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 Broad and potent neutralizing human antibodies to tick-borne flaviviruses protect mice from disease

2021 ◽  
Vol 218 (5) ◽  
Author(s):  
Marianna Agudelo ◽  
Martin Palus ◽  
Jennifer R. Keeffe ◽  
Filippo Bianchini ◽  
Pavel Svoboda ◽  
...  
Keyword(s):  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Specific Treatment ◽  
Neutralizing Antibody ◽  
Hemorrhagic Fever ◽  
Human Antibody ◽  
Lateral Ridge ◽  
Tick Borne Encephalitis Virus ◽  
Domain Iii

Tick-borne encephalitis virus (TBEV) is an emerging human pathogen that causes potentially fatal disease with no specific treatment. Mouse monoclonal antibodies are protective against TBEV, but little is known about the human antibody response to infection. Here, we report on the human neutralizing antibody response to TBEV in a cohort of infected and vaccinated individuals. Expanded clones of memory B cells expressed closely related anti-envelope domain III (EDIII) antibodies in both groups of volunteers. However, the most potent neutralizing antibodies, with IC50s below 1 ng/ml, were found only in individuals who recovered from natural infection. These antibodies also neutralized other tick-borne flaviviruses, including Langat, louping ill, Omsk hemorrhagic fever, Kyasanur forest disease, and Powassan viruses. Structural analysis revealed a conserved epitope near the lateral ridge of EDIII adjoining the EDI–EDIII hinge region. Prophylactic or early therapeutic antibody administration was effective at low doses in mice that were lethally infected with TBEV.

scholarly journals The receptor binding domain of SARS-CoV-2 spike is the key target of neutralizing antibody in human polyclonal sera

2020 ◽  
Author(s):  
Tara L. Steffen ◽  
E. Taylor Stone ◽  
Mariah Hassert ◽  
Elizabeth Geerling ◽  
Brian T. Grimberg ◽  
...  
Keyword(s):  
Antibody Response ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Antigenic Determinants ◽  
Receptor Binding Domain ◽  
Neutralization Capacity

AbstractNatural infection of SARS-CoV-2 in humans leads to the development of a strong neutralizing antibody response, however the immunodominant targets of the polyclonal neutralizing antibody response are still unknown. Here, we functionally define the role SARS-CoV-2 spike plays as a target of the human neutralizing antibody response. In this study, we identify the spike protein subunits that contain antigenic determinants and examine the neutralization capacity of polyclonal sera from a cohort of patients that tested qRT-PCR-positive for SARS-CoV-2. Using an ELISA format, we assessed binding of human sera to spike subunit 1 (S1), spike subunit 2 (S2) and the receptor binding domain (RBD) of spike. To functionally identify the key target of neutralizing antibody, we depleted sera of subunit-specific antibodies to determine the contribution of these individual subunits to the antigen-specific neutralizing antibody response. We show that epitopes within RBD are the target of a majority of the neutralizing antibodies in the human polyclonal antibody response. These data provide critical information for vaccine development and development of sensitive and specific serological testing.

scholarly journals Antibody Response to the BNT162b2 mRNA COVID-19 Vaccine in Subjects with Prior SARS-CoV-2 Infection

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 422
Author(s):  
Federico Gobbi ◽  
Dora Buonfrate ◽  
Lucia Moro ◽  
Paola Rodari ◽  
Chiara Piubelli ◽  
...  
Keyword(s):  
Antibody Response ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Vaccine Dose ◽  
Neutralizing Antibody ◽  
Immune Memory ◽  
Effective Response ◽  
Infected People ◽  
Significant Difference ◽  
Antibody Titers

