Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination

Voss, William N.; Mallory, Michael A.; Byrne, Patrick O.; Marchioni, Jeffrey M.; Knudson, Sean A.; Powers, John M.; Leist, Sarah R.; Dadonaite, Bernadeta; Townsend, Douglas R.; Kain, Jessica; Huang, Yimin; Satterwhite, Ed; Castillo, Izabella N.; Mattocks, Melissa; Paresi, Chelsea; Munt, Jennifer E.; Scobey, Trevor; Seeger, Allison; Premkumar, Lakshmanane; Bloom, Jesse D.; Georgiou, George; McLellan, Jason S.; Baric, Ralph S.; Lavinder, Jason J.; Ippolito, Gregory C.

doi:10.1101/2024.01.22.576742

Cited by 3 publications

(2 citation statements)

References 88 publications

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“… 19 , 23 , 26 – 33 Although cryptic-face mAbs are often less potent in neutralizing activity, there are examples of both broad and potent class 4 antibodies including S2X259, 34 SA55, 18 , 35 VacW-209, 36 AGD20, 17 DH1047 37 , and most recently SC27. 38 These results suggest that if a vaccine could elicit antibodies that bind to the cryptic face of the RBD, it might be possible to create a pan- Sarbecovirus vaccine.…”

Section: Introductionmentioning

confidence: 91%

Engineering a SARS-CoV-2 vaccine targeting the RBD cryptic-face via immunofocusing

Bruun,

Do,

Weidenbacher

et al. 2024

Preprint

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The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is the main target of neutralizing antibodies. Although they are infrequently elicited during infection or vaccination, antibodies that bind to the conformation-specific cryptic face of the RBD display remarkable breadth of binding and neutralization across Sarbecoviruses. Here, we employed the immunofocusing technique PMD (protect, modify, deprotect) to create RBD immunogens (PMD-RBD) specifically designed to focus the antibody response towards the cryptic-face epitope recognized by the broadly neutralizing antibody S2X259. Immunization with PMD-RBD antigens induced robust binding titers and broad neutralizing activity against homologous and heterologous Sarbecovirus strains. A serum-depletion assay provided direct evidence that PMD successfully skewed the polyclonal antibody response towards the cryptic face of the RBD. Our work demonstrates the ability of PMD to overcome immunodominance and refocus humoral immunity, with implications for the development of broader and more resilient vaccines against current and emerging viruses with pandemic potential.

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Section: Introductionmentioning

confidence: 91%

Engineering a SARS-CoV-2 vaccine targeting the RBD cryptic-face via immunofocusing

Bruun,

Do,

Weidenbacher

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The mouse-adapted viruses (Wuhan-Hu-1 SARS-CoV-2 MA10 and Omicron BA.5 SARS-CoV-2) and authentic viruses (D614G Wuhan-Hu-1 SARS-CoV-2 and Omicron BA.5 SARS-CoV-2) nanoluciferase recombinant strains used in this study were described previously 56,63,124,125 . All virus stocks were propagated in VeroE6-TMPRSS2 cells and subjected to next-generation sequencing (Illumina) to confirm the introduction and stability of substitutions.…”

Section: Virusesmentioning

confidence: 99%

Computationally designed mRNA-launched protein nanoparticle vaccines

Hendricks,

Grigoryan,

Navarro

et al. 2024

Preprint

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Both protein nanoparticle and mRNA vaccines were clinically de-risked during the COVID-19 pandemic. These vaccine modalities have complementary strengths: antigen display on protein nanoparticles can enhance the magnitude, quality, and durability of antibody responses, while mRNA vaccines can be rapidly manufactured and elicit antigen-specific CD4 and CD8 T cells. Here we leverage a computationally designed icosahedral protein nanoparticle that was redesigned for optimal secretion from eukaryotic cells to develop an mRNA-launched nanoparticle vaccine for SARS-CoV-2. The nanoparticle, which displays 60 copies of a stabilized variant of the Wuhan-Hu-1 Spike receptor binding domain (RBD), formed monodisperse, antigenically intact assemblies upon secretion from transfected cells. An mRNA vaccine encoding the secreted RBD nanoparticle elicited 5- to 28-fold higher levels of neutralizing antibodies than an mRNA vaccine encoding membrane-anchored Spike, induced higher levels of CD8 T cells than the same immunogen when delivered as an adjuvanted protein nanoparticle, and protected mice from vaccine-matched and -mismatched SARS-CoV-2 challenge. Our data establish that delivering protein nanoparticle immunogens via mRNA vaccines can combine the benefits of each modality and, more broadly, highlight the utility of computational protein design in genetic immunization strategies.

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Spike deep mutational scanning helps predict success of SARS-CoV-2 clades

Dadonaite,

Brown,

McMahon

et al. 2024

Nature

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SARS-CoV-2 variants acquire mutations in the spike protein that promote immune evasion1 and affect other properties that contribute to viral fitness, such as ACE2 receptor binding and cell entry2,3. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning4 to measure how more than 9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully affected ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456 and 473; however, the antigenic effects of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however, many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.

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Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination

Cited by 3 publications

References 88 publications

Engineering a SARS-CoV-2 vaccine targeting the RBD cryptic-face via immunofocusing

Engineering a SARS-CoV-2 vaccine targeting the RBD cryptic-face via immunofocusing

Computationally designed mRNA-launched protein nanoparticle vaccines

Spike deep mutational scanning helps predict success of SARS-CoV-2 clades

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