Induction of antigen specific intrahepatic CD8+ T cell responses by a secreted heat shock protein based gp96-Ig-PfCA malaria vaccine

Laura Padula; Eva Fisher; Wathsala Wijayalath; Noelle B Patterson; Jun Huang; Harini Ganeshan; Tanisha Robinson; François A Bates; Margaret A Hanson; Monica L Martin; Katelyn Rivas; Denisse Garcia; Kimberly A Edgel; Martha Sedegah; Eileen Villasante; Natasa Strbo

doi:10.3389/fimmu.2023.1130054

Induction of antigen specific intrahepatic CD8+ T cell responses by a secreted heat shock protein based gp96-Ig-PfCA malaria vaccine

Front Immunol. 2023 Mar 28:14:1130054. doi: 10.3389/fimmu.2023.1130054. eCollection 2023.

Authors

Laura Padula¹, Eva Fisher¹, Wathsala Wijayalath^{2

3}, Noelle B Patterson^{2

4}, Jun Huang^{2

4}, Harini Ganeshan^{2

4}, Tanisha Robinson^{5

6}, François A Bates⁷, Margaret A Hanson⁸, Monica L Martin⁷, Katelyn Rivas¹, Denisse Garcia¹, Kimberly A Edgel², Martha Sedegah², Eileen Villasante², Natasa Strbo¹

Affiliations

¹ Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, United States.
² Malaria Department, Naval Medical Research Center (NMRC), Silver Spring, MD, United States.
³ CAMRIS International, Bethesda, MD, United States.
⁴ Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF), Bethesda, MD, United States.
⁵ Malaria Serology Lab, Immunology Core, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States.
⁶ Parsons Technical Services Inc., Pasadena, CA, United States.
⁷ Animal Medicine Branch, Veterinary Services Program, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States.
⁸ Necropsy Branch, Veterinary Services Program, Walter Reed Army Institute of Research (WRAIR), Silver Spring, MD, United States.

Abstract

Introduction: A highly efficacious and durable vaccine against malaria is an essential tool for global malaria eradication. One of the promising strategies to develop such a vaccine is to induce robust CD8+ T cell mediated immunity against malaria liver-stage parasites.

Methods: Here we describe a novel malaria vaccine platform based on a secreted form of the heat shock protein, gp96-immunoglobulin, (gp96-Ig) to induce malaria antigen specific, memory CD8+ T cells. Gp96-Ig acts as an adjuvant to activate antigen presenting cells (APCs) and chaperone peptides/antigens to APCs for cross presentation to CD8+ T cells.

Results: Our study shows that vaccination of mice and rhesus monkeys with HEK-293 cells transfected with gp96-Ig and two well-known Plasmodium falciparum CSP and AMA1 (PfCA) vaccine candidate antigens, induces liver-infiltrating, antigen specific, memory CD8+ T cell responses. The majority of the intrahepatic CSP and AMA1 specific CD8+ T cells expressed CD69 and CXCR3, the hallmark of tissue resident memory T cells (Trm). Also, we found intrahepatic, antigen-specific memory CD8+ T cells secreting IL-2, which is relevant for maintenance of effective memory responses in the liver.

Discussion: Our novel gp96-Ig malaria vaccine strategy represents a unique approach to induce liver-homing, antigen-specific CD8+ T cells critical for Plasmodium liver-stage protection.

Keywords: Gp96; liver CD8+ T cells specific; malaria; memory; vaccine.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Antigens, Protozoan
CD8-Positive T-Lymphocytes
HEK293 Cells
Heat-Shock Proteins / metabolism
Humans
Immunoglobulins / metabolism
Malaria Vaccines*
Malaria* / metabolism
Malaria* / prevention & control
Malaria, Falciparum*

Substances

Malaria Vaccines
Heat-Shock Proteins
Immunoglobulins
Antigens, Protozoan

Grants and funding

This work was supported by Peer Reviewed Medical Research Program (PRMRP) Award #W81XWH-13-2-0098 (University of Miami PI NS) and #W81XWH-13-2-0099 (NMRC PI EV).