Fifty-five percent of individuals vaccinated with an attenuated Plasmodium falciparum sporozoite vaccine remained without parasitemia after controlled human malaria infection one year later; immune correlate analysis in humans and non-human primates suggest a role for liver-resident T cells. An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 105 PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21–25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.

Significance: A highly effective malaria vaccine capable of long-term protection against genetically diverse strains is urgently needed. Here, we demonstrate that a three-dose regimen of a live attenuated whole-parasite malaria vaccine conferred durable sterile protection through 33 weeks in ∼50% of subjects against a controlled human malaria infection strain that is heterologous to the vaccine strain. Prior studies by others and us have shown that T cells are critical to mediating sterile protection after live-attenuated malaria vaccination. Here, we provide evidence that this Plasmodium falciparum sporozoite vaccine (PfSPZ Vaccine) induces antigen-specific IFN-γ-producing CD8 and CD4 T cells that recognize both the homologous and the heterologous Pf strain.

In March 2013 the first human infections with a novel avian influenza A(H7N9) virus were reported in China, and since that time hundreds of cases have been documented.^1,2 Most infections are believed to result from poultry exposure, and no evidence of sustained person-to-person spread of H7N9 has yet been found, although limited person-to-person spread appears to have occurred.³ The potential for viral adaptation that would facilitate person-to-person transmission is a major concern.^4,5

Enteroaggregative Escherichia coli (EAEC) is a leading cause of acute and persistent diarrhea worldwide. A recently emerged Shiga-toxin-producing strain of EAEC resulted in significant mortality and morbidity due to progressive development of hemolytic-uremic syndrome. The attachment of EAEC to the human intestinal mucosa is mediated by aggregative adherence fimbria (AAF). Using X-ray crystallography and NMR structures, we present new atomic resolution insight into the structure of AAF variant I from the strain that caused the deadly outbreak in Germany in 2011, and AAF variant II from archetype strain 042, and propose a mechanism for AAF-mediated adhesion and biofilm formation. Our work shows that major subunits of AAF assemble into linear polymers by donor strand complementation where a single minor subunit is inserted at the tip of the polymer by accepting the donor strand from the terminal major subunit. Whereas the minor subunits of AAF have a distinct conserved structure, AAF major subunits display large structural differences, affecting the overall pilus architecture. These structures suggest a mechanism for AAF-mediated adhesion and biofilm formation. Binding experiments using wild type and mutant subunits (NMR and SPR) and bacteria (ELISA) revealed that despite the structural differences AAF recognize a common receptor, fibronectin, by employing clusters of basic residues at the junction between subunits in the pilus. We show that AAF-fibronectin attachment is based primarily on electrostatic interactions, a mechanism not reported previously for bacterial adhesion to biotic surfaces. Enteroaggregative Escherichia coli (EAEC) is a major cause of diarrhea worldwide and is commonly present as an infection in symptomatic travelers returning from developing countries. The attachment of EAEC to the human intestine is mediated protein filaments extending from the bacterial surface known as aggregative adherence fimbria (AAF). Here we use X-ray crystallography and nuclear magnetic resonance (NMR) structures to provide an atomic structure of the protein fibers made by the two major variants, AAF/I and AAF/II. The structures of the major subunit proteins show that the AAFs assemble into flexible, linear polymers that are capped by a single minor protein subunit at the tip. Biochemical assays reveal that the AAFs recognize a common receptor, the extracellular matrix protein fibronectin, via clusters of positively-charged amino acid residues running along the length of the fimbriae. Our structures suggest a unique mechanism based on ionic interactions for AAF-mediated receptor binding and biofilm formation.

Malaria drives the adaptive differentiation of the human γδ T cell repertoire.

γδ T cells are generally considered innate-like lymphocytes, however, an ‘‘adaptive-like’’ γδ compartment has now emerged. To understand transcriptional regulation of adaptive γδ T cell immunobiology, we combined single-cell transcriptomics, T cell receptor (TCR)-clonotype assignment, ATAC-seq, and immunophenotyping. We show that adult Vδ1⁺ T cells segregate into TCF7⁺LEF1⁺Granzyme B^neg (T_naive) or T-bet⁺Eomes⁺ BLIMP-1⁺Granzyme B⁺ (T_effector) transcriptional subtypes, with clonotypically expanded TCRs detected exclusively in T_effector cells. Transcriptional reprogramming mirrors changes within CD8⁺ αβ T cells following antigen-specific maturation and involves chromatin remodeling, enhancing cytokine production and cytotoxicity. Consistent with this, in vitro TCR engagement induces comparable BLIMP-1, Eomes, and T-bet expression in naive Vδ1⁺ and CD8⁺ T cells. Finally, both human cytomegalovirus and Plasmodium falciparum infection in vivo drive adaptive Vδ1 T cell differentiation from T_naive to T_effector transcriptional status, alongside clonotypic expansion. Contrastingly, semi-invariant Vγ9⁺Vδ2⁺ T cells exhibit a distinct ‘‘innate-effector’’ transcriptional program established by early childhood. In summary, adaptive-like γδ subsets undergo a pathogen-driven differentiation process analogous to conventional CD8⁺ T cells.