Geoffrey M. Lynn

In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity

The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer–TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer–TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer–TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer–TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

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.

Antigen expression determines adenoviral vaccine potency independent of IFN and STING signaling

Recombinant adenoviral vectors (rAds) are lead vaccine candidates for protection against a variety of pathogens, including Ebola, HIV, tuberculosis, and malaria, due to their ability to potently induce T cell immunity in humans. However, the ability to induce protective cellular immunity varies among rAds. Here, we assessed the mechanisms that control the potency of CD8 T cell responses in murine models following vaccination with human-, chimpanzee-, and simian-derived rAds encoding SIV-Gag antigen (Ag). After rAd vaccination, we quantified Ag expression and performed expression profiling of innate immune response genes in the draining lymph node. Human-derived rAd5 and chimpanzee-derived chAd3 were the most potent rAds and induced high and persistent Ag expression with low innate gene activation, while less potent rAds induced less Ag expression and robustly induced innate immunity genes that were primarily associated with IFN signaling. Abrogation of type I IFN or stimulator of IFN genes (STING) signaling increased Ag expression and accelerated CD8 T cell response kinetics but did not alter memory responses or protection. These findings reveal that the magnitude of rAd-induced memory CD8 T cell immune responses correlates with Ag expression but is independent of IFN and STING and provide criteria for optimizing protective CD8 T cell immunity with rAd vaccines.

Corrigendum: Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

Nat. Med.; 10.1038/nm.4110; corrected online 18 May 2016 In the version of this article initially published online, the authors omitted a funding source, The Bill and Melinda Gates Foundation (Investment ID: 24922). The error has been corrected for the print, PDF and HTML versions of this article.

Breaking the Mold: Partnering with the National Institutes of Health Intramural Research Program to Accelerate PhD Training

Immunology is an increasingly interdisciplinary field. Here we describe a new model for interinstitutional graduate training as partnerships between complementary laboratories. This collaborative model reduces time to graduation without compromising productivity or alumni outcomes. We offer our experience with one such program and thoughts on the ingredients for their success. Despite tremendous recent advances in technology, communications, and the translation of basic scientific discoveries into new diagnostics and therapies for human diseases, graduate training in immunology and other areas of biomedical research in the United States has remained remarkably unchanged since the early 20th century, with coursework and laboratory rotations taking up much of the first 2 years, and a single mentor shepherding the student through a research project over 3 or more subsequent years. The time to graduation still averages more than 6 years in the biomedical sciences field (http://www.nsf.gov/statistics/2016/nsf16300/), with uncertain benefit of this extended time to research productivity and career advancement.

Erratum: Protection against malaria at 1 year and immune correlates following PfSPZ vaccination (Nature Medicine (2016) DOI: 10.1038/nm.4110))

Nat. Med.; 10.1038/nm.4110; corrected online 18 May 2016 In the version of this article initially published online, the authors omitted a funding source, The Bill and Melinda Gates Foundation (Investment ID: 24922). The error has been corrected for the print, PDF and HTML versions of this article.

Erratum: Corrigendum: Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

Nat. Med.; 10.1038/nm.4110; corrected online 18 May 2016 In the version of this article initially published online, the authors omitted a funding source, The Bill and Melinda Gates Foundation (Investment ID: 24922). The error has been corrected for the print, PDF and HTML versions of this article.