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Beyond tradition: An analysis of modern vaccine technologies

Persistent global health threats posed by both established and emerging viral pathogens — influenza, HIV, tuberculosis, and more recently, SARS-CoV-2, to name only a few — necessitate and drive the continuous evolution of vaccine innovation and development. Traditional approaches to vaccine development and production have relied on inactivating or attenuating whole viral pathogens and presenting these to the human immune system to train and strengthen (through booster injections) a protective immune response. In some cases, this is accomplished using particularly antigenic protein subunits isolated from the pathogen.

These traditional vaccine approaches are effective for many viral diseases and have had historically significant impacts on human health, as exemplified by the eradication of smallpox. They also face several limitations in terms of speed, adaptability, safety profile and the ability to elicit broad, durable protection against the increasing variety of viral pathogens affecting the world today. These limitations are felt most acutely as new infectious threats emerge and global and regional health organisations struggle to respond at speed and scale. This has spurred recent significant innovation in vaccine technologies and leading to the crucial development of innovative non-viral platforms that offer greater flexibility, speed, and precision in vaccine design and production.

Here we explore some of the more promising non-viral vaccine development platforms, detailing their mechanisms, advantages, and limitations.

mRNA Vaccines

To elicit a protective immune response, mRNA vaccines deliver exogenous mRNA, leveraging the host cell's protein synthesis machinery to produce antigens encoded by the mRNA strand. mRNA-based vaccines have been a significant breakthrough for vaccine delivery and response to emerging pathogens due to their rapid development capability. The mRNA-based vaccines have demonstrated exceptional efficacy for multiple infectious diseases.

Their production is highly scalable, and they can be quickly modified for emerging pathogen variants or novel pathogens. As well, mRNA vaccines pose no risk of chromosomal integration or prolonged expression, which can be potential drawbacks of DNA-based vaccines. Their cell-free production system minimises the risk of bacterial contamination, adding an additional layer of reliability to their production process.

Unfortunately, the inherent instability of mRNA, compared to DNA, has been a challenge in adapting it to vaccines. However, efforts to overcome this are underway, with a focus on improving mRNA purity, incorporating specific genetic sequences (Kozak, cap, poly-A), and modifying nucleosides to enhance stability and immunogenicity. Encapsulation in exosomes and the use of RNA-transfected dendritic cells are also being investigated.

mRNA vaccines typically require strict -60-80°C cold chain storage, posing significant logistical hurdles in distribution, especially for underserved regions lacking adequate infrastructure. While promising, human testing has been less extensive, resulting in a lack of established regulatory guidelines specifically for this class of vaccines, although this has been improving. mRNA vaccines may also induce relatively short-lasting immunogenicity compared to other platforms, potentially requiring more frequent boosting. This last challenge can be highly variable depending on age and health status of patients.

DNA-based Vaccines

DNA-based vaccines deliver circularised plasmid DNA encoding antigens, which, like mRNA-based vaccines, are then produced by the host's own cells to elicit an immune response. They are relatively stable at higher temperatures and pose no risk of causing disease. DNA-based vaccines are cost-effective and can be produced through straightforward manufacturing processes. Next-generation advancements in DNA sequencing have significantly shortened development timelines, exemplified by the rapid development of the Zika vaccine.

Challenges remain for eliciting strong and durable immune responses. DNA-based vaccines have demonstrated limited immunogenicity in human and even some animal models, primarily triggering cell-mediated responses due to lower antigen-presenting cell (APC) populations in muscles. While the occurrence is extremely rare, theoretical concerns about occasional random chromosomal integration and incorporation of unwanted bacterial DNA elements into the host genome do exist, which have led to the development of regulatory guidelines to address the possibility. 

Antigen expression from DNA-based vaccines is often localised to the injection site and may explain limited systemic immune responses. Additionally, long-term safety and efficacy data are still limited. Techniques such as gene guns with gold nanoparticles, in vivo electroporation, codon optimisation, and incorporating proteins that specifically target APCs are being explored to boost immunogenicity and delivery of these promising modalities.

Delivery systems

Both DNA and mRNA require protective delivery systems to ensure they reach their cellular targets intact. mRNA, in particular, is highly susceptible to extracellular degradation in the blood stream. To this end, several delivery methods have been proven effective for the delivery of nucleic acid-based vaccine technologies, including viral vectors, virus-like particles and nanoparticles.

Viral Vector Vaccines

To elicit an immune response that is both robust and specifically targeted, vaccines must introduce some component of the target pathogen for the human immune system to respond to. Viral vector platforms accomplish this by using a non-pathogenic viral vector, modified to be harmless, as a carrier to deliver DNA encoding the antigen of the target pathogen into patient cells. Once there, the genetic material is transcribed into mRNA coding for a protein from the target pathogen that can prompt an immune response from the human host. The most well-known examples of this technology are the adenovirus-based vectors.

