scholarly journals A prevaccination validated network that drives the breadth of the protective neutralizing antibody response following Dengue Vaccine TV003 immunization

2021 ◽  
Author(s):  
Adam-Nicolas Pelletier ◽  
Gabriela Pacheco Sanchez ◽  
Mark Watson ◽  
Abdullah Izmirly ◽  
Tiziana Di Pucchio ◽  
...  
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Inflammasome Activation ◽  
Proinflammatory Response ◽  
Protective Antibody ◽  
Secondary Bile Acids

Development of fully protective dengue virus (DV) vaccines has been problematic as infection with DV requires a broad antibody immune response that targets all 4 possible serotypes. Herein, we used an integrated systems vaccinology approach to identify prevaccination features that allow the development of fully protective DV-specific antibody responses. This approach allowed us to identify a transcription network in a subset of monocytes defined by the expression of CD68 and downstream of specific pro- and anti-inflammatory cytokines. Moreover, we identified metabolites as drivers of an immune response that induced neutralizing antibodies to the 4 DV serotypes. Specifically, PC/PE drove the production of TGF-B in CD68 low monocytes, which was a positive correlate of the protective antibody response. In contrast, primary and secondary bile acids triggered a proinflammatory response downstream of TGR5 signaling and inflammasome activation in CD68 high monocytes, which was associated to a non-protective antibody response. These features were validated in vitro in primary myeloid cells. Our results highlight the role of cell and systemic metabolism as regulators of protective immune responses to vaccination, and that systems vaccinology is a key tool to identify such mechanisms.

scholarly journals SARS-CoV-2 escape in vitro from a highly neutralizing COVID-19 convalescent plasma

2020 ◽  
Author(s):  
Emanuele Andreano ◽  
Giulia Piccini ◽  
Danilo Licastro ◽  
Lorenzo Casalino ◽  
Nicole V. Johnson ◽  
...  
Keyword(s):  
South Africa ◽  
Immune Response ◽  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Receptor Binding Domain ◽  
The United Kingdom ◽  
Effective Immune Response ◽  
Recent Emergence ◽  
Natural Variants

ABSTRACTTo investigate the evolution of SARS-CoV-2 in the immune population, we co-incubated authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for 7 passages, but after 45 days, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed at day 80 by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom and South Africa of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed.One Sentence SummaryThree mutations allowed SARS-CoV-2 to evade the polyclonal antibody response of a highly neutralizing COVID-19 convalescent plasma.

scholarly journals Protection from cytomegalovirus viremia following glycoprotein B vaccination is not dependent on neutralizing antibodies

2018 ◽  
Vol 115 (24) ◽  
pp. 6273-6278 ◽  
Author(s):  
Ilona Baraniak ◽  
Barbara Kropff ◽  
Lyn Ambrose ◽  
Megan McIntosh ◽  
Gary R. McLean ◽  
...  
Keyword(s):  
Antibody Response ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Glycoprotein B ◽  
Solid Organ ◽  
Viral Glycoprotein ◽  
Viral Spread

Human cytomegalovirus (HCMV) is an important pathogen in transplant patients and in congenital infection. Previously, we demonstrated that vaccination with a recombinant viral glycoprotein B (gB)/MF59 adjuvant formulation before solid organ transplant reduced viral load parameters post transplant. Reduced posttransplant viremia was directly correlated with antibody titers against gB consistent with a humoral response against gB being important. Here we show that sera from the vaccinated seronegative patients displayed little evidence of a neutralizing antibody response against cell-free HCMV in vitro. Additionally, sera from seronegative vaccine recipients had minimal effect on the replication of a strain of HCMV engineered to be cell-associated in a viral spread assay. Furthermore, although natural infection can induce antibody-dependent cellular cytotoxicity (ADCC) responses, serological analysis of seronegative vaccinees again presented no evidence of a substantial ADCC-promoting antibody response being generated de novo. Finally, analyses for responses against major antigenic domains of gB following vaccination were variable, and their pattern was distinct compared with natural infection. Taken together, these data argue that the protective effect elicited by the gB vaccine is via a mechanism of action in seronegative vaccinees that cannot be explained by neutralization or the induction of ADCC. More generally, these data, which are derived from a human challenge model that demonstrated that the gB vaccine is protective, highlight the need for more sophisticated analyses of new HCMV vaccines over and above the quantification of an ability to induce potent neutralizing antibody responses in vitro.

