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Strategy Trial of Personalized Immunomodulatory Therapy for HIV-related Cryptococcal Meningitis

Award Number: U01AI198071
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Strategy Trial of Personalized Immunomodulatory Therapy for HIV-related Cryptococcal Meningitis - Abstract Fungal infections are a common cause of opportunistic infections (OIs) in immunocompromised individuals. Among the most severe HIV-related OIs is fungal meningitis, with cryptococcal meningitis being the most common cause of adult meningitis in Africa, accounting for approximately 19% of HIV-related deaths globally. Incidence in the United States is ~1.1 per 100,000 population with hospitalizations being long and expensive. Current treatment guidelines in both the United States and internationally recommend intravenous (IV) liposomal amphotericin B with oral flucytosine (5FC) and fluconazole. However, even with this first-line therapy, mortality by 10 weeks is ~25% in low- and middle-income settings. Outcomes in high-income countries are similarly suboptimal, with ~15% early mortality within 90 days and ~25% mortality by 1 year. Historically, treatment has focused solely on antifungal therapy, largely ignoring the host immune response due to its complexity and heterogeneity. Emerging human data suggest that the damage-response immune framework underlies HIV-associated cryptococcal meningitis. Today, individuals with HIV and cryptococcosis are more immunologically complex, as half present while receiving antiretroviral therapy, which may or may not be effective for that person. Additional antifungal therapy is unlikely to further improve outcomes, as we have demonstrated that individuals with enhanced CSF early fungicidal activity (i.e., more rapid fungal killing, >0.60 log10CFU/mL/day) do not have better survival outcomes than those with more modest CSF clearance rates (e.g. 0.20-0.30 log10 CFU/mL/day). To further improve outcomes, we hypothesize that it is necessary to assess where individuals reside on the damage-response immune parabola and address their host immune status. We propose a Phase II/III platform trial to investigate the efficacy and safety of individually customized immunotherapy in HIV-related cryptococcal meningitis. We will conduct a Phase II trial (n=40) followed by a Phase III trial (n=200 in total in the experimental arm). Treatment effect will be compared against 200 concurrently randomized controls receiving standard of care antifungal therapy alone. Adjunctive immunotherapy will be customized based on pathogen burden and host immune status, addressing type 1 T helper cell (Th1) deficits, Th1 excessive responses, or inappropriate type 2 T helper cell (Th2) responses. Specific Aim 1. Validate the damage-response immune framework for HIV-associated cryptococcal meningitis to identify the subgroups with an immunologic contribution to disease. Specific Aim 2. Determine if personalized adjunctive immunomodulatory therapy improves clinical outcomes in HIV-associated cryptococcal meningitis in a randomized controlled trial. Impact: We seek to innovate infectious disease clinical medicine by testing personalized immunotherapy tailored to an individual's immune response and pathogen burden in cryptococcal meningitis.


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: 2026 ( Subtotal = $646,341 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	1	9/14/2026	SUPPLEMENT FOR EXPANSION	$314,988
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	9/2/2026	NEW	$331,353
														Subtotal = $646,341

Grand Total All Awards = $646,341

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Strategy Trial of Personalized Immunomodulatory Therapy for HIV-related Cryptococcal Meningitis

Award Number: U01AI198071

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/21/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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