Characteristics of passive immunity against hantavirus infection in rats

138

133

Hantavirus pulmonary syndrome (HPS) is a rapidly progressing human disease with one of the highest case fatality rates (30 to 50%) of any acute viral disease known. There are no vaccines, effective antiviral drugs, or immunologics to prevent or treat HPS. In an attempt to develop HPS medical countermeasures, we constructed an expression plasmid, pWRG/AND-M, that contains the full-length M genome segment of Andes virus (ANDV), a South American hantavirus. Transfection experiments in cell culture indicated that both the G1 and G2 glycoproteins are expressed from pWRG/AND-M. Rhesus macaques vaccinated by gene gun with pWRG/ AND-M developed remarkably high levels of neutralizing antibodies that not only neutralized ANDV but also cross-neutralized other HPS-associated hantaviruses, including Sin Nombre virus. To determine if the antibodies elicited in the monkeys could confer protection, we performed a series of passive-transfer experiments using a recently described lethal HPS animal model (i.e., adult Syrian hamsters develop HPS and die within 10 to 15 days after challenge with ANDV). When injected into hamsters 1 day before challenge, sera from the vaccinated monkeys either provided sterile protection or delayed the onset of HPS and death. When injected on day 4 or 5 after challenge, the monkey sera protected 100% of the hamsters from lethal disease. These data provide a proof of concept for a gene-based HPS vaccine and also demonstrate the potential value of a postexposure immunoprophylactic to treat individuals after exposure, or potential exposure, to these highly lethal hantaviruses.Hantaviruses are rodent-borne, enveloped RNA viruses in the family Bunyaviridae. These viruses have a trisegmented, negative-sense, single-stranded RNA genome. The three gene segments, L, S, and M, encode the RNA polymerase, nucleoprotein, and envelope glycoproteins (G1 and G2), respectively (27). Hantaviruses cause a spectrum of vascular-leak syndromes in humans ranging from proteinuria and petechia to pulmonary edema and frank hemorrhage (20,21). New World hantaviruses have been associated with a highly lethal disease, hantavirus pulmonary syndrome (HPS), that is characterized by fever and vascular leakage, resulting in noncardiogenic pulmonary edema followed by shock. Case fatality rates for HPS caused by the most prevalent North American and South American hantaviruses, Sin Nombre virus (SNV) and Andes virus (ANDV), are 30 to 50%. Old World hantaviruses have been associated with a mild-to-severe disease, hemorrhagic fever with renal syndrome (HFRS), that is characterized by fever, vascular leakage resulting in hemorrhagic manifestations, and renal failure. The case fatality rate for HFRS ranges from Ͻ0.1% to 15%. The four Old World hantaviruses associated with HFRS include Puumala virus (PUUV), Dobrava virus (DOBV), Seoul virus (SEOV), and Hantaan virus (HTNV).A need for vaccines against HFRS has been recognized since HTNV was isolated in 1978 (16). Inactivated-virus vaccines based on HTNV, SEOV, and PUUV have been developed in...

Section: Discussionmentioning

confidence: 99%

Active and Passive Vaccination against Hantavirus Pulmonary Syndrome with Andes Virus M Genome Segment-Based DNA Vaccine

Custer

Thompson

Schmaljohn

et al. 2003

138

133

“…Passive transfer of neutralizing antibodies can protect susceptible animals from hantavirus infection (8,(53)(54)(55)62), and there is a report that convalescent-human sera can afford some protection in acutely infected individuals (58). Thus, characterizing the structures and functions of these proteins will be important for understanding CCHFV tropism and pathogenesis as well as for vaccine development.…”

mentioning

confidence: 99%

Cellular Localization and Antigenic Characterization of Crimean-Congo Hemorrhagic Fever Virus Glycoproteins

Bertolotti-Ciarlet

Smith

Strecker

et al. 2005

150

202

Crimean-Congo hemorrhagic fever virus (CCHFV), a member of the genus Nairovirus of the family Bunyaviridae, causes severe disease with high rates of mortality in humans. The CCHFV M RNA segment encodes the virus glycoproteins GN and GC. To understand the processing and intracellular localization of the CCHFV glycoproteins as well as their neutralization and protection determinants, we produced and characterized monoclonal antibodies (MAbs) specific for both GN and GC. Using these MAbs, we found that GN predominantly colocalized with a Golgi marker when expressed alone or with GC, while GC was transported to the Golgi apparatus only in the presence of GN. Both proteins remained endo-β-N-acetylglucosaminidase H sensitive, indicating that the CCHFV glycoproteins are most likely targeted to the cis Golgi apparatus. Golgi targeting information partly resides within the GN ectodomain, because a soluble version of GN lacking its transmembrane and cytoplasmic domains also localized to the Golgi apparatus. Coexpression of soluble versions of GN and GC also resulted in localization of soluble GC to the Golgi apparatus, indicating that the ectodomains of these proteins are sufficient for the interactions needed for Golgi targeting. Finally, the mucin-like and P35 domains, located at the N terminus of the GN precursor protein and removed posttranslationally by endoproteolysis, were required for Golgi targeting of GN when it was expressed alone but were dispensable when GC was coexpressed. In neutralization assays on SW-13 cells, MAbs to GC, but not to GN, prevented CCHFV infection. However, only a subset of GC MAbs protected mice in passive-immunization experiments, while some nonneutralizing GN MAbs efficiently protected animals from a lethal CCHFV challenge. Thus, neutralization of CCHFV likely depends not only on the properties of the antibody, but on host cell factors as well. In addition, nonneutralizing antibody-dependent mechanisms, such as antibody-dependent cell-mediated cytotoxicity, may be involved in the in vivo protection seen with the MAbs to GC

“…The large (L) segment encodes the RNA-dependent RNA polymerase the small (S) segment encodes the nucleocapsid protein (N) and the medium (M) segment encodes a polypeptide that is cotranslationally cleaved to yield two membrane-associated glycoproteins, G1 and G2. G1 and G2 form oligomers that comprise the surface morphologic units of the virion and are the targets of neutralizing antibodies (1,9,29). Passive transfer of neutralizing antibodies protects newborn rats (29), suckling mice (2), or hamsters (24) against infection.…”

mentioning

confidence: 99%

“…G1 and G2 form oligomers that comprise the surface morphologic units of the virion and are the targets of neutralizing antibodies (1,9,29). Passive transfer of neutralizing antibodies protects newborn rats (29), suckling mice (2), or hamsters (24) against infection. N-specific antibodies are neither neutralizing nor protective.…”

mentioning

confidence: 99%

DNA Vaccination with the Hantaan Virus M Gene Protects Hamsters against Three of Four HFRS Hantaviruses and Elicits a High-Titer Neutralizing Antibody Response in Rhesus Monkeys

Hooper

Custer

Thompson

et al. 2001

127

139