Dengue Endemicity, Force of Infection, and Variation in Transmission Intensity in 13 Endemic Countries.

Dengue endemicity varies but comparative, multicountry data are extremely limited. An improved understanding is needed to prioritize prevention, including vaccination, which is currently recommended only under specific epidemiological conditions. We used serological study data from 46 geographical sites in 13 countries to estimate dengue force of infection (FOI, the proportion of children seroconverting per year) under assumptions of either age-constant or age-varying FOI, and the age at which 50% and 80% of children had been infected. After exclusions, 13 661 subjects were included. Estimated constant FOI varied widely, from 1.7% (Singapore) to 24.1% (the Philippines). In the site-level analysis 44 sites (96%) reached 50% seroconversion and 35 sites (75%) reached 80% seroconversion by age 18 years, with significant heterogeneity. These findings confirm that children living in dengue-endemic countries receive intense early dengue exposure, increasing risk of secondary infection, and imply serosurveys at fine spatial resolutions are needed to inform vaccination campaigns.

Analysis of Hospitalized and Severe Dengue Cases Over the 6 years of Follow-up of the Tetravalent Dengue Vaccine (CYD-TDV) Efficacy Trials in Asia and Latin America.

BACKGROUND: CYD-TDV, a live, attenuated, tetravalent dengue vaccine, has been approved for the prevention of symptomatic dengue in previously dengue exposed individuals. This post hoc analysis assessed hospitalized and severe virologically confirmed dengue (VCD) over the complete 6-year follow-up of 3 CYD-TDV efficacy studies (CYD14, CYD15, and CYD23/CYD57). METHODS: The main outcomes were hazard ratios (HRs) for hospitalized or severe VCD by baseline dengue serostatus, focusing on those who were seropositive, and by age at immunization (<9 years/≥9 years). Baseline dengue serostatus was measured or inferred using several methods. Hospitalized VCD cases were characterized in terms of clinical signs and symptoms and wild-type viremia level. Antibody persistence was assessed up to 5 years after the last injection. RESULTS: In those aged ≥9 years and baseline seropositive, CYD-TDV protected against hospitalized and severe VCD over 6 years compared to placebo (HR [95% confidence interval] multiple imputation from month 0 method, .19 [.12-.30] and .15 [.06-.39]; other methods were consistent). Vaccine protection was observed over the different study periods, being highest during the first 2 years. Evidence for a decreased risk of hospitalized and severe VCD was also observed in seropositive participants aged 6-8 years. Clinical signs and symptoms, and quantified dengue viremia from participants with hospitalized VCD were comparable between groups. CONCLUSIONS: CYD-TDV demonstrated robust protection against hospitalized and severe VCD over the entire 6-year follow-up in participants who were seropositive and ≥9 years old. Protection was also observed in seropositive 6-8 year-olds. Clinical Trials Registration: NCT00842530, NCT01983553, NCT01373281, NCT01374516.

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 .).

Serological Evidence of Japanese Encephalitis Virus Circulation in Asian Children From Dengue-Endemic Countries.

Background: Japanese encephalitis virus (JEV) is a zoonotic, mosquito-borne flavivirus, distributed across Asia. Infections are mostly mild or asymptomatic, but symptoms include neurological disorders, sequelae, and fatalities. Data to inform control strategies are limited due to incomplete case reporting. Methods: We used JEV serological data from a multicountry Asian dengue vaccine study in children aged 2-14 years to describe JEV endemicity, measuring antibodies by plaque reduction neutralization test (PRNT50). Results: A total 1479 unvaccinated subjects were included. A minimal estimate of pediatric JEV seroprevalence in dengue-naive individuals was 8.1% in Indonesia, 5.8% in Malaysia, 10.8% in the Philippines, and 30.7% in Vietnam, translating to annual infection risks varying from 0.8% (in Malaysia) to 5.2% (in Vietnam). JEV seroprevalence and annual infection estimates were much higher in children with history of dengue infection, indicating cross-neutralization within the JEV PRNT50 assay. Conclusions: These data confirm JEV transmission across predominantly urban areas and support a greater emphasis on JEV case finding, diagnosis, and prevention.

