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Article ; Online: Enhanced immunity after Ad26.COV2.S vaccine breakthrough infection.

Montefiori, David C

Cell reports. Medicine

2022 Volume 3, Issue 3, Page(s) 100579

Abstract: A study by Kitchin, Richardson et al. finds that breakthrough infection with the SARS-CoV-2 Delta variant in Ad26.COV2.S-vaccinated individuals induces strong neutralizing antibody responses against multiple variants, including the Omicron variant. ...

Abstract	A study by Kitchin, Richardson et al. finds that breakthrough infection with the SARS-CoV-2 Delta variant in Ad26.COV2.S-vaccinated individuals induces strong neutralizing antibody responses against multiple variants, including the Omicron variant.
MeSH term(s)	Ad26COVS1 ; Antibodies, Viral ; COVID-19/prevention & control ; Humans ; SARS-CoV-2/genetics ; Viral Vaccines
Chemical Substances	Ad26COVS1 ; Antibodies, Viral ; Viral Vaccines
Language	English
Publishing date	2022-03-15
Publishing country	United States
Document type	News ; Comment
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2022.100579
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Article ; Online: SnapShot: SARS-CoV-2 antibodies.

Montefiori, David C / Acharya, Priyamvada

Cell host & microbe

2021 Volume 29, Issue 7, Page(s) 1162–1162.e1

MeSH term(s)	Antibodies, Monoclonal/therapeutic use ; Antibodies, Viral/immunology ; Antibodies, Viral/therapeutic use ; COVID-19/immunology ; Humans ; Mutation ; SARS-CoV-2/immunology ; Spike Glycoprotein, Coronavirus/genetics ; Spike Glycoprotein, Coronavirus/immunology
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Viral ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2
Language	English
Publishing date	2021-07-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2278004-X
ISSN	1934-6069 ; 1931-3128
ISSN (online)	1934-6069
ISSN	1931-3128
DOI	10.1016/j.chom.2021.06.005
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Article ; Online: Bispecific Antibodies Against HIV.

Montefiori, David C

Cell

2016 Volume 165, Issue 7, Page(s) 1563–1564

Abstract: Synergistic bispecific antibodies against HIV exhibit extraordinary potency and breadth of neutralization as promising candidates for treatment and prevention. ...

Abstract	Synergistic bispecific antibodies against HIV exhibit extraordinary potency and breadth of neutralization as promising candidates for treatment and prevention.
MeSH term(s)	Antibodies, Bispecific/immunology ; Antibodies, Neutralizing/immunology ; HIV Antibodies/immunology ; HIV Infections/immunology ; HIV-1/immunology ; Humans
Chemical Substances	Antibodies, Bispecific ; Antibodies, Neutralizing ; HIV Antibodies
Language	English
Publishing date	2016--16
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2016.06.004
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Article ; Online: Broadly neutralizing monoclonal antibodies for HIV prevention.

Miner, Maurine D / Corey, Lawrence / Montefiori, David

Journal of the International AIDS Society

2021 Volume 24 Suppl 7, Page(s) e25829

Abstract: Introduction: The last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV-specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation ... ...

