Adaptive Immune Response to Vaccinia Virus LIVP Infection of BALB/c Mice and Protection against Lethal Reinfection with Cowpox Virus

Mass vaccination has played a critical role in the global eradication of smallpox. Various vaccinia virus (VACV) strains, whose origin has not been clearly documented in most cases, have been used as live vaccines in different countries. These VACV strains differed in pathogenicity towards various laboratory animals and in reactogenicity exhibited upon vaccination of humans. In this work, we studied the development of humoral and cellular immune responses in BALB/c mice inoculated intranasally (i.n.) or intradermally (i.d.) with the VACV LIVP strain at a dose of 105 PFU/mouse, which was used in Russia as the first generation smallpox vaccine. Active synthesis of VACV-specific IgM in the mice occurred on day 7 after inoculation, reached a maximum on day 14, and decreased by day 29. Synthesis of virus-specific IgG was detected only from day 14, and the level increased significantly by day 29 after infection of the mice. Immunization (i.n.) resulted in significantly higher production of VACV-specific antibodies compared to that upon i.d. inoculation of LIVP. There were no significant differences in the levels of the T cell response in mice after i.n. or i.d. VACV administration at any time point. The maximum level of VACV-specific T-cells was detected on day 14. By day 29 of the experiment, the level of VACV-specific T-lymphocytes in the spleen of mice significantly decreased for both immunization procedures. On day 30 after immunization with LIVP, mice were infected with the cowpox virus at a dose of 46 LD50. The i.n. immunized mice were resistant to this infection, while 33% of i.d. immunized mice died. Our findings indicate that the level of the humoral immune response to vaccination may play a decisive role in protection of animals from orthopoxvirus reinfection.

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TLR4 regulates rabies virus-induced humoral immunity through recruitment of cDC2 to lymph organs

Journal of Virology ◽

10.1128/jvi.00829-21 ◽

2021 ◽

Author(s):

Chen Chen ◽

Chengguang Zhang ◽

Haoqi Li ◽

Zongmei Wang ◽

Yueming Yuan ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Rabies Virus ◽

Humoral Immunity ◽

Humoral Immune Response ◽

Critical Role ◽

Wild Type ◽

Humoral Immune ◽

Specific Igg ◽

Molecular Patterns

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expression of pattern recognition receptors (PRRs) also causes diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not been revealed yet. Based on TLR4-deficient ( TLR4 -/- ) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type-2 dendritic cells (CD8α - CD11b + cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of Tfh cells promotes the proliferation of germinal centre (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. IMPORTANCE Vaccination is the most efficient method to prevent rabies. TLR4, a well-known immune sensor, plays a critical role in initiating innate immune response. Here, we found that TLR4 deficiency ( TLR4 -/- ) mice suppressed the induction of humoral immune response after immunization with rabies virus (RABV), including reduced production of VNAs and RABV-specific IgG, compared with that occurred in wild-type (WT) mice. As a consequence, TLR4 -/- mice exhibited higher mortality than WT mice after challenge with virulent RABV. Importantly, further investigation found that TLR4 signaling promoted the recruitment of cDC2 (CD8α + CD11b - ), a subset of cDCs known to induce CD4 + T cell immunity through their MHC-II presentation machinery. Our results imply that TLR4 is indispensable for an efficient humoral response to rabies vaccine, which provides new insight into the development of novel rabies vaccines.

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Preclinical studies of immunogenity, protectivity, and safety of the combined vector vaccine for prevention of the middle east respiratory syndrome

Acta Naturae ◽

10.32607/actanaturae.11042 ◽

2020 ◽

Vol 12 (3) ◽

pp. 114-123

Author(s):

Inna V. Dolzhikova ◽

D. M. Grousova ◽

O. V. Zubkova ◽

A. I. Tukhvatulin ◽

A. V. Kovyrshina ◽

...