Although antibody levels progressively decrease following SARS-CoV-2 infection, the immune memory persists for months. Thus, individuals who naturally contracted SARS-CoV-2 are expected to develop a more rapid and sustained response to COVID-19 vaccines than naïve individuals. In this study, we analyzed the dynamics of the antibody response to the BNT162b2 mRNA COVID-19 vaccine in six healthcare workers who contracted SARS-CoV-2 in March 2020, in comparison to nine control subjects without a previous infection. The vaccine was well tolerated by both groups, with no significant difference in the frequency of vaccine-associated side effects, with the exception of local pain, which was more common in previously infected subjects. Overall, the titers of neutralizing antibodies were markedly higher in response to the vaccine than after natural infection. In all subjects with pre-existing immunity, a rapid increase in anti-spike receptor-binding domain (RBD) IgG antibodies and neutralizing antibody titers was observed one week after the first dose, which seemed to act as a booster. Notably, in previously infected individuals, neutralizing antibody titers 7 days after the first vaccine dose were not significantly different from those observed in naïve subjects 7 days after the second vaccine dose. These results suggest that, in previously infected people, a single dose of the vaccine might be sufficient to induce an effective response.

scholarly journals Rabies Virus-specific Human T Cell Clones Provide Help for an in vitro Antibody Response against Neutralizing Antibody-inducing Determinants of the Viral Glycoprotein

1989 ◽  
Vol 70 (6) ◽  
pp. 1513-1521 ◽  
Author(s):  
H. Bunschoten ◽  
R. J. Klapmuts ◽  
I. J. Th. M. Claassen ◽  
S. D. Reyneveld ◽  
A. D. M. E. Osterhaus ◽  
...  
Keyword(s):  
T Cell ◽  
Antibody Response ◽  
Rabies Virus ◽  
Neutralizing Antibody ◽  
Viral Glycoprotein ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones

scholarly journals HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates

2017 ◽  
Vol 91 (21) ◽  
Author(s):  
Yimeng Wang ◽  
Sijy O'Dell ◽  
Hannah L. Turner ◽  
Chi-I Chiang ◽  
Lin Lei ◽  
...  
Keyword(s):  
Antibody Response ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Nonhuman Primates ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Tier 2 ◽  
Neutralization Capacity ◽  
Hiv 1 ◽  
Primary Virus

ABSTRACT Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross-reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP.664, a native Env trimer mimetic, as a sorting probe to isolate monoclonal Abs (MAbs). We found striking genetic and functional convergence of the SOSIP-sorted Ig repertoire, with predominant VH4 or VH5 gene family usage and Env V3 specificity. Of these vaccine-elicited V3-specific MAbs, nearly 20% (6/33) displayed cross-reactive tier 2 virus neutralization, which recapitulated the serum neutralization capacity. Substantial similarities in binding specificity, neutralization breadth and potency, and sequence/structural homology were observed between selected macaque cross-reactive V3 NAbs elicited by vaccination and prototypic V3 NAbs derived from natural infections in humans, highlighting the convergence of this subset of primate V3-specific B cell repertories. Our study demonstrated that cross-reactive primary virus neutralizing B cell lineages could be elicited by vaccination as detected using a standardized panel of tier 2 viruses. Whether these lineages could be expanded to acquire increased breadth and potency of neutralization merits further investigation. IMPORTANCE Elicitation of antibody responses capable of neutralizing diverse HIV-1 primary virus isolates (designated broadly neutralizing antibodies [bNAbs]) remains a high priority for the vaccine field. bNAb responses were so far observed only in response to natural infection within a subset of individuals. To achieve this goal, an improved understanding of vaccine-elicited responses, including at the monoclonal Ab level, is essential. Here, we isolated and characterized a panel of vaccine-elicited cross-reactive neutralizing MAbs targeting the Env V3 loop that moderately neutralized several primary viruses and recapitulated the serum neutralizing antibody response. Striking similarities between the cross-reactive V3 NAbs elicited by vaccination in macaques and natural infections in humans illustrate commonalities between the vaccine- and infection-induced responses to V3 and support the feasibility of exploring the V3 epitope as a HIV-1 vaccine target in nonhuman primates.

