Publications by authors named "Rogier W Sanders"

207 Publications

A combination of cross-neutralizing antibodies synergizes to prevent SARS-CoV-2 and SARS-CoV pseudovirus infection.

Cell Host Microbe 2021 May 15;29(5):806-818.e6. Epub 2021 Apr 15.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:

Coronaviruses have caused several human epidemics and pandemics including the ongoing coronavirus disease 2019 (COVID-19). Prophylactic vaccines and therapeutic antibodies have already shown striking effectiveness against COVID-19. Nevertheless, concerns remain about antigenic drift in SARS-CoV-2 as well as threats from other sarbecoviruses. Cross-neutralizing antibodies to SARS-related viruses provide opportunities to address such concerns. Here, we report on crystal structures of a cross-neutralizing antibody, CV38-142, in complex with the receptor-binding domains from SARS-CoV-2 and SARS-CoV. Recognition of the N343 glycosylation site and water-mediated interactions facilitate cross-reactivity of CV38-142 to SARS-related viruses, allowing the antibody to accommodate antigenic variation in these viruses. CV38-142 synergizes with other cross-neutralizing antibodies, notably COVA1-16, to enhance neutralization of SARS-CoV and SARS-CoV-2, including circulating variants of concern B.1.1.7 and B.1.351. Overall, this study provides valuable information for vaccine and therapeutic design to address current and future antigenic drift in SARS-CoV-2 and to protect against zoonotic SARS-related coronaviruses.
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http://dx.doi.org/10.1016/j.chom.2021.04.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049401PMC
May 2021

SARS-CoV-2 can recruit a haem metabolite to evade antibody immunity.

Sci Adv 2021 Apr 22. Epub 2021 Apr 22.

Department of Infectious Disease, St-Mary's Campus, Imperial College London, UK.

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography, we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that SARS-CoV-2 spike NTD harbors a dominant epitope, access to which can be controlled by an allosteric mechanism that is regulated through the recruitment of a metabolite.
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http://dx.doi.org/10.1126/sciadv.abg7607DOI Listing
April 2021

Enhancing glycan occupancy of soluble HIV-1 envelope trimers to mimic the native viral spike.

Cell Rep 2021 Apr;35(1):108933

Department of Medical Microbiology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Microbiology and Immunology, Weill Cornell Medical College, Cornell University, New York, NY, USA. Electronic address:

Artificial glycan holes on recombinant Env-based vaccines occur when a potential N-linked glycosylation site (PNGS) is under-occupied, but not on their viral counterparts. Native-like SOSIP trimers, including clinical candidates, contain such holes in the glycan shield that induce strain-specific neutralizing antibodies (NAbs) or non-NAbs. To eliminate glycan holes and mimic the glycosylation of native BG505 Env, we replace all 12 NxS sequons on BG505 SOSIP with NxT. All PNGS, except N133 and N160, are nearly fully occupied. Occupancy of the N133 site is increased by changing N133 to NxS, whereas occupancy of the N160 site is restored by reverting the nearby N156 sequon to NxS. Hence, PNGS in close proximity, such as in the N133-N137 and N156-N160 pairs, affect each other's occupancy. We further apply this approach to improve the occupancy of several Env strains. Increasing glycan occupancy should reduce off-target immune responses to vaccine antigens.
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http://dx.doi.org/10.1016/j.celrep.2021.108933DOI Listing
April 2021

Pandemic moves and countermoves: vaccines and viral variants.

Lancet 2021 Apr 30;397(10282):1326-1327. Epub 2021 Mar 30.

Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam 1105 AZ, Netherlands.

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http://dx.doi.org/10.1016/S0140-6736(21)00730-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009609PMC
April 2021

Antibody responses to SARS-CoV-2 mRNA vaccines are detectable in saliva.

bioRxiv 2021 Mar 11. Epub 2021 Mar 11.

