Distinct sensitivities to SARS-CoV-2 variants in vaccinated humans and mice

Walls, Alexandra C.; VanBlargan, Laura A.; Wu, Kai; Choi, Angela; Navarro, Mary Jane; Lee, Diana; Avena, Laura E.; Berrueta, Daniela Montes; Pham, Minh N.; Elbashir, Sayda M.; Kraft, John C.; Miranda, Marcos C.; Kepl, Elizabeth; Johnson, Max; Blackstone, Alyssa; Sprouse, Kaitlin R.; Fiala, Brooke; O’Connor, Megan A.; Brunette, Natalie; Arunachalam, Prabhu S.; Shirreff, Lisa; Rogers, Kenneth A.; Carter, Lauren; Fuller, Deborah H.; Villinger, François; Pulendran, Bali; Diamond, Michael S.; Edwards, Darin K.; King, Neil P.; Veesler, David

doi:10.1016/j.celrep.2022.111299

Cited by 11 publications

(7 citation statements)

References 48 publications

(53 reference statements)

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“…Across these studies cited above, the immunogenicity varies little compared to dose. As we have observed in mRNA studies, lowering the dose of vaccine 10–50-fold has little effect on broad protection and only on magnitude of antibody present 31 . However, the protection from disease and viral replication demonstrated in this mouse model in combination with the broadening neutralization demonstrated in our rS-Beta boosted baboon data suggests a benefit to an rS-Beta-directed or bivalent booster in humans to broaden a neutralizing antibody response to future variants.…”

Section: Discussionsupporting

confidence: 51%

Immunogenicity and protection of a variant nanoparticle vaccine that confers broad neutralization against SARS-CoV-2 variants

et al. 2023

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SARS-CoV-2 variants have emerged with elevated transmission and a higher risk of infection for vaccinated individuals. We demonstrate that a recombinant prefusion-stabilized spike (rS) protein vaccine based on Beta/B.1.351 (rS-Beta) produces a robust anamnestic response in baboons against SARS-CoV-2 variants when given as a booster one year after immunization with NVX-CoV2373. Additionally, rS-Beta is highly immunogenic in mice and produces neutralizing antibodies against WA1/2020, Beta/B.1.351, and Omicron/BA.1. Mice vaccinated with two doses of Novavax prototype NVX-CoV2373 (rS-WU1) or rS-Beta alone, in combination, or heterologous prime-boost, are protected from challenge. Virus titer is undetectable in lungs in all vaccinated mice, and Th1-skewed cellular responses are observed. We tested sera from a panel of variant spike protein vaccines and find broad neutralization and inhibition of spike:ACE2 binding from the rS-Beta and rS-Delta vaccines against a variety of variants including Omicron. This study demonstrates that rS-Beta vaccine alone or in combination with rS-WU1 induces antibody-and cell-mediated responses that are protective against challenge with SARS-CoV-2 variants and offers broader neutralizing capacity than a rS-WU1 prime/boost regimen alone. Together, these nonhuman primate and murine data suggest a Beta variant booster dose could elicit a broad immune response to fight new and future SARS-CoV-2 variants.

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Section: Discussionsupporting

confidence: 51%

Immunogenicity and protection of a variant nanoparticle vaccine that confers broad neutralization against SARS-CoV-2 variants

et al. 2023

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“…In a recent study Walls and colleagues showed that the VN antibodies induced by an RBD vaccine or the full S protein, exhibited different neutralization efficacy depending on the animal model used. Neutralizing antibodies induced in mice showed better cross neutralization against Beta and Gamma VOCs (only 2-fold reduction efficiency) than VN antibodies induced in non-human primates (NHP) which were ~6-8-fold less efficient in neutralizing these VOCs 42 . In our study, we also observed that neutralizing antibodies induced in hamsters are affected by VOCs in a similar way as in NHP (~10-fold reduction in neutralization).…”

Section: Discussionmentioning

confidence: 94%

Preclinical immunogenicity and protective efficacy of a SARS-CoV-2 RBD based vaccine produced with the thermophilic filamentous fungal expression system Thermothelomyces heterothallica, C1.