Keyword(s):

Immune Response ◽

Middle East ◽

Mortality Rate ◽

Receptor Gene ◽

Human Adenovirus ◽

T Cell Response ◽

Middle East Respiratory Syndrome ◽

Vector Vaccine ◽

Humoral Immune ◽

Cellular Immune

The Middle East Respiratory Syndrome (MERS) is an acute inflammatory disease of the respiratory system caused by the MERS-CoV coronavirus. The mortality rate for MERS is about 34.5%. Due to its high mortality rate, the lack of therapeutic and prophylactic agents, and the continuing threat of the spread of MERS beyond its current confines, developing a vaccine is a pressing task, because vaccination would help limit the spread of MERS and reduce its death toll. We have developed a combined vector vaccine for the prevention of MERS based on recombinant human adenovirus serotypes 26 and 5. Studies of its immunogenicity have shown that vaccination of animals (mice and primates) induces a robust humoral immune response that lasts for at least six months. Studies of the cellular immune response in mice after vaccination showed the emergence of a specific CD4+ and CD8+ T cell response. A study of the vaccine protectivity conducted in a model of transgenic mice carrying the human DPP4 receptor gene showed that our vaccination protected 100% of the animals from the lethal infection caused by the MERS-CoV virus (MERS-CoV EMC/2012, 100LD50 per mouse). Studies of the safety and tolerability of the developed vaccine in rodents, rabbits, and primates showed a good safety profile and tolerance in animals; they revealed no contraindications for clinical testing.

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Adaptive immunity

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.050103 ◽

2010 ◽

pp. 224-234

Author(s):

Paul Klenerman

Keyword(s):

Infectious Disease ◽

Immune Response ◽

Pattern Recognition ◽

Adaptive Immunity ◽

Adaptive Response ◽

Critical Role ◽

Adaptive Immune Response ◽

Structural Features ◽

Adaptive Immune ◽

Single Organism

Following the innate immune response, which acts very rapidly, the adaptive immune response plays a critical role in host defence against infectious disease. Unlike the innate response, which is triggered by pattern recognition of pathogens, i.e. features that are common to many bacteria or viruses, the adaptive response is triggered by structural features—known as antigens or epitopes—that are typically unique to a single organism....

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Immune-Mediated Protection from Measles Virus-Induced Central Nervous System Disease Is Noncytolytic and Gamma Interferon Dependent

Journal of Virology ◽

10.1128/jvi.76.9.4497-4506.2002 ◽

2002 ◽

Vol 76 (9) ◽

pp. 4497-4506 ◽

Cited By ~ 106

Author(s):

Catherine E. Patterson ◽

Diane M. P. Lawrence ◽

Lisa A. Echols ◽

Glenn F. Rall

Keyword(s):

Central Nervous System ◽

Immune Response ◽

Nervous System ◽

T Cell ◽

Neuronal Death ◽

Measles Virus ◽

Critical Role ◽

Gamma Interferon ◽

T Cell Response ◽

Ifn Γ

ABSTRACT Neurons of the mammalian central nervous system (CNS) are an essential and largely nonrenewable cell population. Thus, virus infections that result in neuronal depletion, either by virus-mediated cell death or by induction of the cytolytic immune response, could cause permanent neurological impairment of the host. In a transgenic mouse model of measles virus (MV) infection of neurons, we have previously shown that the host T-cell response was required for resolution of infection in susceptible adult mice. In this report, we show that this protective response did not result in neuronal death, even during the peak of T-cell infiltration into the brain parenchyma. When susceptible mice were intercrossed with specific immune knockout mice, a critical role for gamma interferon (IFN-γ) was identified in protection against MV infection and CNS disease. Moreover, the addition of previously activated splenocytes or recombinant murine IFN-γ to MV-infected primary neurons resulted in the inhibition of viral replication in the absence of neuronal death. Together, these data support the hypothesis that the host immune response can promote viral clearance without concomitant neuronal loss, a process that appears to be mediated by cytokines.