Vaccines are critical for curtailing the COVID-19 pandemic (1, 2). In the USA, two highly protective mRNA vaccines are available: BNT162b2 from Pfizer/BioNTech and mRNA-1273 from Moderna (3, 4). These vaccines induce antibodies to the SARS-CoV-2 S-protein, including neutralizing antibodies (NAbs) predominantly directed against the Receptor Binding Domain (RBD) (1-4). Serum NAbs are induced at modest levels within ∼1 week of the first dose, but their titers are strongly boosted by a second dose at 3 (BNT162b2) or 4 weeks (mRNA-1273) (3, 4). SARS-CoV-2 is most commonly transmitted nasally or orally and infects cells in the mucosae of the respiratory and to some extent also the gastrointestinal tract (5). Although serum NAbs may be a correlate of protection against COVID-19, mucosal antibodies might directly prevent or limit virus acquisition by the nasal, oral and conjunctival routes (5). Whether the mRNA vaccines induce mucosal immunity has not been studied. Here, we report that antibodies to the S-protein and its RBD are present in saliva samples from mRNA-vaccinated healthcare workers (HCW). Within 1-2 weeks after their second dose, 37/37 and 8/8 recipients of the Pfizer and Moderna vaccines, respectively, had S-protein IgG antibodies in their saliva, while IgA was detected in a substantial proportion. These observations may be relevant to vaccine-mediated protection from SARS-CoV-2 infection and disease.
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http://dx.doi.org/10.1101/2021.03.11.434841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987001PMC
March 2021

Site-specific steric control of SARS-CoV-2 spike glycosylation.

bioRxiv 2021 Mar 9. Epub 2021 Mar 9.

A central tenet in the design of vaccines is the display of native-like antigens in the elicitation of protective immunity. The abundance of N-linked glycans across the SARS-CoV-2 spike protein is a potential source of heterogeneity between the many different vaccine candidates under investigation. Here, we investigate the glycosylation of recombinant SARS-CoV-2 spike proteins from five different laboratories and compare them against infectious virus S protein. We find patterns which are conserved across all samples and this can be associated with site-specific stalling of glycan maturation which act as a highly sensitive reporter of protein structure. Molecular dynamics (MD) simulations of a fully glycosylated spike support s a model of steric restrictions that shape enzymatic processing of the glycans. These results suggest that recombinant spike-based SARS-CoV-2 immunogen glycosylation reproducibly recapitulates signatures of viral glycosylation.
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http://dx.doi.org/10.1101/2021.03.08.433764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986994PMC
March 2021

The effect of spike mutations on SARS-CoV-2 neutralization.

Cell Rep 2021 03 6;34(12):108890. Epub 2021 Mar 6.

Institute of Immunity and Transplantation, Division of Infection and Immunity, University College London, London NW3 2PF, UK. Electronic address:

Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines show protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, spike. Because new SARS-CoV-2 variants are emerging rapidly, as exemplified by the B.1.1.7, B.1.351, and P.1 lineages, it is critical to understand whether antibody responses induced by infection with the original SARS-CoV-2 virus or current vaccines remain effective. In this study, we evaluate neutralization of a series of mutated spike pseudotypes based on divergence from SARS-CoV and then compare neutralization of the B.1.1.7 spike pseudotype and individual mutations. Spike-specific monoclonal antibody neutralization is reduced dramatically; in contrast, polyclonal antibodies from individuals infected in early 2020 remain active against most mutated spike pseudotypes, but potency is reduced in a minority of samples. This work highlights that changes in SARS-CoV-2 spike can alter neutralization sensitivity and underlines the need for effective real-time monitoring of emerging mutations and their effect on vaccine efficacy.
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http://dx.doi.org/10.1016/j.celrep.2021.108890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936541PMC
March 2021

Virus vaccines: proteins prefer prolines.

Cell Host Microbe 2021 03;29(3):327-333

Department of Microbiology and Immunology, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA. Electronic address:

Most viral vaccines are based on inducing neutralizing antibodies (NAbs) against the virus envelope or spike glycoproteins. Many viral surface proteins exist as trimers that transition from a pre-fusion state when key NAb epitopes are exposed to a post-fusion form in which the potential for virus-cell fusion no longer exists. For optimal vaccine performance, these viral proteins are often engineered to enhance stability and presentation of these NAb epitopes. The method involves the structure-guided introduction of proline residues at key positions that maintain the trimer in the pre-fusion configuration. We review how this technique emerged during HIV-1 Env vaccine development and its subsequent wider application to other viral vaccines including SARS-CoV-2.
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http://dx.doi.org/10.1016/j.chom.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7945883PMC
March 2021

Structural and functional ramifications of antigenic drift in recent SARS-CoV-2 variants.

bioRxiv 2021 Feb 17. Epub 2021 Feb 17.

