Increasing Vaccine Efficacy with Novel Adjuvants

In the twentieth century, the development and delivery of vaccines as part of large, systematic immunization programs helped to address many health inequities. However, safety concerns due to reactogenic side effects resulting from the use of older whole-organism vaccines led vaccine developers to use only parts of the microorganism—subunits or purified antigen—which reduced vaccine efficacy (i.e., immunogenicity).¹ It is critical for new vaccines to both improve immunogenicity and decrease reactogenicity, which is why so many modern vaccines based on purified antigens also contain an adjuvant or adjuvant combination.

A brief history of adjuvants

Derived from the Latin adjuvare (to help or aid), adjuvants enhance antigen-specific vaccine immunogenicity. Added only when needed,² modern adjuvants are essential to antigen or dose sparing, broadening immunity to variable antigens, and enhancing responses from vulnerable populations with weak immune responses.³

Vaccine developers have relied on adjuvants for over 90 years, since the serendipitous discovery of the immune-enhancing effects of aluminum salts.⁴ For most of the twentieth century, aluminum was the only adjuvant included in licensed vaccines. Today, modern adjuvants are designed to overcome twenty-first century vaccine challenges. Emerging trends have shaped adjuvant development toward a combination of immunostimulants and delivery systems.² With the introduction of new molecules, adjuvant formulation now focuses on micro- and nanoparticulate platforms,³ including nano-alum; emulsion or Pickering emulsion; liposomes; and combination adjuvants such as ISCOMS, AS04, and PLG.

Recent advances in adjuvant research and development, accelerated by the global pandemic response, have deepened our understanding of the mechanisms of action, safety, and associated risks and benefits of adjuvants. This progress presents an exciting opportunity to realize the full potential of adjuvanted vaccines.

Choosing an adjuvant

Adjuvants target innate immune cells and activate signaling pathways to guide and enhance immune responses.² Nonadjuvanted subunit vaccines typically induce modest T-helper polarizing cytokines, T-cell activation, and antibody production. In contrast, adjuvanted vaccines demonstrate enhanced quality and quantity of antigen-presenting cell maturation and co-stimulation, T-helper polarizing cytokine production, polyfunctional T cells, and antibody production.^2,5

The U.S. Food and Drug Administration has approved six adjuvants for use in human vaccines: aluminum, MF59, AS04, AS03, AS01, and CpG ODN (Table 1). Selecting the right adjuvant can elicit an immune response tailored to specific pathogens. For example, MF59 promotes antigen uptake and migration of cells to lymph nodes, whereas AS03 promotes local production of cytokines and recruitment of innate cells. Depending on the required immune response, developers can select adjuvants to stimulate optimal immunological pathways and maximize immunogenicity.

It is worth noting that combination adjuvants can be a powerful and economical approach. When MF59 was combined with CpG ODN in an influenza antigen formulation, a shift toward a more Th1-biased response was observed, suggesting that this combination might tailor the immune response to stimulate B cells to produce immunoglobulin M. Such insights are important for vaccine developers.⁶

Picking the correct adjuvant can provide remarkable vaccination outcomes. For example, HEPLISAV-B, a hepatitis B vaccine, contains a CpG ODN adjuvant. In comparison with three doses of a conventional aluminum-adjuvanted hepatitis B vaccine, two doses of HEPLISAV-B induce superior immunogenicity.

Arexvy (GSK) and Abrysvo (Pfizer) provide an additional example. Both products are respiratory syncytial virus (RSV) vaccines licensed in the United States. Although the results of separate clinical trial programs cannot be conclusively compared, certain observations raise interesting questions. In their respective clinical trial programs, Arexvy and Abrysvo demonstrated similar efficacy rates of 82.6% versus 88.9% during the first RSV season and 74.5% versus 84.4% over two seasons (22 months versus 17 months).⁷ Both vaccines contained 120 μg of antigen(s) in a 0.5 mL volume, albeit in different forms and buffers. A striking difference is that Arexvy used AS01 whereas Abrysvo contained no adjuvant.

In addition to assessing the necessity of the AS01 adjuvant, exploring the efficacy outcomes between these formulations provides valuable insights. It would be interesting to conduct an additional trial with a reformulated Abrysvo vaccine that includes an adjuvant, the result of which could clarify the impact of adjuvants on the efficacy and safety of RSV vaccines.

In essence, selecting the appropriate adjuvant for a new vaccine requires balancing safety, efficacy, and business considerations. To maximize effectiveness, vaccine developers can prioritize adjuvants based on their ability to elicit an optimal immune response. Developers can consider rigorous side-by-side comparisons instead of relying solely on factors such as an adjuvant’s developmental stage or previous use in similar vaccines.

Managing reactogenicity

By counteracting the poor immunogenicity of pure antigens, adjuvants can lead to an increase in local reactions at the injection site or general symptoms such as fatigue and fever. The properties of these products that lead to stronger immunogenicity can also lead to the development of characteristic adverse events.

For example, although both the aforementioned RSV vaccines have similar efficacies, the 3.8% frequency of severe reactogenicity events in Arexvy trials was nearly four times higher than the 1% frequency demonstrated in Abrysvo trials. Despite the role AS01 might have played in this disparity, it is undeniable that any development program aims to create novel adjuvanted vaccines that should not only be immunogenic but also well tolerated,^1,5 particularly for children, the elderly, pregnant women, and other populations with impaired immune systems.