Abstract	Introduction: The last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV-specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation pathways and epitopes have created new opportunities for vaccine development. In addition, interest exists in passive administration of monoclonal antibodies as a viable option for HIV prevention. Discussion: Recently, two antibody-mediated prevention (AMP) trials of a passively administered monoclonal antibody targeting the HIV envelope CD4 binding site, called VRC01, provided proof-of-concept that monoclonal antibody infusion could offer protection against HIV acquisition. While the trials failed to show overall protection against HIV acquisition, sub-analyses revealed that VRC01 infusion provided a 75% prevention efficacy against HIV strains that were susceptible to the antibody. The study also demonstrated that in vitro neutralizing activity, measured by the TZM-bl/pseudovirus assay, was able to predict HIV prevention efficacy in humans. In addition, the AMP trials defined a threshold protective concentration, or neutralization titer, for the VRC01 class of bnAbs, explaining the observed low overall efficacy and serving as a benchmark for the clinical testing of new bnAbs, bnAb cocktails and neutralizing antibody-inducing vaccines. Newer bnAbs that exhibit greater potency and breadth of neutralization in vitro than VRC01 are available for clinical testing. Combinations of best-in-class bnAbs with complementary magnitude, breadth and extent of complete neutralization are predicted to far exceed the prevention efficacy of VRC01. Some engineered bi- and trispecific mAbs exhibit similar desirable neutralizing activity and afford advantages for manufacturing and delivery. Modifications that prolong the serum half-life and improve genital tissue persistence offer additional advantages. Conclusions: Iterative phase 1 trials are acquiring safety and pharmacokinetic data on dual and triple bnAbs and bi- and trispecific antibodies in preparation for future AMP studies that seek to translate findings from the VRC01 efficacy trials and achieve acceptable levels of overall prevention efficacy.
MeSH term(s)	Antibodies, Monoclonal/therapeutic use ; Broadly Neutralizing Antibodies ; HIV Antibodies ; HIV Infections/drug therapy ; HIV Infections/prevention & control ; HIV-1 ; Humans
Chemical Substances	Antibodies, Monoclonal ; Broadly Neutralizing Antibodies ; HIV Antibodies
Language	English
Publishing date	2021-11-03
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2467110-1
ISSN	1758-2652 ; 1758-2652
ISSN (online)	1758-2652
ISSN	1758-2652
DOI	10.1002/jia2.25829
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Article ; Online: Importance of neutralization sieve analyses when seeking correlates of HIV-1 vaccine efficacy.

Montefiori, David C

Human vaccines & immunotherapeutics

2014 Volume 10, Issue 8, Page(s) 2507–2511

Abstract: This commentary describes a rationale for the use of breakthrough viruses from clinical trial participants to assess neutralizing antibodies as a correlate of HIV-1 vaccine efficacy. The rationale is based on principles of a genetic sieve analysis, where ...

Abstract	This commentary describes a rationale for the use of breakthrough viruses from clinical trial participants to assess neutralizing antibodies as a correlate of HIV-1 vaccine efficacy. The rationale is based on principles of a genetic sieve analysis, where the 2 analyses may be cooperative for delineating neutralizing antibodies as a mechanistic correlate of protection.
MeSH term(s)	AIDS Vaccines/immunology ; Acquired Immunodeficiency Syndrome/prevention & control ; Antibodies, Neutralizing/blood ; Biomarkers/analysis ; Biomedical Research/methods ; HIV Antibodies/blood ; Humans ; Treatment Outcome
Chemical Substances	AIDS Vaccines ; Antibodies, Neutralizing ; Biomarkers ; HIV Antibodies
Language	English
Publishing date	2014
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2664176-8
ISSN	2164-554X ; 2164-5515
ISSN (online)	2164-554X
ISSN	2164-5515
DOI	10.4161/hv.28950
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Article: Mutational basis of serum cross-neutralization profiles elicited by infection or vaccination with SARS-CoV-2 variants.

Wagh, Kshitij / Shen, Xiaoying / Theiler, James / Girard, Bethany / Marshall, Jean-Claude / Montefiori, David C / Korber, Bette

bioRxiv : the preprint server for biology

2023

Abstract: A series of SARS-CoV-2 variants emerged during the pandemic under selection for neutralization resistance. Convalescent and vaccinated sera show consistently different cross-neutralization profiles depending on infecting or vaccine variants. To ... ...