The protective efficacy of neutralizing antibodies (nAbs) elicited during natural infection with SARS-CoV-2 and by vaccination based on its spike protein has been compromised with emergence of the recent SARS-CoV-2 variants. Residues E484 and K417 in the receptor-binding site (RBS) are both mutated in lineages first described in South Africa (B.1.351) and Brazil (B.1.1.28.1). The nAbs isolated from SARS-CoV-2 patients are preferentially encoded by certain heavy-chain germline genes and the two most frequently elicited antibody families (IGHV3-53/3-66 and IGHV1-2) can each bind the RBS in two different binding modes. However, their binding and neutralization are abrogated by either the E484K or K417N mutation, whereas nAbs to the cross-reactive CR3022 and S309 sites are largely unaffected. This structural and functional analysis illustrates why mutations at E484 and K417 adversely affect major classes of nAbs to SARS-CoV-2 with consequences for next-generation COVID-19 vaccines.
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http://dx.doi.org/10.1101/2021.02.16.430500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899451PMC
February 2021

A combination of cross-neutralizing antibodies synergizes to prevent SARS-CoV-2 and SARS-CoV pseudovirus infection.

bioRxiv 2021 Feb 12. Epub 2021 Feb 12.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Coronaviruses have caused several epidemics and pandemics including the ongoing coronavirus disease 2019 (COVID-19). Some prophylactic vaccines and therapeutic antibodies have already showed striking effectiveness against COVID-19. Nevertheless, concerns remain about antigenic drift in SARS-CoV-2 as well as threats from other sarbecoviruses. Cross-neutralizing antibodies to SARS-related viruses provide opportunities to address such concerns. Here, we report on crystal structures of a cross-neutralizing antibody CV38-142 in complex with the receptor binding domains from SARS-CoV-2 and SARS-CoV. Our structural findings provide mechanistic insights into how this antibody can accommodate antigenic variation in these viruses. CV38-142 synergizes with other cross-neutralizing antibodies, in particular COVA1-16, to enhance neutralization of SARS-CoV-2 and SARS-CoV. Overall, this study provides valuable information for vaccine and therapeutic design to address current and future antigenic drift in SARS-CoV-2 and to protect against zoonotic coronaviruses.
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http://dx.doi.org/10.1101/2021.02.11.430866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885913PMC
February 2021

Two-component spike nanoparticle vaccine protects macaques from SARS-CoV-2 infection.

Cell 2021 03 26;184(5):1188-1200.e19. Epub 2021 Jan 26.

Center for Immunology of Viral, Auto-immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Université Paris-Saclay, INSERM, CEA, Fontenay-aux-Roses, France.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic is continuing to disrupt personal lives, global healthcare systems, and economies. Hence, there is an urgent need for a vaccine that prevents viral infection, transmission, and disease. Here, we present a two-component protein-based nanoparticle vaccine that displays multiple copies of the SARS-CoV-2 spike protein. Immunization studies show that this vaccine induces potent neutralizing antibody responses in mice, rabbits, and cynomolgus macaques. The vaccine-induced immunity protects macaques against a high-dose challenge, resulting in strongly reduced viral infection and replication in the upper and lower airways. These nanoparticles are a promising vaccine candidate to curtail the SARS-CoV-2 pandemic.
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http://dx.doi.org/10.1016/j.cell.2021.01.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834972PMC
March 2021

Immunofocusing and enhancing autologous Tier-2 HIV-1 neutralization by displaying Env trimers on two-component protein nanoparticles.

NPJ Vaccines 2021 Feb 9;6(1):24. Epub 2021 Feb 9.

Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands.

The HIV-1 envelope glycoprotein trimer is poorly immunogenic because it is covered by a dense glycan shield. As a result, recombinant Env glycoproteins generally elicit inadequate antibody levels that neutralize clinically relevant, neutralization-resistant (Tier-2) HIV-1 strains. Multivalent antigen presentation on nanoparticles is an established strategy to increase vaccine-driven immune responses. However, due to nanoparticle instability in vivo, the display of non-native Env structures, and the inaccessibility of many neutralizing antibody (NAb) epitopes, the effects of nanoparticle display are generally modest for Env trimers. Here, we generate two-component self-assembling protein nanoparticles presenting twenty SOSIP trimers of the clade C Tier-2 genotype 16055. We show in a rabbit immunization study that these nanoparticles induce 60-fold higher autologous Tier-2 NAb titers than the corresponding SOSIP trimers. Epitope mapping studies reveal that the presentation of 16055 SOSIP trimers on these nanoparticle focuses antibody responses to an immunodominant apical epitope. Thus, these nanoparticles are a promising platform to improve the immunogenicity of Env trimers with apex-proximate NAb epitopes.
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http://dx.doi.org/10.1038/s41541-021-00285-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873233PMC
February 2021

SARS-CoV-2 recruits a haem metabolite to evade antibody immunity.

medRxiv 2021 Jan 26. Epub 2021 Jan 26.

