Fernando Noriega

Efficacy of a Tetravalent Dengue Vaccine in Children in Latin America

BACKGROUND In light of the increasing rate of dengue infections throughout the world despite vector-control measures, several dengue vaccine candidates are in development. METHODS In a phase 3 efficacy trial of a tetravalent dengue vaccine in five Latin American countries where dengue is endemic, we randomly assigned healthy children between the ages of 9 and 16 years in a 2:1 ratio to receive three injections of recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) or placebo at months 0, 6, and 12 under blinded conditions. The children were then followed for 25 months. The primary outcome was vaccine efficacy against symptomatic, virologically confirmed dengue (VCD), regardless of disease severity or serotype, occurring more than 28 days after the third injection. RESULTS A total of 20,869 healthy children received either vaccine or placebo. At baseline, 79.4% of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes. In the per-protocol population, there were 176 VCD cases (with 11,793 person-years at risk) in the vaccine group and 221 VCD cases (with 5809 person-years at risk) in the control group, for a vaccine efficacy of 60.8% (95% confidence interval [CI], 52.0 to 68.0). In the intention-to-treat population (those who received at least one injection), vaccine efficacy was 64.7% (95% CI, 58.7 to 69.8). Serotype-specific vaccine efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74.0% for serotype 3, and 77.7% for serotype 4. Among the severe VCD cases, 1 of 12 was in the vaccine group, for an intention-to-treat vaccine efficacy of 95.5%. Vaccine efficacy against hospitalization for dengue was 80.3%. The safety profile for the CYD-TDV vaccine was similar to that for placebo, with no marked difference in rates of adverse events. CONCLUSIONS The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01374516.).

Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease

BACKGROUND A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian-Pacific and Latin American countries. We report the results of long-term follow-up interim analyses and integrated efficacy analyses. METHODS We are assessing the incidence of hospitalization for virologically confirmed dengue as a surrogate safety end point during follow-up in years 3 to 6 of two phase 3 trials, CYD14 and CYD15, and a phase 2b trial, CYD23/57. We estimated vaccine efficacy using pooled data from the first 25 months of CYD14 and CYD15. RESULTS Follow-up data were available for 10,165 of 10,275 participants (99%) in CYD14 and 19,898 of 20,869 participants (95%) in CYD15. Data were available for 3203 of the 4002 participants (80%) in the CYD23 trial included in CYD57. During year 3 in the CYD14, CYD15, and CYD57 trials combined, hospitalization for virologically confirmed dengue occurred in 65 of 22,177 participants in the vaccine group and 39 of 11,089 participants in the control group. Pooled relative risks of hospitalization for dengue were 0.84 (95% confidence interval [CI], 0.56 to 1.24) among all participants, 1.58 (95% CI, 0.83 to 3.02) among those under the age of 9 years, and 0.50 (95% CI, 0.29 to 0.86) among those 9 years of age or older. During year 3, hospitalization for severe dengue, as defined by the independent data monitoring committee criteria, occurred in 18 of 22,177 participants in the vaccine group and 6 of 11,089 participants in the control group. Pooled rates of efficacy for symptomatic dengue during the first 25 months were 60.3% (95% CI, 55.7 to 64.5) for all participants, 65.6% (95% CI, 60.7 to 69.9) for those 9 years of age or older, and 44.6% (95% CI, 31.6 to 55.0) for those younger than 9 years of age. CONCLUSIONS Although 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. (Funded by Sanofi Pasteur; ClinicalTrials.gov numbers, NCT00842530, NCT01983553, NCT01373281, and NCT01374516.).

Immunogenicity and Safety of a Recombinant Tetravalent Dengue Vaccine in Children and Adolescents Ages 9–16 Years in Brazil

Immunogenicity and safety of a recombinant, live-attenuated, tetravalent dengue disease vaccine (CYD-TDV) was evaluated in children/adolescents in Brazil. In this observer-blind, placebo-controlled, phase II single-center study, children/adolescents (ages 9–16 years) were randomized to receive CYD-TDV or placebo at 0, 6, and 12 months. Immunogenicity was assessed using a 50% plaque neutralization test. Overall, 150 participants were enrolled (CYD-TDV: N = 100; placebo: N = 50). Injection site pain and headache were the most common solicited injection site and systemic reactions. Unsolicited adverse events (AEs) and serious AEs were similar between groups. No serious AEs were vaccine-related. Geometric mean titers against all dengue virus serotypes increased with CYD-TDV vaccination and were 267, 544, 741, and 432 1/dil for serotypes 1–4, respectively, after dose 3, representing a mean fold increase from baseline of 5, 6, 6, and 20, respectively. CYD-TDV vaccination elicited a neutralizing antibody response against serotypes 1–4 and was well-tolerated in children/adolescents in a dengue-endemic region.