Abstract	A series of SARS-CoV-2 variants emerged during the pandemic under selection for neutralization resistance. Convalescent and vaccinated sera show consistently different cross-neutralization profiles depending on infecting or vaccine variants. To understand the basis of this heterogeneity, we modeled serum cross-neutralization titers for 165 sera after infection or vaccination with historically prominent lineages tested against 18 variant pseudoviruses. Cross-neutralization profiles were well captured by models incorporating autologous neutralizing titers and combinations of specific shared and differing mutations between the infecting/vaccine variants and pseudoviruses. Infecting/vaccine variant-specific models identified mutations that significantly impacted cross-neutralization and quantified their relative contributions. Unified models that explained cross-neutralization profiles across all infecting and vaccine variants provided accurate predictions of holdout neutralization data comprising untested variants as infecting or vaccine variants, and as test pseudoviruses. Finally, comparative modeling of 2-dose versus 3-dose mRNA-1273 vaccine data revealed that the third dose overcame key resistance mutations to improve neutralization breadth. Highlights: Modeled SARS-CoV-2 cross-neutralization using mutations at key sitesIdentified resistance mutations and quantified relative impactAccurately predicted holdout variant and convalescent/vaccine sera neutralizationShowed that the third dose of mRNA-1273 vaccination overcomes resistance mutations.
Language	English
Publishing date	2023-08-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.13.553144
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Article ; Online: Contralateral second dose improves antibody responses to a 2-dose mRNA vaccination regimen.

Fazli, Sedigheh / Thomas, Archana / Estrada, Abram E / Ross, Hiro Ap / Xthona Lee, David / Kazmierczak, Steven / Slifka, Mark K / Montefiori, David / Messer, William B / Curlin, Marcel E

The Journal of clinical investigation

2024 Volume 134, Issue 6

Abstract: BACKGROUNDVaccination is typically administered without regard to site of prior vaccination, but this factor may substantially affect downstream immune responses.METHODSWe assessed serological responses to initial COVID-19 vaccination in baseline ... ...

Abstract	BACKGROUNDVaccination is typically administered without regard to site of prior vaccination, but this factor may substantially affect downstream immune responses.METHODSWe assessed serological responses to initial COVID-19 vaccination in baseline seronegative adults who received second-dose boosters in the ipsilateral or contralateral arm relative to initial vaccination. We measured serum SARS-CoV-2 spike-specific Ig, receptor-binding domain-specific (RBD-specific) IgG, SARS-CoV-2 nucleocapsid-specific IgG, and neutralizing antibody titers against SARS-CoV-2.D614G (early strain) and SARS-CoV-2.B.1.1.529 (Omicron) at approximately 0.6, 8, and 14 months after boosting.RESULTSIn 947 individuals, contralateral boosting was associated with higher spike-specific serum Ig, and this effect increased over time, from a 1.1-fold to a 1.4-fold increase by 14 months (P < 0.001). A similar pattern was seen for RBD-specific IgG. Among 54 pairs matched for age, sex, and relevant time intervals, arm groups had similar antibody levels at study visit 2 (W2), but contralateral boosting resulted in significantly higher binding and neutralizing antibody titers at W3 and W4, with progressive increase over time, ranging from 1.3-fold (total Ig, P = 0.007) to 4.0-fold (pseudovirus neutralization to B.1.1.529, P < 0.001).CONCLUSIONSIn previously unexposed adults receiving an initial vaccine series with the BNT162b2 mRNA COVID-19 vaccine, contralateral boosting substantially increases antibody magnitude and breadth at times beyond 3 weeks after vaccination. This effect should be considered during arm selection in the context of multidose vaccine regimens.FUNDINGM.J. Murdock Charitable Trust, OHSU Foundation, NIH.
MeSH term(s)	Adult ; Humans ; Antibody Formation ; COVID-19 Vaccines ; BNT162 Vaccine ; Vaccination ; Antibodies, Viral ; Immunoglobulin G ; RNA, Messenger ; Antibodies, Neutralizing
Chemical Substances	COVID-19 Vaccines ; BNT162 Vaccine ; Antibodies, Viral ; Immunoglobulin G ; RNA, Messenger ; Antibodies, Neutralizing
Language	English
Publishing date	2024-01-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI176411
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Article ; Online: The SARS-CoV-2 Spike variant D614G favors an open conformational state.

Mansbach, Rachael A / Chakraborty, Srirupa / Nguyen, Kien / Montefiori, David C / Korber, Bette / Gnanakaran, S

Science advances

2021 Volume 7, Issue 16

Abstract: The COVID-19 (coronavirus disease 2019) pandemic underwent a rapid transition with the emergence of a dominant viral variant (from the "D-form" to the "G-form") that carried an amino acid substitution D614G in its "Spike" protein. The G-form is more ... ...

