Betzana Zambrano

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.).

The Epidemiology of Dengue in the Americas Over the Last Three Decades: A Worrisome Reality

We have reported the epidemic patterns of dengue disease in the Region of the Americas from 1980 through 2007. Dengue cases reported to the Pan American Health Organization were analyzed from three periods: 1980-1989 (80s), 1990-1999 (90s), and 2000-2007 (2000-7). Age distribution data were examined from Brazil, Venezuela, Honduras, and Mexico. Cases increased over time: 1,033,417 (80s) to 2,725,405 (90s) to 4,759,007 (2000-7). The highest concentrations were reported in the Hispanic Caribbean (39.1%) in the 80s shifting to the Southern Cone in the 90s (55%) and 2000-7 (62.9%). From 1980 through 1987, 242 deaths were reported compared with 1,391 during 2000-7. The most frequently isolated serotypes were DENV-1 and DENV-2 (90s) and DENV-2 and DENV-3 (2000-7). The highest incidence was observed among adolescents and young adults; dengue hemorrhagic fever incidence was highest among infants in Venezuela. Increasing dengue morbidity/mortality was observed in the Americas in recent decades.

Economic Impact of Dengue Illness in the Americas

The growing burden of dengue in endemic countries and outbreaks in previously unaffected countries stress the need to assess the economic impact of this disease. This paper synthesizes existing studies to calculate the economic burden of dengue illness in the Americas from a societal perspective. Major data sources include national case reporting data from 2000 to 2007, prospective cost of illness studies, and analyses quantifying underreporting in national routine surveillance systems. Dengue illness in the Americas was estimated to cost

The History of Dengue Outbreaks in the Americas

2.1 billion per year on average (in 2010 US dollars), with a range of

Live-attenuated Tetravalent Dengue Vaccine in Dengue-naïve Children, Adolescents, and Adults in Mexico City: Randomized Controlled Phase 1 Trial of Safety and Immunogenicity.

1–4 billion in sensitivity analyses and substantial year to year variation. The results highlight the substantial economic burden from dengue in the Americas. The burden for dengue exceeds that from other viral illnesses, such as human papillomavirus (HPV) or rotavirus. Because this study does not include some components (e.g., vector control), it may still underestimate total economic consequences of dengue.

Immunogenicity and safety of tetravalent dengue vaccine in 2-11 year-olds previously vaccinated against yellow fever: randomized, controlled, phase II study in Piura, Peru.

Dengue is a viral disease usually transmitted by Aedes aegypti mosquitoes. Dengue outbreaks in the Americas reported in medical literature and to the Pan American Health Organization are described. The outbreak history from 1600 to 2010 was categorized into four phases: Introduction of dengue in the Americas (1600-1946); Continental plan for the eradication of the Ae. aegypti (1947-1970) marked by a successful eradication of the mosquito in 18 continental countries by 1962; Ae. aegypti reinfestation (1971-1999) caused by the failure of the mosquito eradication program; Increased dispersion of Ae. aegypti and dengue virus circulation (2000-2010) characterized by a marked increase in the number of outbreaks. During 2010 > 1.7 million dengue cases were reported, with 50,235 severe cases and 1,185 deaths. A dramatic increase in the number of outbreaks has been reported in recent years. Urgent global action is needed to avoid further disease spread.

Safety and Immunogenicity of a Recombinant Tetravalent Dengue Vaccine in 9–16 Year Olds: A Randomized, Controlled, Phase Ii Trial in Latin America

