An aluminum hydroxide:CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice
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Abstract
Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.
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SciScore for 10.1101/2021.05.20.444848: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: In order to assess the translational relevance and potential mechanism of an adjuvant formulation, we designed human in vitro study with peripheral blood collected from healthy young adults, aged 18–40 y (n = 6), and older participants, aged ≥ 65 years (n = 6), with approval from the Ethics Committee of the Boston Children’s Hospital (protocol number X07-05-0223) and Institutional Review Board of Brigham and Women’s Hospital, Boston (protocol number 2013P002473).
Consent: All participants signed an informed consent form prior to enrollment.
IACUC: Mice were housed under specific pathogen-free conditions at Boston Children’s Hospital, and all the procedures were approved under the …SciScore for 10.1101/2021.05.20.444848: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IRB: In order to assess the translational relevance and potential mechanism of an adjuvant formulation, we designed human in vitro study with peripheral blood collected from healthy young adults, aged 18–40 y (n = 6), and older participants, aged ≥ 65 years (n = 6), with approval from the Ethics Committee of the Boston Children’s Hospital (protocol number X07-05-0223) and Institutional Review Board of Brigham and Women’s Hospital, Boston (protocol number 2013P002473).
Consent: All participants signed an informed consent form prior to enrollment.
IACUC: Mice were housed under specific pathogen-free conditions at Boston Children’s Hospital, and all the procedures were approved under the Institutional Animal Care and Use Committee (IACUC) and operated under the supervision of the Department of Animal Resources at Children’s Hospital (ARCH) (Protocol number 19-02-3897R).Sex as a biological variable Animals: Female, 3 months old BALB/c mice were purchased from Jackson Laboratory (Bar Harbor, ME). Randomization Mice were randomly assigned to different treatment groups. Blinding Investigators were not blinded. Power Analysis not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources The sample/virus mixture was then incubated at 37°C (5.0% CO2) for 1 hour before transferring to 96-well titer plates with confluent VeroE6 cells. VeroE6suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)luciferase reporter plasmid pLenti-CMV Puro-Luc (Addgene), and spike protein expressing pcDNA3.1-SARSCoV-2 SΔCT of variants were co-transfected into HEK293T cells by lipofectamine 2000 (ThermoFisher). HEK293Tsuggested: NoneThe mixture was incubated at 37°C for 1 h before adding to HEK293T-hACE2 cells. HEK293T-hACE2suggested: RRID:CVCL_A7UK)Experimental Models: Organisms/Strains Sentences Resources Female, 12-13 months old BALB/c mice purchased from Taconic Biosciences (Germantown, NY) were used for aged mice experiments. BALB/csuggested: RRID:IMSR_ORNL:BALB/cRl)Recombinant DNA Sentences Resources Briefly, the packaging plasmid psPAX2 (AIDS Resource and Reagent Program) psPAX2suggested: RRID:Addgene_12260)luciferase reporter plasmid pLenti-CMV Puro-Luc (Addgene), and spike protein expressing pcDNA3.1-SARSCoV-2 SΔCT of variants were co-transfected into HEK293T cells by lipofectamine 2000 (ThermoFisher). pLenti-CMV Puro-Lucsuggested: NonepcDNA3.1-SARSCoV-2suggested: NoneSoftware and Algorithms Sentences Resources All dilutions were performed in DMEM (Quality Biological), supplemented with 10% (v/v) Quality Biologicalsuggested: NoneBriefly, the packaging plasmid psPAX2 (AIDS Resource and Reagent Program) AIDS Resource and Reagent Programsuggested: NoneStatistical analysis: Statistical analyses were performed using Prism v9.0.2 (GraphPad Software) and R software environment v4.0.4. Prismsuggested: (PRISM, RRID:SCR_005375)GraphPadsuggested: (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: We detected the following sentences addressing limitations in the study:As with any research our study also has some limitations, including that (a) we performed in vivo analysis only in mice, establishing the need for future translational research in additional animal models and humans and (b) all adjuvants/antigens were compared in single dose and further analysis should be performed in multiple doses to evaluate both efficacy and reactogenicity. Nevertheless, since we used standard doses of adjuvants/antigens in mouse systems (e.g., 1/30 and 1/18th of the human dose for CpG (12) and BNT162b2 (3) respectively, to compare the CpG-adjuvanted RBD subunit vaccine to the mRNA vaccine), it should be underscored that the results in this study hold promising value from a translational perspective. Recently, several SARS-CoV-2 variants of concern have emerged harboring mutations in the RBD region and showing various degrees of reduced neutralization by serum samples obtained from convalescent or vaccinated individuals (38-40). It is likely that booster doses that account for mutations in the Spike protein will be required in order to achieve complete immunity against such variants (71). Several vaccines composed of multiple protein antigens adsorbed onto aluminum salts alone or co-formulated with MPLA have been produced (55, 72). We speculate that an AH:CpG-adjuvanted coronavirus vaccine formulation incorporating RBD proteins from different SARS-CoV-2 strains (and potentially other coronaviruses) may promote cross-strain protective immunity. Overall, th...
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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