Drug Discovery and Development

Advances in next generation vaccine development for SARS-CoV-2

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Novel coronovirus

Colorized scanning electron micrograph of a cell infected with the Omicron strain of SARS-CoV-2 virus particles (red). Image captured at the NIAID Integrated Research Facility in Fort Detrick, Maryland. Credit: NIAID, licensed under CC BY 2.0. / Wikimedia.

Typical COVID-19 vaccines present fragments of the SARS-CoV-2 spike protein to the body, enabling the immune system to recognize and develop a defense against the virus. However, emerging variants are increasingly evading this immune response due to mutations in their receptor-binding domain (RBD), threatening the effectiveness of existing vaccines.

This challenge has prompted research into a new vaccine that targets conserved regions of the RBD shared by all SARS-like betacoronaviruses. Recent advances in the development of a novel broad-spectrum vaccine – based on the mosaic-8b nanoparticle candidate – aim to provide cross-reactive immunity against both known and future sarbecovirus strains, significantly enhancing pandemic preparedness.

The call for a pan-sarbecovirus solution

The global fight against COVID-19 has highlighted the urgent need for effective vaccines to control the virus and protect public health. Since January 2020, over seven million deaths have occurred worldwide1 – a number that continues to rise daily – yet the advent of COVID-19 vaccines has reduced the risk of death by as much as 57 percent.2 However, SARS-CoV-2 is an RNA virus, meaning that it is able to mutate quickly,3 resulting in the emergence of new variants with high transmissibility. Mutating variants threaten to bypass the underlying immunology behind most current vaccines by expressing new antigenic epitopes that are not easily recognized by existing antibodies, so that the virus does not bind with the same affinity. For example, substitutions in the SARS-2 spike protein RBDs of the Omicron variant have reduced the efficacies of both vaccines and therapeutic monoclonal antibodies,4 leading to breakthrough infections in individuals regardless of their immunity to the initial virus.5 As a result, vaccines in circulation may not be effective at providing long-term protection against the virus due to ongoing viral evolution.6 Developing and distributing reliable vaccines that can induce neutralizing antibodies effective against emerging variants is crucial to maintaining immunity, preventing severe illness and safeguarding against future outbreaks.

Developing variant-specific boosters is one potential approach, however, manufacturing a vaccine – or simply updating an existing one – can take several months to years and requires significant financial investment. The severity of the COVID-19 pandemic meant that this process was efficiently expedited for the first initial vaccines, bolstered by £240 million in investment from the UK Government to scale up vaccine manufacturing.7 This fortunately meant that researchers were able to develop, validate and distribute a first dose in record time, but constantly updating boosters to keep pace with emerging viruses is costly and impractical. A better solution would be a universal vaccine that provides protection against both emerging sarbecoviruses and current SARS-CoV-2 variants, without the need for constant adjustments.

A promising protection against SARS-CoV-2

With this in mind, engineering biology CRDMO Ingenza has partnered with the California Institute of Technology (Caltech), the University of Oxford and the Centre for Process Innovation (CPI) to rapidly formulate a highly effective vaccine against known and future SARS-CoV-2 strains and variants. The principle behind the project – discovered by Prof Pamela J. Bjorkman and her group at Caltech – is to direct the immune response toward conserved parts of the RBD that are shared by viruses in the SARS-like betacoronavirus genus, particularly all sarbecoviruses. Ingenza led the transfer of vaccine candidate production from mammalian cells and E. coli to alternative microbial platforms – specifically Pichia pastoris and Bacillus subtilis – to reduce development time and costs, while establishing a scalable manufacturing process. The company harnessed its proprietary inGenius platform – designed to enhance the efficiency and predictability of bioprocess development – to create manufacturing microbial strains, scalable bioprocesses and the analytical methods required for in-process controls, release assays and drug substance characterization.

The resulting vaccine candidate includes RBDs from SARS-CoV-2 and seven other coronaviruses that form a so-called ‘mosaic-8b’ nanoparticle. These conserved regions should therefore be present and unchanged in both undiscovered sarbecoviruses and novel variants of SARS-CoV-2 that may emerge in the future. Research published in 2022 confirmed that these mosaic-8b nanoparticles elicit protective immune responses against SARS-like betacoronaviruses that match the components presented on the nanoparticles, as well as against other related viruses not represented in the mosaic-8b design.8 These include SARS-like betacoronaviruses found in animals, which have the potential to transfer to humans in the future.

