Correlates of Protection in Dengue Stephen J. Thomas, MD Division of Infectious Diseases State University of New York Upstate Medical University May 2017
Discussion of correlates requires clarity and proper use of terms to avoid confusion. 2
Correlates for numerous vaccines exist, including flaviviruses; defining and redefining is a constant process. 3
4 How do we arrive at correlates of protection? Studies of passive antibody administration Analysis of immune responses in protected and unprotected subjects in nature and in efficacy trials Observing immunosuppressed humans or animals Human challenge studies (infection/disease models) Extrapolation from the results of challenges in animals The nuances of dengue infection and disease make all pathways to a correlate complicated.
5 Overall, the aim of this meeting was to generate consensus on the current understanding of the immune response to and protection from dengue virus infection, identify key unanswered questions, and address how to improve measurement of efficacy in vaccine trials. Publication of meeting results imminent.
Considering a Correlate for Dengue 6 A correlate of protection from what? Infection, disease, severe disease? Monotheism or polytheism? Humor, cellular, both? What can you prove? What is measurable? How do you measure and with what quality? What can you afford? How much time and money will it cost? What will the regulatory agencies accept? Will it be generalizable to unstudied populations?
Progress on Searching for a Dengue CoP Passive Antibody Administration 7 Passive transfer explored as immunization approach and studying immunopathogenesis. Use to define a CoP?
Progress on Searching for a Dengue CoP Protection in Nature and Vaccine Trials 8 In secondary D3V infections, pre-existing D3V-reactive neutralizing Abs appear to ameliorate viral replication and severity of disease. By contrast, in secondary D2V infections, preexisting D2V-reactive neutralizing Abs do not ameliorate viral replication or severity of disease.
Progress on Searching for a Dengue CoP Protection in Nature and Vaccine Trials 9 We observed that a higher median pre-infection NAb titer or NAb titer to the 2º infecting serotype, but not the NAb titer to the 1º serotype, was significantly associated with reduced probability of 2º symptomatic DENV infection, indicating that cross-reactive NAbs determine protection...
Progress on Searching for a Dengue CoP Protection in Nature and Vaccine Trials 10 Nab and vaccine efficacy correlated poorly.
Progress on Searching for a Dengue CoP Protection in Nature and Vaccine Trials 11 Efficacy, Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine (TDV) in Healthy Children (TIDES) NCT02747927 ~21,000 participants Phase III Trial to Evaluate Efficacy and Safety of a Tetravalent Dengue Vaccine NCT02406729 ~17,000 participants Unclear if pursuit of a CoP is a primary, secondary, or exploratory objective of ongoing efficacy trials.
Progress on Searching for a Dengue CoP Human Challenge Studies Infection Model 12 Benchmark immune responses to challenge viruses against natural infection and impact of vaccination on the same.
Progress on Searching for a Dengue CoP Human Challenge Studies Disease Model 13 Assess vaccine performance against challenge viruses which induce mild dengue like illness and associate vaccine induced immune responses.
Progress on Searching for a Dengue CoP Human Challenge Studies Disease Model 14 DENV-3 PRNT <50 = dengue like illness
Summary 15 No proposed immune CoP from dengue disease has been accepted by regulatory agencies. Prospective cohort studies and human challenge studies offer the potential to associate immune profiles with post- DENV exposure outcomes. Defining a CoP in the context of a dengue vaccine trial has been / will be difficult because of the challenge associated with collecting the right number of samples from the right number of volunteers at the right time points measured with the right assay(s).
Thank you.