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A single dose, BCG-adjuvanted SARS-CoV-2 vaccine induces Th1-polarized immunity and high-titre neutralizing antibodies in mice

Claudio Counoupas, Alberto O. Stella, Nayan D. Bhattacharyya, Alice Grey, Karishma Patel, Angela L. Ferguson, Owen Hutchings, Carl G. Feng, Palendira, Megan Steain, Anupriya Aggarwal, Jason K. K. Low, Joel P. Mackay, Anthony D. Kelleher, Warwick J. Britton, Stuart G Turville, James A. Triccas
doi: https://doi.org/10.1101/2020.12.10.419044
Claudio Counoupas
1School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
2Tuberculosis Research Program, Centenary Institute, Sydney, NSW, Australia
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Alberto O. Stella
3Kirby Institute, University of New South Wales, Sydney, NSW, Australia
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Nayan D. Bhattacharyya
1School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
2Tuberculosis Research Program, Centenary Institute, Sydney, NSW, Australia
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Alice Grey
4Department of Clinical Immunology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
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Karishma Patel
5School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006
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Angela L. Ferguson
1School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
2Tuberculosis Research Program, Centenary Institute, Sydney, NSW, Australia
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Owen Hutchings
6RPA Virtual Hospital, Sydney Local Health District, Sydney, NSW, Australia
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Carl G. Feng
1School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
2Tuberculosis Research Program, Centenary Institute, Sydney, NSW, Australia
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Palendira
1School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
2Tuberculosis Research Program, Centenary Institute, Sydney, NSW, Australia
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Megan Steain
1School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
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Anupriya Aggarwal
3Kirby Institute, University of New South Wales, Sydney, NSW, Australia
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Jason K. K. Low
5School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006
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Joel P. Mackay
5School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006
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Anthony D. Kelleher
3Kirby Institute, University of New South Wales, Sydney, NSW, Australia
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Warwick J. Britton
2Tuberculosis Research Program, Centenary Institute, Sydney, NSW, Australia
4Department of Clinical Immunology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
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Stuart G Turville
3Kirby Institute, University of New South Wales, Sydney, NSW, Australia
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James A. Triccas
1School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
7Marie Bashir Institute for Infectious Diseases and Biosecurity, The University of Sydney, Sydney, NSW, Australia
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  • For correspondence: jamie.triccas@sydney.edu.au
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Abstract

Next-generation vaccines that are safe, effective and with equitable access globally are required to prevent SARS-CoV-2 transmission at a population level. One strategy that has gained significant interest is to ‘repurpose’ existing licensed vaccines for use against COVID-19. In this report, we have exploited the immunostimulatory properties of bacille Calmette-Guérin (BCG), the vaccine for tuberculosis, to develop a SARS-CoV-2-specific and highly immunogenic vaccine candidate. Combination of BCG with a stabilized, trimeric form of the SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the sera of vaccinated mice, which could be further augmented by the addition of alum. This vaccine formulation, termed BCG:CoVac, induced a Th1-biased response both in terms of IgG antibody subclass and cytokine release by vaccine-specific CD4+ and CD8+ T cells. A single dose of BCG:CoVac was sufficient to induce high-titre SARS-CoV-2 neutralizing antibodies (NAbs) that were detectable as early as 2 weeks post-vaccination; NAb levels were greater than that seen in the sera of SARS-CoV-2-infected individuals. Boosting of BCG:CoVac-primed mice with a heterologous vaccine combination (spike protein plus alum) could further increase SARS-CoV-2 spike protein-specific antibody response. BCG:CoVac would be broadly applicable for all populations susceptible to SARS-CoV-2 infection and in particular could be readily incorporated into current vaccine schedules in countries where BCG is currently used.

Importance Effective distribution of vaccine to low- and middle-income countries is critical for the control of the COVID-19 pandemic. To achieve this, vaccines must offer effective protective immunity yet should be cheap to manufacture and meet cold chain management requirements. This study describes a unique COVID-19 vaccine candidate, termed BCG:CoVac, that when delivered as a single dose induces potent SARS-CoV-2 specific immunity in mice, particularly through generation of high-titre, anti-viral neutralising antibodies. BCG:CoVac is built on safe and well-characterised vaccine components: 1) the BCG vaccine, used for control of tuberculosis since 1921 which also has remarkable ‘off target’ effects, protecting children and the elderly against diverse respiratory viral infections; 2) Alhydrogel adjuvant (Alum), a low cost, globally accessible vaccine adjuvant with an excellent safety record in humans (part of >20 licensed human vaccines and in use >70 years); 3) Stabilized, trimeric SARS-CoV-2 spike protein, which stimulates immune specificity for COVID-19. Further assessment in humans will determine if BCG:CoVac can impart protective immunity against not only SARS-CoV-2, but also other respiratory infections where BCG has known efficacy.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 10, 2020.
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A single dose, BCG-adjuvanted SARS-CoV-2 vaccine induces Th1-polarized immunity and high-titre neutralizing antibodies in mice
Claudio Counoupas, Alberto O. Stella, Nayan D. Bhattacharyya, Alice Grey, Karishma Patel, Angela L. Ferguson, Owen Hutchings, Carl G. Feng, Palendira, Megan Steain, Anupriya Aggarwal, Jason K. K. Low, Joel P. Mackay, Anthony D. Kelleher, Warwick J. Britton, Stuart G Turville, James A. Triccas
bioRxiv 2020.12.10.419044; doi: https://doi.org/10.1101/2020.12.10.419044
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A single dose, BCG-adjuvanted SARS-CoV-2 vaccine induces Th1-polarized immunity and high-titre neutralizing antibodies in mice
Claudio Counoupas, Alberto O. Stella, Nayan D. Bhattacharyya, Alice Grey, Karishma Patel, Angela L. Ferguson, Owen Hutchings, Carl G. Feng, Palendira, Megan Steain, Anupriya Aggarwal, Jason K. K. Low, Joel P. Mackay, Anthony D. Kelleher, Warwick J. Britton, Stuart G Turville, James A. Triccas
bioRxiv 2020.12.10.419044; doi: https://doi.org/10.1101/2020.12.10.419044

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