Department of Infectious Disease, St-Mary's Campus, Imperial College London, UK.

The coronaviral spike is the dominant viral antigen and the target of neutralizing antibodies. We show that SARS-CoV-2 spike binds biliverdin and bilirubin, the tetrapyrrole products of haem metabolism, with nanomolar affinity. Using cryo-electron microscopy and X-ray crystallography we mapped the tetrapyrrole interaction pocket to a deep cleft on the spike N-terminal domain (NTD). At physiological concentrations, biliverdin significantly dampened the reactivity of SARS-CoV-2 spike with immune sera and inhibited a subset of neutralizing antibodies. Access to the tetrapyrrole-sensitive epitope is gated by a flexible loop on the distal face of the NTD. Accompanied by profound conformational changes in the NTD, antibody binding requires relocation of the gating loop, which folds into the cleft vacated by the metabolite. Our results indicate that the virus co-opts the haem metabolite for the evasion of humoral immunity via allosteric shielding of a sensitive epitope and demonstrate the remarkable structural plasticity of the NTD.
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http://dx.doi.org/10.1101/2021.01.21.21249203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852234PMC
January 2021

Production of HIV-1 Env-specific antibodies mediating innate immune functions depends on cognate IL-21- secreting CD4+ T cells.

J Virol 2021 Jan 27. Epub 2021 Jan 27.

Institute of Virology, University Hospital, University of Bonn, Germany, and German Center for Infection Research (DZIF), partner site Bonn-Cologne, Germany

Antibodies with a functional Fc region were previously associated with protection from HIV-1 acquisition and spontaneous suppression of viral replication. Unlike broadly neutralizing antibodies, they are not restricted to neutralizing epitopes and do not require unconventional structural traits to exert their antiviral activity. They, therefore, develop earlier after infection and can be detected in the majority of cases. The conditions under which these antibodies are generated, however, remain largely unknown. Here we demonstrate that the generation of HIV-1 Env-specific antibodies facilitating Fc-dependent innate immune responses, including neutrophil phagocytosis (ADNP), complement deposition (ADCD), and NK cell activation, likely depends on help provided by CD4+ T and peripheral T follicular helper (pTfh) cells secreting IL-21. Other proteins, including CD40L, IFNγ, and IL-4/13, involved in crosstalk between B and T cells were linked to the production of antibodies with functional Fc region but only when co-expressed with IL-21. As a potential source of these antibodies, we identified a subset of Env-specific memory B cells known to be expanded in chronic HIV-1 infection. The frequency and level of Blimp-1 expression in Env-specific tissue-like memory B cells (TLM) correlated with the functional CD4+ T cell subsets associated with robust antibody-dependent innate responses. Thus, our data suggest a mechanism responsible for the generation of antibodies with functional Fc region in chronically HIV-1 infected individuals that is based on CD4+ T cell-induced activation of memory B cells. To develop a vaccine or immunotherapy that would cure the HIV-1 infection it is important to identify helper T cells able to mount an efficient antibody response. Here, we demonstrate that the generation of HIV-1 Env-specific antibodies facilitating antibody-dependent innate immune responses likely depends on Env-specific IL-21-secreting CD4+ T and peripheral T follicular helper cells.
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http://dx.doi.org/10.1128/JVI.02097-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103692PMC
January 2021

Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity.

Science 2021 02 23;371(6532). Epub 2020 Dec 23.

Department of Rheumatology and Clinical Immunology, Amsterdam UMC, Amsterdam Rheumatology and Immunology Center, Amsterdam, Netherlands.

