{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T21:45:12Z","timestamp":1772142312148,"version":"3.50.1"},"reference-count":62,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: The rise of immune escape variants of the SARS-CoV-2 virus has prompted the development of vaccines based on the variant\u2019s spike antigen sequence. Since variant-specific SARS-CoV-2 vaccines are mostly administered as boosters to individuals previously vaccinated with reference (Ref.) strain-based vaccines, a better understanding of their immunogenicity in this context is essential. Protein subunit vaccines have a well-established track record of safety. Herein, we assessed the ability of variant-specific protein subunit vaccine formulations to boost pre-existing Ref. strain-specific immune responses compared to boosting with a Ref. strain-specific formulation in young and aged female Balb\/c mice. Methods: Following a priming vaccination series with Ref. spike protein adjuvanted with sulfated lactosyl archaeol (SLA) archaeosomes on days 0 and 21, immune responses were evaluated in young and aged female Balb\/c mice. On day 91, mice received a third immunization with Ref., Beta, or Delta spike protein formulations, with or without SLA archaeosomes. Antibody titers, neutralization activity, and cellular immune responses were measured to assess the impact of the booster formulation. Results: Aged mice exhibited lower antibody titers throughout the study and a decline over time compared to young mice. After a third immunization, responses were boosted by all vaccine formulations (Ref., Beta, or Delta), with or without adjuvant. However, variant-specific antigen formulations did not overcome immune imprinting from the priming series or increase neutralization activity against the corresponding SARS-CoV-2 variants in either age group. Conclusions: Variant-specific protein subunit vaccines enhanced immune responses but did not overcome immune imprinting induced by the Ref. strain\u2019s priming. The inclusion of SLA archaeosomes improved cellular immunity, supporting their potential role in optimizing booster vaccine performance, particularly in aged populations.<\/jats:p>","DOI":"10.3390\/vaccines13121257","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T16:42:05Z","timestamp":1766076125000},"page":"1257","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immunogenicity of Sulfated Lactosyl Archaeol Archaeosome-Adjuvanted Versus Non-Adjuvanted SARS-CoV-2 Spike Booster Vaccines in Young and Aged Balb\/c Mice"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7547-8493","authenticated-orcid":false,"given":"Felicity C.","family":"Stark","sequence":"first","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5377-7193","authenticated-orcid":false,"given":"Bassel","family":"Akache","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9196-5021","authenticated-orcid":false,"given":"Tyler M.","family":"Renner","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1207-9858","authenticated-orcid":false,"given":"Gerard","family":"Agbayani","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lise","family":"Deschatelets","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renu","family":"Dudani","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Blair A.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Usha D.","family":"Hemraz","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Montreal, QC H4P 2R2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophie","family":"R\u00e9gnier","sequence":"additional","affiliation":[{"name":"Aquatic and Crop Resource Development, National Research Council of Canada, Montreal, QC H4P 2R2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Stuible","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Montreal, QC H4P 2R2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2268-4111","authenticated-orcid":false,"given":"Yves","family":"Durocher","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Montreal, QC H4P 2R2, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5538-1363","authenticated-orcid":false,"given":"Michael J.","family":"McCluskie","sequence":"additional","affiliation":[{"name":"Human Health Therapeutics, National Research Council of Canada, Ottawa, ON K1A 0R6, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/nrd.2017.243","article-title":"mRNA Vaccines\u2014A New Era in Vaccinology","volume":"17","author":"Pardi","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41577-020-00480-0","article-title":"Viral Targets for Vaccines against COVID-19","volume":"21","author":"Dai","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"120586","DOI":"10.1016\/j.ijpharm.2021.120586","article-title":"mRNA-Lipid Nanoparticle COVID-19 Vaccines: Structure and Stability","volume":"601","author":"Schoenmaker","year":"2021","journal-title":"Int. J. Pharm."