Use of Animal Models in Studying Roles of Antibodies and Their Secretion Cells in Dengue Vaccine Development

The cardinal feature of adaptive immunity is its ability to form memory responses that can be rapidly recalled to contain pathogens upon reencountering. Conferring a robust memory immune response to an infection is a key feature for a successful vaccination program. The plasmablasts are cells that not only can secret non-neutralizing antibodies but also can secrete the specific antibodies essential to neutralize and inactivate the invading pathogens. Dengue has been recognized as one of the most important vector-borne human viral diseases globally. Currently, supportive care with vigilant monitoring is the standard practice since there is as yet no approved therapeutic modality to treat dengue. Even though the approved vaccine has become available, its low efficacy with the potential to cause harm is the major hurdle to promote the widespread usage of the vaccine. Despite the decades of research on dengue, the major challenge in dengue vaccine development is the absence of suitable experimental animal models that reflect the pathological features and clinical symptoms, as seen in humans. Dengue is transmitted by the bite of mosquitoes carrying infectious dengue virus (DENV), which has four distinct serotypes. Recently, cases resulting from unconventional transmission routes, such as blood transfusion, organs as well as stem cells and bone marrow transplantations, and mother-to-infant vertical transmission, have been reported, suggesting an alternate route of DENV transmission exists in nature. This review discusses issues and challenges needing to be resolved to develop an effective dengue vaccine. Development of a robust and reliable dengue animal model that can reflect not only dynamic human clinical symptoms but also can answer around why preexisting neutralizing antibodies do not confer protection upon re-infection and immune protection marker for dengue vaccine efficacy evaluation.

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Overview of Plant-Derived Vaccine Antigens: Dengue Virus

Journal of Pharmacy & Pharmaceutical Sciences ◽

10.18433/j3401k ◽

2011 ◽

Vol 14 (3) ◽

pp. 400 ◽

Cited By ~ 7

Author(s):

Ravindra B Malabadi ◽

Advaita Ganguly ◽

Jaime A Teixeira da Silva ◽

Archana Parashar ◽

Mavanur R Suresh ◽

...

Keyword(s):

Infectious Diseases ◽

Dengue Virus ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Low Cost ◽

Current Status ◽

Human Immune Deficiency Virus ◽

Dengue Vaccine ◽

New Methods ◽

Vaccine Antigens

ABSTRACT - This review highlights the advantages and current status of plant-derived vaccine development with special reference to the dengue virus. There are numerous problems involved in dengue vaccine development, and there is no vaccine against all four dengue serotypes. Dengue vaccine development using traditional approaches has not been satisfactory in terms of inducing neutralizing antibodies. Recently, these issues were addressed by showing a very good response to inducing neutralizing antibodies by plant-derived dengue vaccine antigens. This indicates the feasibility of using plant-derived vaccine antigens as a low-cost method to combat dengue and other infectious diseases. The application of new methods and strategies such as dendritic cell targeting in cancer therapy, severe acute respiratory syndrome, tuberculosis, human immune deficiency virus, and malaria might play an important role. These new methods are more efficient than traditional protocols. It is expected that in the near future, plant-derived vaccine antigens or antibodies will play an important role in the control of human infectious diseases. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

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Safety and Immunogenicity Evaluation of Inactivated whole-virus-SARS-COV-2 As Emerging Vaccine Development In Egypt

10.1101/2021.03.01.433130 ◽

2021 ◽

Author(s):

Amani A. Saleh ◽

Mohamed A. Saad ◽

Islam Ryan ◽

Magdy Amin ◽

Mohamed I. Shindy ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Clinical Symptoms ◽