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Natural Killer Cells as Novel Helpers in Anti-Herpes Simplex Virus Immune Response

Journal of Virology ◽

10.1128/jvi.00365-08 ◽

2008 ◽

Vol 82 (21) ◽

pp. 10820-10831 ◽

Cited By ~ 34

Author(s):

Subhadra Nandakumar ◽

Stacie N. Woolard ◽

Dorothy Yuan ◽

Barry T. Rouse ◽

Uday Kumaraguru

Keyword(s):

Immune Response ◽

T Cells ◽

Herpes Simplex Virus ◽

Herpes Simplex ◽

Nk Cells ◽

Nk Cell ◽

Adaptive Immune Response ◽

T Cell Response ◽

Simplex Virus

ABSTRACT Innate defenses help to eliminate infection, but some of them also play a major role in shaping the magnitude and efficacy of the adaptive immune response. With regard to influencing subsequent adaptive immunity, NK cells aided by dendritic cells may be the most relevant components of the innate reaction to herpes simplex virus (HSV) infection. We confirm that mice lacking or depleted of NK cells are susceptible to HSV-induced lesions. The quantity and quality of CD8+ cytotoxic T lymphocytes generated in the absence of NK cells were diminished, thereby contributing to susceptibility to HSV-induced encephalitis. We demonstrate a novel helper role for NK cells, in that NK cells compensate for the loss of CD4 helper T cells and NK cell supplementation enhances the function of wild type anti-HSV CD8 T cells. In addition, NK cells were able to partially rescue the dysfunctional CD8+ T cells generated in the absence of CD4 T helper cells, thereby performing a novel rescue function. Hence, NK cells may well be exploited for enhancing and rescuing the T-cell response in situations where the CD4 helper response is affected.

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A New Vaccine Paradigm To Break Tolerance with Potential Applications for the Immunotherapy of B Cell Lymphoma.

Blood ◽

10.1182/blood.v104.11.1411.1411 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1411-1411

Author(s):

Ronald P. Taylor ◽

Emily C. Whipple ◽

Margaret A. Lindorfer ◽

Andrew H. Ditto ◽

Ryan S. Shanahan

Keyword(s):

Flow Cytometry ◽

Immune Response ◽

B Cells ◽

B Cell ◽

Humoral Immune Response ◽

Critical Role ◽

B Cell Lymphoma ◽

Breakdown Product ◽

Humoral Immune ◽

Mouse Igg2a

Abstract Complement (C) plays a critical role in the immune response by opsonizing immune complexes (IC) and thymus-independent type 2 antigens with C3 breakdown product C3dg. We investigated the in vivo fate and handling in mice of anti-CR1/CR2 mAb 7G6. We used this rat IgG mAb as a surrogate for C3dg-opsonized IC; mAb 7G6 binds to CR1/CR2 with high affinity, blocks C3dg binding and saturates mouse B cell CR2 at inputs of only 2 ug. RIA, flow cytometry, and fluorescence immunohistochemistry were used to examine the disposition of 0.5–2 ug quantities of mAb 7G6 infused i.v. in mice. The mAb binds to circulating B cells and in the spleen binds preferentially to marginal zone (MZ) B cells. However, within 24 h MZ B cells relocate and transfer the mAb to regions rich in follicular dendritic cells (FDC). Localization of intact antigen to FDC should induce a substantial immune response, and therefore we immunized mice and monkeys i.v. with low doses (1–20 ug/kg) of prototype antigens constructed with anti-CR1/2 mAb 7G6 or anti-CR2 mAb HB135, respectively. We observed a strong immune response characterized by early development of IgG antibodies and long-lasting immunity extending out to at least one year. We applied our immunization paradigm to mouse IgG idiotypes, based on i.v. infusion of mouse IgG2a mAbs which were cross-linked with mAb 7G6. The purpose of these experiments was to determine if tolerance can be broken in order to develop a more powerful vaccine strategy to induce a cytotoxic humoral immune response to malignant B cells based on targeting the idiotype of immunoglobulin molecules expressed on their surfaces. I.V. immunization with the constructs indeed generated a mouse IgG1 immune response to two different mouse IgG2a mAbs, as demonstrated by ELISA. The immune response was idiotype specific, but some anti-isotype antibodies were also detected. Moreover, sera from immunized mice immunoprecipitated the specific radiolabeled mouse mAbs in the presence of 7.5% polyethylene glycol. This humoral immune response was also demonstrable in flow cytometry assays in which IgG1 in sera of immunized mice bound to erythrocytes opsonized with bispecific mAb constructs consisting of the IgG2a mAb crosslinked with an anti-CR1 mAb. The present approach, based on coupling the targeted immunoglobulin to an anti-CR2 mAb for delivery to FDC, may lead to a more effective immunotherapeutic vaccine compared to methods currently in clinical trials which require use of glutaraldehyde to effect crosslinking of the targeted immunoglobulin to KLH.