Osterhaus

González-Hernández

Kaiser

et al. 2023

Preprint

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The emergency use of vaccines has been the most efficient way to control the ongoing COVID-19 pandemic. However, the emergence of SARS-CoV-2 variants of concern has reduced the efficacy of currently used vaccines. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is the main target for virus neutralizing (VN) antibodies. Here, we evaluated the immunogenicity and efficacy of a SARS-CoV-2 RBD vaccine candidate produced in the Thermothelomyces heterothallica (formerly Myceliophthora thermophila), C1 protein expression system, in a Syrian golden hamster (Mesocricetus auratus) infection model. One dose of 10 µg RBD vaccine based on SARS-CoV-2 Wuhan strain, coupled to a nanoparticle in combination with aluminum hydroxide as adjuvant, efficiently induced VN antibodies and reduced viral load and lung damage upon SARS-CoV-2 challenge infection. The VN antibodies, neutralized SARS-CoV-2 variants of concern D614G, Alpha, Beta and Gamma. Our results support the use of the Thermothelomyces heterothallica, C1 protein expression system to produce recombinant vaccines against SARS-CoV-2 and other virus infections, in order to help overcome limitations associated with the use of mammalian expression systems.

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“…In this study, after a single immunization in mice, nAbs increased over time, suggesting a maturation of B cell response allowing for the maintenance of B cell memory and the development of long lived plasmacells. This phenomenon is not observed in vaccinated humans, where nAb response wanes over time ( 46 , 92 ) and suggests that some immunological aspects, including analysis of persistence of immunity and breadth of immune responses, should be verified in other animal models, such as non-human primates ( 93 ). Interestingly, a recent report showed that after three doses of mRNA vaccine in humans, the Spike-specific repertoire of human B cells was significantly increased, allowing for the development of high affinity and cross-neutralizing antibodies ( 94 ), suggesting that multiple antigen exposure is essential for B cell maturation.…”

Section: Discussionmentioning

confidence: 99%

Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profiles

et al. 2023

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Several COVID-19 vaccine strategies utilizing new formulations for the induction of neutralizing antibodies (nAbs) and T cell immunity are still under evaluation in preclinical and clinical studies. Here we used Simian Immunodeficiency Virus (SIV)-based integrase defective lentiviral vector (IDLV) delivering different conformations of membrane-tethered Spike protein in the mouse immunogenicity model, with the aim of inducing persistent nAbs against multiple SARS-CoV-2 variants of concern (VoC). Spike modifications included prefusion-stabilizing double proline (2P) substitutions, mutations at the furin cleavage site (FCS), D614G mutation and truncation of the cytoplasmic tail (delta21) of ancestral and Beta (B.1.351) Spike, the latter mutation to markedly improve IDLV membrane-tethering. BALB/c mice were injected once with IDLV delivering the different forms of Spike or the recombinant trimeric Spike protein with 2P substitutions and FCS mutations in association with a squalene-based adjuvant. Anti-receptor binding domain (RBD) binding Abs, nAbs and T cell responses were detected up to six months from a single immunization with escalating doses of vaccines in all mice, but with different levels and kinetics. Results indicated that IDLV delivering the Spike protein with all the combined modifications, outperformed the other candidates in terms of T cell immunity and level of both binding Abs and nAbs soon after the single immunization and persistence over time, showing the best capacity to neutralize all formerly circulating VoC Alpha, Beta, Gamma and Delta. Although present, the lowest response was detected against Omicron variants (BA.1, BA.2 and BA.4/5), suggesting that the magnitude of immune evasion may be related to the higher genetic distance of Omicron as indicated by increased number of amino acid substitutions in Spike acquired during virus evolution.

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Distinct sensitivities to SARS-CoV-2 variants in vaccinated humans and mice

Cited by 11 publications

References 48 publications

Immunogenicity and protection of a variant nanoparticle vaccine that confers broad neutralization against SARS-CoV-2 variants

Immunogenicity and protection of a variant nanoparticle vaccine that confers broad neutralization against SARS-CoV-2 variants

Preclinical immunogenicity and protective efficacy of a SARS-CoV-2 RBD based vaccine produced with the thermophilic filamentous fungal expression system Thermothelomyces heterothallica, C1.

Different configurations of SARS-CoV-2 spike protein delivered by integrase-defective lentiviral vectors induce persistent functional immune responses, characterized by distinct immunogenicity profiles

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