作者: Polanco, Laura C. ; Sakharkar, Mrunal ; Ulrich, Rainer G. ; Herbert, Andrew S. ; Slough, Megan M. ; Dye, John M. ; O’Brien, Cecilia M. ; Wec, Anna Z. ; Walker, Laura M. ; Abelson, Dafna M. ; Bornholdt, Zachary A. ; Bakken, Russell R. ; Forsell, Mattias N. E. ; Jangra, Rohit K. ; Guardado-Calvo, Pablo ; Serris, Alexandra ; Mittler, Eva ; Geoghegan, James C. ; Bradfute, Steven B. ; Tynell, Janne ; Strandin, Tomas ; Vapalahti, Olli ; Chandran, Kartik ; Wigren-Byström, Julia ; Pehau-Arnaudet, Gerard ; Ahlm, Clas ; Rey, Felix A. ; Keller, Markus ; Zeitlin, Larry

The rodent-borne hantavirus Puumala virus (PUUV) and related agents cause hemorrhagic fever with renal syndrome (HFRS) in humans. Other hantaviruses, including Andes virus (ANDV) and Sin Nombre virus, cause a distinct zoonotic disease, hantavirus cardiopulmonary syndrome (HCPS). Although these infections are severe and have substantial case fatality rates, no FDA-approved hantavirus countermeasures are available. Recent work suggests that monoclonal antibodies may have therapeutic utility. We describe here the isolation of human neutralizing antibodies (nAbs) against tetrameric Gn/Gc glycoprotein spikes from PUUV-experienced donors. We define a dominant class of nAbs recognizing the “capping loop” of Gn that masks the hydrophobic fusion loops in Gc. A subset of nAbs in this class, including ADI-42898, bound Gn/Gc complexes but not Gn alone, strongly suggesting that they recognize a quaternary epitope encompassing both Gn and Gc. ADI-42898 blocked the cell entry of seven HCPS- and HFRS-associated hantaviruses, and single doses of this nAb could protect Syrian hamsters and bank voles challenged with the highly virulent HCPS-causing ANDV and HFRS-causing PUUV, respectively. ADI-42898 is a promising candidate for clinical development as a countermeasure for both HCPS and HFRS, and its mode of Gn/Gc recognition informs the development of broadly protective hantavirus vaccines.

2021-02-01·Vaccine3区 · 医学

Small animal jet injection technique results in enhanced immunogenicity of hantavirus DNA vaccines

3区 · 医学

Article

作者: Cohen, Melanie V ; Zeng, Xiankun ; Long, Simon ; Somerville, Brandon ; Josleyn, Matthew D ; Brocato, Rebecca L ; Hooper, Jay W ; Kwilas, Steven A ; Principe, Lucia M ; Perley, Casey C

DNA vaccine evaluation in small animals is hampered by low immunogenicity when the vaccines are delivered using a needle and syringe. To overcome this technical hurdle we tested the possibility that a device developed for human intradermal medicine delivery might be adapted to successfully deliver a DNA vaccine to small animals. Disposable syringe jet injection (DSJI) does not currently exist for small animals. However, a commercialized, human intradermal device used to to administer medicines to the human dermis in a 0.1 mL volume was evaluated in Syrian hamsters. Here, we found that hantavirus DNA vaccines administered to hamsters using DSJI were substantially more immunogenic than the same vaccines delivered by needle/syringe or particle mediated epidermal delivery (gene gun) vaccination. By adjusting how the device was used we could deliver vaccine to either subcutaneous tissues, or through the skin into the muscle. RNA and/or antigen expression was detected in epidermal, subepidermal and fibroblast cells. We directly compared six optimized and non-optimized hantavirus DNA vaccines in hamsters. Optimization, including codon-usage and mRNA stability, did not necessarily result in increased immunogenicity for all vaccines tested; however, optimization of the Andes virus (ANDV) DNA vaccine protected vaccinated hamsters from lethal disease. This is the first time active vaccination with an ANDV DNA vaccine has shown protective efficacy in the hamster model. The adaptation of a human intradermal jet injection device for use as a method of subcutaneous and intramuscular jet injection of DNA vaccines will advance the development of nucleic acid based medical countermeasures for diseases modeled in hamsters.

2018-12-31·Kidney Research and Clinical Practice3区 · 医学

Effectiveness of inactivated hantavirus vaccine on the disease severity of hemorrhagic fever with renal syndrome

3区 · 医学

ArticleOA

作者: Park, Hayne ; Yi, Yongjin ; Jung, Jaehun

BACKGROUNDAn inactivated Hantaan virus vaccine (iHV) has been broadly used as a preventive strategy for hemorrhagic fever with renal syndrome (HFRS) by the South Korean Army. After the vaccination program was initiated, the overall incidence of HFRS cases was reduced in the military population. While there are about 400 HFRS cases annually, few studies have demonstrated the efficacy of the iHV in field settings. Therefore, this study aimed to evaluate the iHV efficacy on HFRS severity.METHODSFrom 2009 to 2017, HFRS cases were collected in South Korean Army hospitals along with patients' vaccination history. HFRS patients were classified retrospectively into two groups according to vaccination records: no history of iHV vaccination and valid vaccination. Vaccine efficacy on the severity of acute kidney injury (AKI) stage and dialysis events were investigated.RESULTSThe effects of the iHV on renal injury severity in between 18 valid vaccinated and 110 non-vaccinated patients were respectively evaluated. In the valid vaccination group, six of the 18 HFRS patients (33.3%) had stage 3 AKI, compared to 60 of the 110 (54.5%) patients in the non-vaccination group. The iHV efficacy against disease progression (VE_p) was 58.1% (95% confidence interval, 31.3% to 88.0%).CONCLUSIONThe iHV efficacy against the progression of HFRS failed to demonstrate statistically significant protection. However, different severity profiles were observed between the iHV and non-vaccination groups. Additional studies with larger populations are needed to demonstrate the effectiveness of the iHV in patients with HFRS.

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