American Society of Microbiology’s ASM Microbe 2016, Boston, June 19, 2016
- Pneumococcal protein vaccine GEN-004 reduces experimental human pneumococcal carriage in healthy adults
54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) Washington, DC, September 5-9, 2014
IDWeek 2013, San Francisco, CA, October 2-6, 2013
- A lipidated pneumococcal fusion protein confers toll-like receptor 2-dependent IL-17A responses and protection against nasopharyngeal carriage in mice
9th International Symposium on Pneumococci and Pneumococcal Diseases, Hyderabad India, March 9-13, 2014
- Immunization with genetically fused SP2018 and SP0148 proteins primes Th17 responses that are protective in a mouse colonization model
- Th17 responses to pneumococcal protein antigens in children’s nasal associated lymphoid tissue obtained by adenoidectomy could guide vaccine formulations
Chlamydia Basic Research Society Biennial Conference 18-21 March 2011
- High-throughput proteomic screening identifies Chlamydia trachomatis antigens that are capable of eliciting T cell and antibody responses that provide protection against vaginal challenge
- Identification of novel T cell antigens through directed delivery of the Chlamydia trachomatis ORFeome to antigen presentation pathways in human monocyte-derived dendritic cells
World Vaccine Congress, Washington DC, April 10-13, 2012
Toll-Like Receptor 2-Dependent Protection against Pneumococcal Carriage by Immunization with Lipidated Pneumococcal Proteins
Moffitt, K et al. (2014) Infect Immun doi:10.1128/IAI.01632-13
This article explores the mechanism by which the protein antigens we identified as important targets for TH17 responses in humans are inducing TH17 responses as a vaccine. Two of the prioritized antigens are naturally lipidated, and toll-like receptor 2 (TLR2) is a known receptor for lipoproteins. In this set of experiments, we show that the lipidated proteins do indeed trigger the TLR2 receptor, that they can exert their effect in trans (by inducing TH17 responses to non-lipidated proteins that are co-administered), and that pro-inflammatory responses are reduced when the lipid moiety is removed from the proteins. In addition, mice deficient in TLR2 are not protected against colonization after vaccination with the lipidated proteins, but wild-type mice that have normal TLR2 expression are. We hypothesize that triggering TLR2, either through lipidation of antigens or inclusion of an adjuvant with similar properties, may be a generalizable strategy for developing vaccines that induce TH17 responses to mucosal pathogens.
Kayhty, H. et al. (2013) Vaccine doi:10.1016/j.vaccine.2013.05.066
The PneumoCarr project, funded by the Bill & Melinda Gates Foundation Grand Challenges in Global Health, began in 2006. The purpose of the project was to establish reduction of nasopharyngeal colonization as an integral part of the licensure process of new pneumococcal vaccines. They consortium of nine international institutions worked together to develop guidelines for monitoring pneumococcal colonization as an alternative or additional endpoint in vaccine trials. The output of their work was published as an open access section in the Journal Vaccine (Vol 32., Issue 1, 17 December 2013, articles 23-29). In the Case for Carriage (article 29), the consortium members present the justification for including a vaccine-induced impact on colonization in the licensure pathway of pneumococcal vaccines moving forward, and provide experimental and epidemiological evidence for the role of pneumococcal carriage as a precursor to pneumococcal disease.
Distinct effects on diversifying selection by two mechanisms of immunity against Streptococcus pneumoniae
Li, Y et al. (2012) PLoS Pathog 8(11): e1002989
This work discloses the results of screening the ATLAS™ S. pneumoniae library with TH17 cells from human donors, and then compares the TH17 antigens with published antibody targets to determine if antigens are under greater selective pressure than non-antigens. Curiously, the data reveal that antibody targets are significantly more likely to be under diversifying selection (antigenic variation) than TH17 antigen genes. These data suggest that the strategy of using conserved protein antigens as components of a vaccine designed, in part, to induce TH17 responses to prevent colonization is sound. The TH17 antigens will be less subject to selection pressure and therefore the bacteria will be less likely to mutate their targets of the TH17 response and thus evade the host immune system.