scholarly journals Immune response against SARS-CoV-2 variants: the role of neutralization assays

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Alicja Maria Chmielewska ◽  
Anna Czarnota ◽  
Krystyna Bieńkowska-Szewczyk ◽  
Katarzyna Grzyb
Keyword(s):  
Immune Response ◽  
Social Life ◽  
Neutralizing Antibody ◽  
The Novel ◽  
International Scientific Community ◽  
Rapid Spread ◽  
Cost Efficient ◽  
Novel Coronavirus

AbstractSince the emergence of the novel coronavirus SARS-CoV-2 in late 2019, the COVID-19 pandemic has hindered social life and global economic activity. As of July 2021, SARS-CoV-2 has caused over four million deaths. The rapid spread and high mortality of the disease demanded the international scientific community to develop effective vaccines in a matter of months. However, unease about vaccine efficacy has arisen with the spread of the SARS-CoV-2 variants of concern (VOCs). Time- and cost-efficient in vitro neutralization assays are widely used to measure neutralizing antibody responses against VOCs. However, the extent to which in vitro neutralization reflects protection from infection remains unclear. Here, we describe common neutralization assays based on infectious and pseudotyped viruses and evaluate their role in testing neutralizing responses against new SARS-CoV-2 variants. Additionally, we briefly review the recent findings on the immune response elicited by available vaccines against major SARS-CoV-2 variants, including Alpha, Beta, Gamma, and Delta.

scholarly journals Respiratory Syncytial Virus Infection: Immune Response, Immunopathogenesis, and Treatment

1999 ◽  
Vol 12 (2) ◽  
pp. 298-309 ◽  
Author(s):  
Joseph B. Domachowske ◽  
Helene F. Rosenberg
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Respiratory Tract ◽  
Neutralizing Antibodies ◽  
Lower Respiratory Tract ◽  
Immunoglobulin E ◽  
Neutralizing Antibody ◽  
Rsv Infection ◽  
Syncytial Virus

SUMMARY Respiratory syncytial virus (RSV) is the single most important cause of lower respiratory tract infection during infancy and early childhood. Once RSV infection is established, the host immune response includes the production of virus-neutralizing antibodies and T-cell-specific immunity. The humoral immune response normally results in the development of anti-RSV neutralizing-antibody titers, but these are often suboptimal during an infant’s initial infection. Even when the production of RSV neutralizing antibody following RSV infection is robust, humoral immunity wanes over time. Reinfection during subsequent seasons is common. The cellular immune response to RSV infection is also important for the clearance of virus. This immune response, vital for host defense against RSV, is also implicated in the immunopathogenesis of severe lower respiratory tract RSV bronchiolitis. Many details of the immunology and immunopathologic mechanisms of RSV disease known at present have been learned from rodent models of RSV disease and are discussed in some detail. In addition, the roles of immunoglobulin E, histamine, and eosinophils in the immunopathogenesis of RSV disease are considered. Although the treatment of RSV bronchiolitis is primarily supportive, the role of ribavirin is briefly discussed. Novel approaches to the development of new antiviral drugs with promising anti-RSV activity in vitro are also described.

scholarly journals Elicitation of broadly protective immunity to influenza by multivalent hemagglutinin nanoparticle vaccines

