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Article: Nanoparticle Vaccines for Inducing HIV-1 Neutralizing Antibodies.

Brinkkemper, Mitch / Sliepen, Kwinten

2019 Volume 7, Issue 3

Abstract: The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing ...

Abstract	The enormous sequence diversity between human immunodeficiency virus type 1 (HIV-1) strains poses a major roadblock for generating a broadly protective vaccine. Many experimental HIV-1 vaccine efforts are therefore aimed at eliciting broadly neutralizing antibodies (bNAbs) that are capable of neutralizing the majority of circulating HIV-1 strains. The envelope glycoprotein (Env) trimer on the viral membrane is the sole target of bNAbs and the key component of vaccination approaches aimed at eliciting bNAbs. Multimeric presentation of Env on nanoparticles often plays a critical role in these strategies. Here, we will discuss the different aspects of nanoparticles in Env vaccination, including recent insights in immunological processes underlying their perceived advantages, the different nanoparticle platforms and the various immunogenicity studies that employed nanoparticles to improve (neutralizing) antibody responses against Env.
Language	English
Publishing date	2019-07-29
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines7030076
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Article ; Online: A spike virosome vaccine induces pan-sarbecovirus antibody responses in mice.

Brinkkemper, Mitch / Poniman, Meliawati / Siteur-van Rijnstra, Esther / Iddouch, Widad Ait / Bijl, Tom P L / Guerra, Denise / Tejjani, Khadija / Grobben, Marloes / Bhoelan, Farien / Bemelman, Denzel / Kempers, Ronald / van Gils, Marit J / Sliepen, Kwinten / Stegmann, Toon / van der Velden, Yme U / Sanders, Rogier W

iScience

2024 Volume 27, Issue 5, Page(s) 109719

Abstract: Zoonotic events by sarbecoviruses have sparked an epidemic (severe acute respiratory syndrome coronavirus [SARS-CoV]) and a pandemic (SARS-CoV-2) in the past two decades. The continued risk of spillovers from animals to humans is an ongoing threat to ... ...

Abstract	Zoonotic events by sarbecoviruses have sparked an epidemic (severe acute respiratory syndrome coronavirus [SARS-CoV]) and a pandemic (SARS-CoV-2) in the past two decades. The continued risk of spillovers from animals to humans is an ongoing threat to global health and a pan-sarbecovirus vaccine would be an important contribution to pandemic preparedness. Here, we describe multivalent virosome-based vaccines that present stabilized spike proteins from four sarbecovirus strains, one from each clade. A cocktail of four monovalent virosomes or a mosaic virosome preparation induced broad sarbecovirus binding and neutralizing antibody responses in mice. Pre-existing immunity against SARS-CoV-2 and extending the intervals between immunizations enhanced antibody responses. These results should inform the development of a pan-sarbecovirus vaccine, as part of our efforts to prepare for and/or avoid a next pandemic.
Language	English
Publishing date	2024-04-10
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109719
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Article ; Online: Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses.

Radić, Laura / Sliepen, Kwinten / Yin, Victor / Brinkkemper, Mitch / Capella-Pujol, Joan / Schriek, Angela I / Torres, Jonathan L / Bangaru, Sandhya / Burger, Judith A / Poniman, Meliawati / Bontjer, Ilja / Bouhuijs, Joey H / Gideonse, David / Eggink, Dirk / Ward, Andrew B / Heck, Albert J R / Van Gils, Marit J / Sanders, Rogier W / Schinkel, Janke

iScience

2023 Volume 26, Issue 4, Page(s) 106540

Abstract: SARS-CoV-2 variants evade current monoclonal antibody therapies. Bispecific antibodies (bsAbs) combine the specificities of two distinct antibodies taking advantage of the avidity and synergy provided by targeting different epitopes. Here we used ... ...

Abstract	SARS-CoV-2 variants evade current monoclonal antibody therapies. Bispecific antibodies (bsAbs) combine the specificities of two distinct antibodies taking advantage of the avidity and synergy provided by targeting different epitopes. Here we used controlled Fab-arm exchange to produce bsAbs that neutralize SARS-CoV and SARS-CoV-2 variants, including Omicron and its subvariants, by combining potent SARS-CoV-2-specific neutralizing antibodies with broader antibodies that also neutralize SARS-CoV. We demonstrated that the parental antibodies rely on avidity for neutralization using bsAbs containing one irrelevant Fab arm. Using mass photometry to measure the formation of antibody:spike complexes, we determined that bsAbs increase binding stoichiometry compared to corresponding cocktails, without a loss of binding affinity. The heterogeneous binding pattern of bsAbs to spike, observed by negative-stain electron microscopy and mass photometry provided evidence for both intra- and inter-spike crosslinking. This study highlights the utility of cross-neutralizing antibodies for designing bivalent agents to combat circulating and future SARS-like coronaviruses.
Language	English
Publishing date	2023-03-31
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2023.106540
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Article ; Online: SARS-CoV-2 infection activates dendritic cells via cytosolic receptors rather than extracellular TLRs.

