Public health impact of herpes zoster vaccination on older adults in Singapore: a modeling study.

In Singapore, population aging and rising life expectancy are increasing herpes zoster (HZ) burden, which may be reduced by vaccination. The present study modeled the public health impact of HZ vaccination in Singapore using ZOster ecoNomic Analysis (ZONA) model adapted with Singapore-specific key model inputs, where available. Base case analysis was conducted in adults ≥ 50 years of age (YOA), exploring three vaccination strategies (no vaccination, recombinant zoster vaccine [RZV], zoster vaccine live [ZVL]) under mass vaccination setting (30% coverage). Scenario and sensitivity analyses were performed. Out of 1.51 million adults in 2021 (base case population), 406,513 (27.0%) cases of HZ, 68,264 (4.5%) cases of post-herpetic neuralgia (PHN), and 54,949 (3.6%) cases of other complications were projected without vaccination. RZV was estimated to avoid 73,129 cases of HZ, 11,094 cases of PHN, and 9,205 cases of other complications over the subjects' remaining lifetime; ZVL would avoid 17,565 cases of HZ, 2,781 cases of PHN, and 1,834 cases of other complications. The number needed to vaccinate to prevent one case of HZ/PHN was lower for RZV (7/41) than ZVL (26/163). Among all five age-stratified cohorts (50-59/60-64/65-69/70-79/≥80 YOA), RZV (versus no vaccination/ZVL) avoided the largest number of cases in the youngest cohort, 50-59 YOA. Results were robust under scenario and sensitivity analyses. Mass vaccination with RZV is expected to greatly reduce the public health burden of HZ among Singapore individuals ≥ 50 YOA. Findings support value assessment and decision-making regarding public health vaccination strategies for HZ prevention in Singapore.

Risk of shingles (herpes zoster) increases with age, especially from 50 years. Shingles is a major public health concern in Singapore, given its rapidly aging population. Vaccination can prevent shingles and reduce its public health burden. Two shingles vaccines are available in Singapore: recombinant zoster vaccine (RZV) since 2021, zoster vaccine live (ZVL) since 2008. To understand the value of preventing shingles via vaccination, this study assessed the public health impact of shingles vaccination. Three vaccination strategies (no vaccination, vaccination with RZV, vaccination with ZVL) were compared in 1.51 million Singapore adults aged 50 years and above. Without vaccination, public health burden of shingles would be high; an estimated 406,513 (27.0%) would have shingles, 68,264 (4.5%) would have shingles-related long-term nerve pain, 54,949 (3.6%) would have other shingles-related complications, and 17,762 (1.2%) would be hospitalized due to shingles. Shingles vaccination could reduce this public health burden: RZV avoided 73,129 cases of shingles, 11,094 cases of shingles-related long-term nerve pain, 9,205 cases of other shingles-related complications, and 2,827 hospitalizations due to shingles, which was 4­6 times that avoided with ZVL (shingles: 17,565; shingles-related long-term nerve pain: 2,781; other shingles-related complications: 1,834; hospitalizations due to shingles: 484). Shingles vaccination for adults aged 50 years and above, especially early vaccination from 50­59 years, could reduce its public health burden more than vaccination at later ages and contribute toward healthy aging, preventive care, and the Healthier SG initiative. Results support local public health value assessments and decision-making for shingles prevention.

IgG, IgM, and Nonstructural Protein 1 Response Profiles after Receipt of Tetravalent Dengue Vaccine TAK-003 in a Phase 2 Randomized Controlled Trial.