2020 ◽  
Author(s):  
Seyhan Boyoglu-Barnum ◽  
Daniel Ellis ◽  
Rebecca A. Gillespie ◽  
Geoffrey B. Hutchinson ◽  
Young-Jun Park ◽  
...  
Keyword(s):  
Influenza Vaccine ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Neutralizing Antibody ◽  
Influenza Viruses ◽  
Antibody Responses ◽  
Influenza Vaccines ◽  
Next Generation ◽  
Protective Antibody

AbstractInfluenza vaccines that confer broad and durable protection against diverse virus strains would have a major impact on global health. However, next-generation vaccine design efforts have been complicated by challenges including the genetic plasticity of the virus and the immunodominance of certain epitopes in its glycoprotein antigens. Here we show that computationally designed, two-component nanoparticle immunogens induce potently neutralizing and broadly protective antibody responses against a wide variety of influenza viruses. The nanoparticle immunogens display 20 hemagglutinin (HA) trimers in a highly immunogenic array, and their assembly in vitro enables precisely controlled co-display of multiple distinct HAs in defined ratios. Nanoparticle immunogens displaying the four HAs of licensed quadrivalent influenza vaccines (QIV) elicited hemagglutination inhibition and neutralizing antibody responses to vaccine-matched strains that were equivalent or superior to commercial QIV in mice, ferrets, and nonhuman primates. The nanoparticle immunogens—but not QIV—simultaneously induced broadly protective antibody responses to heterologous viruses, including H5N1 and H7N9, by targeting the subdominant yet conserved HA stem. Unlike previously reported influenza vaccine candidates, our nanoparticle immunogens can alter the intrinsic immunodominance hierarchy of HA to induce both potent receptor-blocking and broadly cross-reactive stem-directed antibody responses and are attractive candidates for a next-generation influenza vaccine that could replace current seasonal vaccines.One Sentence SummaryNanoparticle immunogens displaying four seasonal influenza hemagglutinins elicit neutralizing antibodies directed at both the immunodominant head and the conserved stem and confer broad protective immunity.

scholarly journals Vaccination of Rabbits with an Alkylated Toxoid Rapidly Elicits Potent Neutralizing Antibodies against Botulinum Neurotoxin Serotype B

2010 ◽  
Vol 17 (6) ◽  
pp. 930-936 ◽  
Author(s):  
Daniel M. Held ◽  
Amy C. Shurtleff ◽  
Scott Fields ◽  
Christopher Green ◽  
Julie Fong ◽  
...  
Keyword(s):  
Immune Response ◽  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Botulinum Neurotoxin ◽  
Specific Binding ◽  
Neutralizing Antibody ◽  
Neutralization Assay ◽  
Enzyme Linked Immunosorbent Assay ◽  
Elisa Titer ◽  
Serotype B

ABSTRACT New Zealand White (NZW) rabbits were immunized with several different nontoxic botulinum neurotoxin serotype B (BoNT/B) preparations in an effort to optimize the production of a rapid and highly potent, effective neutralizing antibody response. The immunogens included a recombinant heavy chain (rHc) protein produced in Escherichia coli, a commercially available formaldehyde-inactivated toxoid, and an alkylated toxoid produced by urea-iodoacetamide inactivation of the purified active toxin. All three immunogens elicited an antibody response to BoNT/B, detected by enzyme-linked immunosorbent assay (ELISA) and by toxin neutralization assay, by the use of two distinct mouse toxin challenge models. The induction period and the ultimate potency of the observed immune response varied for each immunogen, and the ELISA titer was not reliably predictive of the potency of toxin neutralization. The kinetics of the BoNT/B-specific binding immune response were nearly identical for the formaldehyde toxoid and alkylated toxoid immunogens, but immunization with the alkylated toxoid generated an approximately 10-fold higher neutralization potency that endured throughout the study, and after just 49 days, each milliliter of serum was capable of neutralizing 107 50% lethal doses of the toxin. Overall, the immunization of rabbits with alkylated BoNT/B toxoid appears to have induced a neutralizing immune response more rapid and more potent than the responses generated by vaccination with formaldehyde toxoid or rHc preparations.

