Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses

Abstract

As the SARS-CoV-2 pandemic enters its third year, vaccines that not only prevent disease, but also prevent transmission are needed to help reduce global disease burden. Currently approved parenteral vaccines induce robust systemic immunity, but poor immunity at the respiratory mucosa. Here we describe the development of a novel vaccine strategy, Prime and Spike, based on unadjuvanted intranasal spike boosting that leverages existing immunity generated by primary vaccination to elicit mucosal immune memory within the respiratory tract. We show that Prime and Spike induces robust T resident memory cells, B resident memory cells and IgA at the respiratory mucosa, boosts systemic immunity, and completely protects mice with partial immunity from lethal SARS-CoV-2 infection. Using divergent spike proteins, Prime and Spike enables induction of cross-reactive immunity against sarbecoviruses without invoking original antigenic sin.

One-sentence summary

Broad sarbecovirus protective mucosal immunity is generated by unadjuvanted intranasal spike boost in preclinical model.

SciScore for 10.1101/2022.01.24.477597: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Ethics	IACUC: All procedures were performed in a BSL-3 facility (for SARS-CoV-2–infected mice) with approval from the Yale Institutional Animal Care and Use Committee and Yale Environmental Health and Safety. Euthanasia Agents: Mice were anaesthetized using a mixture of ketamine (50 mg/kg) and xylazine (5 mg/kg), injected intraperitoneally.
Sex as a biological variable	Eight to twelve-week-old female were used for immunization experiments.
Randomization	not detected.
Blinding	A pulmonary pathologist reviewed the slides blinded and identified immune cell infiltration and other related pathologies.
Power Analysis	not detected.
Cell Line Authentication	not detected.

Table 2: Resources

…

SciScore for 10.1101/2022.01.24.477597: (What is this?)

Please note, not all rigor criteria are appropriate for all manuscripts.

Table 1: Rigor

Ethics	IACUC: All procedures were performed in a BSL-3 facility (for SARS-CoV-2–infected mice) with approval from the Yale Institutional Animal Care and Use Committee and Yale Environmental Health and Safety. Euthanasia Agents: Mice were anaesthetized using a mixture of ketamine (50 mg/kg) and xylazine (5 mg/kg), injected intraperitoneally.
Sex as a biological variable	Eight to twelve-week-old female were used for immunization experiments.
Randomization	not detected.
Blinding	A pulmonary pathologist reviewed the slides blinded and identified immune cell infiltration and other related pathologies.
Power Analysis	not detected.
Cell Line Authentication	not detected.

Table 2: Resources

Experimental Models: Cell Lines
Sentences	Resources
Viral titers were measured by standard plaque assay using Vero E6 cells over expressing hACE2 and TMPRSS2.	Vero E6 suggested: RRID:CVCL_XD71)
293T cells were transfected with either spike plasmid, followed by inoculation with replication-deficient VSV-expressing Renilla luciferase for 1 hour at 37°C.	293T suggested: None
Pseudoviruses were titrated in Huh7.5 cells to achieve a relative light unit signal of ∼600 times the cell-only control background.	Huh7.5 suggested: RRID:CVCL_7927)
Experimental Models: Organisms/Strains
Sentences	Resources
Mice: B6.Cg-Tg(K18-ACE2)2Prlmn/J (K18-hACE2) mice were purchased from The Jackson Laboratory and subsequently bred and housed at Yale University.	B6.Cg-Tg(K18-ACE2)2Prlmn/J (K18-hACE2) suggested: None
Recombinant DNA
Sentences	Resources
Vector pCAGGS containing the SARS-CoV-2 Wuhan-Hu-1 spike glycoprotein gene was produced under HHSN272201400008C and obtained through BEI Resources (NR-52310).	pCAGGS suggested: RRID:Addgene_127347)
Software and Algorithms
Sentences	Resources
Cell population data were acquired on an Attune NxT Flow Cytometer and analyzed using FlowJo Software (10.5.3; Tree Star).	FlowJo suggested: (FlowJo, RRID:SCR_008520)
IC50 was calculated as using Prism 9 (GraphPad Software) nonlinear regression.	GraphPad suggested: (GraphPad Prism, RRID:SCR_002798)

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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Unadjuvanted intranasal spike vaccine booster elicits robust protective mucosal immunity against sarbecoviruses

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Abstract

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