Kinetics of protective antibodies are determined by the viral surface antigen

Pinschewer, Daniel D.; Perez, Mar; Jeetendra, E.; Bächi, Thomas; Horvath, Edit; Hengartner, Hans; Whitt, Michael A.; Torre, Juan Carlos de la; Zinkernagel, Rolf M.

doi:10.1172/jci200422374

Cited by 80 publications

(68 citation statements)

References 39 publications

(28 reference statements)

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“…Similar observations of low antivector immunity have been reported for a replication-defective LCMV vector (14) and a replication-competent vesicular stomatitis virus pseudotyped with the LCMV GPC (VSV-GP) (35). The lack of vector-neutralizing antibodies in VSV-GP-immunized mice is a feature attributed to LCMV GPC, since it has been shown that LCMV GPC, and not the vector, determines the kinetics of neutralizing antibody development (36). Our data with the rP18tri vector suggest that PICV GPC may have characteristics similar to those of the LCMV GPC in terms of being a poor inducer of neutralizing antibodies.…”

Section: Discussionsupporting

confidence: 69%

A Novel Live Pichinde Virus-Based Vaccine Vector Induces Enhanced Humoral and Cellular Immunity after a Booster Dose

Dhanwani

Zhou

Huang

et al. 2016

J Virol

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Pichinde virus (PICV) is a bisegmented enveloped RNA virus that targets macrophages and dendritic cells (DCs) early in infection and induces strong innate and adaptive immunity in mice. We have developed a reverse genetics system to produce live recombinant PICV (strain P18) with a trisegmented RNA genome (rP18tri), which encodes all four PICV gene products and as many as two foreign genes. We have engineered the vector to express the green fluorescent protein (GFP) reporter gene (abbreviated as G in virus designations) and either the hemagglutination (HA [H]) or the nucleoprotein (NP [P]) gene of the influenza A/PR8 virus. The trisegmented viruses rP18tri-G/H and rP18tri-G/P showed slightly reduced growth in vitro and expressed HA and NP, respectively. Mice immunized with rP18tri-G/H were completely protected against lethal influenza virus challenge even 120 days after immunization. These rP18tri-based vectors could efficiently induce both neutralizing antibodies and antigen-specific T cell responses via different immunization routes. Interestingly, the immune responses were significantly increased upon a booster dose and remained at high levels even after three booster doses. In summary, we have developed a novel PICV-based live vaccine vector that can express foreign antigens to induce strong humoral and cell-mediated immunity and is ideal for a primeand-boost vaccination strategy. IMPORTANCE We have developed a novel Pichinde virus (PICV)-based live viral vector, rP18tri, that packages three RNA segments and encodes as many as two foreign genes. Using the influenza virus HA and NP genes as model antigens, we show that this rP18tri vector can induce strong humoral and cellular immunity via different immunization routes and can lead to protection in mice. Interestingly, a booster dose further enhances the immune responses, a feature that distinguishes this from other known live viral vectors. In summary, our study demonstrates a unique feature of this live rP18tri vector to be used as a novel vaccine platform for a prime-and-boost vaccination strategy.A renaviruses are enveloped RNA viruses with a bisegmented genome and mostly use rodents as natural hosts. There are at least 27 members that are geographically, serologically, and phylogenetically divided into Old World and New World arenaviruses (1). The prototypic lymphocytic choriomeningitis virus (LCMV) infection of mice has long been used as a valuable model with which to study viral persistence and virus-induced immunity and immunopathology (2, 3). The arenavirus is composed of a total of four genes on two genomic RNA segments in opposite orientations (1). The Z protein, produced from the large (L) genomic segment, is a small RING domain-containing matrix protein that mediates virus budding, regulates viral RNA synthesis, and mediates host immune suppression (4, 5). The large L protein (ϳ200 kDa), also encoded on the L segment, is the RNA-dependent RNA polymerase (RdRp), which is required for viral RNA synthesis (6). The glycoprotein (GPC), encoded...