Neutralizing Antibody ◽

Positive Development ◽

Virus Challenge ◽

Cell Monolayers ◽

Transmission Electron ◽

Dose Concentration ◽

Antibody Titers

AbstractThe current worldwide pandemic COVID-19 is causing severe human health problems, with high numbers of mortality rates and huge economic burdens that require an urgent demand for safe, and effective and vaccine development. Our study was the first trail to development and evaluation of safety and immune response to inactivated whole SARS-COV-2 virus vaccine adjuvanted with aluminium hydroxide. We used characterized SARS-COV-2 strain, severe acute respiratory syndrome coronavirus 2 isolates (SARS-CoV-2/human/EGY/Egy-SERVAC/2020) with accession numbers; MT981440; MT981439; MT981441; MT974071; MT974069 and MW250352 at GenBank that isolated from Egyptian patients SARS-CoV-2-positive. Development of the vaccine was carried out in a BSL - 3 facilities and the immunogenicity was determined in mice at two doses (55µg and 100µg per dose). All vaccinated mice were received a booster dose 14 days post first immunization. Our results demonstrated distinct cytopathic effect on the vero cell monolayers induced through SARS-COV-2 propagation and the viral particles were identified as Coronaviridae by transmission electron microscopy. SARS-CoV-2 was identified by RT-PCR performed on the cell culture. Immunogenicity of the developed vaccine indicated the high antigen-binding and neutralizing antibody titers, regardless the dose concentration, with excellent safety profiles.However, no deaths or clinical symptoms in mice groups. The efficacy of the inactivated vaccine formulation was tested by wild virus challenge the vaccinated mice and detection of viral replication in lung tissues. Vaccinated mice recorded complete protection from challenge infection three weeks post second dose. SARS-COV-2 replication was not observed in the lungs of mice following SARS-CoV-2 challenge, regardless of the level of serum neutralizing antibodies. This finding will support the future trials for evaluation an applicable SARS-CoV-2 vaccine candidate.

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Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers

Journal of Virology ◽

10.1128/jvi.00677-17 ◽

2017 ◽

Vol 91 (15) ◽

Cited By ~ 23

Author(s):

Rajesh P. Ringe ◽

Gabriel Ozorowski ◽

Kimmo Rantalainen ◽

Weston B. Struwe ◽

Katie Matthews ◽

...

Keyword(s):

Animal Models ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Tier 2 ◽

Present Generation ◽

Coreceptor Binding ◽

Tier 1 ◽

Immunogen Design ◽

V3 Region ◽

Hiv 1

ABSTRACT Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such “off-target” immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N-glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man6GlcNAc2 form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan- and E64K-modified trimer variant, BG505 SOSIP.664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged. IMPORTANCE Trimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP.664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against sequence-divergent atypically neutralization-sensitive (tier-1) viruses. A concern in the trimer immunogen design field has been whether the latter off-target antibodies might interfere with the induction of the more desired responses to tier-2 epitopes. Here, we have inserted two glycans into the dominant site for tier-1 NAbs, the gp120 V3 region, to block the induction of off-target antibodies. We characterized the new trimers, tested them as immunogens in rabbits, and found that the blocking glycans eliminated the induction of tier-1 NAbs to V3-epitopes.

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Safety and immunogenicity evaluation of inactivated whole-virus-SARS-COV-2 as emerging vaccine development in Egypt

Antibody Therapeutics ◽

10.1093/abt/tbab012 ◽

2021 ◽

Author(s):

Amani A Saleh ◽

Mohamed A Saad ◽

Islam Ryan ◽

Magdy Amin ◽

Mohamed I Shindy ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Vaccine Development ◽

Clinical Symptoms ◽

Neutralizing Antibody ◽

Positive Development ◽

Effective Vaccine ◽

Inactivated Vaccine ◽

Virus Challenge ◽

Transmission Electron ◽

Dose Concentration

Abstract Background Current worldwide pandemic COVID-19 with high numbers of mortality rates and huge economic problems require an urgent demand for safe and effective vaccine development. Inactivated SARS-CoV2 vaccine with alum. Hydroxide can play an important role in reducing the impacts of the COVID-19 pandemic. In this study, vaccine efficacy was evaluated through the detection of the neutralizing antibodies that protect mice from challenge with SARS-CoV 2 three weeks after the 2nd dose. We conclude that the vaccine described here has safety and desirable properties, and our data support further development and plans for clinical trials. Methods Characterized SARS-COV-2 strain, severe acute respiratory syndrome coronavirus 2 isolates (SARS-CoV-2/human/EGY/Egy-SERVAC/2020) with accession numbers; MT981440; MT981439; MT981441; MT974071; MT974069, and MW250352 at GenBank were isolated from Egyptian patients SARS-CoV-2-positive. Development of inactivated vaccine was carried out in a BSL—3 facilities and the immunogenicity was determined in mice at two doses (55 μg and 100 μg per dose). Results The distinct cytopathic effect (CPE) induced by SARS-COV-2 propagation on Vero cell monolayers and the viral particles were identified as Coronaviridae by transmission electron microscopy and RT-PCR on infected cells cultures. Immunogenicity of the developed vaccine indicated the high antigen-binding and neutralizing antibody titers, regardless of the dose concentration, with excellent safety profiles and no deaths or clinical symptoms in mice groups. The efficacy of the inactivated vaccine formulation was tested by the wild virus challenge of the vaccinated mice and viral replication detection in lung tissues. Conclusions Vaccinated mice recorded complete protection from challenge infection via inhibition of SARS-COV-2 replication in the lung tissues of mice following virus challenge, regardless of the level of serum neutralizing antibodies. This finding will support future trials for the evaluation of an applicable SARS-CoV-2 vaccine candidate.

