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As there is no effective treatment against hemorrhagic fever with renal syndrome (HFRS), the development of effective vaccine is important. An inactivated hantavirus vaccine (IHV) has been used in Korea, but there has been controversy regarding its effectiveness. We conducted a case-control study to evaluate the vaccine effectiveness (VE) of IHV against HFRS in the Korean military. Unadjusted and adjusted VEs of IHV were 59.1% and 58.9%, respectively. VE was higher in divisions with high incidence of HFRS (unadjusted VE, 71.4%; adjusted VE, 78.7%). Our study demonstrated the moderate effectiveness of IHV in high-risk populations residing in endemic area.

Background The potential effect of the inactivated hantavirus vaccine (IHV) remains controversial; however, it appears to be moderately effective for patients at high risk of hemorrhagic fever with renal syndrome (HFRS). This study of the epidemiology of HFRS from 2001 to 2017 aimed to examine those at high risk of HFRS in the Republic of Korea (ROK), particularly in terms of disease distribution according to age. Methods Raw data of HFRS patients recorded in Korea from 2001 to 2017 were obtained from the Korean Center for Disease Control and Prevention. Patients were divided into three age groups: ≤39, 40–69, and ≥ 70 years. The incidence rate per 100,000 individuals in each age group was calculated using population data. The 12-month year was divided into three-month quarters, and the number and proportion of patients corresponding to each quarter were calculated. The effects of time, sex, and quarter on HFRS incidence were assessed in a Poisson regression analysis. Results From 2001 to 2017, 7048 HFRS patients were recorded nationwide. Among these patients, the proportion of patients aged ≥70 years increased gradually from 16.4% in 2001 to 43.9% in 2017. Regarding the quarter-year periods, the fourth quarter contained a significantly higher proportion of patients in the ≥70 years group (69.4%) compared to the other age groups. In the Poisson regression analysis, patients aged ≥70 years had a significantly higher relative risk of HFRS incidence within each quartile compared to those in the other age groups (2.102- and 10.029-fold in the third and fourth quarters, respectively). An analysis of disease incidence revealed a more distinct pattern in seasonal variation among those aged ≥70 years compared with other age groups. Conclusions In this study of the incidence of HFRS in the ROK, subjects aged ≥70 years exhibited a gradual increase in incidence and a distinct pattern of seasonal variation. These results may be important to identify individuals in Korea who are at high risk of developing HFRS. In future, active immunization programs will be needed to control HFRS among these high-risk groups in Korea.

To establish a dual fluorescence quantitative real-time polymerase chain reaction (DFqRT-PCR) method for typing inactivated bivalent vaccines of Hantaan virus (HTNV, type I) and Seoul virus (SEOV, type II) found in China. Primers and probes were designed based on S segment of the Hantavirus. FAM and HEX were added to the probes for the type I and type II vaccines, respectively. The S fragments were cloned into the pMD18-T vector to create pMD18-T/HTNV and pMD18-T/SEOV plasmids, respectively. The DFqRT-PCR reaction conditions were optimized. The specificity, sensitivity, accuracy, and reproducibility of the DFqRT-PCR method within and among batches of the samples and labs were evaluated. The sensitivity of the DFqRT-PCR method for detecting type I and II vaccines was 4.68 × 101 copies/µL and 5 × 101 copies/µL of pMD18-T/HTNV and pMD18-T/SEOV, respectively. This method distinguished the hantavirus vaccines from several other virus genus and distinguished the type I and II vaccines from each other with coefficients of variation (CVs) of the intra- and inter-batch assay of 0.19-0.66% and 0.09-0.69%, respectively. For bivalent inactivated vaccine, the CVs of the intra- and inter-batch assays, and the intra- and inter-laboratory assays were 0.06-1.82% for the samples from the same batches and different batches from the same manufacturer or the samples from the different manufacturers. The DFqRT-PCR method was simple, fast, and sensitive for identifying and determining the inactivated hantavirus vaccine with high accuracy and reproducibility. Therefore, it can be used for quality control of hantavirus vaccines. J. Med. Virol. 89:10-16, 2017. © 2016 Wiley Periodicals, Inc.

