Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein induces genetically and antigenically diverse antibody responses

Mukhamedova, Maryam; Wrapp, Daniel; Shen, Chen‐Hsiang; Gilman, M.S.A.; Ruckwardt, Tracy J.; Schramm, Chaim A.; Ault, Larissa; Chang, Lauren; Derrien-Colemyn, Alexandrine; Lucas, Sarah A.M.; Ransier, Amy; Darko, Samuel; Phung, Emily; Wang, Lingshu; Zhang, Yi; Rush, Scott A.; Madan, Bharat; Stewart‐Jones, Guillaume; Costner, Pamela; Holman, LaSonji A.; Hickman, Somia P.; Berkowitz, Nina M.; Doria‐Rose, Nicole A.; Morabito, Kaitlyn M.; DeKosky, Brandon J.; Gaudinski, Martin R.; Chen, Grace L.; Crank, Michelle C.; Sullivan, Nancy J.; Douek, Daniel C.; Kwong, Peter D.; Graham, Barney S.; McLellan, Jason S.; Mascola, John R.

doi:10.1016/j.immuni.2021.03.004

Cited by 48 publications

(40 citation statements)

References 58 publications

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“…17,28 The recent emergence of single-particle cryo-EM has allowed the solution of medium-to-high-resolution structures of antibodyantigen complexes for viruses such as HIV, [32][33][34][35][36] influenza, [37][38][39][40] and Dengue, [41][42][43] as well as for an RSV PostF-FabR4.C6 complex, 44 and most recently vaccine-elicited antibodies bound to DS-Cav1. 45 Using single particle cryo-EM, we were able to achieve an overall resolution of 3.4 Å, which produced a 3D reconstruction of comparable quality to a 3.6 Å DS-Cav1-AM14 X-ray structure also reported here. This represents another important case of the application of the rapidly evolving cryo-EM technology for the high-resolution characterization of vaccine antigen targets.…”

Section: Discussionmentioning

confidence: 58%

Improved epitope resolution of the prefusion trimer-specific antibody AM14 bound to the RSV F glycoprotein

Harshbarger¹,

Abeyrathne²,

Tian³

et al. 2021

mAbs

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Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory tract infections resulting in medical intervention and hospitalizations during infancy and early childhood, and vaccination against RSV remains a public health priority. The RSV F glycoprotein is a major target of neutralizing antibodies, and the prefusion stabilized form of F (DS-Cav1) is under investigation as a vaccine antigen. AM14 is a human monoclonal antibody with the exclusive capacity of binding an epitope on prefusion F (PreF), which spans two F protomers. The quality of recognizing a trimer-specific epitope makes AM14 valuable for probing PreF-based immunogen conformation and functionality during vaccine production. Currently, only a low-resolution (5.5 Å) X-ray structure is available of the PreF-AM14 complex, revealing few reliable details of the interface. Here, we perform complementary structural studies using X-ray crystallography and cryo-electron microscopy (cryo-EM) to provide improved resolution structures at 3.6 Å and 3.4 Å resolutions, respectively. Both X-ray and cryo-EM structures provide clear side-chain densities, which allow for accurate mapping of the AM14 epitope on DS-Cav1. The structures help rationalize the molecular basis for AM14 loss of binding to RSV F monoclonal antibody-resistant mutants and reveal flexibility for the side chain of a key antigenic residue on PreF. This work provides the basis for a comprehensive understanding of RSV F trimer specificity with implications in vaccine design and quality assessment of PreF-based immunogens.

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Section: Discussionmentioning

confidence: 58%

Improved epitope resolution of the prefusion trimer-specific antibody AM14 bound to the RSV F glycoprotein

Harshbarger¹,

Abeyrathne²,

Tian³

et al. 2021

mAbs

View full text Add to dashboard Cite

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“…In recent years, public B cell clonotypes have been identified in the human antibody repertoires formed in response to diverse viruses, including Ebola (Cohen-Dvashi et al, 2020;Davis et al, 2019;Ehrhardt et al, 2019), influenza (Joyce et al, 2016;Pappas et al, 2014;Zost et al, 2021;Sui et al, 2009;Wheatley et al, 2015), human immunodeficiency virus 1 (HIV-1) (Setliff et al, 2018;Williams et al, 2015;Wu et al, 2011;Zhou et al, 2015), hepatitis C (Bailey et al, 2017;Giang et al, 2012), SARS-CoV-2 (Dong et al, 2021;Nielsen et al, 2020;Yuan et al, 2020a), respiratory syncytial virus (Mukhamedova et al, 2021), and in healthy individuals (Briney et al, 2019;Soto et al, 2019). These studies reveal a convergence of B cell selection resulting in circulating B cells clones with genetically similar antigen receptor genes in multiple individuals.…”

