Cyd child biography sample

Essential revisions:

These revisions either reflect a need to temper some of the claims made in the paper or to improve clarity of the work.

1) The authors assume in their models that immunity wanes in seronegatives (over 1 year) and is stable in seropositives (maintained over time). It is unclear why these assumptions were made and clarification is needed.

We have now amended our analysis to infer these durations, rather than assume them. The original rationale for fixing these values was that they were imprecisely inferred, although the overall picture was that of short-lived seronegative immunity and long-lived seropositive immunity. Further, it is arguable that three years of follow-up data is insufficient to infer duration. On reflection, we agree with the reviewers that it is more transparent to fit these parameters rather than fix them, and explain where they are imprecisely inferred. We have amended the manuscript throughout to reflect these changes.

2) The authors should adjust the statement "vaccinating seropositives gives greater long-lasting immunity than two natural infections" to reflect the fact that immunity in seropositives may also wane over time in a way that cannot be accurately measured with the current data.

This is a fair point and we have amended the text in the abstract to read, “Our modelling indicates that vaccine-induced immunity is long-lived in seropositive recipients, and therefore that vaccinating seropositives gives higher protection than two natural infections.” to make it clearer. We have also included this point in the discussion text (e.g. lines 614-621) where we are less constrained by word limits.

As our model fits the durations of what we now term “transient immunity”, this conclusion is less dependent on our model assumptions and more dependent on fitted parameter values. We think this conclusion is now sufficiently justified and caveated, and that vaccine benefit to multitypic immune subjects remains an importan

Abstract

Background

Two large-scale efficacy studies with the recombinant yellow fever-17D–dengue virus, live-attenuated, tetravalent dengue vaccine (CYD-TDV) candidate undertaken in Asia (NCT01373281) and Latin America (NCT01374516) demonstrated significant protection against dengue disease during two years’ active surveillance (active phase). Long-term follow up of participants for breakthrough disease leading to hospitalization is currently ongoing (hospital phase).

Methodology/Principal findings

We assessed the cytokine profile in acute sera from selected participants hospitalized (including during the active phase) up to the beginning of the second year of long-term follow up for both studies. The serum concentrations of 38 cytokines were measured in duplicate using the Milliplex Human Cytokine MAGNETIC BEAD Premixed 38 Plex commercial kit (Millipore, Billerica, MA, USA). Partial least squares discriminant analyses did not reveal any difference in the overall cytokine profile of CYD-TDV and placebo recipients hospitalized for breakthrough dengue regardless of stratification used. In addition, there was no difference in the cytokine profile for breakthrough dengue among those aged <9 years versus those aged ≥ 9 years.

Conclusions/Significance

These exploratory findings show that CYD-TDV does not induce a particular immune profile versus placebo, corroborating the clinical profile observed.

Author Summary

A live-attenuated, tetravalent dengue vaccine (CYD-TDV) has been shown to provide protection against dengue disease in two large-scale, placebo-controlled, phase III efficacy studies. Continued surveillance of study participants was subsequently undertaken to better define longer term vaccine efficacy and safety. A yet unexplained higher incidence of hospitalization for dengue disease was observed among children aged <9 years in year 3 of follow up. While the clinical outcome of the hospitalized cases was similar between CYD-TDV and placebo reci