The Fc Portion of Antibody to Yellow Fever Virus NS1 Is a Determinant of Protection against YF Encephalitis in Mice

Schlesinger, Jacob J.; Foltzer, Michael; Chapman, Susan

doi:10.1006/viro.1993.1015

Cited by 149 publications

(134 citation statements)

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“…Studies by other groups have shown that passive transfer of MAbs against YF and DEN NS1 prior to infection can protect mice (27,30,57,59). To determine whether anti-NS1 MAbs had therapeutic potential against WNV and to gain insight into the mechanisms of NS1-mediated protection, we produced a soluble recombinant WNV NS1 for immunization to create a large panel of novel anti-WNV NS1 MAbs.…”

Section: Resultsmentioning

confidence: 99%

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Antibodies against West Nile Virus Nonstructural Protein NS1 Prevent Lethal Infection through Fc γ Receptor-Dependent and -Independent Mechanisms

Chung

Nybakken

Thompson

et al. 2006

J Virol

227

239

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The flavivirus nonstructural protein NS1 is a highly conserved secreted glycoprotein that does not package with the virion. Immunization with NS1 elicits a protective immune response against yellow fever, dengue, and tick-borne encephalitis flaviviruses through poorly defined mechanisms. In this study, we purified a recombinant, secreted form of West Nile virus (WNV) NS1 glycoprotein from baculovirus-infected insect cells and generated 22 new NS1-specific monoclonal antibodies (MAbs). By performing competitive binding assays and expressing truncated NS1 proteins on the surface of yeast (Saccharomyces cerevisiae) and in bacteria, we mapped 21 of the newly generated MAbs to three NS1 fragments. Prophylaxis of C57BL/6 mice with any of four MAbs (10NS1, 14NS1, 16NS1, and 17NS1) strongly protected against lethal WNV infection (75 to 95% survival, respectively) compared to saline-treated controls (17% survival). In contrast, other anti-NS1 MAbs of the same isotype provided no significant protection. Notably, 14NS1 and 16NS1 also demonstrated marked efficacy as postexposure therapy, even when administered as a single dose 4 days after infection. Virologic analysis showed that 17NS1 protects at an early stage in infection through a C1q-independent and Fc ␥ receptor-dependent pathway. Interestingly, 14NS1, which maps to a distinct region on NS1, protected through a C1q-and Fc ␥ receptor-independent mechanism. Overall, our data suggest that distinct regions of NS1 can elicit protective humoral immunity against WNV through different mechanisms.West Nile virus (WNV) is a single-stranded, positive-senseenveloped RNA virus that is maintained in nature through a mosquito-bird-mosquito transmission cycle. It is endemic in parts of Africa, Europe, the Middle East, and Asia, and outbreaks now occur annually in North America. Humans, which are dead-end hosts, can develop a febrile illness that progresses to a meningitis or encephalitis syndrome (32). At present, treatment is supportive, and no vaccine exists for human use.A member of the Flaviviridae family, WNV is closely related to other major human pathogens such as yellow fever (YF), dengue (DEN), tick-borne encephalitis (TBE), Japanese encephalitis (JEV), and Murray Valley encephalitis (MVE) viruses. The 10.7-kilobase genome is translated as a single polyprotein, which is then cleaved into three structural proteins (C, prM/M, and E) and seven nonstructural (NS) proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) by both virus-and host-encoded proteases (5). The NS proteins include an RNA-dependent RNA polymerase (NS5), a helicase/protease (NS3), and other proteins that form part of the viral replication complex (36, 37).NS1 is a highly conserved 48-kDa glycoprotein with 12 invariant cysteine residues. Although the disulfide linkage arrangement of MVE and DEN NS1 has been described (4, 66), structural analysis is currently lacking. NS1 is inserted into the lumen of the endoplasmic reticulum via a signal peptide that is cleaved cotranslationally by a cellular signalase to gene...

