A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants
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Evaluation Summary:
In this work, the authors test a multivalent vaccine design they term Mos-tri-RBD, consisting of three linked spike receptor binding domains, one based on Omicron sub-lineage BA.1 and the others with different SARS-CoV-2 variant mutations. Immunization with this construct either as a prime or booster vaccine resulted in better neutralization of the Omicron and Beta variants relative to the same design, but with the ancestral receptor binding domain, and supports the notion that vaccination with variant sequences may broaden the neutralization capacity of vaccines against divergent variants.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody ID50 titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the BIBP inactivated COVID-19 vaccine (BBIBP-CorV). Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.
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Evaluation Summary:
In this work, the authors test a multivalent vaccine design they term Mos-tri-RBD, consisting of three linked spike receptor binding domains, one based on Omicron sub-lineage BA.1 and the others with different SARS-CoV-2 variant mutations. Immunization with this construct either as a prime or booster vaccine resulted in better neutralization of the Omicron and Beta variants relative to the same design, but with the ancestral receptor binding domain, and supports the notion that vaccination with variant sequences may broaden the neutralization capacity of vaccines against divergent variants.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the …
Evaluation Summary:
In this work, the authors test a multivalent vaccine design they term Mos-tri-RBD, consisting of three linked spike receptor binding domains, one based on Omicron sub-lineage BA.1 and the others with different SARS-CoV-2 variant mutations. Immunization with this construct either as a prime or booster vaccine resulted in better neutralization of the Omicron and Beta variants relative to the same design, but with the ancestral receptor binding domain, and supports the notion that vaccination with variant sequences may broaden the neutralization capacity of vaccines against divergent variants.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
Zhang et al. use a mosaic vaccine design, where three SARS-CoV-2 spike receptor domains (RBD) are linked together, to make a multivalent vaccine: one of the RBDs has the Omicron sub-lineage BA.1 sequence, while another has a combination of 8 mutations from different variants. They show that rats immunized with this construct have improved neutralization of Omicron and other variants relative to a mosaic vaccine where all RBDs are ancestral, as well as relative to the Sinopharm BBIBPCorV inactivated virus vaccine either as the primary vaccination or as a booster of BBIBPCorV.
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Reviewer #2 (Public Review):
This manuscript is a very well conducted and well-written study focused on mosaic type trimeric vaccine candidate. The candidate vaccine shows a much stronger immune response, as reported by neutralization assays, against omicron and other recent variants of SARS-CoV-2. It is also very effective as a booster and can be easily modified to new possible mutations.
Overall, I congratulate the authors for their great work. Mos-tri-RBD is a useful vaccine candidate which can be easily modified to keep on par with any upcoming SarsCov2 mutants. The work will have a great impact on the vaccine development studies going on against Covid19. Also, this is another example of developing mosaic-type trimeric vaccines can be utilized for other viruses.
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SciScore for 10.1101/2022.03.29.486173: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Ethics statement: Animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the National Vaccine and Serum Institute (NVSI) and conducted under Chinese animal use guidelines. Sex as a biological variable Rat immunization: To test the immunogenicity of mos-tri-RBD, 10 Wistar rats with half male and half female (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., China) were immunized intramuscularly by two doses, three weeks apart, of mos-tri-RBD (10 μg per dose) mixed with 300μg aluminum hydroxide adjuvant. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: …
SciScore for 10.1101/2022.03.29.486173: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Ethics statement: Animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the National Vaccine and Serum Institute (NVSI) and conducted under Chinese animal use guidelines. Sex as a biological variable Rat immunization: To test the immunogenicity of mos-tri-RBD, 10 Wistar rats with half male and half female (purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., China) were immunized intramuscularly by two doses, three weeks apart, of mos-tri-RBD (10 μg per dose) mixed with 300μg aluminum hydroxide adjuvant. Randomization not detected. Blinding not detected. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Antibodies Sentences Resources After washing three times with PBST, the plate was incubated with HRP-conjugated goat anti-mouse IgG antibody at 37°C for one hour. anti-mouse IgGsuggested: NoneExperimental Models: Cell Lines Sentences Resources The homo-tri-RBD used in this study was stably expressed by CHO cells and purified following the similar processes described above. CHOsuggested: CLS Cat# 603479/p746_CHO, RRID:CVCL_0213)The constructed plasmids encoding the S protein of SARS-CoV-2 variants were transfected into HEK293T cells, which were simultaneously infected with G*ΔG-VSV. HEK293Tsuggested: RRID:CVCL_HA71)Subsequently, 100 µL trypsin-treated HuH-7 cells with the density of 2×105 per mL were added into the well of the plates, and incubated at 37 °C and 5% CO2 for 20 ∼ 24 hours. HuH-7suggested: NoneAfter incubation, Vero cell suspension with a density of 2×105 per mL was added into the mixture. Verosuggested: NoneExperimental Models: Organisms/Strains Sentences Resources To evaluate the immune efficacy of mos-tri-RBD as a booster dose, a total of 30 Wistar rats, half male and half female, were intramuscularly primed with a dose (4μg/dose) of the inactivated vaccine BBIBP-CorV. Wistarsuggested: RRID:RGD_150520162)Recombinant DNA Sentences Resources After adding signal peptide and Kozak sequences to N terminus, the construct was cloned into the PTT5 plasmid vector via the Hin dIII and Not I restriction sites. PTT5suggested: RRID:Addgene_52326)In short, the gene sequences of the S protein of SARS-CoV-2 variants were codon-optimized and synthesized, which were then cloned into pcDNA3.1 plasmid vector. pcDNA3.1suggested: RRID:Addgene_79663)Software and Algorithms Sentences Resources SPR assay: Surface plasmon resonance (SPR) assay was performed to quantify the binding avidity of the recombinant mos-tri-RBD to the receptor hACE2 using BIAcore 8K (GE Healthcare) with NTA chips. BIAcoresuggested: (Biacore T100 System, RRID:SCR_019679)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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