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A dual function TB subunit vaccine designed for non-interference with BCG and post-exposure activity

Award Number: R01AI135721
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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A dual function TB subunit vaccine designed for non-interference with BCG and post-exposure activity - ABSTRACT Despite widespread use, the only licensed tuberculosis (TB) vaccine available for human use, M. bovis Bacille Calmette-Guerin (BCG), has not been able to prevent TB from becoming a global health emergency. To achieve the 2030 targets of the WHO End TB Program, a new TB vaccine strategy is needed. For optimal effect, such a strategy will need to offer both improved efficacy following vaccination of TB-naïve infants, as well as vaccine efficacy in the population of M. tuberculosis (Mtb)-exposed adolescents/adults in endemic regions. Advances in our understanding of TB immunology and vaccinology allow for a more tailored vaccine designed for this dual function. Based on specific antigen selection and adjuvanted administration, we have developed a novel single vaccine with dual use as a co-vaccine alongside BCG for naïve individuals and as a standalone vaccine for previously exposed/infected individuals. This designed hybrid protein subunit vaccine (ESX1-Vax) is composed specifically of secreted ESX-1 related antigens that are missing from BCG, including ESAT-6 whose targeting is uniquely protective against re-growth of pre-existing infection. The hybrid protein is delivered with the CAF01 adjuvant that is highly effective in promoting T cell responses with defined TB-protective phenotype and function. Co-administration of ESX1-Vax/CAF01 with BCG does not hinder BCG effects. Instead, it acts synergistically to complement BCG vaccination by priming differentiation-resistant T cells targeting ESX-1 virulence factor antigens. As a non-replicative subunit vaccine, ESX1-Vax is also readily boostable. Furthermore, administration of ESX1-Vax/CAF01 in a post-exposure setting is highly efficacious against bacterial re-growth. In this proposal, we aim to optimize the immunogencity and efficacy of this ESX1-Vax through molecular modifications to maximize the T cell response against ESAT-6 epitopes. We will compare the modified constructs for efficacy and immunogenicity after BCG co-vaccination and in standard and newly-established post-exposure vaccination models to select the optimal ESX1-Vax construct. The selected construct will then be developed for production as a final GMP-produced ESX1/CAF01 product, verified for vaccine activity and assessed for toxicology. The overall outcome of this product development is, thus, a single boostable vaccine that is uniquely designed to work both together with BCG prophylactically in non-infected neonates, as well as when delivered post Mtb exposure in latently infected individuals, and that is ready for progress to clinical trials.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	STATENS SERUM INSTITUT	ARTILLERIVEJ 5	KOBENHAVN S				DNK	Allergy and Infectious Diseases Research	000	5	7/18/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $647,855 )
2022	2022	STATENS SERUM INSTITUT	ARTILLERIVEJ 5	KOBENHAVN S				DNK	Allergy and Infectious Diseases Research	000	5	12/3/2021	NON-COMPETING CONTINUATION	$647,855
														Subtotal = $647,855

Issue Date FY: 2021 ( Subtotal = $1,155,591 )
2021	2021	STATENS SERUM INSTITUT	ARTILLERIVEJ 5	KOBENHAVN S				DNK	Allergy and Infectious Diseases Research	001	4	1/29/2021	NON-COMPETING CONTINUATION	$1,155,591
2021	2020	STATENS SERUM INSTITUT	ARTILLERIVEJ 5	KOBENHAVN S				DNK	Allergy and Infectious Diseases Research	000	3	10/22/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,155,591

Issue Date FY: 2020 ( Subtotal = $765,521 )
2020	2020	STATENS SERUM INSTITUT	ARTILLERIVEJ 5	KOBENHAVN S		2300		DNK	Allergy and Infectious Diseases Research	000	3	12/2/2019	NON-COMPETING CONTINUATION	$670,614
2020	2020	STATENS SERUM INSTITUT	ARTILLERIVEJ 5	KOBENHAVN S		2300		DNK	Allergy and Infectious Diseases Research	001	3	9/14/2020	NON-COMPETING CONTINUATION	$94,907
														Subtotal = $765,521

Issue Date FY: 2019 ( Subtotal = $642,131 )
2019	2019	STATENS SERUM INSTITUT	ARTILLERIVEJ 5	KOBENHAVN S		2300		DNK	Allergy and Infectious Diseases Research	000	2	11/26/2018	NON-COMPETING CONTINUATION	$642,131
														Subtotal = $642,131

Issue Date FY: 2018 ( Subtotal = $277,002 )
2018	2018	STATENS SERUM INSTITUT	ARTILLERIVEJ 5	KOBENHAVN S		2300		DNK	Allergy and Infectious Diseases Research	000	1	11/27/2017	NEW	$277,002
														Subtotal = $277,002

Grand Total All Awards = $3,488,100

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A dual function TB subunit vaccine designed for non-interference with BCG and post-exposure activity

Award Number: R01AI135721

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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