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Section: Resultsmentioning

confidence: 99%

“…Immunization with purified NS1 or passive administration of some anti-YF and anti-DEN NS1 monoclonal antibodies (MAbs) protects mice against lethal virus challenge (12,22,27,30,33,34,56,57,59). However, no significant virologic analysis was performed in these studies to address the mechanism of protection.…”

mentioning

confidence: 99%

Antibodies against West Nile Virus Nonstructural Protein NS1 Prevent Lethal Infection through Fc γ Receptor-Dependent and -Independent Mechanisms

Chung

Nybakken

Thompson

et al. 2006

J Virol

227

239

View full text Add to dashboard Cite

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“…Accordingly, we previously observed IgG2a-dominated humoral immune responses after a similar immunization against the likewise glycosylated viral surface proteins hemagglutinin of influenza A or F of the respiratory syncytial virus (43). Intriguingly, IgG1 has been shown to be inferior to IgG2a with regard to protection from viral infections (44)(45)(46). Furthermore, even neutralizing Abs against influenza virus and HIV-1 demonstrate enhanced protection if expressed with an IgG2a Fc domain (8,47).…”

Section: Discussionmentioning

confidence: 97%

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Bonsmann

Niezold

Temchura

et al. 2015

The Journal of Immunology

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The importance of Fc-dependent effector functions of Abs induced by vaccination is increasingly recognized. However, vaccination of mice against HIV envelope (Env) induced a skewed Th cell response leading to Env-specific Abs with reduced effector function. To overcome this bias, GagPol-specific Th cells were harnessed to provide intrastructural help for Env-specific B cells after immunization with virus-like particles containing GagPol and Env. This led to a balanced Env-specific humoral immune response with a more inflammatory Fc glycan profile. The increased quality in the Ab response against Env was confirmed by FcγR activation assays. Because the Env-specific Th cell response was also biased in human vaccinees, intrastructural help is an attractive novel approach to increase the efficacy of prophylactic HIV Env-based vaccines and may also be applicable to other particulate vaccines.

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“…This cellular immune response may contribute significantly to the overall protective efficacy of a subunit vaccine. In addition, there is evidence that NS1 may elicit a humoral protective immune response involving the complement fixing activity of antibodies to this protein [29,30], through mechanisms, such as antibody-dependent, complement-mediated cytolysis, or Fc receptor mediated antibody-dependent cellular cytotoxicity [30]. Thus, the inclusion of NS1 in the vaccine formulation can be justified on the basis of a humoral as well as a cellular immune response.…”

Section: Introductionmentioning

confidence: 99%

Preparation and immunogenic properties of a recombinant West Nile subunit vaccine

Lieberman

Clements

Ogata

et al. 2007

Vaccine

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While several West Nile vaccines are being developed, none are yet available for humans. In this study aimed at developing a vaccine for humans, West Nile virus (WNV) envelope protein (E) and non-structural protein 1 (NS1) were produced in the Drosophila S2 cell expression system. The Cterminal 20% of the E protein, which contains the membrane anchor portion, was deleted, thus allowing for efficient secretion of the truncated protein (80E) into the cell culture medium. The proteins were purified by immunoaffinity chromatography (IAC) using monoclonal antibodies that were flavivirus envelope protein group specific (for the 80E) or flavivirus NS1 group specific (for NS1). The purified proteins were produced in high yield and used in conjunction with adjuvant formulations to vaccinate mice. The mice were tested for both humoral and cellular immune responses by a plaque reduction neutralization test and ELISA, and by lymphocyte proliferation and cytokine production assays, respectively. The results revealed that the 80E and the NS1 proteins induced both high-titered ELISA and neutralizing antibodies in mice. Splenocytes from immunized mice, cultured in vitro with the vaccine antigens as stimulants, showed excellent proliferation and production of cytokines . The level of antigen-stimulated lymphocyte proliferation and cytokine production was comparable to the level obtained from mitogen (phytohemagglutinin or pokeweed) stimulation, indicating a robust cellular response as well. These findings are encouraging and warrant further in vivo studies to determine the protective efficacy of the WNV vaccine candidate.

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The Fc Portion of Antibody to Yellow Fever Virus NS1 Is a Determinant of Protection against YF Encephalitis in Mice

Cited by 149 publications

References 0 publications

Antibodies against West Nile Virus Nonstructural Protein NS1 Prevent Lethal Infection through Fc γ Receptor-Dependent and -Independent Mechanisms

Antibodies against West Nile Virus Nonstructural Protein NS1 Prevent Lethal Infection through Fc γ Receptor-Dependent and -Independent Mechanisms

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Preparation and immunogenic properties of a recombinant West Nile subunit vaccine

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