Immunoglobulin G (IgG) antibodies are crucial for protection against invading pathogens. A highly conserved N-linked glycan within the IgG-Fc tail, which is essential for IgG function, shows variable composition in humans. Afucosylated IgG variants are already used in anticancer therapeutic antibodies for their increased activity through Fc receptors (FcγRIIIa). Here, we report that afucosylated IgG (approximately 6% of total IgG in humans) are specifically formed against enveloped viruses but generally not against other antigens. This mediates stronger FcγRIIIa responses but also amplifies brewing cytokine storms and immune-mediated pathologies. Critically ill COVID-19 patients, but not those with mild symptoms, had high concentrations of afucosylated IgG antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), amplifying proinflammatory cytokine release and acute phase responses. Thus, antibody glycosylation plays a critical role in immune responses to enveloped viruses, including COVID-19.
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http://dx.doi.org/10.1126/science.abc8378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919849PMC
February 2021

Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity.

Immunity 2020 12 25;53(6):1272-1280.e5. Epub 2020 Nov 25.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address:

Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.
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http://dx.doi.org/10.1016/j.immuni.2020.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687367PMC
December 2020

Diverse HIV-1 escape pathways from broadly neutralizing antibody PGDM1400 in humanized mice.

MAbs 2020 Jan-Dec;12(1):1845908

Department of Medical Microbiology, Amsterdam UMC, AMC, University of Amsterdam , Amsterdam, the Netherlands.

Recent studies have shown the potential of broadly neutralizing antibodies (bnAbs) for HIV-1 treatment. One of the candidate antibodies moving into clinical trials is the bnAb PGDM1400. Here, we studied the therapeutic potency and escape pathways of bnAb PGDM1400 during monovalent therapy in human immune system (HIS) mice using the BG505, REJO, MJ4 and AMC008 virus isolates. PGDM1400 administered during chronic infection caused a modest decrease in viral load in the first week of administration in 7 out of 10 animals, which correlated with the neutralization sensitivity of the viruses to PGDM1400. As expected for monotherapy, viral loads rebounded after about a week and different viral escape pathways were observed, involving the deletion of glycans in the envelope glycoprotein at positions 130 or 160. (Pre)clinical trials should reveal whether PGDM1400 is a useful component of an antibody combination treatment or as part of a tri-specific antibody.
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http://dx.doi.org/10.1080/19420862.2020.1845908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755169PMC
November 2020

[HIV vaccine: how far along are we?]

Ned Tijdschr Geneeskd 2020 09 3;164. Epub 2020 Sep 3.

Amsterdam UMC, locatie AMC, Amsterdam:Afd. Inwendige Geneeskunde.

The development of an HIV vaccine has been a major challenge for several decades already. In order to cope with the large diversity and mutation rate of the virus, a vaccine needs to offer extraordinarily broad protection. In recent years, a large number of clinical studies all over the world have been investigating promising new vaccine strategies. Findings of these studies will provide important guidance for further optimisation of vaccine candidates, excipients and vaccination schedules in the near future. Vaccines currently under investigation are stimulating either the development of antibodies against HIV or antiviral T-cell immunity. In order to provide broad and long-lasting protection, an effective vaccine should induce both humoral and cellular responses, which could be achieved with sequential immunisations as well as a combination of several different vaccine strategies.
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September 2020

An Alternative Binding Mode of IGHV3-53 Antibodies to the SARS-CoV-2 Receptor Binding Domain.

Cell Rep 2020 10 29;33(3):108274. Epub 2020 Sep 29.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA. Electronic address:

IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.
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http://dx.doi.org/10.1016/j.celrep.2020.108274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522650PMC
October 2020

Neutralizing Antibody Responses Induced by HIV-1 Envelope Glycoprotein SOSIP Trimers Derived from Elite Neutralizers.

J Virol 2020 11 23;94(24). Epub 2020 Nov 23.

Department of Medical Microbiology, Amsterdam Infection & Immunity Institute (AI&II), Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands

The induction of broadly neutralizing antibodies (bNAbs) is a major goal in vaccine research. HIV-1-infected individuals that develop exceptionally strong bNAb responses, termed elite neutralizers, can inform vaccine design by providing blueprints for the induction of similar bNAb responses. We describe a new recombinant native-like envelope glycoprotein (Env) SOSIP trimer, termed AMC009, based on the viral founder sequences of an elite neutralizer. The subtype B AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bNAb epitopes. Overall, its structure at 4.3-Å resolution was similar to that of BG505 SOSIP.664. The AMC009 trimer resembled one from a second elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, the AMC009 trimers did not induce autologous neutralizing antibody (NAb) responses efficiently while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the NAb activity from the rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers. These results advance our understanding of how to use Env trimers in multivalent vaccination regimens and the immunogenicity of trimers derived from elite neutralizers. Elite neutralizers, i.e., individuals who developed unusually broad and potent neutralizing antibody responses, might serve as blueprints for HIV-1 vaccine design. Here, we studied the immunogenicity of native-like recombinant envelope glycoprotein (Env) trimers based on viral sequences from elite neutralizers. While immunization with single trimers from elite neutralization did not recapitulate the breadth and potency of neutralization observed in these infected individuals, a combination of three subtype B Env trimers from elite neutralizers resulted in some neutralization breadth within subtype B viruses. These results should guide future efforts to design vaccines to induce broadly neutralizing antibodies.
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http://dx.doi.org/10.1128/JVI.01214-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925178PMC
November 2020

