of transmission and discovered SNV in multiple rodent species not previously known to carry the virus. Here, we report, for the first time, the use of SNV WGS to pinpoint a likely site of human infection and identify SNV simultaneously in multiple rodent species in an area of known host-to-human transmission. These results will impact epidemiology and infection control for hantaviruses by tracing zoonotic transmission and investigating possible novel host reservoirs. IMPORTANCE Orthohantaviruses cause severe disease in humans and can be lethal in up to 40% of cases. Sin Nombre orthohantavirus (SNV) is the main cause of hantavirus disease in North America. In this study, we sequenced SNV from an infected patient and wild-caught rodents to trace the location of infection. We also discovered SNV in rodent species not previously known to carry SNV. These studies demonstrate for the first time the use of virus sequencing to trace the transmission of SNV and describe infection in novel rodent species.

Intersecting Paths of Emerging and Reemerging Infectious Diseases.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) shares common clinicopathologic features with other severe pulmonary illnesses. Hantavirus pulmonary syndrome was diagnosed in 2 patients in Arizona, USA, suspected of dying from infection with SARS-CoV-2. Differential diagnoses and possible co-infections should be considered for cases of respiratory distress during the SARS-CoV-2 pandemic.

Hantavirus.

Hantaviruses are tri-segmented lipid-enveloped RNA viruses belonging to the Bunyaviridae family. Human infection corresponds to a zoonosis associated with two different clinical syndromes: hemorrhagic fever with renal syndrome that occurs in Asia and Europe and hantavirus cardiopulmonary syndrome (HCPS) that occurs in the North America, Central America and South America. The major pathogenic mechanisms in HCPS include (1) direct microvascular endothelial injury leading to increased capillary permeability and the development of noncardiogenic pulmonary edema and acute respiratory distress syndrome, and (2) exaggerated host immune response leading to secondary organ damage. The incubation period for this disease is quite long (6-39 days, median: 18 days); however, rapid progression to respiratory failure and shock can occur highlighting the importance of high index of clinical suspicion. Management revolves around high-quality supportive care. Various management and preventative strategies are currently being explored and warrant further examination to improve the overall outlook following infection with hantavirus.

Species diversity concurrently dilutes and amplifies transmission in a zoonotic host-pathogen system through competing mechanisms.

In this era of unprecedented biodiversity loss and increased zoonotic disease emergence, it is imperative to understand the effects of biodiversity on zoonotic pathogen dynamics in wildlife. Whether increasing biodiversity should lead to a decrease or increase in infection prevalence, termed the dilution and amplification effects, respectively, has been hotly debated in disease ecology. Sin Nombre hantavirus, which has an ∼35% mortality rate when it spills over into humans, occurs at a lower prevalence in the reservoir host, the North American deermouse, in areas with higher small mammal diversity-a dilution effect. However, the mechanism driving this relationship is not understood. Using a mechanistic mathematical model of infection dynamics and a unique long-term, high-resolution, multisite dataset, it appears that the observed dilution effect is a result of increasing small-mammal diversity leading to decreased deermouse population density and, subsequently, prevalence (a result of density-dependent transmission). However, once density is taken into account, there is an increase in the transmission rate at sites with higher diversity-a component amplification effect. Therefore, dilution and amplification are occurring at the same time in the same host-pathogen system; there is a component amplification effect (increase in transmission rate), but overall a net dilution because the effect of diversity on reservoir host population density is stronger. These results suggest we should focus on how biodiversity affects individual mechanisms that drive prevalence and their relative strengths if we want to make generalizable predictions across host-pathogen systems.

Hantavirus Pulmonary Syndrome in Traveler Returning from Nepal to Spain.

Most human hantavirus infections occur in Asia, but some cases have been described in Europe in travelers returning from Asia. We describe a case of hantavirus pulmonary syndrome in a previously healthy traveler occurring shortly after he returned to Spain from Nepal. Serologic tests suggested a Puumala virus-like infection.

Person-to-Person Transmission of Andes Virus in Hantavirus Pulmonary Syndrome, Argentina, 2014.

Andes virus is unique among hantaviruses because it can be transmitted from person to person. This mechanism was previously supported by epidemiologic data and genetic evidence based only on partial sequences. We used full-length virus sequencing to confirm person-to-person transmission of this virus in a cluster of 3 cases in Argentina in 2014.

Hantavirus Cardiopulmonary Syndrome in Canada.

Hantavirus cardiopulmonary syndrome (HCPS) is a severe respiratory disease caused by Sin Nombre virus in North America (SNV). As of January 1, 2020, SNV has caused 143 laboratory-confirmed cases of HCPS in Canada. We review critical aspects of SNV virus epidemiology and the ecology, biology, and genetics of HCPS in Canada.

Hantavirus Infection with Renal Failure and Proteinuria, Colorado, USA, 2019.

In North America, hantaviruses commonly cause hantavirus pulmonary syndrome (HPS). Clinical descriptions of hantavirus-associated renal disease in the Americas are scarce. Herein, we discuss the case of a 61-year-old man whose predominant manifestations were acute kidney injury and proteinuria. Clinical recognition of renal signs in hantavirus infections can reduce risk for death.