Building on existing vaccine immunity

Further pre-clinical research demonstrated the mosaic-8b vaccine’s effectiveness in triggering an immune response following prior vaccination or exposure to SARS-CoV-2, a key factor given that a large portion of the population has likely encountered the virus by now.9 The mosaic-8b nanoparticles were able to produce both recall antibodies – boosted from previous immune responses – and broadly cross-reactive de novo antibodies targeting multiple sarbecoviruses, including those more distantly related to SARS-CoV-2. These antibodies showed greater ability to recognize various viral strains compared to the homotypic nanoparticles in the admixture. Notably, the antibodies generated by these nanoparticles also exhibited stronger binding and neutralizing activity than those induced by conventional homotypic SARS-CoV-2 vaccines.

Moreover, the trials offered valuable insights into the phenomenon of original antigenic sin (OAS), where the immune system tends to rely on memory cells from an initial exposure when faced with related antigens.9 This vaccine can address some of the challenges associated with OAS by generating new antibodies that target a range of sarbecovirus RBDs, rather than merely enhancing the production of existing antibodies specific to certain SARS-CoV-2 strains. Overall, these findings suggest that a single dose of this vaccine could trigger a more broadly protective immune response in individuals who are not immunologically naïve, compared to a single dose of a standard SARS-CoV-2 homotypic vaccine. This indicates that mosaic-8b could potentially offer wider and longer-lasting protection against a variety of evolving SARS-CoV-2 strains and other sarbecoviruses.

Conclusion

Although still in early development, the mosaic-8b vaccine shows promise as a broad and cross-reactive immunization strategy that could provide comprehensive protection against existing and emerging sarbecoviruses. This project also serves as a template for developing vaccines that are futureproofed against arising variants, reducing the need for frequent iterations and updates. With a multi-pronged defense system that is resilient to viral escape, we can enhance our protection against various viral strains, both now and in the future.

Author biography

Leonardo Magneschi, Ph.D. is Vice President of Research and Technology Development at Ingenza. He has more than 15 years of experience in microbiology and genetic engineering, with a PhD in Plant and Microbial Biotechnology, 17 published papers in peer-reviewed scientific journals, and inventorship on several international patents. He joined Ingenza in 2016, and has since been directly involved in a multitude of customer projects, with applications ranging from pharma and biofuels to renewable materials.

References

  1. World Health Organization. (2024). WHO covid dashboard. https://data.who.int/dashboards/covid19/deaths
  2. World Health Organization. (2024). COVID-19 vaccinations have saved more than 1.4 million lives in the WHO European Region, a new study finds. https://www.who.int/europe/news/item/16-01-2024-covid-19-vaccinations-have-saved-more-than-1.4-million-lives-in-the-who-european-region-a-new-study-finds
  3. Sanjuán, R., & Domingo-Calap, P. (2016). Mechanisms of viral mutation. Cellular and molecular life sciences: CMLS, 73(23), 4433-4448. https://doi.org/10.1007/s00018-016-2299-6
  4. Willett, B.J., Grove, J., MacLean, O.A. et al. (2022). SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway. Nature Microbiology, 7, 1161-1179. https://doi.org/10.1038/s41564-022-01143-7
  5. Bergwerk, M., Gonen, T., Lustig, Y., et al. (2021). COVID-19 Breakthrough Infections in Vaccinated Health Care Workers. The New England journal of medicine, 385(16), 1474-1484. https://doi.org/10.1056/NEJMoa2109072
  6. Beukenhorst, A. L., Koch, C. M., Hadjichrysanthou, C., et al. (2023). SARS-CoV-2 elicits non-sterilizing immunity and evades vaccine-induced immunity: implications for future vaccination strategies. European journal of epidemiology, 38(3), 237-242. https://doi.org/10.1007/s10654-023-00965-x
  7. UK Parliament. (2021). Manufacturing COVID-19 vaccines. https://post.parliament.uk/manufacturing-covid-19-vaccines/
  8. Cohen, A. A., van Doremalen, N., Greaney, A. J., et al. (2022). Mosaic RBD nanoparticles protect against challenge by diverse sarbecoviruses in animal models. Science, 377(6606), eabq0839.
  9. Cohen, A. A., Keeffe, J. R., Schiepers, A., et al. (2024). Mosaic sarbecovirus nanoparticles elicit cross-reactive responses in pre-vaccinated animals. Cell (published online ahead of print), 187, 1-18. https://doi.org/10.1016/j.cell.2024.07.052
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