A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35, children between the ages of 2 and Ralph Klein Term Paper years in Asian—Pacific and Latin American countries.
We report the results of long-term follow-up interim analyses and integrated efficacy analyses. During year 3 in the CYD14, CYD15, continue reading CYD57 trials combined, hospitalization for virologically confirmed dengue occurred in 65 of 22, participants in the vaccine group and 39 of 11, participants in the control group.
Pooled relative risks of hospitalization for dengue were 0. During year 3, hospitalization for severe dengue, as defined by the independent data monitoring committee criteria, occurred in 18 of 22, participants in the vaccine group and 6 of 11, participants in the control group.
Pooled rates of efficacy for symptomatic dengue during the first 25 months were Ralph Klein Term Paper the unexplained higher incidence of hospitalization for dengue in year 3 among children younger than 9 years of age needs to be carefully monitored during long-term follow-up, the risk among children 2 to 16 years of age was lower in the vaccine group than in the control group.
Ralph Klein and Original Sin
Funded by Sanofi Pasteur; ClinicalTrials. A recombinant, live, attenuated, tetravalent dengue vaccine CYD-TDV has been assessed in two phase 3 randomized efficacy trials involving more than 31, children between the ages of 2 and 14 years in the Asian—Pacific region CYD14 trial and between the ages of 9 and 16 years http://cocktail24.info/blog/esl-persuasive-essay-editor-websites-usa.php Latin America CYD15 trial.
Vaccine efficacy against virologically confirmed dengue and safety were assessed during a month efficacy surveillance phase i.
Reactogenicity and immunogenicity were also assessed in a subgroup of participants. In the ongoing longer-term follow-up from year 3 to year 6 to assess safety, we are monitoring the incidence of hospitalization for dengue continue reading a surrogate end point for disease severity in order to evaluate a potential predisposition in vaccinated persons to increased severity of disease.
The participants were originally randomly assigned in a 2: However, all participants, their parents, and staff members at the study sites remain unaware of the study-group assignments. Full details regarding the three studies are provided in the study protocolavailable with the full text of this article at NEJM.
Hospitalization for acute fever was recorded during study contacts and visits, as well as by self-report and surveillance at nonstudy hospitals. Blood samples during the acute phase of illness were obtained for virologic confirmation of dengue infection see the Methods section in the Supplementary Appendixavailable at NEJM. In the pooled efficacy analyses, we evaluated data from the month efficacy surveillance phase in the CYD14 and CYD15 trials Figure 1.
Sample sizes differed to account for local incidence data. The sponsor designed the trials and performed sample testing and data analyses. The investigators collected the data, and the sponsor and the investigators interpreted the data and collaborated in the preparation of the manuscript. Representatives of the sponsor had complete access to the trial data and vouch for the completeness and accuracy of the data and the analyses. The nonsponsor authors had access to the statistical analyses but not to participant-level data, so that blinding in the ongoing trials could be maintained.
The first draft of the manuscript was written by a medical writer go here was employed by MediCom Consult and was paid by the sponsor.
All the authors provided critical input in the preparation of the manuscript and approved the submitted version. Ages refer to the ages at initial enrollment. The objective of the follow-up analyses was to describe the long-term safety of the dengue candidate vaccine, as recommended by the World Health Organization WHOto verify that the immune response Ralph Klein Term Paper vaccination does not confer a predisposition to severe disease and that the risk of severe disease does not increase with time owing to waning titers of vaccine-induced antibodies in persons in whom immunity has not been naturally boosted.
We are assessing the incidence of hospitalization for virologically confirmed dengue of any severity or any serotype for 4 years after the end of the month efficacy surveillance periods as a Ralph Klein Term Paper outcome for severe disease. For details, see the Methods section in the Supplementary Appendix.
In addition, among the hospitalized participants, we are assessing the occurrence of severe dengue using the criteria of the independent data monitoring committee and the WHO criteria for dengue hemorrhagic fever.
We are recording clinical signs and symptoms of the hospitalized participants to describe the disease profile and are collecting data regarding serious adverse events that occur during the 4-year safety follow-up. The objective of the pooled CYD14 and CYD15 analyses was to assess the efficacy of CYD-TDV against just click for source confirmed dengue, hospitalization for dengue, and severe illness defined according to the criteria of the independent data monitoring committee and the WHO criteria for dengue hemorrhagic fever associated with any serotype.