Recent developments in chemistry and formulation science offer promising solutions for mitigating adjuvant-related systemic reactogenicity. For example, small-molecule adjuvants that enter the systemic circulation can trigger cytokine production, thereby heightening reactogenicity. Lipidation of these small-molecule adjuvants represents a strategy to diminish systemic reactogenicity while preserving immunogenicity.

New solutions to modern challenges

Because modern adjuvants have evolved rapidly over the past decade, expertise in the area is new, and may even be considered niche. An interesting part of WuXi Vaccines’ work has been merging aluminum, squalene, QS-21, and CpG experience with development and manufacturing experience, such as the ability to control key process parameters to ensure adjuvant stability.⁸ For example, this work has led to the development of “stable SLA (synthetic lipid adjuvant) emulsions  in the presense of antigens,” and the development of an antigen co-formulated with with aluminum, and the development of an antigen co-formulated with multiple adjuvants.WuXi Vaccines’ expertise enabled the rapid, successful scale-up of commercial COVID-19 vaccine production, the production of prefilled syringes containing a hexavalent vaccine with aluminum, and the production of co-adjuvant vaccines with multiple adjuvants.

Beyond process challenges, developing analytical methods that separate complex compositions of multiple adjuvants or multivalent antigens is crucial and complex. WuXi Vaccines has leveraged its expertise to develop quantitative methods and implement robust quality control strategies that successfully address these issues.

This level of expertise enables solutions to a variety of challenges facing today’s vaccine developers (Table 2). For example, development of a next-generation shingles (herpes zoster) vaccine faced challenges with molecule design, vaccine stability, and adjuvant choice—challenges of the kind that a capable contract research, development, and manufacturing organization can overcome by applying the appropriate technologies. High-throughput engineering platforms can enable structure-based vaccine discovery, cell line development platforms can address low titers and poor stability, and analytics platforms can support process robustness and quality assurance. Finally, experience, screening capabilities, and knowledge in the selection of optimal adjuvants are vital for supporting vaccine development and manufacturing.

For vaccine developers, depth and breadth of knowledge translates to help in accessing diverse adjuvants, evaluating adjuvant-antigen co-vial formulation developability, and advancing mucosal vaccine delivery, ultimately leading to novel vaccines with optimal structural and functional properties, implementation of upscaling capability, and efficient manufacturing.

Concluding points

Modern adjuvants are powerful tools for enhancing the magnitude and quality of an immune response. Their effects can result in broad and durable immunity, as well as dose and antigen sparing. In turn, this can reduce the quantity of costly antigens needed to achieve sufficient protection, reduce the need for clinic visits, and increase the effective vaccination rate for herd immunity.

As we prepare ourselves for the next pandemic, vaccine design has never been more important. Modern adjuvants are already playing an important role in the fight against human pathogens and are poised to reanimate previously “failed” vaccines that showed low efficacy due to poor formulation and a lack of adjuvant.

Over the past decade, vaccine developers have revolutionized adjuvant technology. A greater understanding of the role of adjuvants has yielded products that can tailor immunological responses to challenging pathogens and prolong the duration of immune memory and protection. Not all vaccines require adjuvants, but for those that do, the expertise now exists to ensure optimal vaccine design and the best possible outcomes.

References

1. Castrodeza-Sanz J, Sanz-Muñoz I, Eiros JM. Adjuvants for COVID-19 Vaccines. Vaccines (Basel) 2023; 11(5): 902.
2. Zhao T, Cai Y, Jiang Y, et al. Vaccine adjuvants: Mechanisms and platforms. Signal Transduct. Target. Ther. 2023; 8(1): 283.
3. Reed SG, Orr MT, Fox CB. Key roles of adjuvants in modern vaccines. Nat. Med. 2013; 19(12): 1597–1608.
4. Di Pasquale A, Preiss S, Tavares Da Silva F, Garçon N. Vaccine Adjuvants: From 1920 to 2015 and Beyond. Vaccines (Basel) 2015; 3(2): 320–343.
5. Nanishi E, Dowling DJ, Levy O. Toward precision adjuvants: Optimizing science and safety. Curr. Opin. Pediatr. 2020; 32(1): 125–138.
6. Baudner BC, Ronconi V, Casini D, et al. MF59 emulsion is an effective delivery system for a synthetic TLR4 agonist (E6020). Pharm. Res. 2009; 26(6): 1477–1485.
7. Melgar M, Britton A, Roper LE, et al. Use of respiratory syncytial virus vaccines in older adults: Recommendations of the Advisory Committee on Immunization Practices—United States, 2023. MMWR Morb. Mortal. Wkly. Rep. 2023; 72: 793–801.
8. Yang Y, Su D, Yao X, et al. Key Process Parameters Study for the Fill Finish of Vaccines Containing Aluminum Hydroxide Adjuvant. J. Pharm. Sci. 2024; 113(6): 1478–1487.

Xinhao Ye, PhD, is director of chemistry, manufacturing, and control at WuXi Vaccines, and Hongbing Wu is director of drug product development at WuXi Biologics.