Five-Year Antibody Persistence Following a Japanese Encephalitis Chimeric Virus Vaccine (JE-CV) Booster in JE-CV-Primed Children in the Philippines.

Clinical Trials Registration: NCT01190228.

Impact of Dengue Vaccination on Serological Diagnosis: Insights From Phase III Dengue Vaccine Efficacy Trials.

Background: We previously reported that vaccination with the tetravalent dengue vaccine (CYD-TDV; Dengvaxia) may bias the diagnosis of dengue based on immunoglobulin M (IgM) and immunoglobulin G (IgG) assessments. Methods: We undertook a post hoc pooled analysis of febrile episodes that occurred during the active surveillance phase (the 25 months after the first study injection) of 2 pivotal phase III, placebo-controlled CYD-TDV efficacy studies that involved ≥31000 children aged 2-16 years across 10 countries in Asia and Latin America. Virologically confirmed dengue (VCD) episode was defined with a positive test for dengue nonstructural protein 1 antigen or dengue polymerase chain reaction. Probable dengue episode was serologically defined as (1) IgM-positive acute- or convalescent-phase sample, or (2) IgG-positive acute-phase sample and ≥4-fold IgG increase between acute- and convalescent-phase samples. Results: There were 1284 VCD episodes (575 and 709 in the CYD-TDV and placebo groups, respectively) and 17673 other febrile episodes (11668 and 6005, respectively). Compared with VCD, the sensitivity and specificity of probable dengue definition were 93.1% and 77.2%, respectively. Overall positive and negative predictive values were 22.9% and 99.5%, respectively, reflecting the much lower probability of correctly confirming probable dengue in a population including a vaccinated cohort. Vaccination-induced bias toward false-positive diagnosis was more pronounced among individuals seronegative at baseline. Conclusions: Caution will be required when interpreting IgM and IgG data obtained during routine surveillance in those vaccinated with CYD-TDV. There is an urgent need for new practical, dengue-specific diagnostic algorithms now that CYD-TDV is approved in a number of dengue-endemic countries. Clinical Trials Registration: NCT01373281 and 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.).

Persistence of Wild-Type Japanese Encephalitis Virus Strains Cross-Neutralization 5 Years After JE-CV Immunization.

BACKGROUND: The live-attenuated Japanese encephalitis (JE) vaccine (JE-CV; IMOJEV) induces a protective response in children. A shift in circulating JE virus strains suggests that a genotype shift phenomenon may occur throughout Southeast Asia. We assessed the neutralization of wild-type (WT) JE virus isolates at distal time points after vaccination. METHODS: We analyzed serum samples from a subset of 47 children who had received a JE-CV booster after an inactivated JE vaccine primary immunization. We measured antibody titers (50% plaque reduction neutralization test) using a panel of WT JE strains at baseline, then after the booster at 28 days and 6 months in all subjects present at the time points and in a subset at year 5. Three additional recent isolates were tested at year 5. RESULTS: Of 47 subjects, 43 (91.5%) subjects had JE neutralizing antibody titers ≥10 (reciprocal serum dilution) against the homologous strain before JE-CV boost; all were seroprotected up to year 5 after the JE-CV boost. Baseline WT seroprotection ranged between 78.7% and 87.2%; all subjects were seroprotected against the 4 WT strains at 28 days and 6 months; year 5 seroprotection ranged between 95.7% and 97.9%. Similar rates of protection against 3 additional WT isolates were observed at year 5. CONCLUSIONS: The long-term immune responses induced after a JE-CV booster dose in toddlers were able to neutralize WT viruses from various genotypes circulating in Southeast Asia and India. CLINICAL TRIALS REGISTRATION: NCT00621764.

Replication and Excretion of the Live Attenuated Tetravalent Dengue Vaccine CYD-TDV in a Flavivirus-Naive Adult Population: Assessment of Vaccine Viremia and Virus Shedding.

