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Controversy and debate on dengue vaccine series—paper 2: response to review of a licensed dengue vaccine: inappropriate subgroup analyses and selective reporting may cause harm in mass vaccination programs

      We would like to provide our comments on Dans et al. “Review of a licensed dengue vaccine: Inappropriate subgroup analyses and selective reporting may cause harm in mass vaccination programs”:
      • -
        Dans et al. limited their analysis to the CYD14 (Asian) trial citing that vaccine response may vary between regions and focused only on safety analysis from the 3rd–6th years. An assessment of the impact of any vaccine must be performed in its totality and not over an isolated time window. Observations from year 3 of the studies were described in the original publications; however, it is not possible to extrapolate these to the full study period. Findings from the CYD14 and CYD15 (Latin American) efficacy studies, which have similar study design, report that consistent results demonstrating overall vaccine efficacy does not vary between regions. To date, up to year 5 of the trials [
        • Hadinegoro S.R.
        • Arredondo-García J.L.
        • Capeding M.R.
        • Deseda C.
        • Chotpitayasunondh T.
        • Dietze R.
        • et al.
        Efficacy and long-term safety of a dengue vaccine in regions of endemic disease.
        ,
        • Sabchaeron A.
        • Wallace D.
        • Sirivichayakul C.
        • Limkittikul K.
        • Chanthavanich P.
        • Suvannadabba S.
        • et al.
        Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai school-children: a randomised, controlled phase 2b trial.
        ,
        • Villar L.
        • Dayan G.H.
        • Arredondo-Garcia J.L.
        • Rivera D.M.
        • Cunha R.
        • Deseda C.
        • et al.
        Efficacy of a tetravalent dengue vaccine in children in Latin America.
        ,
        • Capeding M.R.
        • Tran N.H.
        • Hadinegoro S.R.
        • Ismail H.I.
        • Chotpitayasunondh T.
        • Chua M.N.
        • et al.
        Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomized, observer-masked, placebo-controlled trial.
        ,
        • Hadinegoro S.R.
        • Wartel Tram A.
        • Frago C.
        • Zambrano B.
        • Langevin E.
        • Gailhardou S.
        • et al.
        Long-term safety of the CYD-TDV dengue vaccine in Asia-Pacific dengue endemic countries.
        ,
        • Cortes M.
        • Zambrano B.
        • Reynales H.
        • Langevin E.
        • Owen H.
        • Noriega F.
        Long-term safety of a CYD-TDV dengue vaccine in Latin American dengue endemic countries.
        ], we have not detected a significant excess risk in the separate studies, or by meta-analysis.
      • -
        The authors reviewed the limitations of the meta-analysis as a post hoc analysis and suggested there was no biological basis for the 9-year old threshold. The selection of age ≥9 years is primarily driven by preplanned analysis of relative risk in the age group ≥9 years (i.e., CYD15 wherein >20,000 subjects aged 9–16 years participated) showing a consistent trend in results, which was also observed in the subjects aged ≥9 years (post hoc analysis) in CYD14 and CYD57. Consistency of the findings forms part of the Bradford-Hill criteria [
        • Fedak K.M.
        • Bernal A.
        • Capshaw Z.A.
        • Gross S.
        Applying the Bradford Hill criteria in the 21st century: how data integration has changed causal inference in molecular epidemiology.
        ] confirming the robustness of data.
      • -
        Dans et al. failed to note that hospitalized dengue, regardless of severity, was an observational outcome of our study. Hospitalization is open to the assessment of the treating physician and not controlled by standardized clinical criteria; substantial differences between countries are driven by in-country clinical practices.
      • -
        Finally, the authors cannot definitively attribute severe dengue to antibody-dependent enhancement (ADE). ADE, observed with various viral pathogens [
        • Guy B.
        • Jackson N.
        Dengue vaccine: hypotheses to understand CYD-TDV-induced protection.
        ], is one of the possible theories explaining the pathophysiology of severe dengue [
        • Guy B.
        • Jackson N.
        Dengue vaccine: hypotheses to understand CYD-TDV-induced protection.
        ,
        • Gessner B.D.
        • Halsey N.
        Dengue vaccine safety signal:immune enhancement, waning immunity or chance occurrence?.
        ]. In vitro testing of samples from Dengvaxia™ recipients and cell-mediated immunity studies did not support this phenomenon [
        • Guy B.
        • Jackson N.
        Dengue vaccine: hypotheses to understand CYD-TDV-induced protection.
        ,
        • Harenberg A.
        • de Montfort A.
        • Jantet-Blaudez F.
        • Bonaparte M.
        • Boudet F.
        • Saville M.
        • et al.
        Cytokine profile of children hospitalized with virologically-confirmed dengue during two phase III vaccine efficacy trials.
        ,
        • Guy B.
        Which dengue vaccine approach is the most promising and should we be concerned about enhanced disease after vaccination?.
        ]. The vaccine initiates humoral and cell-mediated immune responses against all four serotypes [
        • Vigne C.
        • Dupuy M.
        • Richetin A.
        • Guy B.
        • Jackson N.
        • Bonaparte M.
        • et al.
        Integrated immunogenicity analysis of a tetravalent dengue vaccine up to 4 y after vaccination.
        ]. The excess hospitalized cases during year 3, in younger vaccinees, may be explained by an increase in a susceptible population, primarily composed of baseline naïve subjects with lower immune response [
        • Guy B.
        • Jackson N.
        Dengue vaccine: hypotheses to understand CYD-TDV-induced protection.
        ]. Recent investigations suggest a homotypic type response to one serotype and cross-reactive responses against other serotypes in seronegative individuals [
        • Guy B.
        Which dengue vaccine approach is the most promising and should we be concerned about enhanced disease after vaccination?.
        ]. Vaccination with 3 doses may partially mimic an attenuated, subclinical primary infection in seronegative and attenuated, subclinical heterotypic second wild-type-like infection in seropositive individuals [
        • Guy B.
        Which dengue vaccine approach is the most promising and should we be concerned about enhanced disease after vaccination?.
        ]. There is also the possibility of waning immunity wherein the kinetics differ between vaccine-induced and natural immunity rather than an increased risk of severe disease [
        • Gessner B.D.
        • Halsey N.
        Dengue vaccine safety signal:immune enhancement, waning immunity or chance occurrence?.
        ,
        • Guy B.
        Which dengue vaccine approach is the most promising and should we be concerned about enhanced disease after vaccination?.
        ]. Chance occurrence and a combination of theories had also been proposed [
        • Gessner B.D.
        • Halsey N.
        Dengue vaccine safety signal:immune enhancement, waning immunity or chance occurrence?.
        ]. We therefore recommend that scientific dialogue remains open while more data are gathered and shared with the scientific community when available.
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