Comparative assessment of multiple COVID-19 serological technologies supports continued evaluation of point-of-care lateral flow assays in hospital and community healthcare settings.

PLoS Pathog 2020 09 24;16(9):e1008817. Epub 2020 Sep 24.

Department of Infectious Diseases, School of Immunology & Microbial Sciences, King's College London, London, United Kingdom.

There is a clear requirement for an accurate SARS-CoV-2 antibody test, both as a complement to existing diagnostic capabilities and for determining community seroprevalence. We therefore evaluated the performance of a variety of antibody testing technologies and their potential use as diagnostic tools. Highly specific in-house ELISAs were developed for the detection of anti-spike (S), -receptor binding domain (RBD) and -nucleocapsid (N) antibodies and used for the cross-comparison of ten commercial serological assays-a chemiluminescence-based platform, two ELISAs and seven colloidal gold lateral flow immunoassays (LFIAs)-on an identical panel of 110 SARS-CoV-2-positive samples and 50 pre-pandemic negatives. There was a wide variation in the performance of the different platforms, with specificity ranging from 82% to 100%, and overall sensitivity from 60.9% to 87.3%. However, the head-to-head comparison of multiple sero-diagnostic assays on identical sample sets revealed that performance is highly dependent on the time of sampling, with sensitivities of over 95% seen in several tests when assessing samples from more than 20 days post onset of symptoms. Furthermore, these analyses identified clear outlying samples that were negative in all tests, but were later shown to be from individuals with mildest disease presentation. Rigorous comparison of antibody testing platforms will inform the deployment of point-of-care technologies in healthcare settings and their use in the monitoring of SARS-CoV-2 infections.
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http://dx.doi.org/10.1371/journal.ppat.1008817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7514033PMC
September 2020

Mapping the immunogenic landscape of near-native HIV-1 envelope trimers in non-human primates.

PLoS Pathog 2020 08 31;16(8):e1008753. Epub 2020 Aug 31.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America.

The induction of broad and potent immunity by vaccines is the key focus of research efforts aimed at protecting against HIV-1 infection. Soluble native-like HIV-1 envelope glycoproteins have shown promise as vaccine candidates as they can induce potent autologous neutralizing responses in rabbits and non-human primates. In this study, monoclonal antibodies were isolated and characterized from rhesus macaques immunized with the BG505 SOSIP.664 trimer to better understand vaccine-induced antibody responses. Our studies reveal a diverse landscape of antibodies recognizing immunodominant strain-specific epitopes and non-neutralizing neo-epitopes. Additionally, we isolated a subset of mAbs against an epitope cluster at the gp120-gp41 interface that recognize the highly conserved fusion peptide and the glycan at position 88 and have characteristics akin to several human-derived broadly neutralizing antibodies.
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http://dx.doi.org/10.1371/journal.ppat.1008753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485981PMC
August 2020

Cross-neutralization of a SARS-CoV-2 antibody to a functionally conserved site is mediated by avidity.

bioRxiv 2020 Aug 3. Epub 2020 Aug 3.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

Most antibodies isolated from COVID-19 patients are specific to SARS-CoV-2. COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here we determined a crystal structure of COVA1-16 Fab with the SARS-CoV-2 RBD, and a negative-stain EM reconstruction with the spike glycoprotein trimer, to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long CDR H3, and competes with ACE2 binding due to steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with structural and functional rationale for the epitope conservation, provide a blueprint for development of more universal SARS-like coronavirus vaccines and therapies.
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http://dx.doi.org/10.1101/2020.08.02.233536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418720PMC
August 2020

Structural and functional evaluation of de novo-designed, two-component nanoparticle carriers for HIV Env trimer immunogens.