Background: We assessed replication and excretion of the live attenuated tetravalent dengue vaccine (CYD-TDV) into biological fluids following vaccination in dengue-naive adults in Australia. Methods: Vaccinal viremia/shedding was assessed in a subset of participants enrolled in a lot-to-lot consistency study; 95 participants received 3 subcutaneous doses of CYD-TDV from phase 2/3 lots of the vaccine, and 8 received placebo; doses were administered 6 months apart. Quantitative reverse-transcription polymerase chain reaction (qR-PCR) analysis was used to initially detect the yellow fever virus (YFV) core protein gene in the backbone of CYD-TDV in serum, saliva and urine, followed by serotype-specific qRT-PCR analysis of samples positive for YFV by qRT-PCR (lower limit of detection, 5.16 GEq/mL). Results: YFV viremia was detected by qRT-PCR in 69.5% of participants (66 of 95) who received CYD-TDV, mainly 6-14 days after injection 1. The serotypes detected were serotype 4 (in 68.2% of participants [45 of 95]), serotype 3 (in 19.7% [13 of 95]), and serotype 1 (in 12.1% [8 of 95]); serotype 2 was not detected. None of the placebo recipients had vaccinal viremia/shedding. No participants had detectable viral shedding into saliva at levels above the lower limit of quantitation. Two participants had low-level viral shedding (serotype 3) in urine (5.47 and 5.77 GEq/mL). None of the participants with viremia or shedding experienced concomitant fever. Conclusions: Low-level vaccinal viremia may occur following vaccination with CYD-TDV, but this is not associated with any symptom or adverse event. Clinical Trials Registration: NCT01134263.

Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial.

BACKGROUND: An estimated 100 million people have symptomatic dengue infection every year. This is the first report of a phase 3 vaccine efficacy trial of a candidate dengue vaccine. We aimed to assess the efficacy of the CYD dengue vaccine against symptomatic, virologically confirmed dengue in children. METHODS: We did an observer-masked, randomised controlled, multicentre, phase 3 trial in five countries in the Asia-Pacific region. Between June 3, and Dec 1, 2011, healthy children aged 2-14 years were randomly assigned (2:1), by computer-generated permuted blocks of six with an interactive voice or web response system, to receive three injections of a recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV), or placebo, at months 0, 6, and 12. Randomisation was stratified by age and site. Participants were followed up until month 25. Trial staff responsible for the preparation and administration of injections were unmasked to group allocation, but were not included in the follow-up of the participants; allocation was concealed from the study sponsor, investigators, and parents and guardians. Our primary objective was to assess protective efficacy against symptomatic, virologically confirmed dengue, irrespective of disease severity or serotype, that took place more than 28 days after the third injection. The primary endpoint was for the lower bound of the 95% CI of vaccine efficacy to be greater than 25%. Analysis was by intention to treat and per procotol. This trial is registered with ClinicalTrials.gov, number NCT01373281. FINDINGS: We randomly assigned 10,275 children to receive either vaccine (n=6851) or placebo (n=3424), of whom 6710 (98%) and 3350 (98%), respectively, were included in the primary analysis. 250 cases of virologically confirmed dengue took place more than 28 days after the third injection (117 [47%] in the vaccine group and 133 [53%] in the control group). The primary endpoint was achieved with 56·5% (95% CI 43·8-66·4) efficacy. We recorded 647 serious adverse events (402 [62%] in the vaccine group and 245 [38%] in the control group). 54 (1%) children in the vaccine group and 33 (1%) of those in the control group had serious adverse events that happened within 28 days of vaccination. Serious adverse events were consistent with medical disorders in this age group and were mainly infections and injuries. INTERPRETATION: Our findings show that dengue vaccine is efficacious when given as three injections at months 0, 6, and 12 to children aged 2-14 years in endemic areas in Asia, and has a good safety profile. Vaccination could reduce the incidence of symptomatic infection and hospital admission and has the potential to provide an important public health benefit. FUNDING: Sanofi Pasteur.

Immune response to live-attenuated Japanese encephalitis vaccine (JE-CV) neutralizes Japanese encephalitis virus isolates from south-east Asia and India.