The profiles of vaccine-induced dengue antibodies may differ from those produced following natural infection and could potentially interfere with the interpretation of diagnostic tests. We assessed anti-dengue IgG and IgM antibodies, and nonstructural protein 1 antigen profiles in the serum of adults who received a single dose of the tetravalent dengue vaccine TAK-003 as either an initially developed high-dose formulation or the standard approved formulation in a phase 2 study in Singapore (#NCT02425098). Immunoglobulin G and IgM profiles during the first 30 days postvaccination varied by baseline serostatus (microneutralization assay). Nonstructural protein 1 antigen was not detected in the serum of any participants. Vaccine-induced IgG and IgM antibodies can affect serological confirmation of subsequent dengue infection in vaccinees. These results highlight the limitations of using serological tests for dengue diagnosis, particularly in a postvaccination setting, and emphasize the need for more sensitive antigen- and molecular-based testing for accurate dengue diagnosis.

Modelling the Potential Public Health Impact of Different COVID-19 Vaccination Strategies with an Adapted Vaccine in Singapore.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 has been a dynamically changing virus, requiring the development of adapted vaccines. This study estimated the potential public health impact alternative vaccination strategies for COVID-19 in Singapore. RESEARCH DESIGN AND METHODS: The outcomes of alternative vaccination strategies with a future adapted vaccine were estimated using a combined Markov decision tree model. The population was stratified by high- and standard-risk. Using age-specific inputs informed by local surveillance data and published sources, the model estimated health (case numbers, hospitalizations, and deaths) and economic (medical costs and productivity losses) outcomes in different age and risk subpopulations. RESULTS: Booster vaccination in only the elderly and high-risk subpopulation was estimated to avert 278,614 cases 21,558 hospitalizations, 239 deaths, Singapore dollars (SGD) 277 million in direct medical costs, and SGD 684 million in indirect medical costs. These benefits increased as vaccination was expanded to other subpopulations. Increasing the booster vaccination coverage to 75% of the standard-risk population averted more deaths (3%), hospitalizations (29%), infections (145%), direct costs (90%), and indirect costs (192%) compared to the base case. CONCLUSIONS: Broader vaccination strategies using an adapted booster vaccine could have substantial public health and economic impact in Singapore.

Predictors of disease severity in SARS-CoV-2 omicron variant XBB sublineages and variants of interest.

The Omicron variant has been reported to present with milder disease compared with Delta, although this may be due to immunity from vaccination and prior exposure. Predictors of severity with recent strains have not been well characterized. We retrospectively examined consecutive cases of moderate-to-severe COVID-19 (defined as requiring supplemental oxygenation, intensive care or mortality) admitted to seven tertiary hospitals across Singapore in April 2023. Whole genome sequencing was performed on each isolate to determine the sublineage, while baseline clinical, laboratory data and outcomes were tabulated. We reviewed 182 patients with moderate-to-severe illness and 466 controls hospitalized at the same time. Advanced age and presence of chronic kidney disease predicted adverse outcome. Previously reported markers such as radiographic evidence of pneumonia, elevated C-reactive protein and serum creatinine levels at presentation also correlated with adverse outcomes. There were no observable differences in outcomes with any specific Omicron XBB sublineage. We did not find any specific Omicron XBB sublineage that was associated with worse outcomes. Larger multinational studies would be important to track the clinical evolution of the virus in its current endemic state.

Impact of vaccination and non-pharmacological interventions on COVID-19: a review of simulation modeling studies in Asia.

