Using high titer West Nile intravenous immunoglobulin from selected Israeli donors for treatment of West Nile virus infection

Ben‐Nathan, D.; Gershoni-Yahalom, Orly; Samina, Itzchak; Khinich, Yevgeny; Nur, Israel; Laub, Orgad; Gottreich, Ahuva; Simanov, Michael; Porgador, Angel; Rager-Zisman, Bracha; Orr, Nadav

doi:10.1186/1471-2334-9-18

Cited by 80 publications

(53 citation statements)

References 34 publications

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“…We previously showed that IVIG could temper CNS infiltration by pathogenic Ly6C high monocytes and Ly6G + neutrophils, and thereby protect mice from lethal HSV1 encephalitis (Ramakrishna et al, 2011). Additionally, earlier studies showed that high titrated IVIG collected from WNV endemic areas, but not non-immune IVIG, was protective in mouse WNV challenge studies when given at low doses (0.1-0.6 g kg 21 ) (Ben-Nathan et al, 2009;. To determine the therapeutic potential of generic IVIG as an anti-inflammatory agent, we investigated the effects of high-dose (¢1 g kg 21 ) and lowdose (160 mg kg 21 ) IVIG on the development of WNV encephalitis.…”

Section: Resultsmentioning

confidence: 99%

Anti-inflammatory activity of intravenous immunoglobulins protects against West Nile virus encephalitis

Srivastava

Ramakrishna

Cantin

2015

Journal of General Virology

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West Nile virus (WNV), an important global human pathogen, targets neurons to cause lethal encephalitis, primarily in elderly and immunocompromised patients. Currently, there are no approved therapeutic agents or vaccines to treat WNV encephalitis. Recent studies have suggested that inflammation is a major contributor to WNV encephalitis morbidity. In this study we evaluated the use of IVIG (intravenous immunoglobulins -a clinical product comprising pooled human IgG) as an anti-inflammatory treatment in a model of lethal WNV infection. We report here that IVIG and pooled human WNV convalescent sera (WNV-IVIG) inhibited development of lethal WNV encephalitis by suppressing central nervous system (CNS) infiltration by CD45 high leukocytes. Pathogenic Ly6C high CD11b + monocytes were the major infiltrating subset in the CNS of infected control mice, whereas IVIG profoundly reduced infiltration of these pathogenic Ly6C high monocytes into the CNS of infected mice. Interestingly, WNV-IVIG was more efficacious than IVIG in controlling CNS inflammation when mice were challenged with a high-dose inoculum (10 5 versus 10 4 p.f.u.) of WNV. Importantly, adsorption of WNV E-glycoprotein neutralizing antibodies did not abrogate IVIG protection, consistent with virus neutralization not being essential for IVIG protection. These findings confirmed the potent immunomodulatory activity of generic IVIG, and emphasized its potential as an effective immunotherapeutic drug for encephalitis and other virus induced inflammatory diseases.

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Section: Resultsmentioning

confidence: 99%

Anti-inflammatory activity of intravenous immunoglobulins protects against West Nile virus encephalitis

Srivastava

Ramakrishna

Cantin

2015

Journal of General Virology

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“…When a virus or microbial agent is expanding its geographical range, exposure of the formerly naïve population to this novel agent is reflected in the Ab content of IVIG. This was demonstrated, e.g., for US-IVIG after the introduction of WNV into the United States in 1999 (4,25,31) and recently also for EU-IVIG, where increasing WNV-neutralizing Ab titers were detected in EU-IVIG lots manufactured after 2009, even though no human WNV infections have yet been reported from the countries in which the plasma was sourced (31).To further increase the understanding of the geographical difference in IVIG Ab content, we determined the neutralizing Ab titers of IVIG preparations for tick-borne encephalitis virus (TBEV). This member of the Flaviviridae, for which three subtypes (European, Siberian, and Far Eastern) are distinguished, may cause tick-borne encephalitis (TBE), a potentially serious neurological disease with high fever and encephalitis (33), while 70 to 95% of human infections in regions in which the virus is endemic are either subclinical or totally asymptomatic (12).…”

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confidence: 99%

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confidence: 99%

Tick-Borne Encephalitis Virus-Neutralizing Antibodies in Different Immunoglobulin Preparations

Rabel¹,

Planitzer²,

Farcet³

et al. 2012

Clin. Vaccine Immunol.