BACKGROUND: During clinical development of the licensed Japanese encephalitis chimeric virus vaccine (JE-CV), the neutralization capacity of vaccine-induced antibodies was assessed against the vaccine virus and against well characterized wild-type (wt) viruses isolated between 1949-1991. We assessed whether JE-CV-induced antibodies can also neutralize more recent wt Japanese encephalitis virus (JEV) isolates including a genotype 1 isolate. METHODS: Sera from 12-18 month-old children who received a single dose of JE-CV in a phase III study in Thailand and the Philippines (ClinicalTrials.gov NCT00735644) were randomly selected and pooled according to neutralization titer against JE-CV into eight samples. Neutralization was assessed by plaque reduction neutralization tests (PRNT50) against three recent isolates from JEV genotypes 1 and 3 in addition to four JEV previously tested. RESULTS: Neutralization titers against the three recent JEV strains were comparable to those observed previously against other strains and the vaccine virus. The observed differences between responses to genotype 1 and 3 viruses were within assay variability for the PRNT50. CONCLUSIONS: The results were consistent with previously generated data on the neutralization of wt JEV isolates, immune responses induced by JE-CV neutralize recently isolated virus from southeast (SE) Asia and India.

Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial.

BACKGROUND: Roughly half the world's population live in dengue-endemic countries, but no vaccine is licensed. We investigated the efficacy of a recombinant, live, attenuated tetravalent dengue vaccine. METHODS: In this observer-masked, randomised, controlled, monocentre, phase 2b, proof-of-concept trial, healthy Thai schoolchildren aged 4-11 years were randomly assigned (2:1) to receive three injections of dengue vaccine or control (rabies vaccine or placebo) at months 0, 6, and 12. Randomisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system. Participants were actively followed up until month 25. All acute febrile illnesses were investigated. Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA. The primary objective was to assess protective efficacy against virologically confirmed, symptomatic dengue, irrespective of severity or serotype, occurring 1 month or longer after the third injection (per-protocol analysis). This trial is registered at ClinicalTrials.gov, NCT00842530. FINDINGS: 4002 participants were assigned to vaccine (n=2669) or control (n=1333). 3673 were included in the primary analysis (2452 vaccine, 1221 control). 134 cases of virologically confirmed dengue occurred during the study. Efficacy was 30·2% (95% CI -13·4 to 56·6), and differed by serotype. Dengue vaccine was well tolerated, with no safety signals after 2 years of follow-up after the first dose. INTERPRETATION: These data show for the first time that a safe vaccine against dengue is possible. Ongoing large-scale phase 3 studies in various epidemiological settings will provide pivotal data for the CYD dengue vaccine candidate. FUNDING: Sanofi Pasteur.

Human rotavirus vaccine Rotarix™ provides protection against diverse circulating rotavirus strains in African infants: a randomized controlled trial.

BACKGROUND: Rotaviruses are the most important cause of severe acute gastroenteritis worldwide in children <5 years of age. The human, G1P[8] rotavirus vaccine Rotarix™ significantly reduced severe rotavirus gastroenteritis episodes in a Phase III clinical trial conducted in infants in South Africa and Malawi. This paper examines rotavirus vaccine efficacy in preventing severe rotavirus gastroenteritis, during infancy, caused by the various G and P rotavirus types encountered during the first rotavirus-season. METHODS: Healthy infants aged 5-10 weeks were enrolled and randomized into three groups to receive either two (10 and 14 weeks) or three doses of Rotarix™ (together forming the pooled Rotarix™ group) or three doses of placebo at a 6,10,14-week schedule. Weekly home visits were conducted to identify gastroenteritis episodes. Rotaviruses were detected by ELISA and genotyped by RT-PCR and nucleotide sequencing. The percentage of infants with severe rotavirus gastroenteritis caused by the circulating G and P types from 2 weeks post-last dose until one year of age and the corresponding vaccine efficacy was calculated with 95% CI. RESULTS: Overall, 4939 infants were vaccinated and 4417 (pooled Rotarix™ = 2974; placebo = 1443) were included in the per protocol efficacy cohort. G1 wild-type was detected in 23 (1.6%) severe rotavirus gastroenteritis episodes from the placebo group. This was followed in order of detection by G12 (15 [1%] in placebo) and G8 types (15 [1%] in placebo). Vaccine efficacy against G1 wild-type, G12 and G8 types were 64.1% (95% CI: 29.9%; 82%), 51.5% (95% CI:-6.5%; 77.9%) and 64.4% (95% CI: 17.1%; 85.2%), respectively. Genotype P[8] was the predominant circulating P type and was detected in 38 (2.6%) severe rotavirus gastroenteritis cases in placebo group. The remaining circulating P types comprised of P[4] (20 [1.4%] in placebo) and P[6] (13 [0.9%] in placebo). Vaccine efficacy against P[8] was 59.1% (95% CI: 32.8%; 75.3%), P[4] was 70.9% (95% CI: 37.5%; 87.0%) and P[6] was 55.2% (95% CI: -6.5%; 81.3%) CONCLUSIONS: Rotarix™ vaccine demonstrated efficacy against severe gastroenteritis caused by diverse circulating rotavirus types. These data add to a growing body of evidence supporting heterotypic protection provided by Rotarix™. TRIAL REGISTRATION NUMBER: NCT00241644.