Introduction: Epidemiological modeling is widely used to offer insights into the COVID-19 pandemic situation in Asia. We reviewed published computational (mathematical/simulation) models conducted in Asia that assessed impacts of pharmacological and non-pharmacological interventions against COVID-19 and their implications for vaccination strategy. Methods: A search of the PubMed database for peer-reviewed, published, and accessible articles in English was performed up to November 2022 to capture studies in Asian populations based on computational modeling of outcomes in the COVID-19 pandemic. Extracted data included model type (mechanistic compartmental/agent-based, statistical, both), intervention type (pharmacological, non-pharmacological), and procedures for parameterizing age. Findings are summarized with descriptive statistics and discussed in terms of the evolving COVID-19 situation. Results: The literature search identified 378 results, of which 59 met criteria for data extraction. China, Japan, and South Korea accounted for approximately half of studies, with fewer from South and South-East Asia. Mechanistic models were most common, either compartmental (61.0%), agent-based (1.7%), or combination (18.6%) models. Statistical modeling was applied less frequently (11.9%). Pharmacological interventions were examined in 59.3% of studies, and most considered vaccination, except one study of an antiviral treatment. Non-pharmacological interventions were also considered in 84.7% of studies. Infection, hospitalization, and mortality were outcomes in 91.5%, 30.5%, and 30.5% of studies, respectively. Approximately a third of studies accounted for age, including 10 that also examined mortality. Four of these studies emphasized benefits in terms of mortality from prioritizing older adults for vaccination under conditions of a limited supply; however, one study noted potential benefits to infection rates from early vaccination of younger adults. Few studies (5.1%) considered the impact of vaccination among children. Conclusion: Early in the COVID-19 pandemic, non-pharmacological interventions helped to mitigate the health burden of COVID-19; however, modeling indicates that high population coverage of effective vaccines will complement and reduce reliance on such interventions. Thus, increasing and maintaining immunity levels in populations through regular booster shots, particularly among at-risk and vulnerable groups, including older adults, might help to protect public health. Future modeling efforts should consider new vaccines and alternative therapies alongside an evolving virus in populations with varied vaccination histories.

Evidence synthesis and pooled analysis of vaccine effectiveness for COVID-19 mRNA vaccine BNT162b2 as a heterologous booster after inactivated SARS-CoV-2 virus vaccines.

Introduction of primary COVID-19 vaccination has helped reduce severe disease and death caused by SARS-CoV-2 infection. Understanding the protection conferred by heterologous booster regimens informs alternative vaccination strategies that enable programmatic resilience and can catalyze vaccine confidence and coverage. Inactivated SARS-CoV-2 vaccines are among the most widely used vaccines worldwide. This review synthesizes the available evidence identified as of May 26, 2022, on the safety, immunogenicity, and effectiveness of a heterologous BNT162b2 (Pfizer-BioNTech) mRNA vaccine booster dose after an inactivated SARS-CoV-2 vaccine primary series, to help protect against COVID-19. Evidence showed that the heterologous BNT16b2 mRNA vaccine booster enhances immunogenicity and improves vaccine effectiveness against COVID-19, and no new safety concerns were identified with heterologous inactivated primary series with mRNA booster combinations.

Robust SARS-CoV-2 Antibody Responses in Asian COVID-Naïve Subjects 180 Days after Two Doses of BNT162b2 mRNA COVID-19 Vaccine.

BACKGROUND: Subjects with previous COVID-19 have augmented post-vaccination responses. However, the antibody response in COVID-naïve subjects from Southeast Asia is not well known. METHODS: 77 COVID-naïve vaccinees were tested with a full antibody panel [spike antibodies (total (T-Ab), IgG, IgM) and neutralizing antibodies (N-Ab)] pre-vaccination, 10 days after dose 1, and 20/40/60/90/120/150/180 days after dose 2. RESULTS: 10 days after dose 1, 67.6% (48/71)/69.0% (49/71) were T-Ab/IgG positive; only 15.5% (11/71)/14.1% (10/71) were N-Ab/IgM positive. While all (100%) subjects had brisk T-Ab, IgG and N-Ab antibody responses 20 days after complete vaccination, only 79.1% (53/67) were IgM positive. At 180 days (n = 8), T-Ab/IgG/N-Ab were still reactive (lowest T-Ab 186 U/mL, IgG 617 AU/mL, N-Ab 0.39 µg/mL), but IgM was negative in all samples. Spike antibody thresholds of T-Ab 74.1 U/mL (r = 0.95) and IgG 916 AU/mL (r = 0.95) corresponded to N-Ab reactivity (>0.3 µg/mL). Non-linear regression analysis showed that N-Ab would decrease to 0.3 µg/mL by 241 days, whereas T-Ab/IgG would need 470/163 days to reach titers of T-Ab/IgG associated with a N-Ab 0.3 µg/mL (76.4 U/mL and 916 AU/mL respectively). CONCLUSIONS: The antibody responses of T-Ab, IgG and N-Ab remain high and durable even at 180 days. N-Ab titers are expected to remain reactive up to 241 days post-vaccination.

