SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center Responses Associated with Neutralizing Antibody Generation

Lederer, Katlyn; Castaño, Diana; Atria, Daniela Gómez; Oguin, Thomas H.; Wang, Sidney; Manzoni, Tomaz B.; Muramatsu, Hiromi; Hogan, Michael J.; Amanat, Fatima; Cherubin, Patrick; Lundgreen, Kendall A.; Tam, Ying K.; Fan, Steven H.Y.; Eisenlohr, Laurence C.; Maillard, Ivan; Weissman, Drew; Bates, Paul; Krammer, Florian; Sempowski, Gregory D.; Pardi, Norbert; Locci, Michela

doi:10.1016/j.immuni.2020.11.009

Cited by 324 publications

(347 citation statements)

References 64 publications

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“…IgG subclasses can provide information regarding whether a given response is biased toward a Th1- or Th2-like response. 70 − 73 Adjuvants are known to play a major role in influencing the polarization of vaccine immune responses, and prior work has shown that Quil-A and MPLA adjuvants can lead to a Th1-biased response. 70 , 71 Some vaccine candidates against SARS-CoV were found to cause pulmonary immunopathology potentially due to Th2-type responses in small animal models, 74 − 77 and thus one focus for SARS-CoV-2 vaccine development has been to favor a Th1-type response.…”

Section: Resultsmentioning

confidence: 99%

“… 70 , 71 Some vaccine candidates against SARS-CoV were found to cause pulmonary immunopathology potentially due to Th2-type responses in small animal models, 74 − 77 and thus one focus for SARS-CoV-2 vaccine development has been to favor a Th1-type response. 72 , 73 A comparison of the ratio of IgG2a/IgG1 antibody titers among antigen groups demonstrated that, except for the RBD, the antigens exhibit a balanced IgG2a and IgG1 response, which was slightly skewed toward IgG2a for both the SΔC-Fer and S-GCN4 groups ( Figure S8A,B ). Notably, the RBD elicited a substantially higher IgG1 response as compared to both IgG2a and IgG2b, suggesting that this antigen in combination with Quil-A/MPLA caused a Th2-biased immune response ( Figure S8B,C ).…”

Section: Resultsmentioning

confidence: 99%

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A Single Immunization with Spike-Functionalized Ferritin Vaccines Elicits Neutralizing Antibody Responses against SARS-CoV-2 in Mice

et al. 2021

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The development of a safe and effective SARS-CoV-2 vaccine is a public health priority. We designed subunit vaccine candidates using self-assembling ferritin nanoparticles displaying one of two multimerized SARS-CoV-2 spikes: full-length ectodomain (S-Fer) or a C-terminal 70 amino-acid deletion (SΔC-Fer). Ferritin is an attractive nanoparticle platform for production of vaccines, and ferritin-based vaccines have been investigated in humans in two separate clinical trials. We confirmed proper folding and antigenicity of spike on the surface of ferritin by cryo-EM and binding to conformation-specific monoclonal antibodies. After a single immunization of mice with either of the two spike ferritin particles, a lentiviral SARS-CoV-2 pseudovirus assay revealed mean neutralizing antibody titers at least 2-fold greater than those in convalescent plasma from COVID-19 patients. Additionally, a single dose of SΔC-Fer elicited significantly higher neutralizing responses as compared to immunization with the spike receptor binding domain (RBD) monomer or spike ectodomain trimer alone. After a second dose, mice immunized with SΔC-Fer exhibited higher neutralizing titers than all other groups. Taken together, these results demonstrate that multivalent presentation of SARS-CoV-2 spike on ferritin can notably enhance elicitation of neutralizing antibodies, thus constituting a viable strategy for single-dose vaccination against COVID-19.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Single Immunization with Spike-Functionalized Ferritin Vaccines Elicits Neutralizing Antibody Responses against SARS-CoV-2 in Mice

et al. 2021

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“…A key feature of mRNA vaccines, particularly those delivered via cationic LNPs, is the induction of potent antibody responses via germinal centers. While the molecular basis for the robust induction of germinal centers with mRNA vaccines is still being unraveled, the generation of antigen-specific TFH cells is likely a paramount feature [ 139 , 158 ]. As discussed in Section 3.2.5 , lipid nanoparticles exhibit inherent adjuvant properties, which likely contributes to the induction of germinal centers.…”

Section: Overcoming the Challenges To Hiv Vaccination With Mrna-bamentioning

confidence: 99%

HIV mRNA Vaccines—Progress and Future Paths

Haynes

Cain

2021

Vaccines

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The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.

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“…Both vaccines are administered intramuscularly in two doses, 3 (Pfizer BioNTech COVID-19) or 4 (Moderna COVID-19) weeks apart. Both contain modified mRNA packed in lipid nanoparticles which after vaccination is incorporated into human cells and leads to the production of the viral spike glycoprotein S. 10 – 12 Such vaccines are highly immunogenic in humans eliciting strong B cell (production of protective antibodies) and T cell responses, 11 , 13 – 16 although the duration of their protection remains to be determined.…”

Section: How Are the Mrna Vaccines Being Administered And How Do Thementioning

confidence: 99%

Vaccination Against SARS-CoV-2 in Immunosuppressed Patients with Rheumatic Diseases: Position Statement of the Greek Rheumatology Society

2020

MJR

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SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center Responses Associated with Neutralizing Antibody Generation

Cited by 324 publications

References 64 publications

A Single Immunization with Spike-Functionalized Ferritin Vaccines Elicits Neutralizing Antibody Responses against SARS-CoV-2 in Mice

A Single Immunization with Spike-Functionalized Ferritin Vaccines Elicits Neutralizing Antibody Responses against SARS-CoV-2 in Mice

HIV mRNA Vaccines—Progress and Future Paths

Vaccination Against SARS-CoV-2 in Immunosuppressed Patients with Rheumatic Diseases: Position Statement of the Greek Rheumatology Society

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