Protective immunity differs between routes of administration of attenuated malaria parasites independent of parasite liver load

• Published in: Scientific reports Vol. 7; no. 1; pp. 10372 - 19
• Main Authors: Haeberlein, Simone, Chevalley-Maurel, Séverine, Ozir-Fazalalikhan, Arifa, Koppejan, Hester, Winkel, Beatrice M F, Ramesar, Jai, Khan, Shahid M, Sauerwein, Robert W, Roestenberg, Meta, Janse, Chris J, Smits, Hermelijn H, Franke-Fayard, Blandine
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 04.09.2017; Nature Publishing Group UK
• Subjects: Animal models; Animals; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Dendritic cells; Disease Models, Animal; Humans; Immune response; Immunization; Immunological memory; Interleukin 10; Intravenous administration; Life Cycle Stages; Liver; Liver - immunology; Liver - parasitology; Lymph nodes; Lymphocyte Count; Lymphocytes B; Lymphocytes T; Malaria; Malaria - immunology; Malaria - parasitology; Memory cells; Mice; Parasite Load; Parasitemia - parasitology; Parasites; Plasmodium - physiology; Plasmodium falciparum - immunology; Skin; Sporozoites; T cell receptors; Vaccines
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-10480-1

In humans and murine models of malaria, intradermal immunization (ID-I) with genetically attenuated sporozoites that arrest in liver induces lower protective immunity than intravenous immunization (IV-I). It is unclear whether this difference is caused by fewer sporozoites migrating into the liver or by suboptimal hepatic and injection site-dependent immune responses. We therefore developed a Plasmodium yoelii immunization/boost/challenge model to examine parasite liver loads as well as hepatic and lymph node immune responses in protected and unprotected ID-I and IV-I animals. Despite introducing the same numbers of genetically attenuated parasites in the liver, ID-I resulted in lower sterile protection (53-68%) than IV-I (93-95%). Unprotected mice developed less sporozoite-specific CD8 and CD4 effector T-cell responses than protected mice. After immunization, ID-I mice showed more interleukin-10-producing B and T cells in livers and skin-draining lymph nodes, but fewer hepatic CD8 memory T cells and CD8 dendritic cells compared to IV-I mice. Our results indicate that the lower protection efficacy obtained by intradermal sporozoite administration is not linked to low hepatic parasite numbers as presumed before, but correlates with a shift towards regulatory immune responses. Overcoming these immune suppressive responses is important not only for live-attenuated malaria vaccines but also for other live vaccines administered in the skin.