Negative cerebrospinal fluid ß-d-glucan levels as an indicator for treatment cessation ahead of biochemical resolution: A case report of Candida glabrata meningitis.

Candida infections of the central nervous system (CNS) are rare. We report a case of Candida glabrata meningitis successfully treated with combination antifungal therapy followed by step-down therapy with fluconazole. New-onset hypercalcaemia, an uncommon side effect of the prolonged fluconazole treatment, prompted early treatment cessation. A negative cerebrospinal fluid (CSF) ß-d-glucan supported the decision of treatment cessation despite incomplete resolution of CSF biochemical parameters. No disease relapse was encountered after 2 years post-treatment.

Predictors and Clinical Outcomes of Poor Platelet Recovery in Adult Dengue With Thrombocytopenia: A Multicenter, Prospective Study.

BACKGROUND: Platelet transfusion is common in dengue patients with thrombocytopenia. We previously showed in a randomized clinical trial that prophylactic platelet transfusion did not reduce clinical bleeding. In this study, we aimed to characterize the predictors and clinical outcomes of poor platelet recovery in transfused and nontransfused participants. METHODS: We analyzed patients from the Adult Dengue Platelet Study with laboratory-confirmed dengue with ≤20 000 platelets/µL and without persistent mild bleeding or any severe bleeding in a post hoc analysis. Poor platelet recovery was defined as a platelet count of ≤20 000/µL on Day 2. We recruited 372 participants from 5 acute care hospitals located in Singapore and Malaysia between 29 April 2010 and 9 December 2014. Of these, 188 were randomly assigned to the transfusion group and 184 to the control group. RESULTS: Of 360 patients, 158 had poor platelet recovery. Age, white cell count, and day of illness at study enrollment were significant predictors of poor platelet recovery after adjustment for baseline characteristics and platelet transfusion. Patients with poor platelet recovery had longer hospitalizations but no significant difference in other clinical outcomes, regardless of transfusion. We found a significant interaction between platelet recovery and transfusion; patients with poor platelet recovery were more likely to bleed if given a prophylactic platelet transfusion (odds ratio 2.34, 95% confidence interval 1.18-4.63). CONCLUSIONS: Dengue patients with thrombocytopenia who were older or presented earlier and with lower white cell counts were more likely to have poor platelet recovery. In patients with poor platelet recovery, platelet transfusion does not improve outcomes and may actually increase the risk of bleeding. The mechanisms of poor platelet recovery need to be determined. CLINICAL TRIALS REGISTRATION: NCT01030211.

Safety and immunogenicity of a single dose of a tetravalent dengue vaccine with two different serotype-2 potencies in adults in Singapore: A phase 2, double-blind, randomised, controlled trial.

BACKGROUND: Early formulations of Takeda's tetravalent dengue vaccine candidate (TAK-003) have demonstrated notably higher neutralizing antibody responses against serotype 2 than other serotypes. Here, we assessed the immunogenicity and tolerability in adults living in Singapore of two TAK-003 formulations: an early formulation, referred to as HD-TDV, and a new formulation with 10-fold lower serotype 2 potency, referred to as TDV (NCT02425098). METHODS: Subjects aged 21-45 years were stratified by baseline dengue serostatus and randomised 1:1 to receive a single dose of either HD-TDV or TDV. Immunogenicity was evaluated at Days 15, 30, 90, 180, and 365 post-vaccination as geometric mean titres (GMTs) of neutralising antibodies and seropositivity rates. Viremia was assessed per vaccine strain. Solicited and unsolicited adverse events (AEs) were assessed by severity and causality. RESULTS: Of 351 subjects randomised, 176 received HD-TDV and 175 received TDV. Peak GMTs against all serotypes were observed at Day 30, with highest GMTs against DENV-2 in both groups. In subjects seronegative at baseline, the response to DENV-2 was less dominant with TDV (Day 30 GMTs: 813 for TDV, 10,966 for HD-TDV). In these subjects, DENV-4 seropositivity rates and GMTs were higher with TDV (Day 30 GMTs: 58 for TDV, 21 for HD-TDV; seropositivity rates: 76% for TDV, 60% for HD-TDV). Viremia mainly occurred for TDV-2 in both vaccine groups, with a lower incidence in TDV recipients, and mostly resolved by Day 30. Both vaccine formulations showed an acceptable safety profile with similar overall rates of solicited and unsolicited AEs across vaccine groups. CONCLUSIONS: These results suggest a more balanced immune response with the new formulation TDV compared with the early formulation HD-TDV, particularly in subjects who were seronegative prior to vaccination, and support the choice of the new formulation for the phase 3 efficacy assessment.