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Evidence of arbovirus co-infection in suspected febrile malaria and typhoid patients in Nigeria

The Journal of Infection in Developing Countries ◽

10.3855/jidc.2411 ◽

2013 ◽

Vol 7 (01) ◽

pp. 051-059 ◽

Cited By ~ 62

Author(s):

Marycelin Baba ◽

Christopher Hugh Logue ◽

Bamidele Oderinde ◽

Hauwa Abdulmaleek ◽

Joshua Williams ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Clinical Symptoms ◽

Neutralization Test ◽

Salmonella Typhi ◽

Test Results ◽

Widal Test ◽

Virus Surveillance ◽

Vector Borne ◽

Arbovirus Infection ◽

Sera Samples

Introduction: Clinical symptoms of malaria and typhoid infections are virtually indistinguishable from those initially seen in many arbovirus infections. Here we describe arbovirus co-infection detected in 310 sera samples collected from febrile, clinically suspected malaria/typhoid patients in Borno State, Nigeria. Methodology: Tested initially for Plasmodium falciparum by microscopy and for Salmonella Typhi by Widal test, samples were subsequently tested for chikungunya (CHIKV), yellow fever (YFV), dengue (DENV) and West Nile viruses (WNV) by plaque reduction neutralization test. Results: While 92% of patients tested positive for malaria, typhoid, an arbovirus infection, or a combination of one or more of these types of infections, less than 1% of the patients tested positive for malaria alone and only 3.9% tested positive for typhoid alone. Approximately half of the patients tested positive for infection with a single arbovirus (48%) regardless of the presence or absence of malaria or typhoid. Of those who showed 90% to 95% virus neutralization, 67.7% had neutralizing antibodies against DENV, 50% against CHIKV, 25% against WNV and 8.7% against YFV. Eight per cent tested negative against all six pathogens, suggesting that other arboviruses not tested for in this study may also be circulating in Nigeria. Conclusions: The results suggest that misdiagnosis of arbovirus co-infections as malaria infections, combined with a lack of virus surveillance and underreporting of arbovirus infections, increases the potential for undetected and uncontrolled spread of important vector-borne arboviruses becoming serious underlying public health concerns in Nigeria.

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Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

10.1101/2020.09.23.308817 ◽

2020 ◽

Author(s):

Laura J. White ◽

Ellen Young ◽

Mark Stoops ◽

Sandra Henein ◽

Ralph S. Baric ◽

...

Keyword(s):

Dengue Virus ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Severe Disease ◽

Effective Vaccine ◽

Dengue Vaccine ◽

Unique Type ◽

Vaccine Component ◽

Virus Serotype

AbstractThe four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naïve adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. We conclude that the DENV2 component in the vaccine is immunodominant because of the high levels of serum neutralizing antibodies targeting type-specific epitopes. We also conclude that DENV1, 3 and 4 vaccine components are less immunogenic because most study subjects did not develop type-specific serum neutralizing antibodies to these serotypes. While DENV vaccine development has been guided by the presence of neutralizing antibodies to each serotype as a benchmark, our results indicate that the presence of neutralizing antibodies alone are not a reliable indicator of the immunogenicity of each vaccine component.Author summaryThe development of tetravalent dengue vaccines has been guided by neutralizing antibodies to each serotype as a correlate of safe and effective vaccine induced immunity. However, the absolute levels of neutralizing antibodies to each serotype has proven to be an unreliable correlate of protection. Levels of antibodies to epitopes that are unique to each serotype, which are measures of immunity independently stimulated by each vaccine component, rather than total quantity of neutralizing antibodies, are likely to be better correlates of protection. Here, we mapped the specificity of antibodies induced by the Takeda tetravalent dengue vaccine TAK-003 in monkeys and humans with no prior immunity to dengue. The TAK-003 vaccine induces high levels of serotype 2 specific neutralizing antibodies that map to known protective epitopes. In contrast, the serotype 1, 3 and 4 neutralizing antibody responses are lower and mainly consist of cross-reactive antibodies binding to epitopes conserved between serotypes. These heterotypic antibodies, which are most likely derived from the serotype 2 component, may not provide long term protection in vivo.