PLoS Pathog 2020 08 11;16(8):e1008665. Epub 2020 Aug 11.

Department of Integrative, Structural and Computational Biology, Scripps Research, La Jolla, California, United States of America.

Two-component, self-assembling nanoparticles represent a versatile platform for multivalent presentation of viral antigens. Computational design of protein nanoparticles with differing sizes and geometries enables combination with antigens of choice to test novel multimerization concepts in immunization strategies where the goal is to improve the induction and maturation of neutralizing antibody lineages. Here, we describe detailed antigenic, structural, and functional characterization of computationally designed tetrahedral, octahedral, and icosahedral nanoparticle immunogens displaying trimeric HIV envelope glycoprotein (Env) ectodomains. Env trimers, based on subtype A (BG505) or consensus group M (ConM) sequences and engineered with SOSIP stabilizing mutations, were fused to an underlying trimeric building block of each nanoparticle. Initial screening yielded one icosahedral and two tetrahedral nanoparticle candidates, capable of presenting twenty or four copies of the Env trimer. A number of analyses, including detailed structural characterization by cryo-EM, demonstrated that the nanoparticle immunogens possessed the intended structural and antigenic properties. When the immunogenicity of ConM-SOSIP trimers presented on a two-component tetrahedral nanoparticle or as soluble proteins were compared in rabbits, the two immunogens elicited similar serum antibody binding titers against the trimer component. Neutralizing antibody titers were slightly elevated in the animals given the nanoparticle immunogen and were initially more focused to the trimer apex. Altogether, our findings indicate that tetrahedral nanoparticles can be successfully applied for presentation of HIV Env trimer immunogens; however, the optimal implementation to different immunization strategies remains to be determined.
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http://dx.doi.org/10.1371/journal.ppat.1008665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418955PMC
August 2020

Optimized Hepatitis C Virus (HCV) E2 Glycoproteins and their Immunogenicity in Combination with MVA-HCV.

Vaccines (Basel) 2020 Aug 5;8(3). Epub 2020 Aug 5.

Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CNB), Consejo Superior de Investigaciones Científicas (CSIC), 28049 Madrid, Spain.

Hepatitis C virus (HCV) represents a major global health challenge and an efficient vaccine is urgently needed. Many HCV vaccination strategies employ recombinant versions of the viral E2 glycoprotein. However, recombinant E2 readily forms disulfide-bonded aggregates that might not be optimally suited for vaccines. Therefore, we have designed an E2 protein in which we strategically changed eight cysteines to alanines (E2.C8A). E2.C8A formed predominantly monomers and virtually no aggregates. Furthermore, E2.C8A also interacted more efficiently with broadly neutralizing antibodies than conventional E2. We used mice to evaluate different prime/boost immunization strategies involving a modified vaccinia virus Ankara (MVA) expressing the nearly full-length genome of HCV (MVA-HCV) in combination with either the E2 aggregates or the E2.C8A monomers. The combined MVA-HCV/E2 aggregates prime/boost strategy markedly enhanced HCV-specific effector memory CD4 T cell responses and antibody levels compared to MVA-HCV/MVA-HCV. Moreover, the aggregated form of E2 induced higher levels of anti-E2 antibodies in vaccinated mice than E2.C8A monomers. These antibodies were cross-reactive and mainly of the IgG1 isotype. Our findings revealed how two E2 viral proteins that differ in their capacity to form aggregates are able to enhance to different extent the HCV-specific cellular and humoral immune responses, either alone or in combination with MVA-HCV. These combined protocols of MVA-HCV/E2 could serve as a basis for the development of a more effective HCV vaccine.
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http://dx.doi.org/10.3390/vaccines8030440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563715PMC
August 2020

Tailored design of protein nanoparticle scaffolds for multivalent presentation of viral glycoprotein antigens.

Elife 2020 08 4;9. Epub 2020 Aug 4.

Department of Biochemistry, University of Washington, Seattle, United States.