Klebsiella Pneumoniae Visceral Organ Abscesses - Clinical Characteristics.

INTRODUCTION: In recent years, Klebsiella pneumonia (KP) has emerged as the predominant cause of pyogenic liver abscess in Asia. KP - as the causative microorganism in other visceral organ abscesses-is less described. In this study, we seeked to describe the clinical characteristics of KP visceral organ abscesses in our institution and evaluated the prescription practices of physicians with regard to antibiotic therapy. MATERIALS AND METHODS: A retrospective analysis of patients with culture positive (blood or abscess aspirate) KP visceral organ abscesses from May 2014 to April 2016 requiring hospitalisation in Changi General Hospital was conducted. RESULTS: A total of 140 adult patients with KP visceral organ abscesses were identified. The commonest site of involvement was the liver (77.9%), followed by genitourinary tract (20.7%). Diabetic patients were more likely to have liver abscesses, genitourinary abscesses, abscesses in 2 or more organs, genitourinary disease with abscess formation outside of the genitourinary tract, and endovascular infection. Patients with extended spectrum beta-lactamase producing KP, were more likely to have an obstructive lesion related to the site of the abscess. Overall mortality rate was 7.1%. Amongst survivors, the mean total duration of parenteral antimicrobial therapy was 2.5 weeks before switching to oral antimicrobial agents. CONCLUSION: Genitourinary tract is the commonest extra-hepatic site for visceral organ abscess in KP infections. Parenteral to oral switch of antimicrobial agents appears to be a safe and effective treatment option.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and 4vHPV vaccine administered according to two- or three-dose schedules in girls aged 9-14 years: Results to month 36 from a randomized trial.

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of two doses (2D) of the HPV-16/18 AS04-adjuvanted vaccine (2D of AS04-HPV-16/18) vs. two or three doses of the 4vHPV vaccine [2D or 3D of 4vHPV] in 1075 healthy girls aged 9-14 years. Girls were randomized (1:1:1) to receive 2D of AS04-HPV-16/18 at months (M) 0, 6 (N = 359), 2D of 4vHPV at M0, 6 (N = 358) or 3D of 4vHPV at M0, 2, 6 (N = 358). 351, 339 and 346 girls, respectively, returned for the concluding visit at M36. Superiority was demonstrated at M7 and M12; comparison of the immune response to both vaccine antigens was made between 2D of AS04-HPV-16/18 and 2D or 3D of 4vHPV at subsequent time points in the according-to-protocol immunogenicity cohort (ATP-I; N = 958 at M36) and the total vaccinated cohort (TVC: N = 1036 at M36). HPV-16/18-specific T-cell- and B-cell-mediated immune responses and safety were also investigated. At M36, anti-HPV-16/18 ELISA responses in the 2D AS04-HPV-16/18 group remained superior to those of the 2D and 3D 4vHPV groups. In the M36 TVC, geometric mean titers were 2.78-fold (HPV-16) and 6.84-fold (HPV-18) higher for 2D of AS04-HPV-16/18 vs. 2D of 4vHPV and 2.3-fold (HPV-16) and 4.14-fold (HPV-18) higher vs. 3D of 4vHPV. Results were confirmed by vaccine pseudovirion-based neutralisation assay. Numbers of circulating CD4+ T cells and B cells appeared similar across groups. Safety was in line with the known safety profiles of both vaccines. In conclusion, superior HPV-16/18 antibody responses were elicited by 2D of the AS04-HPV-16/18 compared with 2D or 3D of the 4vHPV vaccine in girls aged 9-14 years. CLINICAL TRIAL REGISTRATION: NCT0146235.