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Section: Discussionsupporting

confidence: 69%

A Novel Live Pichinde Virus-Based Vaccine Vector Induces Enhanced Humoral and Cellular Immunity after a Booster Dose

Dhanwani

Zhou

Huang

et al. 2016

J Virol

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“…5), antibodies to LCMV have a limited capacity to prevent reinfection 6,8 , a property that could have explained the superior performance of rLCMV-OVA in homologous prime-boost immunizations (Fig. 2b).…”

Section: Resultsmentioning

confidence: 99%

“…LCMV-induced T cell responses are broad and long-lived 7 , and LCMV infection has been widely studied as a model of CTL-mediated protection. The neutralizing antibody response to LCMV is extraordinarily weak, and convalescent serum fails to prevent re-infection 6,8 . These characteristics suggested that modified LCMV might serve as a vector for the induction of CTL immunity.…”

mentioning

confidence: 99%

Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity

Flatz

Hegazy

Bergthaler

et al. 2010

Nat Med

126

167

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Lymphocytic choriomeningitis virus (LCMV) exhibits natural tropism for dendritic cells and represents the prototypic infection that elicits protective CD8+ T cell (cytotoxic T lymphocyte (CTL)) immunity. Here we have harnessed the immunobiology of this arenavirus for vaccine delivery. By using producer cells constitutively synthesizing the viral glycoprotein (GP), it was possible to replace the gene encoding LCMV GP with vaccine antigens to create replication-defective vaccine vectors. These rLCMV vaccines elicited CTL responses that were equivalent to or greater than those elicited by recombinant adenovirus 5 or recombinant vaccinia virus in their magnitude and cytokine profiles, and they exhibited more effective protection in several models. In contrast to recombinant adenovirus 5, rLCMV failed to elicit vector-specific antibody immunity, which facilitated re-administration of the same vector for booster vaccination. In addition, rLCMV elicited T helper type 1 CD4+ T cell responses and protective neutralizing antibodies to vaccine antigens. These features, together with low seroprevalence in humans, suggest that rLCMV may show utility as a vaccine platform against infectious diseases and cancer.

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“…Although the absence of an initial robust nAb response has been primarily attributed to antiviral escape mechanisms (32, 48), the immunological processes that drive the disruption of humoral immunity during persistent infection are yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Type I Interferon Impairs Specific Antibody Responses Early during Establishment of LCMV Infection

et al. 2016

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Elicitation of type I interferon (IFN-I) has been shown to both enhance and impair cell-mediated immune responses in acute and persistent viral infections, respectively. Here, we show that, in addition to its effect on T cells, IFN-I drives impairment of specific antibody responses through interaction with B cells in the acute phase of lymphocytic choriomeningitis virus (LCMV) infection. This impairment was limited to the T cell-dependent B cell response and was associated with disruption of B cell follicles, development of hypergammaglobulinemia (HGG), and expansion of the T follicular helper cell population. Antigen-specific antibody responses were restored by ablation of IFN-I signaling through antibody-mediated IFN-I receptor blockade and B cell-specific IFN-I receptor knockout. Importantly, IFN-I receptor deficiency in B cells also accelerated the development of LCMV neutralizing antibodies and alleviated HGG. These results provide a potential therapeutic target toward efficient treatment measures that limit immunopathology in persistent viral infections.

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Kinetics of protective antibodies are determined by the viral surface antigen

Cited by 80 publications

References 39 publications

A Novel Live Pichinde Virus-Based Vaccine Vector Induces Enhanced Humoral and Cellular Immunity after a Booster Dose

A Novel Live Pichinde Virus-Based Vaccine Vector Induces Enhanced Humoral and Cellular Immunity after a Booster Dose

Development of replication-defective lymphocytic choriomeningitis virus vectors for the induction of potent CD8+ T cell immunity

Type I Interferon Impairs Specific Antibody Responses Early during Establishment of LCMV Infection

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