Effect of Different Adjuvants on the Performance of SARS-CoV-2 Vaccines: A Narrative Review of Phase III Trials
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Abstract
Background: The rapid development of vaccines against severe acute respiratory syndrome coronavirus 2 introduced diverse technological platforms, antigen designs, dosing schedules, delivery routes, and adjuvant systems. Adjuvants are important components of several inactivated, recombinant protein, protein-subunit, and conjugated vaccines because they can strengthen innate and adaptive immune responses. However, the clinical performance of an adjuvanted vaccine is determined by the complete formulation and cannot be attributed to the adjuvant alone. Objective: To narratively review the characteristics and reported efficacy of late-phase SARS-CoV-2 vaccines, with particular emphasis on the biological role, clinical context, and apparent performance patterns of their adjuvant systems. Methods: A structured narrative review was undertaken using literature identified through PubMed, the Cochrane Library, ScienceDirect, Google Scholar, ClinicalTrials.gov, and CenterWatch. Phase III and combined Phase II/III vaccine trials, supporting immunological studies, and relevant publications on SARS-CoV-2 vaccine platforms and adjuvants were considered. Evidence was organized thematically according to vaccine platform, adjuvant system, dosing regimen, trial-level efficacy, infection outcomes, and implementation characteristics. Numerical findings were interpreted descriptively because the included trials differed substantially in populations, circulating variants, endpoints, follow-up periods, baseline risks, and trial settings. Results: The reviewed vaccines included inactivated whole-virus, adenoviral-vector, recombinant protein, protein-subunit, DNA, conjugated protein, and intranasal live-attenuated platforms. Reported adjuvants included alum, aluminium hydroxide, alumina, AS03, CpG-1018 combined with alum, Advax-SM, and a toll-like receptor 7/8 agonist combined with alum. Trial-reported efficacy ranged from 15.3% to 92.2%. Most vaccine–control comparisons demonstrated lower infection frequencies among vaccinated participants, although marked variation existed across formulations and trial contexts. The evidence did not permit separation of the independent contribution of an adjuvant from that of the antigen, platform, dosage, route, schedule, or epidemiological setting. Conclusion: Adjuvants contributed to the immunological architecture of several successful SARS-CoV-2 vaccines, but available cross-trial evidence did not establish the independent superiority of any individual adjuvant. Future research should directly compare alternative adjuvant formulations using standardized endpoints, comparable populations, and consistent follow-up periods.
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1. Edalat F, Tabatabaie FH, Moattari A, Letafati A, Sarvari J, Hosseini SY. Delving into revolutionary SARS-CoV-2 vaccine approaches: molecular and virological examinations; principles of SARS-CoV-2 vaccine platforms. Vacunas. 2023.
2. Wang C, Horby PW, Hayden FG, Gao GF. A novel coronavirus outbreak of global health concern. Lancet. 2020;395(10223):470–3.
3. Kupferschmidt K, Wadman M. Delta variant triggers new phase in the pandemic. Science. 2021.
4. Atluri K, Aimlin I, Arora S. Current effective therapeutics in the management of COVID-19. J Clin Med. 2022;11(13):3838.
5. Guruprasad L. Human SARS-CoV-2 spike protein mutations. Proteins. 2021;89(5):569–76.
6. Chiba S, Halfmann PJ, Iida S, Hirata Y, Sato Y, Kuroda M, et al. Recombinant spike protein vaccines coupled with adjuvants that have different modes of action induce protective immunity against SARS-CoV-2. Vaccine. 2023;41(41):6025–35.
7. Buntinx E, Brochado L, Borja-Tabora C, Charles YY, Alberto ER, Montellano MEB, et al. Immunogenicity of an adjuvanted SARS-CoV-2 trimeric S-protein subunit vaccine in SARS-CoV-2-naïve and exposed individuals in a phase 2/3 double-blind randomized study. Vaccine. 2023;41(11):1875–84.
8. Ganesan S, Al Ketbi LMB, Al Kaabi N, Al Mansoori MM, Al Maskari NN, Al Shamsi MS, et al. Vaccine side effects following COVID-19 vaccination among residents of the United Arab Emirates: an observational study. Front Public Health. 2022;10:876336.
9. Das MK. Adverse events following immunization: the known unknowns and black box. Indian J Pediatr. 2023;90(8):817–25.
10. Food and Drug Administration. Finding and learning about side effects (adverse reactions). Silver Spring: US Food and Drug Administration; 2021.
11. Gliklich RE, Dreyer NA, Leavy MB. Adverse event detection, processing, and reporting. In: Registries for Evaluating Patient Outcomes: A User’s Guide. 3rd ed. Rockville: Agency for Healthcare Research and Quality; 2014.
12. Alves A, Metz A, Render J. Microscopic and ultrastructural pathology in medical devices. In: Boutrand JP, editor. Biocompatibility and Performance of Medical Devices. Cambridge: Woodhead Publishing; 2012. p. 457–99.
13. Yang J, Li B, Yang D, Wu J, Yang A, Wang W, et al. Immunogenicity of an alum plus CpG-adjuvanted SARS-CoV-2 inactivated vaccine in mice. Vaccine. 2023;41(41):6064–71.
14. Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart A, et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N Engl J Med. 2020;383(27):2603–15.