van der Donk, Lieve E H / Eder, Julia / van Hamme, John L / Brouwer, Philip J M / Brinkkemper, Mitch / van Nuenen, Ad C / van Gils, Marit J / Sanders, Rogier W / Kootstra, Neeltje A / Bermejo-Jambrina, Marta / Geijtenbeek, Teunis B H

European journal of immunology

2022 Volume 52, Issue 4, Page(s) 646–655

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potentially multiorgan ... ...

Abstract	Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), an infectious disease characterized by strong induction of inflammatory cytokines, progressive lung inflammation, and potentially multiorgan dysfunction. It remains unclear how SARS-CoV-2 infection leads to immune activation. The Spike (S) protein of SARS-CoV-2 has been suggested to trigger TLR4 and thereby activate immunity. Here, we have investigated the role of TLR4 in SARS-CoV-2 infection and immunity. Neither exposure of isolated S protein, SARS-CoV-2 pseudovirus nor primary SARS-CoV-2 isolate induced TLR4 activation in a TLR4-expressing cell line. Human monocyte-derived DCs express TLR4 but not angiotensin converting enzyme 2 (ACE2), and DCs were not infected by SARS-CoV-2. Notably, neither S protein nor SARS-CoV-2 induced DC maturation or cytokines, indicating that both S protein and SARS-CoV-2 virus particles do not trigger extracellular TLRs including TLR4. Ectopic expression of ACE2 in DCs led to efficient infection by SARS-CoV-2 and, strikingly, efficient type I IFN and cytokine responses. These data strongly suggest that not extracellular TLRs but intracellular viral sensors are key players in sensing SARS-CoV-2. These data imply that SARS-CoV-2 escapes direct sensing by TLRs, which might underlie the lack of efficient immunity to SARS-CoV-2 early during infection.
MeSH term(s)	COVID-19/immunology ; Cell Line ; Dendritic Cells/immunology ; Humans ; SARS-CoV-2 ; Spike Glycoprotein, Coronavirus/immunology ; Toll-Like Receptor 4/immunology
Chemical Substances	Spike Glycoprotein, Coronavirus ; TLR4 protein, human ; Toll-Like Receptor 4 ; spike protein, SARS-CoV-2
Language	English
Publishing date	2022-02-16
Publishing country	Germany
Document type	Journal Article
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202149656
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Zs.A 489: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Probing Affinity, Avidity, Anticooperativity, and Competition in Antibody and Receptor Binding to the SARS-CoV-2 Spike by Single Particle Mass Analyses.

Yin, Victor / Lai, Szu-Hsueh / Caniels, Tom G / Brouwer, Philip J M / Brinkkemper, Mitch / Aldon, Yoann / Liu, Hejun / Yuan, Meng / Wilson, Ian A / Sanders, Rogier W / van Gils, Marit J / Heck, Albert J R

ACS central science

2021 Volume 7, Issue 11, Page(s) 1863–1873

Abstract: Determining how antibodies interact with the spike (S) protein of the SARS-CoV-2 virus is critical for combating COVID-19. Structural studies typically employ simplified, truncated constructs that may not fully recapitulate the behavior of the original ... ...

Abstract	Determining how antibodies interact with the spike (S) protein of the SARS-CoV-2 virus is critical for combating COVID-19. Structural studies typically employ simplified, truncated constructs that may not fully recapitulate the behavior of the original complexes. Here, we combine two single particle mass analysis techniques (mass photometry and charge-detection mass spectrometry) to enable the measurement of full IgG binding to the trimeric SARS-CoV-2 S ectodomain. Our experiments reveal that antibodies targeting the S-trimer typically prefer stoichiometries lower than the symmetry-predicted 3:1 binding. We determine that this behavior arises from the interplay of steric clashes and avidity effects that are not reflected in common antibody constructs (i.e., Fabs). Surprisingly, these substoichiometric complexes are fully effective at blocking ACE2 binding despite containing free receptor binding sites. Our results highlight the importance of studying antibody/antigen interactions using complete, multimeric constructs and showcase the utility of single particle mass analyses in unraveling these complex interactions.
Language	English
Publishing date	2021-11-04
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.1c00804
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Article ; Online: Triple tandem trimer immunogens for HIV-1 and influenza nucleic acid-based vaccines.