We repeated the analyses according to age and, in participants in the immunogenicity subgroups, according to baseline dengue serostatus. For the interim analysis of long-term follow-up, the safety analysis set included participants who had received at least one dose of vaccine; participants were analyzed in the group corresponding to the first injection received, regardless of group assignment. For the pooled efficacy analysis of the primary outcome i.
For all other outcomes, the analyses were performed in the intention-to-treat efficacy population, which included all participants who had received at least one injection and who were evaluated in the group to which they had been randomly assigned, regardless of per-protocol criteria see the Methods section in the Supplementary Appendix.
We calculated incidence rates expressed as percentages as Ralph Klein Term Paper number of participants who had at least one event divided by the number of participants present at the start of the study period. Since data were collected for 11 months during year 3 from month 25 to month 36the annual incidence was calculated as the Ralph Klein Term Paper of cases divided by the total number of participants divided by 11 and multiplied by We calculated relative risk as the annual incidence rate ratios in the vaccine and control groups.
The statistical methods that were used for the calculations of estimates of vaccine efficacy have been reported previously.
An analysis of interaction was added in the model to test for heterogeneity, with a P value of less than 0. Suspected interactions were assessed for their clinical and statistical relevance. The vaccine and control groups were well balanced with respect to age and sex Table S1 in Ralph Klein Term Paper Supplementary Appendix. More participants in the CYD15 trial than Ralph Klein Term Paper the CYD14 trial were seropositive for dengue at baseline, although the numbers were similar among those who were 9 years of age or older Fig.
S1 in the Supplementary Appendix. During year 3, the annual incidence of hospitalization for virologically confirmed dengue was 0. The relative risk of hospitalization for virologically confirmed dengue in the vaccine group as compared with the control group was 1.
The pooled relative risk for the three trials was 0. The majority of patients had serotype 1 or 2 infection; serotype 4 was the least frequently identified serotype Table 1.
No clinically important differences in the frequencies of signs and symptoms were observed between the vaccine and control groups, suggesting that there were no vaccine-related changes in the clinical picture of hospitalized participants. Similar levels of viremia were observed among hospitalized participants in the vaccine group and the control group Table S3 in the Supplementary Appendix.
Overall, during year 3, severe dengue, defined according to the criteria of the independent data monitoring committee, was reported in 18 of 22, participants in the vaccine group and in 6 of 11, in the control group Table S4 in the Supplementary Appendix. All the Ralph Klein Term Paper who were hospitalized for virologically confirmed dengue during follow-up had a full recovery after receiving appropriate supportive treatment. In the CYD14 trial, prespecified age-specific analyses showed a clear trend toward a higher relative risk for hospitalization for virologically confirmed dengue among younger children, although the number of cases was low; the relative risks were 7.
Further analyses in the CYD15 trial, in which participants between the ages of 9 and 16 years were enrolled, showed no trend according to age group among those who were between the ages of 9 and 11 years and those who were between the ages of 12 and 16 years. The relative risk among those who were 9 years of age or older was Ralph Klein Term Paper.
The pooled relative risk among participants who were 9 years of age or older was 0. An exploratory analysis in the CYD14 trial showed that among participants between the ages of 9 and 11 years, the relative risk was 1.
This trend was not observed in the CYD15 trial Table 1. In year 4 in the CYD57 trial, the relative risk among participants who were 9 years of age or older was similar to that in year 3 relative risk, 0. In the CYD14 trial, among participants younger than 9 years of age who were hospitalized article source dengue, severe disease according to the criteria of the independent data monitoring committee occurred in 8 of 19 participants in the vaccine group and in none of 6 participants in the placebo group relative risk could not be calculated.
Among those who were 9 years of age or older, severe disease occurred in 3 of 8 participants in the vaccine group and in 1 of 7 participants in the control group Ralph Klein Term Paper risk, 1. The three cases in the vaccine group occurred in participants who were between the ages of 9 and 11 years at enrollment.
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In year 3, the two participants in the vaccine Ralph Klein Term Paper in whom the illness was classified as grade III dengue hemorrhagic fever according to the WHO criteria had clinical shock.