Associations of human leukocyte antigen with neutralizing antibody titers in a tetravalent dengue vaccine phase 2 efficacy trial in Thailand.

The recombinant, live, attenuated, tetravalent dengue vaccine CYD-TDV has shown efficacy against all four dengue serotypes. In this exploratory study (CYD59, NCT02827162), we evaluated potential associations of host human leukocyte antigen (HLA) alleles with dengue antibody responses, CYD-TDV vaccine efficacy, and virologically-confirmed dengue (VCD) cases. Children 4-11 years old, who previously completed a phase 2b efficacy study of CYD-TDV in a single center in Thailand, were included in the study. Genotyping of HLA class I and II loci was performed by next-generation sequencing from DNA obtained from 335 saliva samples. Dengue neutralizing antibody titers (NAb) were assessed as a correlate of risk and protection. Regression analyses were used to assess associations between HLA alleles and NAb responses, vaccine efficacy, and dengue outcomes. Month 13 NAb log geometric mean titers (GMTs) were associated with decreased risk of VCD. In the vaccine group, HLA-DRB1*11 was significantly associated with higher NAb log GMT levels (beta: 0.76; p = 0.002, q = 0.13). Additionally, in the absence of vaccination, HLA associations were observed between the presence of DPB1*03:01 and increased NAb log GMT levels (beta: 1.24; p = 0.005, q = 0.17), and between DPB1*05:01 and reduced NAb log GMT levels (beta: -1.1; p = 0.001, q = 0.07). This study suggests associations of HLA alleles with NAb titers in the context of dengue outcomes. This study was registered with clinicaltrials.gov: NCT02827162.

Humoral and cellular immunogenicity and safety following a booster dose of a tetravalent dengue vaccine 5+ years after completion of the primary series in Singapore: 2-year follow-up of a randomized phase II, placebo-controlled trial.

The tetravalent dengue vaccine (CYD-TDV) is approved for use as a 3-dose series for the prevention of dengue in seropositive individuals ≥9 years. A randomized, placebo-controlled, phase II study of a booster dose of CYD-TDV in individuals who completed the 3-dose schedule >5 years previously (NCT02824198), demonstrated that a booster restored neutralizing antibody titers to post-dose 3 levels. We present additional immunogenicity assessments up to 24 months post-booster, and B- and T-cell responses in a participant subset. Participants aged 9-45 years that had received all three doses of CYD-TDV were randomized 3:1 to receive a booster dose of CYD-TDV (n = 89) or placebo (n = 29). Neutralizing antibody levels at Months 1, 6, 12, and 24 post-booster were assessed by plaque reduction neutralization test. In a subset, B-cell responses were assessed by a fluorescent immunospot assay, and T-cells analyzed by flow cytometry at Days 0, 7, 12, Months 1 and 12. We observed an increase of antibody titers Month 1 post-booster, then a gradual decline to Month 24. In the CYD-TDV booster group, an increase in plasmablasts was seen at Day 7 declining by Day 14, an increase in memory B-cells was observed at Day 28 with no persistence at Month 12. CYD-TDV booster recalled a CD8+ T-cell response, dominated by IFN-γ secretion, which decreased 12 months post-booster. This study showed a short-term increase in antibody titers and then gradual decrease following CYD-TDV booster injection >5 years after primary immunization, and the presence of memory B-cells activated following the booster, but with low persistence.