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Humoral immune response elicited by highly attenuated variants of vaccinia virus and by an attenuated recombinant expressing HIV-1 envelope protein

Virology ◽

10.1016/0042-6822(89)90250-x ◽

1989 ◽

Vol 173 (1) ◽

pp. 323-329 ◽

Cited By ~ 12

Author(s):

Shatha Dallo ◽

Juehn-Shin Maa ◽

Juan-Ramon Rodriguez ◽

Dolores Rodriguez ◽

Mariano Esteban

Keyword(s):

Immune Response ◽

Vaccinia Virus ◽

Humoral Immune Response ◽

Envelope Protein ◽

Humoral Immune ◽

Hiv 1

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NFκB activation by modified vaccinia virus as a novel strategy to enhance neutrophil migration and HIV-specific T-cell responses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1424341112 ◽

2015 ◽

Vol 112 (11) ◽

pp. E1333-E1342 ◽

Cited By ~ 18

Author(s):

Mauro Di Pilato ◽

Ernesto Mejías-Pérez ◽

Manuela Zonca ◽

Beatriz Perdiguero ◽

Carmen Elena Gómez ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Vaccinia Virus ◽

Neutrophil Migration ◽

T Cell Responses ◽

T Cell Response ◽

Infection Site ◽

Cell Responses ◽

Novel Strategy ◽

Nfκb Pathway

Neutrophils are antigen-transporting cells that generate vaccinia virus (VACV)-specific T-cell responses, yet how VACV modulates neutrophil recruitment and its significance in the immune response are unknown. We generated an attenuated VACV strain that expresses HIV-1 clade C antigens but lacks three specific viral genes (A52R, K7R, and B15R). We found that these genes act together to inhibit the NFκB signaling pathway. Triple ablation in modified virus restored NFκB function in macrophages. After virus infection of mice, NFκB pathway activation led to expression of several cytokines/chemokines that increased the migration of neutrophil populations (Nα and Nβ) to the infection site. Nβ cells displayed features of antigen-presenting cells and activated virus-specific CD8 T cells. Enhanced neutrophil trafficking to the infection site correlated with an increased T-cell response to HIV vector-delivered antigens. These results identify a mechanism for poxvirus-induced immune response and alternatives for vaccine vector design.

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COVID-19 and HIV-Associated Immune Reconstitution Inflammatory Syndrome: Emergence of Pathogen-Specific Immune Responses Adding Fuel to the Fire

Frontiers in Immunology ◽

10.3389/fimmu.2021.649567 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nabila Seddiki ◽

Martyn French

Keyword(s):

