From Concept to Clinic Advancing TB mRNA Vaccine Development and Manufacturing in South Africa
From Concept to Clinic Advancing TB mRNA Vaccine Development and Manufacturing in South Africa
Dr Pia Steigler, Afrigen Biologics PTY Ltd, South Africa
Pia Steigler¹, Frances Lees¹, Kerisha Batohi¹, Fulufhedzani Savhasa¹, Nikita Deyal¹, Nai-Jen Hsu¹, Sumayah Salie², Ian Mban⁰², Conchita Kamana², Nozipho Moitshewa³, Nyasha Gorogodo³, Fardeil Abbass³, Konanani Phaswana³, Neliswa Mngomeni³, Nomasolider Mngwengwi³, Nonwde Titi³, Michelle Fisher⁴, Abdullah Ely⁴, Muazzam Jacobs², Patrick Arbuthnot³, Thomas J Scriba⁴, Gerhardt Boukes¹, Caryn Fenner¹, Petro Terblanche¹, Kristie Bloom¹, and Munyaradzi Musvosvi⁴
¹ Afrigen Biologics, Cape Town, South Africa
² Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa
³ Antiviral Gene Therapy Research Unit, University of the Witwatersrand and the South African Medical Research Council (SAMRC), Johannesburg, South Africa
⁴ South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, and Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa
Tuberculosis (TB) is the deadliest disease caused by a single pathogen. The development of TB vaccines is hampered by TB complexity, low commercial incentives, and limited vaccine manufacturing infrastructure in low- and middle-income countries (LMICs). mRNA technology offers a promising, cost-effective alternative to conventional vaccine production. Strategic collaborations between Afrigen and the Universities of Cape Town and Witwatersrand in South Africa have enabled the development of two TB mRNA vaccine candidates.
T cell clonotypes targeting the Mycobacterium tuberculosis (Mtb) antigens PE13, PPE18, WBBL1, and CFP-10 were significantly more abundant in individuals who controlled Mtb infection compared to those who progressed to TB disease, implying that responses to these antigens are protective. These four antigens were designed as a monocistronic mRNA to facilitate cost-effective vaccine production. Murine pilot immunogenicity studies in C3HeB/FeJ (Kramnik), C57BL/6, and BALB/c mice resulted in the down-selection of two constructs, TB-L2-M4 and TB-M7. TB-L2-M4 demonstrated similar protection to BCG against aerosol Mtb challenge in Kramnik mice, while TB-M7 did not reduce bacterial load.
Afrigen has initiated upscaling of both TB mRNA vaccine candidates for a head-to-head comparison in clinical trials. Master and working cell banks have been established to produce large quantities of plasmid DNA. A gradual upscaling of in vitro transcription (IVT) reactions, starting from a small 100 μL to 20 mL volume, is necessary to ensure product quality. Small-scale IVTs have been successfully established. The 20 mL IVT scale will be produced using a novel automated mRNA production system from Quantoom Biosciences. In the second quarter of this year, the drug substance and drug product of both TB mRNA vaccine candidates will be assessed for critical quality attributes, including potency, purity, immunogenicity, and efficacy in mice.
