Major Areas of Research
- Immunologically complex emerging and reemerging viral diseases, including dengue and Zika
- Host immunologic correlates of enduring protection and disease
- Antigenic and genetic viral evolution
- Virus transmission dynamics
Dr. Leah Katzelnick pursued a Ph.D. studying antigenic variation among dengue viruses at the University of Cambridge and the National Institutes of Health as an NIH OxCam Scholar and Gates Cambridge Scholar. After receiving her Ph.D. in 2016, she conducted her postdoctoral work at the University of California, Berkeley and University of Florida on determinants of dengue and Zika disease, spending a year in Ecuador and Nicaragua to work closely with research teams conducting longitudinal cohort studies. In September of 2020, Leah became an Earl Stadtman tenure-track investigator and NIH Distinguished Scholar in the Laboratory of Infectious Diseases in NIAID. She is Chief of the new Viral Epidemiology and Immunity Unit.
Mosquito-borne flaviviruses infect hundreds of millions of people globally each year and cause a spectrum of life-threatening diseases, including hemorrhagic fevers, encephalitis, and severe congenital abnormalities. There are still no licensed, broadly protective vaccines against two of the most important flaviviruses: dengue virus and Zika virus. Dengue viruses 1-4 are challenging vaccine targets because sub-protective vaccines can increase risk of Dengue Hemorrhagic Fever/Dengue Shock Syndrome, the disease dengue vaccines are designed to prevent. The only licensed dengue vaccine to date significantly increases risk of severe dengue disease in those without a prior dengue virus exposure. Zika viruses emerged across the Americas in 2014-2017, causing major pandemics and congenital Zika syndrome, making development of a Zika vaccine a high priority.
The Viral Epidemiology and Immunity Unit (VEIU) uses a multidisciplinary approach to investigate immunological protection against and susceptibility to emerging and re-emerging viral diseases with the goal of informing how vaccines can be effectively and safely licensed and introduced through vaccination programs. Our work focuses on immunologically complex diseases caused by flaviviruses, including dengue and Zika viruses, as well as coronaviruses. We collaborate with research teams to study determinants of disease in longitudinal cohort and vaccine studies in Nicaragua, Sri Lanka, Thailand, Ecuador, the Philippines, and other sites. To address questions about virus antigenicity, host protective immunity, and population-level viral transmission dynamics, we use biologically relevant immunological assays and diverse computational and epidemiological methods to measure and evaluate the role of immunity in protection against disease in human cohort studies.
Key findings from previous research:
- Pre-infection anti-dengue virus binding antibodies at concentrations within a 'danger zone' are associated with significantly increased risk of severe dengue disease, providing evidence from a large human study for antibody-dependent enhancement (Katzelnick et al., Science 2017).
- Like a single prior dengue virus infection, one prior Zika virus infection increases future risk of severe dengue disease; further, pre-existing anti-flavivirus immunity differentially modulates future disease caused by different dengue virus serotypes (Katzelnick et al., Science 2020).
- Diverse dengue virus strains only loosely cluster antigenically by serotype and many strains are as similar antigenically to strains of a different serotype as to some strains of the same serotype (Katzelnick et al., Science 2015).
- In a cohort study in Nicaragua, dramatic change in dengue virus transmission intensity over a 20-year period resulted in the age of seroconversion dropping from within to outside the recommended range specified by the World Health Organization for dengue vaccination (Katzelnick, Ben-Shachar et al., PNAS 2018).
Basic science and translational research objectives
The VEIU aims to identify drivers of antiviral immunity in population studies to inform basic science, vaccine design, and other public health and preventative measures. Specifically, we will study quaternary ‘super-antibodies', which bind epitopes across viral envelope proteins, and test whether these antibodies are mechanistic immune correlates of protection against dengue and other viral diseases. We will also characterize virus-specific neutralizing antibodies, which target variable viral epitopes that can evolve away from existing immunity. Overall, we aim to identify correlates of natural and vaccine protection and antibody-dependent enhancement in order to develop better next generation vaccines, extend the longevity of vaccine-induced immunity, and characterize how vaccines may affect viral evolution and transmission.
Ana Coello Escoto, Biologist and Lab Manager
Fernando Echegaray, Postbac IRTA
- Katzelnick LC, Narvaez C, Arguello S, Lopez Mercado B, Collado D, Ampie O, Elizondo D, Miranda T, Bustos Carrillo F, Mercado JC, Latta K, Schiller A, Segovia-Chumbez B, Ojeda S, Sanchez N, Plazaola M, Coloma J, Halloran ME, Premkumar L, Gordon A, Narvaez F, de Silva A, Kuan G, Balmaseda A, Harris E. Zika virus infection enhances future risk of severe dengue disease. Science. 2020 Aug;369(6507):1123-1128.
- Katzelnick LC, Ben-Shachar R, Mercado JC, Rodriguez-Barraquer I, Elizondo D, Arguello S, Nuñez A, Ojeda S, Sanchez N, Lopez Mercado B, Gresh L, Burger-Calderon R, Kuan G, Gordon A, Balmaseda A, Harris E. Dynamics and determinants of the force of infection of dengue virus from 1994 to 2015 in Managua, Nicaragua. Proc Natl Acad Sci USA. 2018 Oct;115(42):10762-10767.
- Katzelnick LC, Coello Escoto A, McElvany BD, Chávez C, Salje H, Luo W, Rodriguez-Barraquer I, Jarman R, Durbin AP, Diehl SA, Smith DJ, Whitehead SS, Cummings DAT. Viridot: An automated virus plaque (immunofocus) counter for the measurement of serological neutralizing responses with application to dengue virus. PLoS Negl Trop Dis. 2018 Oct;12(10):e0006862.
- Katzelnick LC, Gresh L, Halloran ME, Mercado JC, Kuan G, Gordon A, Balmaseda A, Harris E. Antibody-dependent enhancement of severe dengue disease in humans. Science. 2017 Nov ;358(6365):929-932.
- Katzelnick LC, Montoya M, Gresh L, Balmaseda A, Harris E. Neutralizing antibody titers against dengue virus correlate with protection from symptomatic infection in a longitudinal cohort. Proc Natl Acad Sci USA. 2016 Jan;113(3):728-33.
- Katzelnick LC, Fonville JM, Gromowski GD, Bustos Arriaga J, Green A, James SL, Lau L, Montoya M, Wang C, VanBlargan LA, Russell CA, Thu HM, Pierson TC, Buchy P, Aaskov JG, Muñoz-Jordán JL, Vasilakis N, Gibbons RV, Tesh RB, Osterhaus AD, Fouchier RA, Durbin A, Simmons CP, Holmes EC, Harris E, Whitehead SS, Smith DJ. Dengue viruses cluster antigenically but not as discrete serotypes. Science. 2015 Sep;349(6254):1338-43.