Del Moral-Sánchez, Iván / Wee, Edmund G / Xian, Yuejiao / Lee, Wen-Hsin / Allen, Joel D / Torrents de la Peña, Alba / Fróes Rocha, Rebeca / Ferguson, James / León, André N / Koekkoek, Sylvie / Schermer, Edith E / Burger, Judith A / Kumar, Sanjeev / Zwolsman, Robby / Brinkkemper, Mitch / Aartse, Aafke / Eggink, Dirk / Han, Julianna / Yuan, Meng /

Crispin, Max / Ozorowski, Gabriel / Ward, Andrew B / Wilson, Ian A / Hanke, Tomáš / Sliepen, Kwinten / Sanders, Rogier W

NPJ vaccines

2024 Volume 9, Issue 1, Page(s) 74

Abstract: Recombinant native-like HIV-1 envelope glycoprotein (Env) trimers are used in candidate vaccines aimed at inducing broadly neutralizing antibodies. While state-of-the-art SOSIP or single-chain Env designs can be expressed as native-like trimers, ... ...

Abstract	Recombinant native-like HIV-1 envelope glycoprotein (Env) trimers are used in candidate vaccines aimed at inducing broadly neutralizing antibodies. While state-of-the-art SOSIP or single-chain Env designs can be expressed as native-like trimers, undesired monomers, dimers and malformed trimers that elicit non-neutralizing antibodies are also formed, implying that these designs could benefit from further modifications for gene-based vaccination approaches. Here, we describe the triple tandem trimer (TTT) design, in which three Env protomers are genetically linked in a single open reading frame and express as native-like trimers. Viral vectored Env TTT induced similar neutralization titers but with a higher proportion of trimer-specific responses. The TTT design was also applied to generate influenza hemagglutinin (HA) trimers without the need for trimerization domains. Additionally, we used TTT to generate well-folded chimeric Env and HA trimers that harbor protomers from three different strains. In summary, the TTT design is a useful platform for the design of HIV-1 Env and influenza HA immunogens for a multitude of vaccination strategies.
Language	English
Publishing date	2024-04-06
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-024-00862-8
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Article: Curcuminoids as EBV Lytic Activators for Adjuvant Treatment in EBV-Positive Carcinomas.

Ramayanti, Octavia / Brinkkemper, Mitch / Verkuijlen, Sandra A W M / Ritmaleni, Leni / Go, Mei Lin / Middeldorp, Jaap M

Cancers

2018 Volume 10, Issue 4

Abstract: Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase ... ...

Abstract	Epstein-Barr virus (EBV) persists in nasopharyngeal (NPC) and gastric carcinomas (EBVaGC) in a tightly latent form. Cytolytic virus activation (CLVA) therapy employs gemcitabine and valproic acid (GCb+VPA) to reactivate latent EBV into the lytic phase and antiviral valganciclovir to enhance cell death and prevent virus production. CLVA treatment has proven safe in phase-I/II trials with promising clinical responses in patients with recurrent NPC. However, a major challenge is to maximize EBV lytic reactivation by CLVA. Curcumin, a dietary spice used in Asian countries, is known for its antitumor property and therapeutic potential. Novel curcuminoids that were developed to increase efficacy and bioavailability may serve as oral CLVA adjuvants. We investigated the potential of curcumin and its analogs (curcuminoids) to trigger the EBV lytic cycle in EBVaGC and NPC cells. EBV-reactivating effects were measured by immunoblot and immunofluorescence using monoclonal antibodies specific for EBV lytic proteins. Two of the hit compounds (
Language	English
Publishing date	2018-03-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers10040089
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Article ; Online: Co-display of diverse spike proteins on nanoparticles broadens sarbecovirus neutralizing antibody responses.

iScience

2022 Volume 25, Issue 12, Page(s) 105649

Abstract: The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses continuous challenges in combating the virus. Here, we describe vaccination strategies to broaden SARS-CoV-2 and sarbecovirus immunity by combining spike ... ...

