Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity

Jensen, Jaime L.; Sankhala, Rajeshwer S.; Dussupt, Vincent; Bai, Hongjun; Hajduczki, Agnes; Lal, Kerri G.; Chang, William C.; Martinez, Elizabeth; Peterson, Caroline E.; Golub, Emily; Rees, Phyllis A.; Mendez-Rivera, Letzibeth; Zemil, Michelle; Kavusak, Erin; Mayer, Sandra V.; Wieczorek, Lindsay; Kannan, Shruthi; Doranz, Benjamin J.; Davidson, Edgar; Yang, Eun Sung; Zhang, Yi; Chen, Man; Choe, Misook; Wang, Lingshu; Gromowski, Gregory D.; Koup, Richard A.; Michael, Nelson L.; Polonis, Victoria R.; Rolland, Morgane; Modjarrad, Kayvon; Krebs, Shelly J.; Joyce, Michael

doi:10.1128/jvi.01596-22

Cited by 11 publications

(21 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previously, we have described a set of RBD neutralizing antibodies (WRAIR-2057, WRAIR-2063, and WRAIR-2134) isolated from a convalescent human subject which were of particular interest because of their novel epitope on the SARS-CoV-2 RBD 34 , 54 . Our binding competition and alanine scanning experiments indicated that WRAIR-5001 also targets a similar epitope (Fig.…”

Section: Resultsmentioning

confidence: 99%

Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques

Sankhala,

Lal,

Jensen

et al. 2024

Nat Commun

Self Cite

View full text Add to dashboard Cite

The repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants.

show abstract

Section: Resultsmentioning

confidence: 99%

Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques

Sankhala,

Lal,

Jensen

et al. 2024

Nat Commun

Self Cite

View full text Add to dashboard Cite

show abstract

“…Consequently, the clinical application of anti-RBD antibodies has led to reduced neutralization and inhibitory activities. 22 , 26 , 30 , 31 , 58 Although efforts to develop broadly neutralizing antibodies that target pan-coronavirus conserved epitopes are actively underway, 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 the possibility of emerging immune-evading mutant variants remains, posing a recurrent challenge to monoclonal antibody therapy. Therefore, the exploration of alternative approaches is attractive.…”

Section: Discussionmentioning

confidence: 99%

Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

Inoue,

Yamamoto,

Sato

et al. 2024

iScience

View full text Add to dashboard Cite

“…It is worth noting that despite the rapid evolution of the SARS-CoV-2 virus, this region is highly conserved, suggesting that the design of glycan modifications should avoid targeting these highly conserved regions. Interestingly, antibodies targeting this epitope demonstrate moderate neutralizing potency with cross-reactivity within sarbecoviruses ( 54 ). Additionally, in a separate study, the introduction of glycans at non-conserved sites within the core antigenic sequence of sarbecovirus RBD effectively enhanced the presentation of conserved epitopes to the immune system.…”

Section: Discussionmentioning

confidence: 99%

Inducing enhanced neutralizing antibodies against broad SARS-CoV-2 variants through glycan-shielding multiple non-neutralizing epitopes of RBD

Zhang,

Yang,

Lan

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

IntroductionSince the outbreak of SARS-CoV-2, vaccines have demonstrated their effectiveness in resisting virus infection, reducing severity, and lowering the mortality rate in infected individuals. However, due to the rapid and ongoing mutations of SARS-CoV-2, the protective ability of many available vaccines has been challenged. Therefore, there is an urgent need for vaccines capable of eliciting potent broadly neutralizing antibodies against various SARS-CoV-2 variants.MethodsIn this study, we developed a novel subunit vaccine candidate for SARS-CoV-2 by introducing a series of shielding glycans to the Fc-fused receptor-binding domain (RBD) of the prototypic spike protein. This approach aims to mask non-neutralizing epitopes and focus the immune response on crucial neutralizing epitopes.ResultsAll modified sites were confirmed to be highly glycosylated through mass spectrometry analysis. The binding affinity of the glycan-shielded RBD (gsRBD) to the human ACE2 receptor was comparable to that of the wildtype RBD (wtRBD). Immunizing mice with gsRBD when combined with either Freund’s adjuvant or aluminum adjuvant demonstrated that the introduction of the glycan shield did not compromise the antibody-inducing ability of RBD. Importantly, the gsRBD significantly enhanced the generation of neutralizing antibodies against SARS-CoV-2 pseudoviruses compared to the wtRBD. Notably, it exhibited remarkable protective activity against Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529), approximately 3-fold, 7- fold, and 17-fold higher than wtRBD, respectively.DiscussionOur data proved this multiple-epitope masking strategy as an effective approach for highly active vaccine production.

show abstract

Targeting the Spike Receptor Binding Domain Class V Cryptic Epitope by an Antibody with Pan-Sarbecovirus Activity

Cited by 11 publications

References 67 publications

Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques

Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques

Overcoming antibody-resistant SARS-CoV-2 variants with bispecific antibodies constructed using non-neutralizing antibodies

Inducing enhanced neutralizing antibodies against broad SARS-CoV-2 variants through glycan-shielding multiple non-neutralizing epitopes of RBD

Contact Info

Product

Resources

About