Ernesto T Marques

Contributions to Public Health

• Diagnostics: I developed a diagnostic test that distinguishes antibody responses from Dengvaxia vaccination versus natural dengue infection. This revealed that dengue-naive individuals vaccinated with Dengvaxia had an increased risk of severe disease. The findings led to changes in the vaccine label and WHO usage recommendations, ultimately saving countless lives.
  • E. J. M. Nascimento et al., Development of an anti-dengue NS1 IgG ELISA to evaluate exposure to dengue virus. J Virol Methods 257, 48–57 (2018).
  • E. J. M. Nascimento et al., Development of antibody biomarkers of long term and recent dengue virus infections. J Virol Methods 257, 62–68 (2018).
• Vaccine adjuvant: I co-developed a molecular adjuvant using LAMP technology to enhance MHC class II presentation and CD4/CD8 T-cell responses. This innovation led to 40+ publications, multiple patents, and a $300M licensing deal. LAMP has been applied to vaccines against HIV, dengue, Ebola, cancer, and allergies. Two therapeutic vaccines using this technology are in clinical trials: one targets cytomegalovirus for glioblastoma, and the other targets Merkel cell polyomavirus for Merkel cell carcinoma.
  • E. T. Marques, Jr. et al., HIV-1 p55Gag encoded in the lysosome-associated membrane protein-1 as a DNA plasmid vaccine chimera is highly expressed, traffics to the major histocompatibility class II compartment, and elicits enhanced immune responses. J Biol Chem 278, 37926–37936 (2003).
  • L. B. Arruda et al., Dendritic cell-lysosomal-associated membrane protein (LAMP) and LAMP-1-HIV-1 Gag chimeras have distinct cellular trafficking pathways and prime T and B cell responses to a diverse repertoire of epitopes. Journal of Immunology 177, 2265–2275 (2006).
• Epitope-Based Vaccine Design: Vaccine development for some pathogens fails because they divert immune responses toward irrelevant targets. To address this, I developed a “forward and backward” approach combining computational tools and high-throughput assays to identify T-cell epitopes in clinical samples and HLA-transgenic models. Using LAMP technology, we engineered a dengue epitope-based vaccine incorporating epitope clusters that elicit CD4/CD8 responses in 95% of the HLA alleles in the population, enhancing targeted and effective immune responses.
  • E. J. Nascimento et al., Identification of conserved and HLA promiscuous DENV3 T-cell epitopes. PLoS Negl Trop Dis 7, e2497 (2013).
  • U. M. Braga-Neto, E. T. Marques, Jr., From functional genomics to functional immunomics: new challenges, old problems, big rewards. PLoS Comput Biol 2, e81 (2006).
• Congenital Zika Syndrome: In 2003, I launched a hospital-based study in Recife, Brazil, on dengue and other arboviral diseases. In 2015, we identified the first Zika cases and detected the virus in cerebrospinal fluid of adults with demyelinating diseases, preceding the microcephaly outbreak. Later we confirmed the link between Zika and congenital disease, estimated risks for WHO, and developed an anti-Zika NS1 IgG3 assay to identify women at risk. We also found that high dengue antibody levels reduced Zika infection risk.
  • T. Magalhaes et al., Zika virus displacement by a chikungunya outbreak in Recife, Brazil. PLoS Negl Trop Dis 11, e0006055 (2017).
  • T. Jaenisch et al., Risk of microcephaly after Zika virus infection in Brazil, 2015 to 2016. Bull World Health Organ 95, 191–198 (2017).
• Zika immunopathology: Zika infection during pregnancy increases the risk of microcephaly and other congenital abnormalities, though only 3–7% of infections result in Congenital Zika Syndrome (CZS), depending on gestational age. Socioeconomic and environmental factors may also influence risk. We investigated CZS pathogenesis and were first to detect Zika virus and IgM in cerebrospinal fluid from initial 2015 cases. We also demonstrated that anti-dengue antibodies facilitate Zika infection of immune cells in blood and in ex vivo skin explant models. The identification of these mechanisms helps develop vaccines and other measures to prevent Zika infection.
  • M. T. Cordeiro, L. J. Pena, C. A. Brito, L. H. Gil, E. T. Marques, Positive IgM for Zika virus in the cerebrospinal fluid of 30 neonates with microcephaly in Brazil. Lancet 387, 1811–1812 (2016).
  • P. M. S. Castanha et al., Dengue Virus-Specific Antibodies Enhance Brazilian Zika Virus Infection. J Infect Dis 215, 781–785 (2017).