A phase II randomized study to determine the safety and immunogenicity of the novel PIKA rabies vaccine containing the PIKA adjuvant using an accelerated regimen.

BACKGROUND: Human Rabies infection continues to be potentially fatal despite the availability of post-exposure prophylaxis with rabies vaccine. The PIKA Rabies vaccine adjuvant is a TLR3 agonist and has been shown to be safe and immunogenic in clinical phase I studies. METHODS: We conducted a phase II, open label, randomized study in healthy adults to assess the safety and immunogenicity of the PIKA rabies vaccine under an accelerated regimen. 126 subjects were randomized into two groups: control vaccine classic regimen ("control-classic") and PIKA vaccine accelerated regimen ("PIKA-accelerated"). Subjects were followed up for safety and rabies virus neutralizing antibodies (RVNA). RESULTS: Both the control and PIKA vaccines were generally well tolerated. 57.6% of subjects in the PIKA vaccine group, compared with 43.8% of subjects in the control-classic group, achieved the target RVNA titer of ≥0.5 IU/mL by Day 7. All subjects achieved the target RVNA titer by Day 14. The RVNA geometric mean titer at Day 7 was 0.60 IU/ml in the PIKA vaccine group and 0.39 IU/ml in the control-classic group. At Day 14, the RVNA geometric mean titer was 18.25 IU/ml in the PIKA-accelerated group and 19.24 IU/ml in the control-classic group. The median time taken to reach the target RVNA titer level of ≥0.5 IU/mL was 7.0 days (95% CI: 7.0-42.0 days) in the PIKA-accelerated group and 14.0 days (95% CI: 7.0-42.0 days) in the control-classic group. CONCLUSION: The accelerated regimen using the investigational PIKA Rabies vaccine was well-tolerated and demonstrated non-inferior immunogenicity compared to the classic regimen using the commercially available vaccine in healthy adults. Clinical trial registry: The study was registered with clinicaltrials.gov (NCT02956421).

Prevalence of Healthcare-Associated Infections and Antimicrobial Use Among Adult Inpatients in Singapore Acute-Care Hospitals: Results From the First National Point Prevalence Survey.

BACKGROUND: We conducted a national point prevalence survey (PPS) to determine the prevalence of healthcare-associated infections (HAIs) and antimicrobial use (AMU) in Singapore acute-care hospitals. METHODS: Trained personnel collected HAI, AMU, and baseline hospital- and patient-level data of adult inpatients from 13 private and public acute-care hospitals between July 2015 and February 2016, using the PPS methodology developed by the European Centre for Disease Prevention and Control. Factors independently associated with HAIs were determined using multivariable regression. RESULTS: Of the 5415 patients surveyed, there were 646 patients (11.9%; 95% confidence interval [CI], 11.1%-12.8%) with 727 distinct HAIs, of which 331 (45.5%) were culture positive. The most common HAIs were unspecified clinical sepsis (25.5%) and pneumonia (24.8%). Staphylococcus aureus (12.9%) and Pseudomonas aeruginosa (11.5%) were the most common pathogens implicated in HAIs. Carbapenem nonsusceptibility rates were highest in Acinetobacter species (71.9%) and P. aeruginosa (23.6%). Male sex, increasing age, surgery during current hospitalization, and presence of central venous or urinary catheters were independently associated with HAIs. A total of 2762 (51.0%; 95% CI, 49.7%-52.3%) patients were on 3611 systemic antimicrobial agents; 462 (12.8%) were prescribed for surgical prophylaxis and 2997 (83.0%) were prescribed for treatment. Amoxicillin/clavulanate was the most frequently prescribed (24.6%) antimicrobial agent. CONCLUSIONS: This survey suggested a high prevalence of HAIs and AMU in Singapore's acute-care hospitals. While further research is necessary to understand the causes and costs of HAIs and AMU in Singapore, repeated PPSs over the next decade will be useful to gauge progress at controlling HAIs and AMU.