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Qian, G., Gao, C., Zhang, M., Chen, Y., and Xie, L. (2024). A Review of Protein-Based COVID-19 Vaccines: From Monovalent to Multivalent Formulations. Vaccines, 12.","DOI":"10.3390\/vaccines12060579"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.shpsc.2017.05.004","article-title":"Biotechnology and the Transformation of Vaccine Innovation: The Case of the Hepatitis B Vaccines 1968\u20132000","volume":"64","author":"Huzair","year":"2017","journal-title":"Stud. Hist. Philos. Sci. Part C Stud. Hist. Philos. Biol. Biomed. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/324506c0","article-title":"New Hepatitis-B Vaccine Launched","volume":"324","author":"Ward","year":"1986","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6567","DOI":"10.1016\/j.vaccine.2022.09.064","article-title":"With Established Safe and Effective Use, Protein Vaccines Offer Another Choice against COVID-19","volume":"40","author":"Marchese","year":"2022","journal-title":"Vaccine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1056\/NEJMoa2107659","article-title":"Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine","volume":"385","author":"Heath","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"102587","DOI":"10.1016\/j.eclinm.2024.102587","article-title":"Effectiveness of the Sanofi\/GSK (VidPrevtyn Beta) and Pfizer-BioNTech (Comirnaty Original\/Omicron BA.4-5) Bivalent Vaccines against Hospitalisation in England","volume":"71","author":"Kirsebom","year":"2024","journal-title":"EClinicalMedicine"},{"key":"ref_10","first-page":"162","article-title":"SARS-CoV-2 Variant Biology: Immune Escape, Transmission and Fitness","volume":"21","author":"Carabelli","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1126\/science.abn7591","article-title":"Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA Vaccine\u2013Elicited Human Sera","volume":"375","author":"Muik","year":"2022","journal-title":"Science"},{"key":"ref_12","unstructured":"(2024, February 13). Pfizer and BioNTech Receive Positive CHMP Opinion for Omicron BA.1-Adapted Bivalent COVID-19 Vaccine Booster in European Union. Available online: https:\/\/www.pfizer.com\/news\/press-release\/press-release-detail\/pfizer-and-biontech-receive-positive-chmp-opinion-omicron."},{"key":"ref_13","unstructured":"FDA (2025, January 24). FDA Approves and Authorizes Updated mRNA COVID-19 Vaccines to Better Protect Against Currently Circulating Variants, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-and-authorizes-updated-mrna-covid-19-vaccines-better-protect-against-currently."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1056\/NEJMoa2213082","article-title":"Bivalent Omicron BA.1\u2013Adapted BNT162b2 Booster in Adults Older than 55 Years","volume":"388","author":"Winokur","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1093\/infdis\/jiad419","article-title":"Effectiveness of mRNA COVID-19 Monovalent and Bivalent Vaccine Booster Doses Against Omicron Severe Outcomes Among Adults Aged \u226550 Years in Ontario, Canada: A Canadian Immunization Research Network Study","volume":"229","author":"Grewal","year":"2023","journal-title":"J. Infect. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"5490","DOI":"10.1016\/j.vaccine.2023.07.071","article-title":"Protection against Symptomatic SARS-CoV-2 Infection Conferred by the Pfizer-BioNTech Original\/BA.4-5 Bivalent Vaccine Compared to the mRNA Original Monovalent Vaccines\u2014A Matched Cohort Study in France","volume":"41","author":"Auvigne","year":"2023","journal-title":"Vaccine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2300173","DOI":"10.2807\/1560-7917.ES.2023.28.48.2300173","article-title":"Relative Vaccine Effectiveness of mRNA COVID-19 Boosters in People Aged at Least 75 Years during the Spring-Summer (Monovalent Vaccine) and Autumn-Winter (Bivalent Vaccine) Booster Campaigns: A Prospective Test Negative Case-Control Study, United Kingdom, 2022","volume":"28","author":"Chatzilena","year":"2023","journal-title":"Eurosurveillance"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1056\/NEJMoa2208343","article-title":"A Bivalent Omicron-Containing Booster Vaccine against Covid-19","volume":"387","author":"Chalkias","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1016\/S1473-3099(23)00365-1","article-title":"Duration of Protection of Ancestral-Strain Monovalent Vaccines and Effectiveness of Bivalent BA.1 Boosters against COVID-19 Hospitalisation in England: A Test-Negative Case-Control Study","volume":"23","author":"Kirsebom","year":"2023","journal-title":"Lancet Infect. Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1056\/NEJMc2211055","article-title":"Immune Imprinting and Protection against Repeat Reinfection with SARS-CoV-2","volume":"387","author":"Chemaitelly","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e162192","DOI":"10.1172\/JCI162192","article-title":"van Impact of Antigenic Evolution and Original Antigenic Sin on SARS-CoV-2 Immunity","volume":"133","author":"Fouchier","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1856","DOI":"10.1016\/j.immuni.2022.07.020","article-title":"Antibodies from Primary Humoral Responses Modulate the Recruitment of Naive B Cells during Secondary Responses","volume":"55","author":"Tas","year":"2022","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e20221786","DOI":"10.1084\/jem.20221786","article-title":"Antibody Feedback Contributes to Facilitating the Development of Omicron-Reactive Memory B Cells in SARS-CoV-2 mRNA Vaccinees","volume":"220","author":"Inoue","year":"2022","journal-title":"J. Exp. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/s41586-022-05609-w","article-title":"Antibody Feedback Regulates Immune Memory after SARS-CoV-2 mRNA Vaccination","volume":"613","author":"Wang","year":"2023","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1016\/j.immuni.2024.05.009","article-title":"Opposing Effects of Pre-Existing Antibody and Memory T Cell Help on the Dynamics of Recall Germinal Centers","volume":"57","author":"Schiepers","year":"2024","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Grifoni, A., Alonzi, T., Alter, G., Noonan, D.M., Landay, A.L., Albini, A., and Goletti, D. (2023). Impact of Aging on Immunity in the Context of COVID-19, HIV, and Tuberculosis. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1146704"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/s41586-023-06025-4","article-title":"SARS-CoV-2 Omicron Boosting Induces de Novo B Cell Response in Humans","volume":"617","author":"Alsoussi","year":"2023","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41586-023-06753-7","article-title":"Repeated Omicron Exposures Override Ancestral SARS-CoV-2 Immune Imprinting","volume":"625","author":"Yisimayi","year":"2024","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-020-2607-z","article-title":"Single-Shot Ad26 Vaccine Protects against SARS-CoV-2 in Rhesus Macaques","volume":"586","author":"Mercado","year":"2020","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"586","DOI":"10.4161\/hv.27567","article-title":"Single-Dose Monomeric HA Subunit Vaccine Generates Full Protection from Influenza Challenge","volume":"10","author":"Mallajosyula","year":"2014","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.jconrel.2022.05.017","article-title":"STING Agonist-Containing Microparticles Improve Seasonal Influenza Vaccine Efficacy and Durability in Ferrets over Standard Adjuvant","volume":"347","author":"Gallovic","year":"2022","journal-title":"J. Control. Release"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"126463","DOI":"10.1016\/j.vaccine.2024.126463","article-title":"SARS-CoV-2 Spike-Based Virus-like Particles Incorporate Influenza H1\/N1 Antigens and Induce Dual Immunity in Mice","volume":"42","author":"Stuible","year":"2024","journal-title":"Vaccine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"21849","DOI":"10.1038\/s41598-021-01363-7","article-title":"Immunogenic and Efficacious SARS-CoV-2 Vaccine Based on Resistin-Trimerized Spike Antigen SmT1 and SLA Archaeosome Adjuvant","volume":"11","author":"Akache","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/s41541-022-00540-7","article-title":"Immunogenicity of SARS-CoV-2 Spike Antigens Derived from Beta & Delta Variants of Concern","volume":"7","author":"Akache","year":"2022","journal-title":"NPJ Vaccines"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Renner, T.M., Akache, B., Stuible, M., Rohani, N., Cepero-Donates, Y., Deschatelets, L., Dudani, R., Harrison, B.A., Baardsnes, J., and Koyuturk, I. (2023). Tuning the Immune Response: Sulfated Archaeal Glycolipid Archaeosomes as an Effective Vaccine Adjuvant for Induction of Humoral and Cell-Mediated Immunity towards the SARS-CoV-2 Omicron Variant of Concern. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1182556"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Akache, B., Stark, F.C., Jia, Y., Deschatelets, L., Dudani, R., Harrison, B.A., Agbayani, G., Williams, D., Jamshidi, M.P., and Krishnan, L. (2018). Sulfated Archaeol Glycolipids: Comparison with Other Immunological Adjuvants in Mice. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0208067"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"513231","DOI":"10.1155\/2012\/513231","article-title":"Synthetic Archaeosome Vaccines Containing Triglycosylarchaeols Can Provide Additive and Long-Lasting Immune Responses That Are Enhanced by Archaetidylserine","volume":"2012","author":"Sprott","year":"2012","journal-title":"Archaea"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8332","DOI":"10.1021\/acs.jmedchem.2c00072","article-title":"Effect of Chiral Purity on Adjuvanticity of Archaeol-Based Glycolipids","volume":"65","author":"Lam","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.carres.2009.10.011","article-title":"Development of New Glycosylation Methodologies for the Synthesis of Archaeal-Derived Glycolipid Adjuvants","volume":"345","author":"Whitfield","year":"2010","journal-title":"Carbohydr. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9772","DOI":"10.1038\/s41598-022-13819-5","article-title":"Intranasal Immunization with a Proteosome-Adjuvanted SARS-CoV2 Spike Protein-Based Vaccine Is Immunogenic and Efficacious in Mice and Hamsters","volume":"12","author":"Stark","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/978-1-0716-0795-4_31","article-title":"Measurement of Antigen-Specific IgG Titers by Direct ELISA","volume":"2183","author":"Akache","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Rossotti, M.A., Ryan, S., Hussack, G., Tanha, J., Akache, B., and Renner, T.M. (2025). A Safe and Accessible Cell-Based Spike\u2013ACE2 Binding Assay for Evaluating SARS-CoV-2 Neutralization Activity in Biological Samples Using Flow Cytometry. Methods Protoc., 8.","DOI":"10.3390\/mps8050104"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/978-1-0716-0795-4_30","article-title":"The Quantification of Antigen-Specific T Cells by IFN-\u03b3 ELISpot","volume":"2183","author":"Akache","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1038\/s41467-021-21336-8","article-title":"Discrete SARS-CoV-2 Antibody Titers Track with Functional Humoral Stability","volume":"12","author":"Bartsch","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1126\/science.abc4776","article-title":"SARS-CoV-2 Infection Protects against Rechallenge in Rhesus Macaques","volume":"369","author":"Chandrashekar","year":"2020","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1126\/science.abc6284","article-title":"DNA Vaccine Protection against SARS-CoV-2 in Rhesus Macaques","volume":"369","author":"Yu","year":"2020","journal-title":"Science"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/s41541-021-00427-z","article-title":"Passive Transfer of Ad26.COV2.S-Elicited IgG from Humans Attenuates SARS-CoV-2 Disease in Hamsters","volume":"7","author":"Tostanoski","year":"2022","journal-title":"NPJ Vaccines"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"eabj0299","DOI":"10.1126\/science.abj0299","article-title":"Immune Correlates of Protection by mRNA-1273 Vaccine against SARS-CoV-2 in Nonhuman Primates","volume":"373","author":"Corbett","year":"2021","journal-title":"Science"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"630","DOI":"10.1038\/s41586-020-03041-6","article-title":"Correlates of Protection against SARS-CoV-2 in Rhesus Macaques","volume":"590","author":"McMahan","year":"2021","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1056\/NEJMc2119270","article-title":"Effectiveness of BNT162b2 Vaccine against Omicron Variant in South Africa","volume":"386","author":"Collie","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/s41591-022-01753-y","article-title":"Effectiveness of mRNA-1273 against SARS-CoV-2 Omicron and Delta Variants","volume":"28","author":"Tseng","year":"2022","journal-title":"Nat. Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1532","DOI":"10.1056\/NEJMoa2119451","article-title":"Covid-19 Vaccine Effectiveness against the Omicron (B.1.1.529) Variant","volume":"386","author":"Andrews","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2441","DOI":"10.1056\/NEJMc2205357","article-title":"Protection by a Fourth Dose of BNT162b2 against Omicron in Israel","volume":"386","author":"Wohl","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1016\/j.cell.2022.03.038","article-title":"mRNA-1273 or mRNA-Omicron Boost in Vaccinated Macaques Elicits Similar B Cell Expansion, Neutralizing Responses, and Protection from Omicron","volume":"185","author":"Gagne","year":"2022","journal-title":"Cell"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1056\/NEJMra2206573","article-title":"Covid-19 Vaccines\u2014Immunity, Variants, Boosters","volume":"387","author":"Barouch","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7274","DOI":"10.1016\/j.vaccine.2023.10.058","article-title":"Understanding COVID-19 Vaccine Hesitancy in Canada","volume":"41","author":"Corsten","year":"2023","journal-title":"Vaccine"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"100582","DOI":"10.1016\/j.jvacx.2024.100582","article-title":"COVID-19 Vaccine or Booster Uptake and Hesitancy for Children Aged 6 Months-5 Years in the United States: A National Descriptive Study Using the Household Pulse Survey between March and May 2023","volume":"21","author":"Park","year":"2024","journal-title":"Vaccine X"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"20376","DOI":"10.1038\/s41598-022-24938-4","article-title":"Early CD4+ T Cell Responses Induced by the BNT162b2 SARS-CoV-2 mRNA Vaccine Predict Immunological Memory","volume":"12","author":"Bai","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2021.01.007","article-title":"Adaptive Immunity to SARS-CoV-2 and COVID-19","volume":"184","author":"Sette","year":"2021","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1016\/j.ymthe.2024.04.019","article-title":"mRNA-LNP Vaccine-Induced CD8+ T Cells Protect Mice from Lethal SARS-CoV-2 Infection in the Absence of Specific Antibodies","volume":"32","author":"Montoya","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/s41590-021-01122-w","article-title":"The T Cell Immune Response against SARS-CoV-2","volume":"23","author":"Moss","year":"2022","journal-title":"Nat. Immunol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Jia, Y., Akache, B., Agbayani, G., Chandan, V., Dudani, R., Harrison, B.A., Deschatelets, L., Hemraz, U.D., Lam, E., and R\u00e9gnier, S. (2021). The Synergistic Effects of Sulfated Lactosyl Archaeol Archaeosomes When Combined with Different Adjuvants in a Murine Model. 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