A safe and effective Hantaan virus (HTNV) vaccine is highly desirable because HTNV causes an acute and often fatal disease (hemorrhagic fever with renal syndrome, HFRS). Since the immunity of the inactivated vaccine is weak and the safety is poor, HTNV virus-like particles (VLPs) offer an attractive and safe alternative. These particles lack the viral genome but are perceived by the immune system as virus particles. We hypothesized that adding immunostimulatory signals to VLPs would enhance their efficacy. To accomplish this enhancement, we generated chimeric HTNV VLPs containing glycosylphosphatidylinositol (GPI)-anchored granulocyte macrophage colony-stimulating factor (GM-CSF) or CD40 ligand (CD40L) and investigated their biological activity in vitro. The immunization of mice with chimeric HTNV VLPs containing GM-CSF or CD40L induced stronger humoral immune responses and cellular immune responses compared to the HTNV VLPs and Chinese commercial inactivated hantavirus vaccine. Chimeric HTNV VLPs containing GM-CSF or CD40L also protected mice from an HTNV challenge. Altogether, our results suggest that anchoring immunostimulatory molecules into HTNV VLPs can be a potential approach for the control and prevention of HFRS.

Sin Nombre virus (SNV; family Bunyaviridae, genus Hantavirus) causes a hemorrhagic fever known as hantavirus pulmonary syndrome (HPS) in North America. There have been approximately 200 fatal cases of HPS in the United States since 1993, predominantly in healthy working-age males (case fatality rate 35%). There are no FDA-approved vaccines or drugs to prevent or treat HPS. Previously, we reported that hantavirus vaccines based on the full-length M gene segment of Andes virus (ANDV) for HPS in South America, and Hantaan virus (HTNV) and Puumala virus (PUUV) for hemorrhagic fever with renal syndrome (HFRS) in Eurasia, all elicited high-titer neutralizing antibodies in animal models. HFRS is more prevalent than HPS (>20,000 cases per year) but less pathogenic (case fatality rate 1–15%). Here, we report the construction and testing of a SNV full-length M gene-based DNA vaccine to prevent HPS. Rabbits vaccinated with the SNV DNA vaccine by muscle electroporation (mEP) developed high titers of neutralizing antibodies. Furthermore, hamsters vaccinated three times with the SNV DNA vaccine using a gene gun were completely protected against SNV infection. This is the first vaccine of any kind that specifically elicits high-titer neutralizing antibodies against SNV. To test the possibility of producing a pan-hantavirus vaccine, rabbits were vaccinated by mEP with an HPS mix (ANDV and SNV plasmids), or HFRS mix (HTNV and PUUV plasmids), or HPS/HFRS mix (all four plasmids). The HPS mix and HFRS mix elicited neutralizing antibodies predominantly against ANDV/SNV and HTNV/PUUV, respectively. Furthermore, the HPS/HFRS mix elicited neutralizing antibodies against all four viruses. These findings demonstrate a pan-hantavirus vaccine using a mixed-plasmid DNA vaccine approach is feasible and warrants further development.

A safe and effective hantavirus vaccine is highly desirable since hantaviruses are distributed worldwide and cause an acute and often fatal disease (hemorrhagic fever with renal syndrome, HFRS). Virus-like particles (VLPs) displaying functional viral proteins could provide effective vaccines against a few viruses, but their ability to induce hantavirus-specific immune response has not been adequately investigated. To measure the immunogenicity of Hantaan virus-like particles (HTN-VLPs) vaccine, we generated recombinant HTN-VLPs by co-expressing Hantaan virus nucleocapsid (N) protein and glycoproteins (Gn and Gc) in Chinese hamster ovary (CHO) cells. We compared intramuscular versus subcutaneous administration of HTN-VLPs for the ability to induce specific immune response against Hantaan virus infection. Mice that received both intramuscular and subcutaneous immunizations of HTN-VLPs were sufficiently stimulated specific antibody response against Hantaan virus N protein and glycoproteins, which was comparable to Chinese commercial inactivated bivalent hantaviruses vaccine. Moreover, vaccination with HTN-VLPs also resulted in the induction of higher levels of specific cellular response to N protein than that of inactivated vaccine. Our results provide an important insight towards the development of hantaviruses-like particles as a potential candidate vaccine for the control and prevention of hantaviruses infection.

Seoul virus (SEOV) is one of the four hantaviruses known to cause haemorrhagic fever with renal syndrome. The medium genome segment encodes the Gn/Gc glycoproteins of SEOV, which form the major structural part of the virus envelope. Gc and/or Gn are the candidate antigens of hantavirus for induction of a highly immunogenic response for hantavirus vaccine. In this study, the immune response induced by a replication-competent recombinant canine adenovirus type 2 expressing the Gc protein of SEOV was evaluated in BALB/c mice. Sera from immunized mice contained neutralizing antibodies that could specifically recognize SEOV and neutralize its infectivity in vitro. Moreover, the recombinant virus induced complete protection against an intensive infectious challenge with approximately 1000 50 % infective doses for SEOV strain CC-2. Protective-level neutralizing antibodies were maintained for at least 20 weeks. This recombinant virus is therefore a potential alternative to the inactivated vaccine.