Abstract	The COVID-19 (coronavirus disease 2019) pandemic underwent a rapid transition with the emergence of a dominant viral variant (from the "D-form" to the "G-form") that carried an amino acid substitution D614G in its "Spike" protein. The G-form is more infectious in vitro and is associated with increased viral loads in the upper airways. To gain insight into the molecular-level underpinnings of these characteristics, we used microsecond all-atom simulations. We show that changes in the protein energetics favor a higher population of infection-capable states in the G-form through release of asymmetry present in the D-form inter-protomer interactions. Thus, the increased infectivity of the G-form is likely due to a higher rate of profitable binding encounters with the host receptor. It is also predicted to be more neutralization sensitive owing to enhanced exposure of the receptor binding domain, a key target region for neutralizing antibodies. These results are critical for vaccine design.
MeSH term(s)	Amino Acid Sequence ; Angiotensin-Converting Enzyme 2/chemistry ; Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Neutralizing/immunology ; COVID-19/pathology ; COVID-19/virology ; Glycosylation ; Humans ; Hydrogen Bonding ; Molecular Dynamics Simulation ; Mutation ; Protein Binding ; Protein Structure, Quaternary ; Protein Subunits/chemistry ; Protein Subunits/immunology ; SARS-CoV-2/genetics ; SARS-CoV-2/immunology ; SARS-CoV-2/isolation & purification ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism ; Virus Internalization
Chemical Substances	Antibodies, Neutralizing ; Protein Subunits ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.abf3671
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Article: Bispecific Antibodies Against HIV

Montefiori, DavidÂ C

Cell. 2016 June 16, v. 165

2016

Abstract: Synergistic bispecific antibodies against HIV exhibit extraordinary potency and breadth of neutralization as promising candidates for treatment and prevention. ...

Abstract	Synergistic bispecific antibodies against HIV exhibit extraordinary potency and breadth of neutralization as promising candidates for treatment and prevention.
Keywords	Human immunodeficiency virus ; antibodies ; neutralization
Language	English
Dates of publication	2016-0616
Size	p. 1563-1564.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2016.06.004
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Article: Correlation of Binding and Neutralizing Antibodies against SARS-CoV-2 Omicron Variant in Infection-Naïve and Convalescent BNT162b2 Recipients.

Fu, Jia / Shen, Xiaoying / Anderson, Mark / Stec, Michael / Petratos, Tia / Cloherty, Gavin / Montefiori, David C / Landay, Alan / Moy, James N

Vaccines

2022 Volume 10, Issue 11

Abstract: In vaccine clinical trials, both binding antibody (bAb) levels and neutralization antibody (nAb) titers have been shown to be correlates of SARS-CoV-2 vaccine efficacy. We report a strong correlation bAb and nAb responses against the SARS-CoV-2 Omicron ( ... ...

Abstract	In vaccine clinical trials, both binding antibody (bAb) levels and neutralization antibody (nAb) titers have been shown to be correlates of SARS-CoV-2 vaccine efficacy. We report a strong correlation bAb and nAb responses against the SARS-CoV-2 Omicron (BA.1) variant in infection-naïve and previously infected (convalescent) individuals after one and two doses of BNT162b2 vaccination. The vaccine-induced bAb levels against Omicron were significantly lower compared to previous variants of concern in both infection-naive and convalescent individuals, with the convalescent individuals showing significantly higher bAb compared to the naïve individuals at all timepoints. The finding that bAb highly correlated with nAb provides evidence for utilizing binding antibody assays as a surrogate for neutralizing antibody assays. Our data also revealed that after full vaccination, a higher percentage of individuals had undetectable Omicron nAb (58.6% in naive individuals, 7.4% in convalescent individuals) compared to the percentage of individuals who had negative Omicron bAb (0% in naive individuals, 0% in convalescent individuals). The discordance between bAb and nAb activities and the high degree of immune escape by Omicron may explain the high frequency of Omicron infections after vaccination.
Language	English
Publishing date	2022-11-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines10111904
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