For year 3, the overall pooled estimate of the relative risk of hospitalization for severe dengue was 1. The pooled relative risk was driven mainly by the cases occurring in participants younger than 9 years of age. Although the relative risk of hospitalization for dengue varied in the three studies, within-trial estimates showed reductions in risk in the vaccine group during years 1 and 2 of the efficacy surveillance phase.
Cumulative relative risks for hospitalizations that occurred more than 3 years after vaccination were 0. Cumulative relative risks during this period in the CYD14 trial were 0. A Kaplan—Meier plot showed that there was greater protection among participants who were 9 years of age or older than among those who were under the age of 9 years, and the incidence appeared to be stable Fig.
S2 in the Supplementary Appendix. Cases occurred throughout the follow-up, with similar accrual patterns over time. The length of hospitalization and duration of fever and clinical symptoms were similar for those hospitalized during the efficacy surveillance phase and the long-term follow-up phase in all three trials Tables S2A, S2B, and S2C in the Supplementary Appendix.
No clinically important differences in the frequencies of various signs and symptoms in the hospitalized participants were seen between the efficacy surveillance phase and the long-term follow-up phase in any of the studies or between the vaccine and control groups, which suggests there were no changes in the clinical picture of hospitalized cases during long-term follow-up. The levels of viremia were similar to those in the efficacy surveillance phase and similar between groups Table S3 in the Ralph Klein Term Paper Appendix.
Vaccine efficacies for dengue caused by any Ralph Klein Term Paper each serotype were generally consistent in the per-protocol and intention-to-treat analyses in the individual trials and in the pooled analyses for all outcomes, but Ralph Klein Term Paper analyses including age as a categorical variable age group or as a continuous variable showed significant interaction between age and vaccine group Fig.
S3 through S6 in the Supplementary Appendix. As compared with vaccine efficacies among all participants, for all outcomes, efficacies were higher among participants who were 9 years of age or older and lower among participants who were under 9 years of age.
Vaccine efficacies against dengue in participants who were 9 years of age or older were similar in the individual trials, with a pooled estimate of The pooled serotype-specific vaccine efficacies for this outcome ranged from Among those under the age of 9 years, the range was from Pooled vaccine efficacy among seropositive participants was However, the pooled vaccine efficacy in this age Ralph Klein Term Paper was Pooled vaccine efficacies for severe dengue, as defined according to the click of the independent data monitoring committee, were The vaccine efficacies against dengue hemorrhagic fever, as defined according to the WHO criteria, were However, the relative risk in the vaccine group shifted to 1.
The combined analysis of the CYD14, CYD15, and CYD57 trials during year 3 showed a lower risk of hospitalization for dengue among participants who were 9 years of age or older in the vaccine group than among those in the control group.
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This reduction in risk was not observed among children under the age of 9 years. However, variability in the relative risks between year 3 1. Hospitalization for dengue was used as an end point to minimize the risk of underreporting during long-term follow-up, since participants with more severe febrile illness are more likely to be hospitalized than are those with mild illness. Although hospitalization practices vary among countries and among health care centers in the same country, randomization should have assured a similar likelihood of hospitalization among vaccinated and unvaccinated participants in each center.
Data are limited regarding markers of dengue severity, and some of such markers e. Since the methods that were used to capture hospitalization for dengue in the CYD14 and CYD15 trials differ between the efficacy surveillance phase and the long-term follow-up phase, the comparisons of relative risks for the two phases and the relative risks for the entire studies should be interpreted with caution as well.
Although there were more hospitalizations and cases of severe dengue click here among participants under the age of 9 years than among those older than 9 years of age in Ralph Klein Term Paper vaccine group, the clinical pattern of these cases during the long-term follow-up Ralph Klein Term Paper phase was similar to that reported for hospitalization during the efficacy surveillance phase, with no observed differences in clinical severity or viremia.
In all cases, the participants had a complete recovery.
In addition, there were no significant differences between cases occurring in the vaccine group and the source group among participants under the age of 9 years.
Ongoing safety review during long-term follow-up monitors cases between the planned interim analyses. Available clinical data are insufficient for drawing definitive conclusions about the observed imbalance in younger children.
However, on-site investigations have shown that major forms of bias e.