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The antigenic and genetic variability of bovine respiratory syncytial virus with emphasis on the G protein

Veterinární Medicína ◽

10.17221/5778-vetmed ◽

2012 ◽

Vol 48 (No. 9) ◽

pp. 254-266 ◽

Cited By ~ 5

Author(s):

V. Valentova

Keyword(s):

Respiratory Syncytial Virus ◽

Genetic Variability ◽

G Protein ◽

Viral Protein ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Clinical Symptoms ◽

Bovine Respiratory Syncytial Virus ◽

Th2 Response ◽

Syncytial Virus

Bovine respiratory syncytial virus (BRSV) and related human respiratory syncytial virus (HRSV) are major respiratory tract pathogens in calves and infants, respectively. Great attention is now paid to prevention of the disease caused by these agents. Glycoprotein G is the most variable viral protein and antigenic grouping of RSV isolates is based on distinct antigenic reactivity patterns determined with a set of G protein specific mAbs. Genetic variability of the G protein is used during epidemiology and epizootiology studies of HRSV and BRSV diseases, respectively. The constant genetic drift can be observed within G protein sequences. Both cell-mediated and antibody-mediated immune responses contribute to efficient protection against RSV infection. The neutralizing antibodies are induced by F and G proteins. The G protein fails to induce cytotoxic lymphocytes response and may causes aberrant Th2 response leading to enhancement of clinical symptoms in subsequently infected vaccines. The G as the most variable viral protein associated with immunopathologic effect is a critical factor in vaccine development.

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Dengue virus envelope domain III immunization elicits predominantly cross-reactive, poorly neutralizing antibodies localized to the AB loop: implications for dengue vaccine design

Journal of General Virology ◽

10.1099/vir.0.055178-0 ◽

2013 ◽

Vol 94 (10) ◽

pp. 2191-2201 ◽

Cited By ~ 16

Author(s):

Xiao-Quan Li ◽

Li-Wen Qiu ◽

Yue Chen ◽

Kun Wen ◽

Jian-Piao Cai ◽

...

Keyword(s):

Antibody Response ◽

Dengue Virus ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Surface Display ◽

Yeast Surface Display ◽

Protein Domain ◽

Dengue Vaccine ◽

Denv Serotypes ◽

Domain Iii

Dengue virus (DENV) is a mosquito-borne virus that causes severe health problems. An effective tetravalent dengue vaccine candidate that can provide life-long protection simultaneously against all four DENV serotypes is highly anticipated. A better understanding of the antibody response to DENV envelope protein domain III (EDIII) may offer insights into vaccine development. Here, we identified 25 DENV cross-reactive mAbs from immunization with Pichia pastoris-expressed EDIII of a single or all four serotype(s) using a prime–boost protocol, and through pepscan analysis found that 60 % of them (15/25) specifically recognized the same highly conserved linear epitope aa 309–320 of EDIII. All 15 complex-reactive mAbs exhibited significant cross-reactivity with recombinant EDIII from all DENV serotypes and also with C6/36 cells infected with DENV-1, -2, -3 and -4. However, neutralization assays indicated that the majority of these 15 mAbs were either moderately or weakly neutralizing. Through further epitope mapping by yeast surface display, two residues in the AB loop, Q316 and H317, were discovered to be critical. Three-dimensional modelling analysis suggests that this epitope is surface exposed on EDIII but less accessible on the surface of the E protein dimer and trimer, especially on the surface of the mature virion. It is concluded that EDIII as an immunogen may elicit cross-reactive mAbs toward an epitope that is not exposed on the virion surface, therefore contributing inefficiently to the mAbs neutralization potency. Therefore, the prime–boost strategy of EDIII from a single serotype or four serotypes mainly elicited a poorly neutralizing, cross-reactive antibody response to the conserved AB loop of EDIII.

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