# Mechanisms of compromised CD8 T cell responses to vaccination in malaria experienced hosts

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2024 · $765,058

## Abstract

Malaria, caused by Plasmodium species, is an unresolved global health burden. Although insecticide
treated bed nets and antimalarial drugs have reduced the incidence and severity of malaria in some
regions, infections are on the rise with 247,000,000 cases and >600,000 fatalities in 2021. Of additional
concern, front line artesminin drug therapies are threatened by emerging drug resistant parasites. Thus,
effective vaccines remain a critical goal to combat the global threat of malaria. Due to logistics and the
development of Controlled Human Malaria Infection (CHMI) challenge in humans, most initial clinical trials
of candidate vaccines are carried out in malaria naïve individuals rather than in malaria endemic regions.
Unquestionably, the most successful of these candidates are Radiation Attenuated Sporozoites (RAS). RAS
vaccination, originally described in mice, elicits pre-erythrocytic (liver-stage) immunity that can completely
prevent development of symptomatic blood-stage infection after exposure to virulent sporozoites in
humans3. RAS vaccination (by the i.v. route with cryopreserved RAS) in malaria naïve individuals can be up
to 100% effective and immunity can last for at least a year. However, a major hurdle for progress in malaria
vaccines is the finding of substantially reduced efficacy of RAS vaccination in malaria endemic regions
 To address this knowledge gap, we generated a mouse model where prior exposure to non-lethal P.
yoelii 17XNL (Py) blood-stage infection compromises P. berghei ANKA (Pb) RAS-induced protective
immunity against virulent Pb sporozoite challenge (Please see Fig. 1 for experimental design schematic).
We further show that prior malaria exposure results in a prolonged (>12 month) reduction in the capacity to
make malaria-specific CD8 T cell responses against RAS immunization. In considering how such durable
immune dysfunction could occur, we noted that one long-term signature of malaria exposure in humans and
mice is the essentially lifelong persistence of hemozoin (Hz) in specific tissues (liver, spleen, bone marrow).
Hz is a non-degradable biocrystal formed during blood-stage infection as Plasmodium metabolizes
hemoglobin in infected RBC. Importantly, we determined that injection of synthetic Hz and equilibration in
tissues also compromised CD8 T cell responses to RAS immunization. The goal of this RO1 is to gain
mechanistic insight into Hz-mediated T cell dysfunction in an effort to improve the efficacy of malaria
vaccines in endemic areas. Aim 1. Determine how Hz disrupts antigen-presenting functions required for
CD8 T cell priming after RAS immunization. Aim 2: Define the extent to which Hz compromises RAS-
induced liver T resident memory (Trm) and circulating T cell memory (Tcircm) protective functions. Aim 3.
Identify translatable immunization regimens to overcome Hz-mediated disruption of CD8 T cell priming and
liver stage immunity after RAS vaccination.

## Key facts

- **NIH application ID:** 10934502
- **Project number:** 1R01AI185725-01
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** John T Harty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $765,058
- **Award type:** 1
- **Project period:** 2024-06-24 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934502

## Citation

> US National Institutes of Health, RePORTER application 10934502, Mechanisms of compromised CD8 T cell responses to vaccination in malaria experienced hosts (1R01AI185725-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10934502. Licensed CC0.

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