Tackling Safety Issues Of Adjuvanted Vaccines

By Tim Sandle, Ph.D.

Late in 2022, the FDA authorized a new vaccine including an adjuvant, available under emergency use authorization to prevent COVID-19 in individuals 12 years of age and older.¹ The important word is “adjuvant,” the use of which is sometimes open to misinterpretation, especially with traditional adjuvants made from aluminum salts.

An adjuvant is a substance added to some vaccines to enhance (stimulate) the immune response of vaccinated individuals. Adjuvants are included in vaccines to improve the immune response and to reduce the number of doses required to achieve a protective effect. By slowing down release of vaccine components, they may also incidentally reduce the reactogenicity of some formulations. An example of the types of vaccines containing adjuvants are some of the vaccines used against influenza. Incorporation of the adjuvant reduces the amount of influenza protein per dose of vaccine that would be otherwise required to elicit the desired immune response. By lowering the quantity of influenza protein per dose, this helps to increase the total number of doses of a vaccine that can be available. Some adjuvants also increase the stability of the antigen component.²

Rigorous safety assessments and clinical research of adjuvants are required. This article looks at the role adjuvants play in vaccines and considers the requirements for safety assessment and approval, as well as the advancements with nanotechnologies and molecular biology that have pushed the use of new adjuvant components forward.

The Slow But Emerging Use Of Adjuvants

While numerous substances have been shown to exert adjuvant activity, only a few have received regulatory approval for use in vaccines. From the 1920s to the 1990s, only insoluble aluminum salts were approved, and it remains true today that by far the most widely used adjuvants are aluminum hydroxide (hydrated aluminum oxide) and aluminum phosphate gel. Sometimes these are combined in a single formulation.

Latterly, more adjuvant candidates have emerged. An example of a relatively safe adjuvant is a virosome. The FDA has approved several virosomes as nanocarriers for human use based on their relatively high tolerance and safety profile. Virosomes are non-replicating “artificial viruses” (liposomes) that can aid the delivery of vaccine antigens directly into the host cell.⁵³Calcium phosphate gel is also used in human vaccines. Other types of adjuvants are oil-in-water emulsions, including squalene (which is manufactured in the liver and circulates in the bloodstream), and the stabilizer polysorbate 80 and compounds like cytosine phosphoguanosine (CpG) 1018.

A wider regulatory control and quality assurance of immunological products have expanded the range of adjuvants, including mineral oil emulsions, saponin, Quillaia glycoside complexes (immune stimulating complexes, or ISCOMs), block polymers. In addition, muramyl peptides have been used in veterinary vaccines.

When developing a new adjuvant, regulatory approval is not given for the chemicals that create the adjuvant as a separate formulation. Instead, when evaluating a vaccine for safety and efficacy, FDA considers adjuvants as a component of the vaccine (that is, they are not licensed separately). This has probably slowed the introduction of new types of preparations into large-scale use.

Selecting The Appropriate Adjuvant

For vaccine developers, selecting the appropriate adjuvant is important. Where an existing adjuvant can be used, the process of gaining approval is relatively straightforward. For example, while aluminum in certain vaccines may appear strange to the general reader, aluminum adjuvant-containing vaccines have established safety profiles and they are only atypically associated with severe local reactions.⁴ The medical consensus has long been that the benefits of aluminum-containing vaccines outweigh any theoretical concerns. The use of well-tried adjuvants such as aluminum salts is unlikely to meet with opposition from regulatory authorities provided it is supported by the preclinical and Phase 1 clinical trial data.⁵

For novel adjuvants, a series of criteria need to be met and there is a related challenge in that the way adjuvants work, even the established alum ones, is not fully understood. The criteria required by regulators includes specific safety requirements, such as the avoidance of excessive activation of the innate immune system response as this leads to local and systemic toxicities, including fever. A second criterion relates to improved potency and efficacy, including eliciting a more targeted immune response. For these reasons, rigorous preclinical and clinical research into adjuvant development is essential.

Assessing Safety Issues

Many adjuvants reach the preclinical phase, but they are not progressed further due to tolerability concerns or uncertainty as to their longer-term effects on the human body.

You will need a thorough understanding of the effects of adjuvants on the immune response and related mechanisms. This requires you to take into account the current scientific data available on the pharmacokinetics of vaccine adjuvants. This includes understanding the pharmacological properties of the adjuvant in combination with the remainder of the vaccine formulation.

Other forms of safety profiling include understanding the half-life of the adjuvant as a means of determining the likelihood of any residual activity. To minimize safety concerns, a short half-life is preferable, although this limits the use of some materials where depot formulations are required (as with slow-release medications).