Multivalent presentation of viral glycoproteins can substantially increase the elicitation of antigen-specific antibodies. To enable a new generation of anti-viral vaccines, we designed self-assembling protein nanoparticles with geometries tailored to present the ectodomains of influenza, HIV, and RSV viral glycoprotein trimers. We first designed trimers tailored for antigen fusion, featuring N-terminal helices positioned to match the C termini of the viral glycoproteins. Trimers that experimentally adopted their designed configurations were incorporated as components of tetrahedral, octahedral, and icosahedral nanoparticles, which were characterized by cryo-electron microscopy and assessed for their ability to present viral glycoproteins. Electron microscopy and antibody binding experiments demonstrated that the designed nanoparticles presented antigenically intact prefusion HIV-1 Env, influenza hemagglutinin, and RSV F trimers in the predicted geometries. This work demonstrates that antigen-displaying protein nanoparticles can be designed from scratch, and provides a systematic way to investigate the influence of antigen presentation geometry on the immune response to vaccination.
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http://dx.doi.org/10.7554/eLife.57659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402677PMC
August 2020

An alternative binding mode of IGHV3-53 antibodies to the SARS-CoV-2 receptor binding domain.

bioRxiv 2020 Jul 27. Epub 2020 Jul 27.

IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally have a short CDR H3 due to structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.
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http://dx.doi.org/10.1101/2020.07.26.222232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386498PMC
July 2020

HIV envelope trimer-elicited autologous neutralizing antibodies bind a region overlapping the N332 glycan supersite.

Sci Adv 2020 Jun 5;6(23):eaba0512. Epub 2020 Jun 5.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

To date, immunization studies of rabbits with the BG505 SOSIP.664 HIV envelope glycoprotein trimers have revealed the 241/289 glycan hole as the dominant neutralizing antibody epitope. Here, we isolated monoclonal antibodies from a rabbit that did not exhibit glycan hole-dependent autologous serum neutralization. The antibodies did not compete with a previously isolated glycan hole-specific antibody but did compete with N332 glycan supersite broadly neutralizing antibodies. A 3.5-Å cryoEM structure of one of the antibodies in complex with the BG505 SOSIP.v5.2 trimer demonstrated that while the epitope recognized overlapped the N332 glycan supersite by contacting the GDIR motif at the base of V3, primary contacts were located in the variable V1 loop. These data suggest that strain-specific responses to V1 may interfere with broadly neutralizing responses to the N332 glycan supersite and vaccine immunogens may require engineering to minimize these off-target responses or steer them toward a more desirable pathway.
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http://dx.doi.org/10.1126/sciadv.aba0512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274786PMC
June 2020

Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability.

Science 2020 08 15;369(6504):643-650. Epub 2020 Jun 15.

Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.

The rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a large impact on global health, travel, and economy. Therefore, preventative and therapeutic measures are urgently needed. Here, we isolated monoclonal antibodies from three convalescent coronavirus disease 2019 (COVID-19) patients using a SARS-CoV-2 stabilized prefusion spike protein. These antibodies had low levels of somatic hypermutation and showed a strong enrichment in VH1-69, VH3-30-3, and VH1-24 gene usage. A subset of the antibodies was able to potently inhibit authentic SARS-CoV-2 infection at a concentration as low as 0.007 micrograms per milliliter. Competition and electron microscopy studies illustrate that the SARS-CoV-2 spike protein contains multiple distinct antigenic sites, including several receptor-binding domain (RBD) epitopes as well as non-RBD epitopes. In addition to providing guidance for vaccine design, the antibodies described here are promising candidates for COVID-19 treatment and prevention.
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http://dx.doi.org/10.1126/science.abc5902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299281PMC
August 2020

Networks of HIV-1 Envelope Glycans Maintain Antibody Epitopes in the Face of Glycan Additions and Deletions.

Structure 2020 08 19;28(8):897-909.e6. Epub 2020 May 19.

School of Biological Sciences, University of Southampton, Southampton SO17 1BJ, UK; Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. Electronic address:

Numerous broadly neutralizing antibodies (bnAbs) have been identified that target the glycans of the HIV-1 envelope spike. Neutralization breadth is notable given that glycan processing can be substantially influenced by the presence or absence of neighboring glycans. Here, using a stabilized recombinant envelope trimer, we investigate the degree to which mutations in the glycan network surrounding an epitope impact the fine glycan processing of antibody targets. Using cryo-electron microscopy and site-specific glycan analysis, we reveal the importance of glycans in the formation of the 2G12 bnAb epitope and show that the epitope is only subtly impacted by variations in the glycan network. In contrast, we show that the PG9 and PG16 glycan-based epitopes at the trimer apex are dependent on the presence of the highly conserved surrounding glycans. Glycan networks underpin the conservation of bnAb epitopes and are an important parameter in immunogen design.
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http://dx.doi.org/10.1016/j.str.2020.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416112PMC
August 2020