Invited Abstract 9th Australasian Vaccines & Immunotherapeutics Development Meeting 2022

Developing a 'warm' vaccine to combat SARS-CoV-2 variants of concern and address inequity (#5)

S.S. Vasan 1 , Petrus Jansen van Vuren 1 , Alexander J. McAuley 1 , Michael J. Kuiper 2 , Nagendrakumar Singanallur 1 , Matthew P. Bruce 1 , Shane Riddell 1 , Sarah Goldie 1 , Shruthi Mangalaganesh 1 3 , Simran Chahal 1 , Trevor W. Drew 1 , Kim R. Blasdell 1 , Mary Tachedjian 1 , Leon Caly 4 , Julian D. Druce 4 , Shahbaz Ahmed 5 , Mohammad Khan 5 , Sameer Malladi 5 , Randhir Singh 6 , Suman Pandey 6 , Raghavan Varadarajan 5
  1. Australian Centre for Disease Preparedness, Commonwealth Scientific and Industrial Research Organisation, Geelong, VIC, Australia
  2. Data61, Commonwealth Scientific and Industrial Research Organisation, Docklands, VIC, Australia
  3. Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
  4. Victorian Infectious Diseases Reference Laboratory, The Royal Melbourne Hospital and The Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia
  5. Molecular Biophysics Unit, ndian Institute of Science, Bengaluru, India
  6. Society for Innovation and Development, Indian Institute of Science, Bengalura, India

Abstract: The world is facing COVID-19 vaccine inequity – with low-income countries having administered 13-fold fewer doses compared to upper middle income and high income countries – and existing vaccines even after two doses failing to completely prevent infections or community transmission [1]. We have an urgent unmet need for ‘warm’ vaccines that can better combat SARS-CoV-2 variants of concern (VOC) as well as overcome cold chain requirements.  We previously reported highly thermo-tolerant receptor-binding domain derivatives that can withstand 100°C for 90 minutes and 37°C for four weeks. These were formulated as trimers [2] or monomers [3], and were effective against Alpha, Beta and Gamma VOC [4]. In this study, we show that mice immunised with these vaccine formulations elicit high titres of antibodies that neutralise SARS-CoV-2 variants VIC31 (with Spike: D614G mutation), Delta, and Omicron (BA.1.1) VOC. Compared to VIC31, there was an average 14.4-fold reduction in neutralisation against BA.1.1 for the three monomeric antigen-adjuvant combinations and a 16.5-fold reduction for the three trimeric antigen-adjuvant combinations; the corresponding values against Delta were 2.5 and 3.0 [5]. These findings are consistent with  transmission electron microscopy, in silico modelling and AlphaFold2 predictions, which reveal two opposing effects. The first effect is that an oligomeric presentation is likely to induce higher titres of binding and neutralising antibodies, while the opposing effect is due to steric hindrance of important epitopes (containing important Omicron mutations) required for effective B-cell responses. It appears that the second effect dominates and contributes to this host’s (mice) response to the trimeric antigen formulations, which also carries the additional risk of eliciting irrelevant antibodies against the oligomerisation domain (that halted the progress of the University of Queensland’s candidate) [6]. Our findings suggest that monomeric formulations are suitable for upcoming Phase I human clinical trials and that there is potential for increasing the efficacy with vaccine matching to improve the responses against emerging variants [7]. For instance, the monomeric formulation which had 50% of antigens matched against Beta VOC only had a 10-fold reduction in neutralisation against Omicron compared to VIC31, while the other five formulations yielded an average fold decrease of 16.5 (range 11- to 22-fold). The thermostability of this vaccine and its ability to withstand transient heat shocks is particularly promising to address the vaccine inequity that affects most low- and lower middle-income countries [4,7].

 

Funding: This work was supported by funding (Principal Investigator: S.S.V.) from United States Food and Drug Administration Medical Countermeasures Initiative (75F40121C00144), Australia’s National Health and Medical Research Council (MRF2009092), and Department of Finance funding to the CSIRO. The article does not represent the views or policies of the funding agencies, including the FDA.

  1. Singanallur, N.B., Jansen van Vuren, P., McAuley, A.J., …, Vasan, S.S. (21 February 2022). At least three doses of leading vaccines essential for neutralisation of SARS-CoV-2 Omicron variant. Frontiers in Immunology, in press. doi: 10.3389/fimmu.2022.883612. Pre-print available at: https://www.medrxiv.org/content/10.1101/2022.02.20.22271237v3.full-text.
  2. Malladi, S.K., …, Vasan, S.S., Ringe, R.P., Varadarajan, R. (2021). Immunogenicity and protective efficacy of a highly thermotolerant, trimeric SARS-CoV-2 receptor binding domain derivative. ACS Infectious Diseases, 7(8): 2546-2564. doi: 10.1021/acsinfecdis.1c00276. Available at: https://pubs.acs.org/doi/10.1021/acsinfecdis.1c00276.
  3. Ahmed, S., …, Vasan, S.S., Ringe, R.P., Varadarajan, R. (2021). A stabilized, monomeric, receptor binding domain elicits high-titer neutralizing antibodies against all SARS-CoV-2 variants of concern. Frontiers in Immunology, 12: 765211. doi: 10.3389/fimmu.2021.765211. Available at: https://doi.org/10.3389/fimmu.2021.765211.
  4. Nature Research Highlight. (16 July 2021). 'Warm vaccine' shows immune response against SARS-CoV-2 variants. doi: 10.1038/d44151-021-00013-1. Available at: https://www.nature.com/articles/d44151-021-00013-1.
  5. Jansen van Vuren, P., McAuley, A.J., Kuiper, M.J., …, Vasan, S.S. (2022). Highly thermotolerant SARS-CoV-2 vaccine elicits neutralising antibodies against Delta and Omicron in mice. Viruses, 14(4): 800. doi: 10.3390/v14040800. Available at: https://www.mdpi.com/1999-4915/14/4/800.
  6. Chappell, K.J., et al. (2021). Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: A randomised, double-blind, placebo-controlled, phase I trial. Lancet Infectious Diseases. 21(10): 1383–1394. doi: 10.1016/S1473-3099(21)00200-0. Available at: https://doi.org/10.1016/S1473-3099(21)00200-0.
  7. Nature Research Highlight. (13 April 2022). Monomer vaccines fare better than trimers against SARS-CoV-2 variants. doi: 10.1038/ d44151-022-00040-6. Available at: https://www.nature.com/articles/d44151-022-00040-6