A comparative study on active and passive epidemiological surveillance for dengue in five countries of Latin America

BACKGROUND Dengue is a notifiable infectious disease in many countries, but under-reporting of cases to National Epidemiological Surveillance Systems (NESSs) conceals the true extent of the disease burden. The incidence of dengue identified in a cohort study was compared with those reported to NESSs. METHODS A randomized, placebo-controlled study was undertaken in Brazil, Colombia, Honduras, Mexico, and Puerto Rico to assess the efficacy of a tetravalent dengue vaccine (CYD-TDV) in children aged 9-16 years. The incidence of dengue in the placebo group was compared with that reported to NESSs in a similar age group (10-19 years) from June 2011 to April 2014. RESULTS Three thousand six hundred and fifteen suspected dengue cases were identified in the study over 13527 person-years of observation. The overall incidence of confirmed dengue was 2.9 per 100 person-years (range 1.5 to 4.1 per 100 person-years). In the NESSs combined, over 3.2 million suspected dengue cases were reported during the same period, corresponding to over 1 billion person-years of observation. The incidence of confirmed dengue reported by the NESSs in the same locality where the study took place was 0.286 per 100 person-years across Brazil, Colombia, and Mexico (range 0.180 to 0.734 per 100 person-years). The incidence of confirmed dengue was 10.0-fold higher in the study than that reported to NESSs in the same localities (range 3.5- to 19.4-fold higher). CONCLUSIONS There is a substantial under-reporting of dengue in the NESSs. Understanding the level of under-reporting would allow more accurate estimates of the dengue burden in Latin America.

Tetravalent Dengue Vaccine Reduces Symptomatic and Asymptomatic Dengue Virus Infections in Healthy Children and Adolescents Aged 2–16 Years in Asia and Latin America

Background. Asymptomatic dengue virus–infected individuals are thought to play a major role in dengue virus transmission. The efficacy of the recently approved quadrivalent CYD-TDV dengue vaccine against asymptomatic dengue virus infection has not been previously assessed. Methods. We pooled data for 3 736 individuals who received either CYD-TDV or placebo at 0, 6, and 12 months in the immunogenicity subsets of 2 phase 3 trials (clinical trials registration NCT01373281 and NCT01374516). We defined a seroconversion algorithm (ie, a ≥4-fold increase in the neutralizing antibody titer and a titer of ≥40 from month 13 to month 25) as a surrogate marker of asymptomatic infection in the vaccine and placebo groups. Results. The algorithm detected seroconversion in 94% of individuals with a diagnosis of virologically confirmed dengue between months 13 and 25, validating its discriminatory power. Among those without virologically confirmed dengue (n = 3 669), 219 of 2 485 in the vaccine group and 157 of 1 184 in the placebo group seroconverted between months 13 and 25, giving a vaccine efficacy of 33.5% (95% confidence interval [CI], 17.9%–46.1%) against asymptomatic infection. Vaccine efficacy was marginally higher in subjects aged 9–16 years (38.6%; 95% CI, 22.1%–51.5%). The annual incidence of asymptomatic dengue virus infection in this age group was 14.8%, which was 4.4 times higher than the incidence for symptomatic dengue (3.4%). Conclusions. The observed vaccine efficacy against asymptomatic dengue virus infections is expected to translate into reduced dengue virus transmission if sufficient individuals are vaccinated in dengue-endemic areas.

Prediction of pertussis vaccine efficacy using a correlates of protection model

A previously developed statistical model relates vaccine immune responses to protection against pertussis disease in a household contact setting. Before this model can be used to predict the risk of disease based on immune responses, it must be validated to demonstrate reliable predictions. The model is shown here to be validated in terms of statistical criteria (Prentice surrogacy measures) as well as predictive capability in an independent efficacy trial (meta-analysis). Additionally, the model is used to predict efficacy from two recent immunogenicity trials comparing a 5-component acellular pertussis pentavalent combination vaccine with separate administration of its vaccine components. The model predicted similar protective efficacy rates: 82% after three doses and 83% after four doses. Follow-up of these subjects the model also predicted sustained and comparable efficacy for the combination and separate vaccines (75%) up to the pre-school booster age.