The hantaviruses of the Americas are being recognized as a numerous and growing group of rodent-borne viruses that cause a disease called hantavirus pulmonary syndrome (HPS). The American viruses all belong to the genus Hantavirus of the family Bunyaviridae. There are recent general reviews of hantaviruses and their molecular genetics, but this chapter emphasizes some of the recent findings in the Americas. Only two hantaviruses were known in the Americas before 1993: Prospect Hill virus from the meadow vole Microtus pennsylvanicus and Seoul virus from the Old World rodent Rattus norvegicus. In 1993 an epidemic of unexplained adult respiratory distress syndrome in the southwestern U.S. was serologically linked to hantaviruses. The most commonly used serological tests are the indirect fluorescent antibody (IFA) test and more recently the enzyme-linked immunosorbent assay (ELISA). Hantavirus vaccine development faces some formidable tasks. There is no animal model of HPS or hemorrhagic fever with renal syndrome (HFRS) to measure attenuation or to study possible immunopathological interactions with vaccines. The diversity of the rodent taxon (Muridae and subfamily Sigmodontinae) suggests that there will be variation in the epidemiology and clinical presentation of HPS according to the individual causative virus, although to date the syndrome has been recognizable as HPS, and the epidemiology can be largely understood by patterns of rodent-human interactions.

Rodent-borne hantaviruses are associated with two main clinical disorders in humans: hemorrhagic fever with renal syndrome and hantavirus cardiopulmonary syndrome. Although hantavirus diseases can be life threatening and numerous research efforts are focused on the development of hantavirus prevention, no specific antiviral therapy is yet available and, at this time, no WHO-approved vaccine has gained widespread acceptance. This review will summarize the current knowledge and recent progress as well as new speculative approaches in the development of hantavirus vaccines.

Seoul virus glycoprotein Gn is a major structural protein and candidate antigen of hantavirus that induces a highly immunogenic response for hantavirus vaccine. In this study, a replication-competent recombinant canine adenovirus type-2 expressing Gn was constructed by the in vitro ligation method. The Gn expression cassette, including the human cytomegalovirus (hCMV) promoter/enhancer and the SV40 early mRNA polyadenylation signal, was cloned into the SspI site of the E3 region which is not essential for proliferation of CAV-2. Expression of Gn was confirmed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting.

We examined whether a vesicular stomatitis virus (VSV) pseudotype bearing the hantavirus envelope glycoproteins (GPs) G1 and G2 (VSVdeltaG*HTN) could be used as a safe and effective alternative to native hantavirus. Mice were immunized with purified particles of VSVdeltaG*HTN. After the second immunization, all mice produced anti-GP antibody as detected in ELISA and a neutralization test. After the third immunization, the mice were challenged with Hantaan virus. Neither anti-NP antibody production nor Hantaan virus-specific CD8 T-cell reactions were detected in these mice. The present study demonstrated the potential of using a pseudotype VSV system as a tool for developing a hantavirus vaccine.

A case-control study in the Republic of Korea evaluated the protective effectiveness of the hantavirus vaccine. Point estimates showed increasing effectiveness with increasing numbers of doses received: 25% for one dose, 46% for two doses, and 75% for three doses. All 95% confidence intervals overlapped zero; therefore, the findings could be due to chance.