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Patients with primary immunodeficiency (PIDs) depend on the presence of a variety of antibody specificities in intravenous immunoglobulin (IVIG). Using the tick-borne encephalitis virus (TBEV), geographic variability in IVIG antibody content was shown. Care should therefore be exercised when treating PIDs in a given geography, as only locally sourced plasma contains the antibody specificities against the circulating pathogens in the given locality. Intravenous immunoglobulin (IVIG) contains the pooled antibodies (Abs) from at least 3,000 to 60,000 healthy blood and plasma donors (10). One of the main areas of IVIG application is as Ab replacement therapy in patients with primary immunodeficiency (PIDs) (22). These persons critically depend on the presence of a variety of antibody specificities in IVIG, which ensures continued protection against any infectious agent they might encounter. As IVIG is manufactured from the variable resource human plasma, lot-to-lot variation in Ab levels of IVIG products are inevitable and have been reported (18). In addition, the Ab content in IVIG differs depending on the geographic origin of the plasma that was used in manufacture: U.S.-sourced (US-IVIG) or European Union-sourced (EU-IVIG) IVIG contains significantly different Ab levels against hepatitis A virus (8, 21), West Nile virus (WNV) (25), cytomegalovirus (21,27), and the different echovirus serotypes (24), with some evidence of a difference in Ab content for measles and rubella (21). The reason for this geographic variability in IVIG Ab content is often not clear, yet one of the more obvious variables affecting the quantity and specificity of Abs in IVIG is the endemicity of a pathogen, where a change in the temporal or geographic pattern of virus circulation affects the antibody content of the final IVIG. When a virus or microbial agent is expanding its geographical range, exposure of the formerly naïve population to this novel agent is reflected in the Ab content of IVIG. This was demonstrated, e.g., for US-IVIG after the introduction of WNV into the United States in 1999 (4,25,31) and recently also for EU-IVIG, where increasing WNV-neutralizing Ab titers were detected in EU-IVIG lots manufactured after 2009, even though no human WNV infections have yet been reported from the countries in which the plasma was sourced (31).To further increase the understanding of the geographical difference in IVIG Ab content, we determined the neutralizing Ab titers of IVIG preparations for tick-borne encephalitis virus (TBEV). This member of the Flaviviridae, for which three subtypes (European, Siberian, and Far Eastern) are distinguished, may cause tick-borne encephalitis (TBE), a potentially serious neurological disease with high fever and encephalitis (33), while 70 to 95% of human infections in regions in which the virus is endemic are either subclinical or totally asymptomatic (12). During the last 30 years, TBE morbidity has increased by 400% in Europe (36), and TBEV is currently expanding from its geographical range in Central...

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“…Moreover, partially mature flavivirus virions containing some uncleaved prM also retain infectivity (29,33,51 (22,74). Moreover, preexposure prophylaxis and postexposure therapy with WNV-specific monoclonal antibody (MAb) or polyclonal antibodies conferred protection in both mice and hamsters (6,7,22,48,53,71,74,75). The E protein of WNV is the principal target of neutralizing antibodies.…”

mentioning

confidence: 99%

Poorly Neutralizing Cross-Reactive Antibodies against the Fusion Loop of West Nile Virus Envelope Protein ProtectIn Vivovia Fcγ Receptor and Complement-Dependent Effector Mechanisms

Vogt

Dowd

Engle

et al. 2011

J Virol

117

104

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The human antibody response to flavivirus infection is dominantly directed against a cross-reactive epitope on the fusion loop of domain II (DII-FL) of the envelope (E) protein. Although antibodies against this epitope fail to recognize fully mature West Nile virus (WNV) virions and accordingly neutralize infection poorly in vitro,their functional properties in vivo remain less well understood. Here, we show that while passive transfer of poorly neutralizing monoclonal antibodies (MAb) and polyclonal antibodies against the DII-FL epitope protect against lethal WNV infection in wild-type mice, they fail to protect mice lacking activating Fc␥ receptors (Fc␥R) and the complement opsonin C1q. Consistent with this, an aglycosyl chimeric mouse-human DII-FL MAb (E28) variant that lacks the ability to engage Fc␥R and C1q also did not protect against WNV infection in wild-type mice. Using a series of immunodeficient mice and antibody depletions of individual immune cell populations, we demonstrate that the nonneutralizing DII-FL MAb E28 does not require T, B, or NK cells, inflammatory monocytes, or neutrophils for protection. Rather, E28 treatment decreased viral load in the serum early in the course of infection, which resulted in blunted dissemination to the brain, an effect that required phagocytic cells, C1q, and Fc␥RIII (CD16). Overall, these studies enhance our understanding of the functional significance of immunodominant, poorly neutralizing antibodies in the polyclonal human antiflavivirus response and highlight the limitations of current in vitro surrogate markers of protection, such as cell-based neutralization assays, which cannot account for the beneficial effects conferred by these antibodies. West Nile virus (WNV) is a zoonotic mosquito-transmittedFlavivirus that can infect and cause disease in humans and many other vertebrate animals. The Flavivirus genus also contains other human pathogens of global relevance, including dengue virus (DENV), yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus. Most human WNV infections are asymptomatic, but about 20% of infected individuals experience a mild fever, and less than 1% develop severe neuroinvasive disease (67). Risk factors for symptomatic disease include an age of greater than 55 years, a compromised immune status, genetic variation in the OAS1 gene, and a CC5⌬32 genotype (17,26,40,41). Although WNV first appeared in the Western Hemisphere in 1999 in New York and spread rapidly through North America, surprisingly few human clinical infections have been reported in Central and South America, despite the migration of avian hosts and appropriate vectors for transmission (35,56).WNV infection requires attachment to cell surface receptors, which remain poorly defined, endocytosis, and acid-catalyzed fusion of the virus within the late endosome. After translation of input-strand RNA and viral replication, progeny virion assembly occurs within the endoplasmic reticulum (ER), with the capsid protein and genomic RNA associating with pre...

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Using high titer West Nile intravenous immunoglobulin from selected Israeli donors for treatment of West Nile virus infection

Cited by 80 publications

References 34 publications

Anti-inflammatory activity of intravenous immunoglobulins protects against West Nile virus encephalitis

Anti-inflammatory activity of intravenous immunoglobulins protects against West Nile virus encephalitis

Tick-Borne Encephalitis Virus-Neutralizing Antibodies in Different Immunoglobulin Preparations

Poorly Neutralizing Cross-Reactive Antibodies against the Fusion Loop of West Nile Virus Envelope Protein ProtectIn Vivovia Fcγ Receptor and Complement-Dependent Effector Mechanisms

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