Following an assessment of literature, the next safety evaluation step requires animal studies to help establish the safety profile. However, no single experimental animal can fully address the immunological aspects of adjuvant safety (such as tolerance effects, hypersensitivity, and generation of autoimmunity).⁶ Furthermore, while a number of adjuvants have demonstrated significant immunogenicity and efficacy in animal models, many have yet to be proven to be safe and effective in humans.⁷ For adjuvants that pass this measure, additional information needs to be drawn from clinical trials, where both the short-term and long-term safety can be evaluated. These include randomized double-blind Phase 3 trials run over a sufficiently long period of time to establish the safety profile.

Vaccines are required to be sterile. Since the sterilization of some types of adjuvant is problematic, this poses process validation and safety and efficacy problems. Unless essential to the formulation, such adjuvants that cannot be demonstrably sterilized are best avoided by vaccine manufacturers.⁸

Following approval, a new adjuvant, once combined with a vaccine, needs to be continually assessed, including field reports relating to the surveillance of any adverse immunological events. This review will need to consider, in particular, any rare and unusual adverse reactions not detected in animal studies. To do so effectively requires the establishment of clear case definitions.

Advancing Adjuvant Technology

Although adjuvant technology has progressed haphazardly, recent advancements with nanotechnologies are leading to new and promising adjuvant candidates. The advantages of nanomaterials relate to their defined compositions and commonly modular construction, which enable more accurate targeting of key immune pathways. Metallic nanoparticles are among the most promising nanoparticles under development as vaccine adjuvants, with iron in particular showing an improved immune response against pathogens.⁹

A different direction is in the form of emulsions, which are favored where distinct immunological responses are required. Advances in emulsions are focused on improving the adjuvant effect while ensuring acceptable tolerability. More success has been achieved with squalene-based adjuvants than with other water-oil combinations. Because squalene has traditionally been animal derived, synthetic biology techniques are being investigated to create non-animal sourced alternatives.¹⁰ Across the adjuvant range, the future iterations are likely to be based on synthetic or biosynthetic materials.

Other promising development paths include microcrystalline plant-based polysaccharide particles; bacterial protein flagellin; and attenuated viral vectors. These examples signal that additional adjuvants will most likely soon emerge and these will reach approval in licensed products, heralding a generation of safer and more effective vaccines.

References

1. FDA. Novavax COVID-19 Vaccine, Adjuvanted, November 2022: https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/novavax-covid-19-vaccine-adjuvanted
2. Apostólico, J.S., Lunardelli, V.A., Coirada, F.C., Boscardin, S.B., Rosa, D.S. Adjuvants: Classification, Modus Operandi, and Licensing. J. Immunol. Res. 2016, 2016, 1459394
3. Liu, Hanqing; Tu, Zhigang; Feng, Fan; Shi, Haifeng; Chen, Keping; Xu, Ximing Virosome, a hybrid vehicle for efficient and safe drug delivery and its emerging application in cancer treatment". Acta Pharmaceutica. 2015; 65 (2): 105–116
4. Keith. LS, Jones DE, Chou CH. Aluminum toxicokinetics regarding infant diet and vaccinations. Vaccine 2002;20(Sppl. 3):513-7
5. Cortez, A. et al. Incorporation of phosphonate into benzonaphthyridine Toll-like receptor 7 agonists for adsorption to aluminum hydroxide. J. Med. Chem. 59, 5868–5878 (2016)
6. Gonzalez-Lopez, A. et al. Adjuvant effect of TLR7 agonist adsorbed on aluminum hydroxide (AS37): a phase I randomized, dose escalation study of an AS37-adjuvanted meningococcal C conjugated vaccine. Clin. Immunol. 209, 108275 (2019)
7. Pulendran, B. and Davis, M. M. The science and medicine of human immunology. Science 369, eaay4014 (2020).
8. Sesardic D, Dobbelaer R. Review. European Union regulatory developments for new vaccine adjuvants and delivery systems. Vaccine 2004; 22: 2452–2456
9. Behzadi M, Vakili B, Ebrahiminezhad A, Nezafat N. Iron nanoparticles as novel vaccine adjuvants. Eur J Pharm Sci. 2021 1;159:105718. doi: 10.1016/j.ejps.2021.105718
10. O’Hagan, D.T., van der Most, R., Lodaya, R.N. et al. “World in motion” – emulsion adjuvants rising to meet the pandemic challenges. npj Vaccines 6, 158 (2021)

About The Author:

Tim Sandle, Ph.D., is a pharmaceutical professional with wide experience in microbiology and quality assurance. He is the author of more than 30 books relating to pharmaceuticals, healthcare, and life sciences, as well as over 170 peer-reviewed papers and some 500 technical articles. Sandle has presented at over 200 events and he currently works at Bio Products Laboratory Ltd. (BPL), and he is a visiting professor at the University of Manchester and University College London, as well as a consultant to the pharmaceutical industry. Visit his microbiology website at https://www.pharmamicroresources.com.