Background: Preliminary results in healthy, young US adults showed that a tetravalent, live-attenuated dengue vaccine (TDV) was safe and immunogenic, but no data are available in children. Methods: In a multicenter, randomized, controlled, observer-blinded study in the city of Mexico, children aged 2 to 5, 6 to 11, and 12 to 17 years (36 children per age group), and adults (n = 18) aged <45 years received the following: 3 injections of TDV at months 0, 3.5, and 12 (TDV-TDV-TDV), or 1 injection of yellow fever vaccine (YF) at month 0, and 2 injections of TDV at months 3.5 and 12 (YF-TDV-TDV). Adverse events and biologic safety (biochemistry and hematology) were documented. Plaque reduction neutralization test (PRNT50) antibody titers against the TDV parental viruses were measured 28 days after vaccination. Seropositivity was defined as antibody titers ≥10 1/dil. Results: No vaccine-related serious adverse events, other significant clinical adverse events, or clinically significant trends in biologic safety were observed. Reactogenicity did not increase with successive TDV injections, and mild-to-moderate injection site pain, headache, myalgia, and malaise were most commonly reported (14%–40% after each vaccination). After 3 TDV vaccinations, the seropositivity rate against each dengue serotype was in the range 77% to 92%, compared with 85% to 94% after completion of the YF-TDV-TDV regimen. Of the 2- to 11-year-old participants, 95% were seropositive against ≥3 serotypes after 3 vaccinations. Conclusions: A 3-dose TDV regimen had a favorable safety profile in children and adults and elicited neutralizing antibody responses against all 4 serotypes. These findings support the continued development of this vaccine.

Symptomatic Dengue in Children in 10 Asian and Latin American Countries

In a randomized, placebo-controlled, monocenter, observer blinded study conducted in an area where dengue is endemic, we assessed the safety and immunogenicity of a recombinant, live, attenuated, tetravalent dengue vaccine candidate (CYD-TDV) in 2-11 year-olds with varying levels of pre-existing yellow-fever immunity due to vaccination 1-7 years previously. 199 children received 3 injections of CYD-TDV (months 0, 6 and 12) and 99 received placebo (months 0 and 6) or pneumococcal polysaccharide vaccine (month 12). One month after the third dengue vaccination, serotype specific neutralizing antibody GMTs were in the range of 178-190 (1/dil) (versus 16.7-38.1 in the control group), a 10-20 fold-increase from baseline, and 94% of vaccines were seropositive to all four serotypes (versus 39% in the control group). There were no vaccine-related SAEs. The observed reactogenicity profile was consistent with phase I studies, with severity grade 1-2 injection site pain, headache, malaise and fever most frequently reported and no increase after subsequent vaccinations. Virologically confirmed dengue cases were seen after completion of the 3 doses: 1 in the CYD-TDV group (N=199), and 3 in the control group (N=99). A 3-dose regimen of CYD-TDV had a good safety profile in 2-11 year olds with a history of YF vaccination and elicited robust antibody responses that were balanced against the four serotypes.

Immunogenicity and safety of a novel yeast Hansenula polymorpha-derived recombinant Hepatitis B candidate vaccine in healthy adolescents and adults aged 10-45 years.

Background: The dengue virus is a member of the Flavivirus (FV) genus, which also includes the yellow fever virus. Dengue disease is caused by any 1 of 4 dengue virus serotypes and is a serious public health concern in Latin America. This study evaluated the safety and immunogenicity of a candidate recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) in 9–16 year olds in Latin America. Methods: In this randomized, blinded, controlled study, volunteers received either 3 doses of CYD-TDV (n = 401) or placebo as first and second injection and tetanus/diphtheria/acellular pertussis vaccine as third injection (n = 199) at 0, 6 and 12 months. Adverse events were documented. Plaque reduction neutralization test antibody titers against the 4 CYD-TDV parental strains were measured before and 28 days after each dose. Seropositivity was defined as antibody titers ≥10 1/dil. Results: The number of adverse reactions decreased after each successive CYD-TDV dose. After each CYD-TDV dose, antibody titers against all 4 serotypes were higher than baseline and respective predose titers. After the third dose of CYD-TDV, 100%, 98.6% and 93.4% of participants were seropositive for at least 2, at least 3 or all 4 serotypes, respectively. Higher antibody titers were observed in participants in the CYD-TDV group who were FV-seropositive at baseline compared with those who were FV-seronegative. Conclusions: CYD-TDV had a favorable safety profile and elicited antibody responses against all 4 dengue virus serotypes in 9–16 year olds in Latin America. These findings support the continued development of CYD-TDV.