Moffitt, KL et al. (2011) Cell Host & Microbe 9(2): 158-165
The work described in this article is focused on the screening of the ATLAS™ S. pneumoniae library with CD4+ T cells from mice vaccinated with whole, killed, unencapsulated S. pneumoniae to identify the antigen specificity of IL-17A-secreting TH17 cells. TH17 cells mediate resistance of mucosal colonization. The paper shows that antigens identified in mice are also recognized by human PBMC as a result of natural exposure. In addition, after intranasal administration with cholera toxin adjuvant, the identified antigens protect mice from pneumococcal colonization in challenge experiments. Colonization protection is dependent on TH17 cells since it is completely abrogated by neutralizing IL-17 or blocking CD4+ T cells.
Antibody and cell-mediated immunity to Streptococcus pneumoniae: implications for vaccine development
Malley, R (2010) J Mol Med 88(2):135-42
This review article from our collaborator Rick Malley at Boston Children’s Hospital provides a nice summary of the role for pneumococcus-specific CD4+ TH17 cells in reducing the duration of pneumococcal carriage and impacting mucosal disease. This is appropriate context for understanding the Genocea antigen discovery targets for the Pneumococcus program
Protection against pneumococcal colonization and fatal pneumonia by a trivalent conjugate of a fusion protein with the cell wall polysaccharide
Lu, YJ et al. (2009) Infect Immun 77(5): 2076-83
Our collaborator published this article describing a novel trivalent conjugate containing protein antigens designed to induce TH17 responses to impact colonization as well as cell wall polysaccharide to induce antibody to protect against invasive disease. This is the first evidence that a conjugate vaccine can be designed that contains a pneumococcal-specific antigen as a carrier (rather than an unrelated carrier such as CRM) to induce robust antibody and TH17 responses to protect against both pneumococcal carriage and invasive disease.
Lu, YJ et al. (2008) PLoS Pathogens 4(9):e1000159
This article shows that TH17 immunity does not prevent initiation of pneumococcal carriage in mice, but accelerates clearance over several days with the help of neutrophils. The paper also sheds light on the mechanisms of protection, confirming that both TH17 cells and neutrophils are required. Related to the above review article, this reinforces the notion that a vaccine inducing pneumococcal-specific TH17 responses could functionally reduce or eliminate pneumococcal carriage in the nasopharynx and prevent systemic disease.
Picard M. et al. (2015) Clinical and Vaccine Immunology, In press
Chlamydia trachomatis is the most frequently reported source of bacterial sexually transmitted infections. These infections are largely asymptomatic, yet cause a wide range of complications, including pelvic inflammatory disease and infertility. This publication describes the identification of specific T cell immune response profiles associated with spontaneous chlamydia clearance, paving the way toward the development of novel efficacious vaccines.
Roan, NR et al. (2006) Proc Natl Acad Sci USA 103(32): 12069-74
This article describes the use of the Chlamydia ATLAS™ library to identify the antigenic specificity of a T cell line derived from mice challenged intraperitoneally with Chlamydia trachomatis.
High-throughput proteomic screening identifies Chlamydia trachomatis antigens that are capable of eliciting T cell and antibody responses that provide protection against vaginal challenge
Picard, MD et al. (2012) Vaccine 30(29):4387-93
Preclinical data from a novel Chlamydia vaccine are described in this article. The vaccine is designed based upon the results of proteomic screening of the Chlamydia ATLAS™ library with CD4+ and CD8+ T cells from Chlamydia-challenged mice. The paper describes that T cells specific for the identified antigens home to the uterine draining lymph nodes after intravaginal challenge in the absence of vaccination. The article continues by describing the robust CD4+ and CD8+ T cells responses that are induced after immunization of the protein antigens with the AbISCO-100 adjuvant (Matrix M), and shows that immunized mice clear bacteria from their lower reproductive tract more quickly than controls after intravaginal challenge. The paper concludes by showing that T cells, and not antibody responses, are mediating protection.
Davies H. et al. Vaccine 33 (2015) 7496-7505
This publication describes different approaches to screening the genomes of the malaria parasite, Plasmodium falciparum, to identify targets of either antibody responses or cellular immune responses using samples from humans treated with experimental malaria treatments or under conditions of natural exposure in the field. These genome, proteome and transcriptome based approaches offer enormous potential for the development of novel efficacious vaccines against malaria.