Section: Introductionmentioning

confidence: 99%

Convergent antibody responses to the SARS-CoV-2 spike protein in convalescent and vaccinated individuals

et al. 2021

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Unrelated individuals can produce genetically similar clones of antibodies, known as public clonotypes, which have been seen in responses to different infectious diseases as well as healthy individuals. Here we identify 37 public clonotypes in memory B cells from convalescent survivors of SARS-CoV-2 infection or in plasmablasts from an individual after vaccination with mRNA-encoded spike protein. We identified 29 public clonotypes, including clones recognizing the receptor-binding domain (RBD) in the spike protein S1 subunit (including a neutralizing, ACE2-blocking clone that protects in vivo ), and others recognizing non-RBD epitopes that bound the S2 domain. Germline-revertant forms of some public clonotypes bound efficiently to spike protein, suggesting these common germline-encoded antibodies are preconfigured for avid recognition. Identification of large numbers of public clonotypes provides insight into the molecular basis of efficacy of SARS-CoV-2 vaccines and sheds light on the immune pressures driving the selection of common viral escape mutants.

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“…Structural biology offers infinite potential to design next generation of vaccines. One example is the "2P spike" made by introducing two proline substitutions into the spike protein to keep its structure stable in the prefusion state, thereby significantly increasing its antigenicity for producing more effective neutralizing antibodies [36]. A first HLA-I immunopeptidome analysis of virally infected human cell lines identified T cell epitopes in out of frame viral S, N, and non-structural proteins, providing new vaccine designs to target infected host cells against variants [37].…”

Section: Development Production and Applicationmentioning

confidence: 99%

Leishmaniac Quest for Developing a Novel Vaccine Platform. Is a Roadmap for Its Advances Provided by the Mad Dash to Produce Vaccines for COVID-19?

et al. 2022

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“Bugs as drugs” in medicine encompasses the use of microbes to enhance the efficacy of vaccination, such as the delivery of vaccines by Leishmania—the protozoan etiological agent of leishmaniasis. This novel approach is appraised in light of the successful development of vaccines for Covid-19. All relevant aspects of this pandemic are summarized to provide the necessary framework in contrast to leishmaniasis. The presentation is in a side-by-side matching format with particular emphasis on vaccines. The comparative approach makes it possible to highlight the timeframe of the vaccine workflows condensed by the caveats of pandemic urgency and, at the same time, provides the background of Leishmania behind its use as a vaccine carrier. Previous studies in support of the latter are summarized as follows. Leishmaniasis confers life-long immunity on patients after cure, suggesting effective vaccination is achievable with whole-cell Leishmania. A new strategy was developed to inactivate these cells in vitro, rendering them non-viable, hence non-disease causing, albeit retaining their immunogenicity and adjuvanticity. This was achieved by installing a dual suicidal mechanism in Leishmania for singlet oxygen (1O2)-initiated inactivation. In vitro cultured Leishmania were genetically engineered for cytosolic accumulation of UV-sensitive uroporphyrin I and further loaded endosomally with a red light-sensitive cationic phthalocyanine. Exposing these doubly dye-loaded Leishmania to light triggers intracellular production of highly reactive but extremely short-lived 1O2, resulting in their rapid and complete inactivation. Immunization of susceptible animals with such inactivated Leishmania elicited immunity to protect them against experimental leishmaniasis. Significantly, the inactivated Leishmania was shown to effectively deliver transgenically add-on ovalbumin (OVA) to antigen-presenting cells (APC), wherein OVA epitopes were processed appropriately for presentation with MHC molecules to activate epitope-specific CD8+ T cells. Application of this approach to deliver cancer vaccine candidates, e.g., enolase-1, was shown to suppress tumor development in mouse models. A similar approach is predicted to elicit lasting immunity against infectious diseases, including complementation of the spike protein-based vaccines in use for COVID-19. This pandemic is devastating, but brings to light the necessity of considering many facets of the disease in developing vaccination programs. Closer collaboration is essential among those in diverse disciplinary areas to provide the roadmap toward greater success in the future. Highlighted herein are several specific issues of vaccinology and new approaches worthy of consideration due to the pandemic.

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Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein induces genetically and antigenically diverse antibody responses

Cited by 48 publications

References 58 publications

Improved epitope resolution of the prefusion trimer-specific antibody AM14 bound to the RSV F glycoprotein

Improved epitope resolution of the prefusion trimer-specific antibody AM14 bound to the RSV F glycoprotein

Convergent antibody responses to the SARS-CoV-2 spike protein in convalescent and vaccinated individuals

Leishmaniac Quest for Developing a Novel Vaccine Platform. Is a Roadmap for Its Advances Provided by the Mad Dash to Produce Vaccines for COVID-19?

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