Spatiotemporal Heterogeneity of Zika Virus Transmission in Indonesia: Serosurveillance Data from a Pediatric Population.

The presence of Zika virus (ZIKV) in Indonesia has been recognized since the 1970s, but its transmission dynamics there have been poorly understood. To understand more fully the geographic distribution and burden of ZIKV infection, we performed retrospective serological tests on specimens collected from asymptomatic children age 5 to 9 years old living at 30 sites in 14 provinces. Of 870 serum samples tested, 9.2% were found to be positive for anti-ZIKV antibodies, as confirmed by plaque reduction neutralization assays. This was the same overall prevalence reported previously for 1- to 4-year-old children collected at the same sites at the same time. Together with geographic differences in seroprevalence between the age groups, these data suggest that, although ZIKV might be endemic in Indonesia, its occurrence has been focal and episodic.

A review of rotavirus infection in and vaccination of human immunodeficiency virus-infected children.

Diarrhea caused by infection with rotavirus annually results in an estimated 611,000 deaths among infants and young children <5 years of age worldwide, and these deaths primarily occur in developing countries. Infection with human immunodeficiency virus (HIV) is also common among young children in many developing countries, particularly in sub-Saharan Africa and Asia. The need for a vaccine to reduce the number of deaths caused by rotavirus infection among children in developing countries is substantial, but current rotavirus vaccines comprise live attenuated oral viruses, the behaviors of which are unknown in HIV-infected children. Therefore, we reviewed available data on natural rotavirus infection in HIV-infected children and examined unpublished data on a small group of HIV-infected infants in South Africa who were given a live rotavirus vaccine. Together, these data suggest that vaccination programs against rotavirus infection could include HIV-infected populations. However, studies addressing the safety, reactogenicity, and immunogenicity of rotavirus vaccines in an HIV-infected population are urgently needed.

Immunogenicity and safety of a dengue vaccine given as a booster in Singapore: a randomized Phase II, placebo-controlled trial evaluating its effects 5-6 years after completion of the primary series.

The tetravalent dengue vaccine (CYD-TDV; Dengvaxia®) is administered on a three-dose schedule, 6 months apart in those aged ≥9 years in a number of dengue-endemic countries in Asia and Latin America. In this study, CYD63 (NCT02824198), participants aged 9-45 years at first vaccination, and who had received three doses of CYD-TDV in the CYD28 study more than 5 years previously, were randomized 3:1 to receive a booster CYD-TDV dose (Group 1) or placebo (Group 2). Dengue neutralizing antibody geometric mean titres (PRNT50 GMTs) for each of the four dengue serotypes were assessed in sera collected before and 28 days after booster injections. Non-inferiority of the booster immune response versus that induced after the third dose was demonstrated for each serotype if the lower limit of the two-sided 95% confidence interval (CI) was >0.5 for the GMT ratios (GMTRs) between post-booster CYD-TDV dose and post-dose 3 in Group 1. Overall, 118 participants received CYD-TDV booster or placebo and 116 (98.3%) completed the study; two participants were withdrawn because of noncompliance. GMTs in the booster CYD-TDV group increased across all serotypes post-booster injection by 1.74- (serotype 1) to 3.58-fold (serotype 4). No discernible increases were observed in the placebo group. Non-inferiority was demonstrated for serotypes 1, 3, and 4, but not for serotype 2 (GMTR; 0.603 [95% CI, 0.439- 0.829]). No safety issues were observed. These data show that the CYD-TDV booster given 5 or more years later tended to restore GMTs back to levels observed post-dose 3.