Effect of Dengue Serostatus on Dengue Vaccine Safety and Efficacy

Background In efficacy trials of a tetravalent dengue vaccine (CYD‐TDV), excess hospitalizations for dengue were observed among vaccine recipients 2 to 5 years of age. Precise risk estimates according to observed dengue serostatus could not be ascertained because of the limited numbers of samples collected at baseline. We developed a dengue anti–nonstructural protein 1 (NS1) IgG enzyme‐linked immunosorbent assay and used samples from month 13 to infer serostatus for a post hoc analysis of safety and efficacy. Methods In a case–cohort study, we reanalyzed data from three efficacy trials. For the principal analyses, we used baseline serostatus determined on the basis of measured (when baseline values were available) or imputed (when baseline values were missing) titers from a 50% plaque‐reduction neutralization test (PRNT50), with imputation conducted with the use of covariates that included the month 13 anti‐NS1 assay results. The risk of hospitalization for virologically confirmed dengue (VCD), of severe VCD, and of symptomatic VCD according to dengue serostatus was estimated by weighted Cox regression and targeted minimum loss–based estimation. Results Among dengue‐seronegative participants 2 to 16 years of age, the cumulative 5‐year incidence of hospitalization for VCD was 3.06% among vaccine recipients and 1.87% among controls, with a hazard ratio (vaccine vs. control) through data cutoff of 1.75 (95% confidence interval [CI], 1.14 to 2.70). Among dengue‐seronegative participants 9 to 16 years of age, the cumulative incidence of hospitalization for VCD was 1.57% among vaccine recipients and 1.09% among controls, with a hazard ratio of 1.41 (95% CI, 0.74 to 2.68). Similar trends toward a higher risk among seronegative vaccine recipients than among seronegative controls were also found for severe VCD. Among dengue‐seropositive participants 2 to 16 years of age and those 9 to 16 years of age, the cumulative incidence of hospitalization for VCD was 0.75% and 0.38%, respectively, among vaccine recipients and 2.47% and 1.88% among controls, with hazard ratios of 0.32 (95% CI, 0.23 to 0.45) and 0.21 (95% CI, 0.14 to 0.31). The risk of severe VCD was also lower among seropositive vaccine recipients than among seropositive controls. Conclusions CYD‐TDV protected against severe VCD and hospitalization for VCD for 5 years in persons who had exposure to dengue before vaccination, and there was evidence of a higher risk of these outcomes in vaccinated persons who had not been exposed to dengue. (Funded by Sanofi Pasteur; ClinicalTrials.gov numbers, NCT00842530, NCT01983553, NCT01373281, and NCT01374516.)

Epidemiology of Clostridium difficile: a hospital-based descriptive study in Argentina and Mexico

A prospective study was conducted in four tertiary hospitals in Argentina and Mexico in order to describe the occurrence of Clostridium difficile infection (CDI) in these settings. The objective was to evaluate the incidence of CDI in at-risk populations in Argentina (one center) and Mexico (three centers) and to further explore potential study sites for vaccine development in this region. A prospective, descriptive, CDI surveillance study was conducted among hospitalized patients aged ≥40 years who had received ≥48h of antibiotic treatment. Stool samples were collected from those with diarrhea within 30 days after starting antibiotics and analyzed for toxins A and B by ELISA, and positive samples were further tested by toxinogenic culture and restriction endonuclease analysis type assay. Overall, 466 patients were enrolled (193 in Argentina and 273 in Mexico) of whom 414 completed the follow-up. Of these, 15/414 (3.6%) experienced CDI episodes occurring on average 18.1 days after admission to hospital and 15.9 days after the end of antibiotics treatment. The incidence rate of CDI was 3.1 (95% CI 1.7-5.2) per 1000 patient-days during hospitalization, and 1.1 (95% CI 0.6-1.8) per 1000 patient-days during the 30-day follow-up period. This study highlighted the need for further evaluation of the burden of CDI in both countries, including the cases occurring after discharge from hospital.

Neutralizing Antibody Correlates Analysis of Tetravalent Dengue Vaccine Efficacy Trials in Asia and Latin America

Background In the CYD14 and CYD15 Phase 3 trials of the CYD-TDV dengue vaccine, estimated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue (VCD) occurring between months 13 and 25 was 56.5% and 60.8%, respectively. Methods Neutralizing antibody titers to the 4 dengue serotypes in the CYD-TDV vaccine insert were measured at month 13 in a randomly sampled immunogenicity subcohort and in all VCD cases through month 25 (2848 vaccine, 1574 placebo) and studied for their association with VCD and with the level of VE to prevent VCD. Results For each trial and serotype, vaccinees with higher month 13 titer to the serotype had significantly lower risk of VCD with that serotype (hazard ratios, 0.19-0.43 per 10-fold increase). Moreover, for each trial, vaccinees with higher month 13 average titer to the 4 serotypes had significantly higher VE against VCD of any serotype (P < .001). Conclusions Neutralizing antibody titers postdose 3 correlate with CYD-TDV VE to prevent dengue. High titers associate with high VE for all serotypes, baseline serostatus groups, age groups, and both trials. However, lowest titers do not fully correspond to zero VE, indicating that other factors influence VE.

Prospective Cohort Study with Active Surveillance for Fever in Four Dengue Endemic Countries in Latin America

To prepare for a Phase III dengue vaccine efficacy trial, 20 investigational sites were selected for this observational study to identify dengue infections in a closed cohort (N = 3,000 children 9–16 years of age). Of 255 acute febrile episodes experienced by 235 children, 50 (21.3%) were considered serologically probable dengue, and 18 (7.7%) were considered virologically confirmed (i.e., dengue NS1 antigen positive) dengue cases. Considering the disease-free and at-risk period from study start to onset of symptoms, the overall incidence density of acute febrile episodes was 17.7 per 100 person-years of follow-up, ranging from 15.3 in Colombia to 22.0 in Puerto Rico. This study showed that all sites were capable of capturing and following up acute febrile episodes within a specific timeframe among the established cohort and to detect dengue cases.