Abstract	The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses continuous challenges in combating the virus. Here, we describe vaccination strategies to broaden SARS-CoV-2 and sarbecovirus immunity by combining spike proteins based on different viruses or viral strains displayed on two-component protein nanoparticles. First, we combined spike proteins based on ancestral and Beta SARS-CoV-2 strains to broaden SARS-CoV-2 immune responses. Inclusion of Beta spike improved neutralizing antibody responses against SARS-CoV-2 Beta, Gamma, and Omicron BA.1 and BA.4/5. A third vaccination with ancestral SARS-CoV-2 spike also improved cross-neutralizing antibody responses against SARS-CoV-2 variants, in particular against the Omicron sublineages. Second, we combined SARS-CoV and SARS-CoV-2 spike proteins to broaden sarbecovirus immune responses. Adding SARS-CoV spike to a SARS-CoV-2 spike vaccine improved neutralizing responses against SARS-CoV and SARS-like bat sarbecoviruses SHC014 and WIV1. These results should inform the development of broadly active SARS-CoV-2 and pan-sarbecovirus vaccines and highlight the versatility of two-component nanoparticles for displaying diverse antigens.
Language	English
Publishing date	2022-11-22
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.105649
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Article ; Online: Probing Affinity, Avidity, Anti-Cooperativity, and Competition in Antibody and Receptor Binding to the SARS-CoV-2 Spike by Single Particle Mass Analyses

Yin, Victor C / Lai, Szu-Hsueh / Caniels, Tom G / Brouwer, Philip J.M. / Brinkkemper, Mitch / Aldon, Yoann / Liu, Hejun / Yuan, Meng / Wilson, Ian A. / Sanders, Rogier W / van Gils, Marit / Heck, Albert J.R.

bioRxiv

Abstract	Determining how antibodies interact with the spike (S) protein of the SARS-CoV-2 virus is critical for combating COVID-19. Structural studies typically employ simplified, truncated constructs that may not fully recapitulate the behaviour of the original complexes. Here, we combine two single particle mass analysis techniques (mass photometry and charge-detection mass spectrometry) to enable measurement of full IgG binding to the trimeric SARS-CoV-2 S ectodomain. Our experiments reveal that antibodies targeting the S-trimer typically prefer stoichiometries lower than the symmetry-predicted 3:1 binding. We determine that this behaviour arises from the interplay of steric clashes and avidity effects that are not reflected in common antibody constructs (i.e. Fabs). Surprisingly, these sub-stoichiometric complexes are fully effective at blocking ACE2 binding despite containing free receptor binding sites. Our results highlight the importance of studying antibody/antigen interactions using complete, multimeric constructs and showcase the utility of single particle mass analyses in unraveling these complex interactions.
Keywords	covid19
Language	English
Publishing date	2021-06-18
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.06.18.448939
Database	COVID19

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Article ; Online: A third SARS-CoV-2 spike vaccination improves neutralization of variants-of-concern.

Brinkkemper, Mitch / Brouwer, Philip J M / Maisonnasse, Pauline / Grobben, Marloes / Caniels, Tom G / Poniman, Meliawati / Burger, Judith A / Bontjer, Ilja / Oomen, Melissa / Bouhuijs, Joey H / van der Linden, Cynthia A / Villaudy, Julien / van der Velden, Yme U / Sliepen, Kwinten / van Gils, Marit J / Le Grand, Roger / Sanders, Rogier W

NPJ vaccines

2021 Volume 6, Issue 1, Page(s) 146

Abstract: The emergence of SARS-CoV-2 variants that are more resistant to antibody-mediated neutralization pose a new hurdle in combating the COVID-19 pandemic. Although vaccines based on the original Wuhan sequence have been shown to be effective at preventing ... ...

Abstract	The emergence of SARS-CoV-2 variants that are more resistant to antibody-mediated neutralization pose a new hurdle in combating the COVID-19 pandemic. Although vaccines based on the original Wuhan sequence have been shown to be effective at preventing COVID-19, their efficacy is likely to be decreased against more neutralization-resistant variants-of-concern (VOC), in particular, the Beta variant originating in South Africa. We assessed, in mice, rabbits, and non-human primates, whether a third vaccination with experimental Wuhan-based Spike vaccines could alleviate this problem. Our data show that a third immunization improves neutralizing antibody titers against the variants-of-concern, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), and Delta (B.1.617.2). After three vaccinations, the level of neutralization against Beta was similar to the level of neutralization against the original strain after two vaccinations, suggesting that simply providing a third immunization could nullify the reduced activity of current vaccines against VOC.
Language	English
Publishing date	2021-12-03
Publishing country	England
Document type	Journal Article
ISSN	2059-0105
ISSN (online)	2059-0105
DOI	10.1038/s41541-021-00411-7
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