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Engineering of genetically attenuated pre-erythrocytic Plasmodium parasites for cross-stage protective immunity

Award Number: R01AI125706
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT The development of an effective malaria vaccine remains an important global health priority. A benchmark of malaria vaccine efficacy has been the observation that immunization with whole, live Plasmodium sporozoites that are adminstered by mosquito bite, confers complete sterile protection to malaria parasite infection in animal models and controlled human malaria infection (CHMI) trials with Plasmodium falciparum. Recent clinical trials also demonstrated complete protection to CHMI after immunization of human volunteers with parenterally administered attenuated sporozoites. This level of protection has yet to be matched by malaria vaccine candidate subunit formulations. Next to challenges in manufacturing, a formidably challenging aspect of live sporozoite immunization is ensuring safety by means of complete attenuation, while maintaining optimal immunogenicity. There are three main methodologies for live sporozoite immunization: radiation-attenuated sporozoites (RAS), chemoprophylaxis with sporozoites (CPS) and genetically attenuated parasites (GAP). In contrast to CPS and RAS, GAP are attenuated with well- characterized, consistent gene deletions that allow the control of the time point of parasite arrest during liver stage development. This has the potential for greater safety but also for superior efficacy, the latter demonstrated by the finding that late liver stage-arresting rodent malaria GAPs confer long lasting, superior pre-erythrocytic immunity and cross-stage immunity in mice. Furthermore, we have recently engineered a P. falciparum early liver stage-arresting GAP by triple gene deletion that showed for the first time complete pre-erythrocytic attenuation in human volunteers at high dose inoculation by mosquito bite. Here we will build on these successes and propose to design and engineer the next generation of GAP. We will take a two-pronged approach: In Aim 1 we will modify early liver stage-arresting GAP, that show complete attenuation in the P. yoelii rodent malaria model and in P. falciparum, to express blood stage and gametocyte antigens via transgene engineering. In Aim 2 we will generate novel late liver stage-arresting-, fully attenuated GAPs by combinatorial deletion of genes that affect late liver stage development, then augment their cross-stage protective capacity with blood stage and gametocyte antigens via transgene engineering. Finally in Aim 3, we will evaluate the capacity of all novel GAPs to induce completely sterilizing pre-erythrocytic immunity, cross-stage immunity to asexual blood stages as well as sexual stage transmision blocking immunity. We will also elucidate immune mechanisms of protection engendered by immunization with novel GAPs. The ultimate deliverable of this aplication will be a next generation P. falciparum GAP that is safe and is predicted, based on convincing experimental evidence, to afford protection against pre-erythrocytic infection, asexual blood stage parasitemia and will also prevent parasite transmission to the mosquito vector.


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: 2022 ( Subtotal = $8,159 )
2022	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	1/28/2022	NON-COMPETING CONTINUATION	$0
2022	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	001	3	9/26/2022	NON-COMPETING CONTINUATION	$8,159
														Subtotal = $8,159

Issue Date FY: 2020 ( Subtotal = $448,675 )
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	6	6/25/2020	NON-COMPETING CONTINUATION	$448,675
														Subtotal = $448,675

Issue Date FY: 2019 ( Subtotal = $431,573 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	002	5	6/27/2019	NON-COMPETING CONTINUATION	$448,675
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	12/19/2018	NON-COMPETING CONTINUATION	-$286,885
2019	2018	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	4	12/20/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$269,783
2019	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	003	3	7/23/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $431,573

Issue Date FY: 2018 ( Subtotal = $490,000 )
2018	2018	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	3	6/20/2018	NON-COMPETING CONTINUATION	$490,000
														Subtotal = $490,000

Issue Date FY: 2017 ( Subtotal = $472,500 )
2017	2017	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	2	6/20/2017	NON-COMPETING CONTINUATION	$472,500
														Subtotal = $472,500

Issue Date FY: 2016 ( Subtotal = $472,500 )
2016	2016	SEATTLE BIOMEDICAL RESEARCH INSTITUTE	307 WESTLAKE AVE N, STE 500	SEATTLE	WA	98109	KING	USA	Allergy and Infectious Diseases Research	000	1	7/1/2016	NEW	$472,500
														Subtotal = $472,500

Grand Total All Awards = $2,323,407

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Engineering of genetically attenuated pre-erythrocytic Plasmodium parasites for cross-stage protective immunity

Award Number: R01AI125706

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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