Viral vector vaccines are capable of eliciting a strong adaptive immune response without requiring additional adjuvants (substances in vaccine end-products that enhance the immune response) typically included in traditional vaccines. Once delivered, DNA in the cell is relatively stable and long-lasting, and can continue to elicit a durable and robust immune response with very little input. Viral vectors are extremely good at protecting and delivering this genetic material. Additionally, these vaccines are stable under standard refrigeration. In combination, these traits make for a very flexible and robust vaccine platform that is well suited to serving large patient populations without having to scale up bioproduction capacity to that typically needed for traditional vaccines. 

Viral vector vaccines have already demonstrated efficacy against various pathogens, including the Ebola vaccine (rVSV-ZEBOV) and the multi-species Rift Valley Fever vaccine (ChAdOx1 RVF). However, a potential danger exists where the weakened viral vector could revert to a virulent condition, particularly with replication-competent vectors. As well, vector selection can be difficult or prohibitive if there is already pre-existing immunity to the vector in the target population, which may interfere with vaccine efficacy. And, while production is well suited to large infectious disease vaccination efforts, it is also costly and time-consuming, hindering the possibility for rapid response to emerging threats.

Virus-like Particle Vaccines

Virus-like particles (VLPs) are multi-protein structures that mimic the overall structure of a virus but lack the viral genome, rendering them non-infectious and non-replicating. They are formed by the self-assembly of antigenic proteins or by chemically attaching peptides to pre-existing viral vector frameworks. Like viral vector vaccines, VLP-based vaccines elicit an immune response by delivering genetic material — in this case RNA — into immune cells. VLPs are typically engineered to be “decorated” with antigenic protein that can be presented and bound to human B cells. Once taken up by B cells, they deliver their RNA and elicit a durable antibody response. 

Because of this strong interaction with the B cell population, VLP-based vaccines are able to offer rapid, strong and durable immune responses with a high degree of specificity for target pathogens. They offer enhanced safety due to their inability to replicate, and are highly immunogenic, as their repetitive, organised presentation of antigenic epitopes triggers potent cellular and humoral immune responses. VLPs exhibit increased stability compared to many other vaccines, and have proven effective for various diseases, including HPV and Hepatitis B. They are currently under clinical investigation for influenza, malaria, and other pathogens.

Unfortunately, the manufacturing process can be very complex and expensive. In some cases, there is potential for serotype bias, as observed in dengue VLP vaccine development.

Nanoparticle Vaccines

Nanoparticle vaccines encapsulate or link protein antigens to nanoscale carriers — which can be polymeric, metal-based, or lipid-based — to trigger a host immune response. In general, nanoparticle vaccines offer several advantages over other platforms. They are simpler to produce, cost-effective, consistently repeatable, and have a high safety profile, because they do not require multiple protein components. They are highly engineered, conferring a large degree of specificity, making them ideal for targeting immune cells.

Nanoparticles enhance antigen stability and delivery and can be administered via various routes, including intranasally or as aerosols. This, in particular, makes them very well-suited to rapid response programs, especially at wide regional scales. However, compared to VLPs, nanoparticles have a limited inherent ability to stimulate the innate immune response, which often necessitates the use of adjuvants to boost immunogenicity. This, and the highly engineered nature of their assembly processes, means manufacturing can be complex, and scalability can be a challenge.

Conclusion

The landscape of vaccine development is continuously evolving, driven by the persistent global health threats posed by both established and emerging pathogens. From traditional inactivated and live attenuated vaccines to the cutting-edge nucleic acid, VLP, and nanoparticle platforms, the industry has seen a significant diversification of technologies, each offering distinct advantages and facing unique challenges. While these innovations often introduce complexity in design and execution, their potential to accelerate the delivery of safe and effective vaccines, particularly during public health emergencies, is immense. The collaborative efforts exemplified by initiatives like FLUniversal — the European initiative pursuing a universal seasonal influenza vaccine — underscore the necessity of interdisciplinary partnerships to address global health needs and strengthen pandemic preparedness for the future. To this end, scientific advancements across vaccine platforms and methodologies have tremendous potential to strengthen the work of these partnerships and shape the trajectory of vaccinology for years to come.

References

  1. Renu P, Kala D, Rupak N, et al. Vaccine development: Current trends and technologies. Life Sciences. 2024;336:122331-122331. doi: https://doi.org/10.1016/j.lfs.2023.122331
  2. St John AL, Ooi EE. Evolving vaccine discovery and development pathways for emerging pathogens. EBioMedicine. 2024;109:105445-105445. doi: https://doi.org/10.1016/j.ebiom.2024.105445
  3. Cnossen VM, Moreira PCL, Engelhardt OG, et al. Development of an intranasal, universal influenza vaccine in an EU-funded public-private partnership: the FLUniversal consortium. Frontiers in Immunology. 2025;16. doi: https://doi.org/10.3389/fimmu.2025.1568778

 

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