Immune Response ◽

Immune Responses ◽

Immune Reconstitution Inflammatory Syndrome ◽

Immune Reconstitution ◽

Macrophage Activation ◽

Adaptive Immune Response ◽

T Cell Response ◽

B Cell Differentiation ◽

Adaptive Immune ◽

Inflammatory Syndrome

Both coronavirus disease 2019 (COVID-19) and mycobacterial immune reconstitution inflammatory syndrome (IRIS) in patients with HIV-1 infection result from immunopathology that is characterized by increased production of multiple pro-inflammatory chemokines and cytokines associated with activation of myeloid cells (monocytes, macrophages and neutrophils). We propose that both conditions arise because innate immune responses generated in the absence of effective adaptive immune responses lead to monocyte/macrophage activation that is amplified by the emergence of a pathogen-specific adaptive immune response skewed towards monocyte/macrophage activating activity by the immunomodulatory effects of cytokines produced during the innate response, particularly interleukin-18. In mycobacterial IRIS, that disease-enhancing immune response is dominated by a Th1 CD4+ T cell response against mycobacterial antigens. By analogy, it is proposed that in severe COVID-19, amplification of monocyte/macrophage activation results from the effects of a SARS-CoV-2 spike protein antibody response with pro-inflammatory characteristics, including high proportions of IgG3 and IgA2 antibodies and afucosylation of IgG1 antibodies, that arises from B cell differentiation in an extra-follicular pathway promoted by activation of mucosa-associated invariant T cells. We suggest that therapy for the hyperinflammation underlying both COVID-19 and mycobacterial IRIS might be improved by targeting the immunomodulatory as well as the pro-inflammatory effects of the ‘cytokine storm’.

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Comparison of Personal and Shared Frameshift Neoantigen Vaccines in a Mouse Mammary Cancer Model.

10.21203/rs.2.23006/v2 ◽

2020 ◽

Author(s):

Milene Peterson ◽

Sierra Nicole Murphy ◽

John Lainson ◽

Jian Zhang ◽

Luhui Shen ◽

...

Keyword(s):

Immune Response ◽

Cancer Vaccines ◽

Lung Metastases ◽

T Cell Response ◽

Control Group ◽

Cancer Model ◽

Secondary Tumor ◽

Humoral Immune ◽

Dna Mutations ◽

Number Of Patients

Abstract Background: It is widely hoped that personal cancer vaccines will extend the number of patients benefiting from checkpoint and other immunotherapies. However, it is clear creating such vaccines will be challenging. It requires obtaining and sequencing tumor DNA/RNA, predicting potentially immunogenic neoepitopes and manufacturing a one-use vaccine. This process takes time and considerable cost. Importantly, most mutations will not produce an immunogenic peptide and many patient’s tumors do not contain enough DNA mutations to make a vaccine. We have discovered that frameshift peptides (FSP) created from errors in the production of RNA rather than from DNA mutations are potentially a rich source of neoantigens for cancer vaccines. These errors are predictable, enabling the production of a FSP microarray. Previously we found that these microarrays can identify both personal and shared neoantigens. Here, we compared the performance of personal cancer vaccines (PCVs) with that of a shared antigen vaccine, termed Frameshift Antigen Shared Therapeutic (FAST) vaccine , using the 4T1 breast cancer model. Sera from 4T1-tumor bearing mice were assayed on the peptide microarray containing 200 Fs neoantigens, for the PCV, the top 10 candidates were select and personal vaccines constructed and administrated to the respective mice. For the FAST, we selected the top 10 candidates with higher prevalence among all the mice challenged. Seven to 12 days challenged mice were immunized, combined or not with immune checkpoint inhibitor (ICI) (αPD-L1 and αCTLA-4). Primary and secondary tumor clearance and growth were evaluated as well as cellular and humoral immune response against the vaccine targets by IFN-γ ELISPOT and ELISA. Lastly, we analyzed the immune response of the FAST-vaccinated mice by flow cytometry in comparison to the control group. Results: We found that PCVs and FAST vaccines both reduced primary tumor incidence and growth as well as lung metastases when delivered as monotherapies or in combination with ICI. Additionally, the FAST vaccine induces a robust and effective T-cell response. Conclusions: These results suggest that FSPs produced from RNA-based errors are potent neoantigens that could enable production of off-the-shelf shared antigen vaccines for solid tumors with efficacy comparable to that of PCVs.

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