Prophylactic platelet transfusion plus supportive care versus supportive care alone in adults with dengue and thrombocytopenia: a multicentre, open-label, randomised, superiority trial.

BACKGROUND: Dengue is the commonest vector-borne infection worldwide. It is often associated with thrombocytopenia, and prophylactic platelet transfusion is widely used despite the dearth of robust evidence. We aimed to assess the efficacy and safety of prophylactic platelet transfusion in the prevention of bleeding in adults with dengue and thrombocytopenia. METHODS: We did an open-label, randomised, superiority trial in five hospitals in Singapore and Malaysia. We recruited patients aged at least 21 years who had laboratory-confirmed dengue (confirmed or probable) and thrombocytopenia (≤20 000 platelets per µL), without persistent mild bleeding or any severe bleeding. Patients were assigned (1:1), with randomly permuted block sizes of four or six and stratified by centre, to receive prophylactic platelet transfusion in addition to supportive care (transfusion group) or supportive care alone (control group). In the transfusion group, 4 units of pooled platelets were given each day when platelet count was 20 000 per µL or lower; supportive care consisted of bed rest, fluid therapy, and fever and pain medications. The primary endpoint was clinical bleeding (excluding petechiae) by study day 7 or hospital discharge (whichever was earlier), analysed by intention to treat. Safety outcomes were analysed according to the actual treatment received. This study was registered with ClinicalTrials.gov, number NCT01030211, and is completed. FINDINGS: Between April 29, 2010, and Dec 9, 2014, we randomly assigned 372 patients to the transfusion group (n=188) or the control group (n=184). The intention-to-treat analysis included 187 patients in the transfusion group (one patient was withdrawn immediately) and 182 in the control group (one was withdrawn immediately and one did not have confirmed or probable dengue). Clinical bleeding by day 7 or hospital discharge occurred in 40 (21%) patients in the transfusion group and 48 (26%) patients in the control group (risk difference -4·98% [95% CI -15·08 to 5·34]; relative risk 0·81 [95% CI 0·56 to 1·17]; p=0·16). 13 adverse events occurred in the transfusion group and two occurred in the control group (5·81% [-4·42 to 16·01]; 6·26 [1·43 to 27·34]; p=0·0064). Adverse events that were possibly, probably, or definitely related to transfusion included three cases of urticaria, one maculopapular rash, one pruritus, and one chest pain, as well as one case each of anaphylaxis, transfusion-related acute lung injury, and fluid overload that resulted in serious adverse events. No death was reported. INTERPRETATION: In adult patients with dengue and thrombocytopenia, prophylactic platelet transfusion was not superior to supportive care in preventing bleeding, and might be associated with adverse events. FUNDING: National Medical Research Council, Singapore.

Safety and Immunogenicity of a Tetravalent Dengue Vaccine Candidate in Healthy Children and Adults in Dengue-Endemic Regions: A Randomized, Placebo-Controlled Phase 2 Study.

