Investigating Plasmodium vaccination in 'dirty' mice

PROJECT SUMMARY/ABSTRACT
Malaria, which results from infection with Plasmodium parasites, is a significant global health problem
with nearly 250 million clinical cases and over 600,000 deaths annually worldwide. With growing anti-malarial
drug and insecticide resistance, new therapeutic strategies and highly effective vaccines are urgently needed.
Whole sporozoite vaccines are the only strategy to elicit high levels of sterilizing immunity in humans, including
>90% in controlled human malaria infection (CHMI) studies. Whole sporozoite vaccine strategies include
genetically attenuated parasites (GAPs), in which parasite arrest is mediated by the targeted deletion of genes
critical for liver stage development. However, Plasmodium vaccines have largely failed to induce durable
protection in endemic countries. Additionally, there is considerable evidence that ongoing exposure to
pathogens within malaria endemic areas, both co-infections and historic malaria exposure, as well as
microbiota can modulate vaccine immunity. To address this gap in knowledge, this proposal will utilize an
improved small animal model that mimics human immune responses more closely to define the immune
response Plasmodium vaccination and test an adjuvant to boost immunity against Plasmodium.
Our group has shown that specific pathogen-free (SPF) mice cohoused with pet store mice acquire
diverse microbial exposure (DME) and undergo immune system changes that better recapitulate the human
immune system. Comparing SPF and DME mice will allow us to test whether and how microbial exposure and
resulting inflammation impact Plasmodium vaccine immunogenicity and efficacy. There is also a need to
optimize sporozoite vaccine immunogenicity such as via an adjuvant. In mice, liver-resident CD8+ T (Trm) cells
are critical for sterilizing immunity following sporozoite vaccination, and liver Trm formation is highly dependent
on IL-15. Thus, IL-15 could be harnessed as a vaccine adjuvant to enhance Trm formation. Indeed, we show
that, in SPF mice, complexing IL-15 with the IL-15R (IL-15C) boosts liver Trm formation following GAP
vaccination and results in reduced liver parasite load after challenge. Interestingly, expression of the IL-15Rβ/γ
chains is significantly increased in liver leukocytes from DME mice, suggesting that liver Trm cells in DME mice
may be especially susceptible to augmentation by IL-15C. In Aim 1, we will define the T cell and antibody
response to Plasmodium vaccination in DME mice and test IL-15C as a vaccine adjuvant to boost Trm
formation. In Aim 2, we will determine GAP vaccine efficacy in DME and SPF mice with or without IL-15C and
compare vaccine efficacy to a CSP protein-subunit vaccine in SPF and DME mice. In sum, our data support
the hypothesis that DME mice represent a more physiologically relevant model to define Plasmodium vaccine
immunogenicity and efficacy and that IL-15C represents a novel Plasmodium vaccine adjuvant. This will
facilitate improved control of Plasmodium infection and protection from disease by informing vaccine design.

Grant Number: 1R21AI182639-01A1
NIH Institute/Center: NIH
Principal Investigator: Kristina Burrack