Serum Markers Associated with Severity and Outcome of Hantavirus Pulmonary Syndrome.

BACKGROUND: Hantavirus pulmonary syndrome (HPS) is caused by Andes virus (ANDV) and related hantaviruses in the Americas. Despite a fatality rate of 40%, the pathogenesis of HPS is poorly understood and factors associated with severity, fatality, and survival remain elusive. METHODS: Ninety-three ANDV-infected HPS patients, of whom 34 had a fatal outcome, were retrospectively studied. Serum levels of cytokines and other inflammation-associated markers were analyzed using multiplex immunoassay and enzyme-linked immunosorbent assay. Associations with disease severity, fatal outcome, and survival were identified using logistic regression. RESULTS: HPS patients exhibited increased serum levels of markers associated with inflammation, intestinal damage, and microbial translocation compared to controls. Patients with fatal outcome displayed higher levels of interleukin (IL) 6, IL-10, interferon-γ, soluble tumor necrosis factor-related apoptosis-inducing ligand, and intestinal fatty acid-binding protein (I-FABP) than survivors. Levels of complement factor 5/5a were higher in survivors compared with fatal cases. IL-6 and I-FABP, the latter a marker for intestinal damage, were by multivariate analyses identified as independent markers associated with disease severity (odds ratio [OR], 2.25; 95% confidence interval [CI], 1.01-5.01) and fatal outcome (OR, 1.64; 95% CI, 1.01-2.64), respectively. CONCLUSIONS: HPS patients displayed a multifaceted, systemic inflammatory response, with IL-6 and I-FABP as independent markers of disease severity and fatality, respectively.

New Exposure Location for Hantavirus Pulmonary Syndrome Case, California, USA, 2018.

We describe a case of hantavirus pulmonary syndrome in a patient exposed to Sin Nombre virus in a coastal county in California, USA, that had no previous record of human cases. Environmental evaluation coupled with genotypic analysis of virus isolates from the case-patient and locally trapped rodents identified the likely exposure location.

Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus-associated syndromes.

Two related hyperinflammatory syndromes are distinguished following infection of humans with hantaviruses: haemorrhagic fever with renal syndrome (HFRS) seen in Eurasia and hantavirus pulmonary syndrome (HPS) seen in the Americas. Fatality rates are high, up to 10% for HFRS and around 35%-40% for HPS. Puumala virus (PUUV) is the most common HFRS-causing hantavirus in Europe. Here, we describe recent insights into the generation of innate and adaptive cell-mediated immune responses following clinical infection with PUUV. First described are studies demonstrating a marked redistribution of peripheral blood mononuclear phagocytes (MNP) to the airways, a process that may underlie local immune activation at the site of primary infection. We then describe observations of an excessive natural killer (NK) cell activation and the persistence of highly elevated numbers of NK cells in peripheral blood following PUUV infection. A similar vigorous CD8 Tcell response is also described, though Tcell responses decline with viraemia. Like MNPs, many NK cells and CD8 T cells also localize to the lung upon acute PUUV infection. Following this, findings demonstrating the ability of hantaviruses, including PUUV, to cause apoptosis resistance in infected target cells, are described. These observations, and associated inflammatory cytokine responses, may provide new insights into HFRS and HPS disease pathogenesis. Based on similarities between inflammatory responses in severe hantavirus infections and other hyperinflammatory disease syndromes, we speculate whether some therapeutic interventions that have been successful in the latter conditions may also be applicable in severe hantavirus infections.

Human hantavirus infection elicits pronounced redistribution of mononuclear phagocytes in peripheral blood and airways.

Hantaviruses infect humans via inhalation of virus-contaminated rodent excreta. Infection can cause severe disease with up to 40% mortality depending on the viral strain. The virus primarily targets the vascular endothelium without direct cytopathic effects. Instead, exaggerated immune responses may inadvertently contribute to disease development. Mononuclear phagocytes (MNPs), including monocytes and dendritic cells (DCs), orchestrate the adaptive immune responses. Since hantaviruses are transmitted via inhalation, studying immunological events in the airways is of importance to understand the processes leading to immunopathogenesis. Here, we studied 17 patients infected with Puumala virus that causes a mild form of hemorrhagic fever with renal syndrome (HFRS). Bronchial biopsies as well as longitudinal blood draws were obtained from the patients. During the acute stage of disease, a significant influx of MNPs expressing HLA-DR, CD11c or CD123 was detected in the patients' bronchial tissue. In parallel, absolute numbers of MNPs were dramatically reduced in peripheral blood, coinciding with viremia. Expression of CCR7 on the remaining MNPs in blood suggested migration to peripheral and/or lymphoid tissues. Numbers of MNPs in blood subsequently normalized during the convalescent phase of the disease when viral RNA was no longer detectable in plasma. Finally, we exposed blood MNPs in vitro to Puumala virus, and demonstrated an induction of CCR7 expression on MNPs. In conclusion, the present study shows a marked redistribution of blood MNPs to the airways during acute hantavirus disease, a process that may underlie the local immune activation and contribute to immunopathogenesis in hantavirus-infected patients.