BACKGROUND: A safe, effective tetravalent dengue vaccine is a global health priority. The safety and immunogenicity of a live attenuated, recombinant tetravalent dengue vaccine candidate (TDV) were evaluated in healthy volunteers from dengue-endemic countries. METHODS: This multicenter, double-blind, phase 2 study was conducted in Puerto Rico, Colombia, Singapore, and Thailand. During stage I, 148 volunteers aged 1.5-45 years were sequentially enrolled into 4 age-descending groups and randomized at a ratio of 2:1 to receive TDV or placebo. In stage II (group 5), 212 children aged 1.5-11 years were randomized at a ratio of 3:1 to receive TDV or placebo. Participants received a subcutaneous injection of TDV or placebo on days 0 and 90 and were followed for analysis of safety, seropositivity, and neutralizing antibodies to DENV-1-4. RESULTS: Injection site pain, itching, and erythema (mostly mild) were the only solicited adverse events more frequently reported with TDV than with placebo in all age groups. After 2 TDV doses, seropositivity was >95% in all 5 groups for DENV-1-3 and 72.7%-100% for DENV-4; geometric mean titers ranged from 582 to 1187 for DENV-1, from 582 to 1187 for DENV-2, from 196 to 630 for DENV-3, and from 41 to 210 for DENV-4 among the 5 groups. CONCLUSIONS: TDV was well tolerated and immunogenic in volunteers aged 1.5-45 years, irrespective of prevaccination dengue exposure.

Severe Pediatric Adenovirus 7 Disease in Singapore Linked to Recent Outbreaks across Asia.

During November 2012-July 2013, a marked increase of adenovirus type 7 (Ad7) infections associated with severe disease was documented among pediatric patients in Singapore. Phylogenetic analysis revealed close genetic links with severe Ad7 outbreaks in China, Taiwan, and other parts of Asia.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine and HPV-6/11/16/18 vaccine administered according to 2- and 3-dose schedules in girls aged 9-14 years: Results to month 12 from a randomized trial.

This observer-blind study (clinicaltrials.gov NCT01462357) compared the immunogenicity and safety of 2 doses of the HPV-16/18 AS04-adjuvanted vaccine (HPV-16/18(2D)) vs. 2 or 3 doses of the HPV-6/11/16/18 vaccine (HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D)) in healthy girls aged 9-14 y. Girls were randomized (1:1:1) to receive HPV-16/18(2D) at months (M) 0,6 (N = 359), HPV-6/11/16/18(2D) at M0,6 (N = 358) or HPV-6/11/16/18(3D) at M0,2,6 (N = 358). The primary objective was non-inferiority/superiority of HPV-16/18 antibodies by ELISA for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) at M7 in the according-to-protocol immunogenicity cohort (ATP-I) and total vaccinated cohort, respectively. Secondary objectives included non-inferiority/superiority of HPV-16/18(2D) vs. HPV-6/11/16/18(3D) at M7, non-inferiority/superiority at M12, HPV-16/18 neutralizing antibodies, frequencies of T-cells/B-cells, reactogenicity and safety. Antibody responses at M7 for HPV-16/18(2D) were superior to those for HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) (lower limit of 95% confidence interval for geometric mean titer ratio (GMR) was >1): HPV-16/18(2D)/HPV-6/11/16/18(2D) GMRs were 1.69 [1.49-1.91] for anti-HPV-16 and 4.52 [3.97-5.13] for anti-HPV-18; HPV-16/18(2D)/HPV-6/11/16/18(3D) GMRs were 1.72 [1.54-1.93] for anti-HPV-16 and 3.22 [2.82-3.68] for anti-HPV-18; p = 0.0001 for all comparisons. Non-inferiority/superiority was also demonstrated at M12. Among initially seronegative girls in the ATP-I, neutralizing antibody titers were at least 1.8-fold higher for HPV-16/18(2D) vs. HPV-6/11/16/18(2D) and HPV-6/11/16/18(3D) at M7 and M12. Frequencies of HPV-16/18-specific T-cells and B-cells were in similar ranges between groups. Reactogenicity and safety were in line with the known profile of each vaccine. In conclusion, superior HPV-16/18 antibody responses were elicited by 2 doses of the HPV-16/18 AS04-adjuvanted vaccine compared with 2 or 3 doses of the HPV-6/11/16/18 vaccine in girls (9-14 years).