Purpose of review This article focuses on recent developments in knowledge about hantavirus infections and hantavirus cardiopulmonary syndrome in children. We highlight clinical characterization, epidemiology, pathogenesis, diagnostic techniques, and current alternatives for treatment and prevention. Recent findings After the first description of hantavirus pulmonary syndrome (HPS) in 1993 in the United States, new cases of HPS and new hantavirus species have been described throughout the Americas. The factors involved in the expression of hantavirus disease have, in part, been recognized, but there have been descriptions of newer viruses and newer rodent reservoirs. Several seroprevalence studies suggest that the virus-host interaction has been taking place for many years, and changes in human behavior and wild rodent ecology, sometimes secondary to industrial progress, facilitate the clinical recognition of disease. Sin nombre virus (SNV) and Andes virus (ANDV) are examples of the same disease with differences in the virus virulence and in the host response. The North American syndrome and the Southern HPS differ in epidemiologic patterns and in the spectrum of disease. Summary Currently, no Food and Drug Administration (FDA)-approved antiviral drugs, vaccines, or immunotherapeutic agents are available for treatment of the disease, and therapy is primarily supportive. Intensive care medicine has played an outstanding role in decreasing the lethality of HPS. A ribavirin trial in the United States did not support the use of the drug in fully developed HCPS. Recently published data suggest that a strong neutralizing antibody response may be a predictor of effective clearance of and recovery from SNV infection. This has raised the possibility that passive immunotherapy may be useful in HCPS. Extensive work has been done to develop a hantavirus vaccine, but at present it seems unlikely that a vaccine will be in commercial development in the near future.

Objective: Hantaviruses cause haemorrhagic fever with renal syndrome and result in severe morbidity and mortality in humans. Safe and effective vaccines are needed to reduce the incidence of human illness. In this study, the immune response to an inactivated hantavirus vaccine was measured in 64 human volunteers for Hantavax® and 10 human volunteers for a Hantaan-Puumala virus combination vaccine at high risk of infection by virtue of their residence and occupation. Methods: A serum sample was obtained from each volunteer before the initial vaccination (day 0), 30 days after each inoculation and 1 year after the initial dose. All sera were kept at –20° until tested. IgG-specific antibody titres were tested by ELISA and immunofluorescence assay (IFA). Neutralizing antibody titres were determined by a plaque reduction neutralizing test. Results: Thirty days after vaccination, 79 and 62% of the subjects had developed a significant hantavirus antibody titre as measured by IFA and ELISA, respectively. Seroconversion rates increased to 97% 1 month after the booster dose. Neutralizing antibody titres paralleled this trend, with 13% of vaccine recipients producing neutralizing antibody 1 month after the first dose and 75% of vaccine recipients responding 1 month after boosting. Antibody titres had declined by 1 year, however, with only 37 and 43% of sera found to be positive by IFA and ELISA, respectively. Re-vaccination at this time produced a vigorous anamnestic response, with 94 and 100% of vaccine recipients yielding positive antibody titres. Only 50% of the sampled population, however, produced neutralizing antibodies following the booster dose 1 year later. Conclusions: The vaccine was well tolerated and there were no apparent differences in the responses in human subjects. However, further improvement of this vaccine is necessary in order to induce a longer-lasting humoral immune response.

Hantaviruses cause haemorrhagic fever with renal syndrome (HFRS) and result in severe human morbidity and mortality. Safe and effective vaccines are needed urgently in order to reduce the incidence of human illness. Hitherto studies of hantavirus vaccine efficiency have been limited to individuals at low risk of infection. In this study the immune response to an inactivated hantavirus vaccine was measured in 64 human volunteers at high risk of infection by virtue of residence and occupation. 30 d after vaccination, 79% of subjects developed a significant hantavirus antibody titre as measured by immunofluorescence (IFA) and 62% by enzyme linked immunosorbent assay (ELISA). Seroconversion rates increased to 97% one month after the booster dose. Neutralising antibody titres paralleled this trend with 13% of vaccine recipients producing neutralising antibody one month after the first dose and 75% of vaccine recipients responding one month after boosting. Antibody titres had declined by one year, however, with only 37% and 43% of sera positive by IFA and ELISA, respectively. Re-vaccination at this time produced a vigorous anamnestic response with 94% and 100% of vaccine recipients yielding positive antibody titres. Only 50% of the sampled population, however, produced neutralising antibodies following the booster dose one year later. The vaccine was well tolerated and there were no apparent differences in the responses of males and females. However, further improvement of this vaccine is necessary in order to induce a more longlasting humoral immune response.

A recombinant vaccine against hantavirus is undergoing clinical development by US researchers. The hantavirus vaccine, designed to prevent haemorrhagic fever with renal syndrome, has shown encouraging results in preclinical studies. In a phase I study, immunisation with hantavirus vaccine elicited both humoral and cellular immune responses against Hantaan virus, a type of hantavirus. However, pre-existing immunity to vaccinia virus interferes with the immunogenicity of hantavirus vaccine in humans. Researchers are now looking at ways of overcoming this and improving the potential of hantavirus vaccine. These new approaches, as well as the findings from the preclinical and phase I studies, were discussed at the 19th International Congress of Chemotherapy [Montreal, Canada; July 1995].