15. Lai CY, To A, Wong TAS, Lieberman MM, Clements DE, Senda JT, et al. Recombinant protein-subunit SARS-CoV-2 vaccines formulated with CoVaccine HT adjuvant induce broad, Th1-biased humoral and cellular immune responses in mice. Hum Vaccin Immunother. 2021;9:100126.
16. Falsey AR, Sobieszczyk ME, Hirsch I, Sproule S, Robb ML, Corey L, et al. Phase 3 safety and efficacy of AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine. N Engl J Med. 2021;385(25):2348–60.
17. Anderson EJ, Rouphael NG, Widge AT, Jackson LA, Roberts PC, Makhene M, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med. 2020;383(25):2427–38.
18. Al Kaabi N, Zhang Y, Xia S, Yang Y, Al Qahtani MM, Abdulrazzaq N, et al. Effect of two inactivated SARS-CoV-2 vaccines on symptomatic COVID-19 infection in adults: a randomized clinical trial. JAMA. 2021;326(1):35–45.
19. Akahata W, Sekida T, Nogimori T, Ode H, Tamura T, Kono K, et al. Safety and immunogenicity of a SARS-CoV-2 self-amplifying RNA vaccine expressing an anchored receptor-binding domain: a randomized observer-blind phase 1 study. 2023;4(8).
20. Walz J, Heitmann J, Bilich T, Tandler C, Nelde A, Maringer Y, et al. Phase I trial of a multi-peptide COVID-19 vaccine for the induction of SARS-CoV-2 T-cell immunity. 2021.
21. Heitmann JS, Bilich T, Tandler C, Nelde A, Maringer Y, Marconato M, et al. A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T-cell immunity. Nature. 2022;601(7894):617–22.
22. To A. Insect cell-expressed recombinant viral glycoproteins are effective immunogens [dissertation]. Honolulu: University of Hawai‘i at Mānoa; 2020.
23. Jugler C, Sun H, Nguyen K, Palt R, Felder M, Steinkellner H, et al. A novel plant-made monoclonal antibody enhances the synergistic potency of an antibody cocktail against the SARS-CoV-2 Omicron variant. Plant Biotechnol J. 2023;21(3):549–59.
24. Phoolcharoen W, Shanmugaraj B, Khorattanakulchai N, Sunyakumthorn P, Pichyangkul S, Taepavarapruk P, et al. Preclinical evaluation of the immunogenicity, efficacy, and safety of a recombinant plant-based SARS-CoV-2 receptor-binding-domain vaccine formulated with 3M-052-alum adjuvant. Vaccine. 2023;41(17):2781–92.
25. Gary EN, Tursi NJ, Warner B, Parzych EM, Ali AR, Frase D, et al. A mucosal chemokine adjuvant enhances synthetic DNA vaccine-mediated responses to SARS-CoV-2 and provides heterologous protection in vivo. Cell Rep Med. 2022;3(7):100693.
26. Lee KS, Rader NA, Miller-Stump OA, Cooper M, Wong TY, Amin MS, et al. Intranasal VLP-RBD vaccine adjuvanted with BECC470 confers immunity against Delta SARS-CoV-2 challenge in K18-hACE2 mice. Vaccine. 2023;41(34):5003–17.
27. Wang S, Cui H, Zhang C, Li W, Wang W, He W, et al. Oral delivery of a chitosan-adjuvanted COVID-19 vaccine provides long-lasting and broad-spectrum protection against SARS-CoV-2 variants of concern in golden hamsters. Int J Biol Macromol. 2023;220:105765.
28. Gupta T, Gupta SK. Potential adjuvants for the development of a SARS-CoV-2 vaccine based on experimental results from similar coronaviruses. Int Immunopharmacol. 2020;86:106717.
29. Dayan GH, Rouphael N, Walsh SR, Chen A, Grunenberg N, Allen M, et al. Efficacy of a bivalent D614 plus B.1.351 SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3 parallel randomized modified double-blind placebo-controlled trial. Lancet Respir Med. 2023;11(11):975–90.
30. Javadi MM, Hosseinzadeh MT, Soleimani N, Rommasi F. Evaluating the immunogenicity of gold nanoparticles conjugated to the receptor-binding domain with Freund’s adjuvant as a potential vaccine against SARS-CoV-2. Mol Pharm. 2022;170:105687.
31. Mohraz M, Vahdat K, Ghamari SH, Abbasi-Kangevari M, Ghasemi E, Ghabdian Y, et al. Efficacy and safety of an inactivated virus-particle vaccine for SARS-CoV-2, BIV1-CovIran: a randomized placebo-controlled double-blind multicentre phase 3 clinical trial. BMJ. 2023;382.
32. Tanriover MD, Doğanay HL, Akova M, Güner HR, Azap A, Akhan S, et al. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine: interim results of a double-blind randomized placebo-controlled phase 3 trial in Turkey. Lancet. 2021;398(10296):213–22.
33. Ella R, Reddy S, Blackwelder W, Potdar V, Yadav P, Sarangi V, et al. Efficacy, safety, and lot-to-lot immunogenicity of an inactivated SARS-CoV-2 vaccine: interim results of a randomized double-blind controlled phase 3 trial. Lancet. 2021;398(10317):2173–84.