scholarly journals Enveloped Virus-Like Particle Expression of Human Cytomegalovirus Glycoprotein B Antigen Induces Antibodies with Potent and Broad Neutralizing Activity

2013 ◽  
Vol 21 (2) ◽  
pp. 174-180 ◽  
Author(s):  
Marc Kirchmeier ◽  
Anne-Catherine Fluckiger ◽  
Catalina Soare ◽  
Jasminka Bozic ◽  
Barthelemy Ontsouka ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Human Cytomegalovirus ◽  
Neutralizing Antibodies ◽  
Matrix Protein ◽  
High Titer ◽  
Neutralizing Antibody ◽  
Glycoprotein B ◽  
Solid Organ ◽  
Neutralizing Activity ◽  
Enveloped Virus

ABSTRACTA prophylactic vaccine to prevent the congenital transmission of human cytomegalovirus (HCMV) in newborns and to reduce life-threatening disease in immunosuppressed recipients of HCMV-infected solid organ transplants is highly desirable. Neutralizing antibodies against HCMV confer significant protection against infection, and glycoprotein B (gB) is a major target of such neutralizing antibodies. However, one shortcoming of past HCMV vaccines may have been their failure to induce high-titer persistent neutralizing antibody responses that prevent the infection of epithelial cells. We used enveloped virus-like particles (eVLPs), in which particles were produced in cells after the expression of murine leukemia virus (MLV) viral matrix protein Gag, to express either full-length CMV gB (gB eVLPs) or the full extracellular domain of CMV gB fused with the transmembrane and cytoplasmic domains from vesicular stomatitis virus (VSV)-G protein (gB-G eVLPs). gB-G-expressing eVLPs induced potent neutralizing antibodies in mice with a much greater propensity toward epithelial cell-neutralizing activity than that induced with soluble recombinant gB protein. An analysis of gB antibody binding titers and T-helper cell responses demonstrated that high neutralizing antibody titers were not simply due to enhanced immunogenicity of the gB-G eVLPs. The cells transiently transfected with gB-G but not gB plasmid formed syncytia, consistent with a prefusion gB conformation like those of infected cells and viral particles. Two of the five gB-G eVLP-induced monoclonal antibodies we examined in detail had neutralizing activities, one of which possessed particularly potent epithelial cell-neutralizing activity. These data differentiate gB-G eVLPs from gB antigens used in the past and support their use in a CMV vaccine candidate with improved neutralizing activity against epithelial cell infection.

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 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.

scholarly journals The quantitative landscape of the neutralizing antibody response to SARS-CoV-2

2020 ◽  
Author(s):  
Pranesh Padmanabhan ◽  
Rajat Desikan ◽  
Narendra M Dixit
Keyword(s):  
Clinical Trials ◽  
Antibody Response ◽  
Dose Response ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Virtual Patient ◽  
Plasma Samples ◽  
Response Curves

Neutralizing antibodies (NAbs) appear promising interventions against SARS-CoV-2 infection. Over 100 NAbs have been identified so far and several are in clinical trials. Yet, which NAbs would be the most potent remains unclear. Here, we analysed reported in vitro dose-response curves (DRCs) of >70 NAbs and estimated corresponding 50% inhibitory concentrations, slope parameters, and instantaneous inhibitory potentials (IIPs), presenting a comprehensive quantitative landscape of NAb responses to SARS-CoV-2. NAbs with high IIPs are likely to be potent. To assess the applicability of the landscape in vivo, we analysed available DRCs of NAbs from individual patients and found that the responses closely resembled the landscape. Further, we created virtual patient plasma samples by randomly sampling NAbs from the landscape and found that they recapitulated plasma dilution assays from convalescent patients. The landscape thus offers a facile tool for benchmarking NAbs and would aid the development of NAb-based therapies for SARS-CoV-2 infection.

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