scholarly journals Design of the SARS-CoV-2 RBD vaccine antigen improves neutralizing antibody response

2021 ◽  
Author(s):  
Thayne H Dickey ◽  
Wai Kwan Tang ◽  
Brandi Butler ◽  
Tarik Ouahes ◽  
Sachy Orr-Gonzalez ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Computational Design ◽  
Vaccine Antigen ◽  
Primary Target ◽  
Screening Platform ◽  
Almost All

The receptor binding domain (RBD) of the SARS-CoV-2 spike protein is the primary target of neutralizing antibodies and is a component of almost all vaccine candidates. Here, RBD immunogens were created with stabilizing amino acid changes that improve the neutralizing antibody response, as well as characteristics for production, storage, and distribution. A computational design and in vitro screening platform identified three improved immunogens, each with approximately nine amino acid changes relative to the native RBD sequence and four key changes conserved between immunogens. The changes are adaptable to all vaccine platforms, are compatible with established changes in SARS-CoV-2 vaccines, and are compatible with mutations in emerging variants of concern. The immunogens elicit higher levels of neutralizing antibodies than native RBD, focus the immune response to structured neutralizing epitopes, and have increased production yields and thermostability. Incorporating these variant-independent amino acid changes in next-generation vaccines may enhance the neutralizing antibody response and lead to pan-SARS-CoV-2 protection.

scholarly journals In vitro neutralizing activity of BNT162b2 mRNA-induced antibodies against full B.1.351 SARS-CoV-2 variant

2021 ◽  
Author(s):  
Federico García ◽  
Esther Serrano-Conde ◽  
Alba Leyva ◽  
Ana Fuentes-Lopez ◽  
Adolfo de Salazar ◽  
...  
Keyword(s):  
Single Dose ◽  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Healthcare Workers ◽  
Neutralizing Antibody ◽  
Neutralization Activity ◽  
Neutralizing Activity ◽  
Study Participants ◽  
Prior Infection

Background: SARS-CoV-2 variation represents a serious challenge to current COVID-19 vaccines. Recent reports suggest that B.1.351 and other variants may escape the neutralization activity of the antibodies generated by current vaccines. Methods: Ninety-nine healthcare workers undertaking BNT162b2 mRNA vaccination were sampled at baseline, on the day of the second dose, and 14 days after the latter. Neutralization activity against SARS-CoV-2 B.1, B.1.1.7 and B.1.351 was investigated using a Vero-E6 model. Results: Eleven of the study participants had prior infection with SARS-CoV-2. Neutralization titers against the B.1 and the B.1.1.7 variants were not statistically different and were significantly higher than titers against the B.1.351 variant across pre-exposed and non-pre-exposed vaccinated individuals ( p<0.01). While all vaccinated individuals presented neutralizing antibodies against B.1 and B 1.1.7 after the second dose, 14% were negative against B.1.351, and 76% had low titers (1/20-1/80). Pre-exposed vaccinated individuals showed higher titers than non-pre-exposed after the first (median titers of 1/387 versus 1/28, respectively) and the second doses (1/995 versus 1/703, respectively). As high as 72% of the pre-exposed vaccinees presented titers >1/80 after a single dose, while only 11% of non-exposed vaccinated individuals had titers >1/80. Conclusions: BNT162b2 mRNA-induced antibodies show a lower in vitro neutralizing activity against B.1.351 variant compared to neutralization against B.1.1.7 or B.1 variants. Interestingly, for individuals pre-exposed to SARS-CoV-2, one dose of BNT162b2 mRNA may be adequate to produce neutralizing antibodies against B.1.1.7 and B.1, while two doses of BNT162b2 mRNA provide optimal neutralizing antibody response against B.1.351 too.

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