Pre-vaccination screening strategies for the use of the CYD-TDV dengue vaccine: A meeting report

The first licensed dengue vaccine, CYD-TDV (Dengvaxia) is efficacious in seropositive individuals, but increases the risk for severe dengue in seronegative persons about two years after administration of the first dose. For countries considering the introduction of Dengvaxia, WHO recommends a pre-vaccination screening strategy whereby only persons with evidence of a past dengue infection would be vaccinated. Policy-makers need to consider the risk-benefit of vaccination strategies based on such screening tests, the optimal age to introduce the vaccine, communication and implementation strategies. To address these questions, the Global Dengue and Aedes-transmitted diseases Consortium (GDAC) organized a 3-day workshop in January 2019 with country representatives from Asia and Latin America.The meeting discussions highlighted many challenges in introducing Dengvaxia, in terms of screening test characteristics, costs of such tests combined with a 3-dose schedule, logistics, achieving high coverage rates, vaccine confidence and communication; more challenges than for any other vaccine introduction programme. A screening test would require a high specificity to minimize individual risk, and at the same time high sensitivity to maximize individual and population benefit. The underlying seroprevalence dependent positive predictive value is the best indicator for an acceptable safety profile of a pre-vaccination screening strategy. The working groups discussed many possible implementation strategies. Addressing the bottlenecks in school-based vaccine introduction for Dengvaxia will also benefit other vaccines such as HPV and booster doses for tetanus and pertussis. Levels of public trust are highly variable and context specific, and understanding of population perceptions and concerns is essential to tailor interventions, monitor and mitigate risks.     

Estimating the public health importance of the CYD-tetravalent dengue vaccine: Vaccine preventable disease incidence and numbers needed to vaccinate

BackgroundTo evaluate the potential public health impact of the live attenuated tetravalent Sanofi Pasteur dengue vaccine (CYD-TDV) we analyzed data from the reported clinical trials to calculate vaccine preventable disease incidence (VPDI) and number needed to vaccinate (NNV) based on the licensure indication for persons age 9 years and above.MethodsVPDI is defined as incidence in an unvaccinated population X vaccine efficacy (VE), and thus incorporates both VE and the underlying burden of disease. NNV was calculated as 100,000 divided by VPDI divided by 2-year length of study. We compared these values to data for three newer vaccines that are currently integrated into some national immunization programs in Asia and Latin America, namely pneumococcal conjugate, Haemophilus influenzae type b, and rotavirus vaccines.ResultsIn the Asian-Pacific trial, in the first 25 months after the first dose of the dengue vaccine, CYD-TDV prevented annually 2639 cases of virologically confirmed dengue for every 100,000 persons vaccinated, for an NNV of 18. In the Latin American trial, given the overall lower annual dengue incidence compared to Asia, VPDI was 1707, and NNV 28. For the Asian-Pacific and Latin American studies, the VPDIs for hospitalized virologically confirmed disease at the trials’ end were 638 and 239 per 100,000 population per year, respectively, with NNVs of 75 and 201. VPDI for confirmed dengue hospitalization was higher than that for Hib vaccine against Hib meningitis or all cause severe pneumonia while lower than that for rotavirus vaccine against severe rotavirus gastroenteritis.ConclusionsOur analysis found that the CYD-TDV dengue vaccine had favorable VPDI and NNV, also when compared to existing vaccines used in Latin America and Asia. VPDI and NNV varied by serotype distribution, extent of prior dengue exposure (baseline seroprevalence) and country. These findings will help policy-makers decide where and how to introduce this vaccine post-licensure.     

Safety,immunogenicity and efficacy of a recombinant tetravalent dengue vaccine: A meta-analysis of randomized trials

The World Health Organization has stipulated a target: reduce the mortality rate caused by dengue disease by 50% until 2020. Most likely, this goal can be achieved by means of a dengue vaccine. Accordingly, the recombinant and tetravalent dengue vaccine (CYD-TDV), developed by the Sanofi Pasteur Group, is in an advanced stage of human testing. Although there are multiple randomized, placebo-controlled trials evaluating the CYD-TDV, individual results may have little power to identify differences between the populations studied. Thus, we conducted a meta-analysis to determine a more precise estimate of the overall parameters of safety, immunogenicity and efficacy of CYD-TDV. A data search was conducted in the PubMed, Medline, Cochrane Central Register of Controlled Trials and SciELO databases with defined selection criteria. We included for meta-analysis seven randomized and placebo-controlled studies that included 6678 patients randomized to receive the CYD-TDV (4586) or placebo (2092). Regarding vaccine safety, it was found that there was no significant difference between treated and placebo groups, as only approximately 5.5% of patients were withdrawn from the study. Regarding immunogenicity, the levels of neutralizing antibodies were measured by weighted mean differences (WMD), which were always higher in the vaccinated group (WMD/DENV1 = 59.7, 95% confidence interval [CI] 57–61; WMD/DENV2 = 99, 95% CI 95–102; WMD/DENV3 = 138, 95% CI 133–142; WMD/DENV4 = 123, 95% CI 119–126). The clinical efficacy of the vaccine was 59% (95% CI 15–80; RR = 0.41, 95% CI 0.2–0.85, I² = 30.9%). In conclusion, safety and a balanced immune response to the CYD-TDV were found. However, to fully establish the clinical effectiveness and robustness of immunogenicity, it is necessary to perform further studies to assess the long-term effects of the vaccine.     

The dengue vaccine pipeline: Implications for the future of dengue control

Dengue has become the most rapidly expanding mosquito-borne infectious disease on the planet, surpassing malaria and infecting at least 390 million people per year. There is no effective treatment for dengue illness other than supportive care, especially for severe cases. Symptoms can be mild or life-threatening as in dengue hemorrhagic fever and dengue shock syndrome. Vector control has been only partially successful in decreasing dengue transmission. The potential use of safe and effective tetravalent dengue vaccines is an attractive addition to prevent disease or minimize the possibility of epidemics. There are currently no licensed dengue vaccines. This review summarizes the current status of all dengue vaccine candidates in clinical evaluation. Currently five candidate vaccines are in human clinical trials. One has completed two Phase III trials, two are in Phase II trials, and three are in Phase I testing.     

A multi-country study of dengue vaccination strategies with Dengvaxia and a future vaccine candidate in three dengue-endemic countries: Vietnam,Thailand, and Colombia

BackgroundThe dengue vaccination era began when Dengvaxia (CYD-TDV) became available in 2016. In addition, several second-generation vaccine candidates are currently in phase 3 trials, suggesting that a broader availability of dengue vaccines may be possible in the near future. Advancing on the recent WHO-SAGE recommendations for the safe and effective use of CYD-TDV at the regional level on average, this study investigates the vaccination impacts and cost-effectiveness of CYD-TDV and of a hypothetical new vaccine candidate (NVC) in a country-specific manner for three endemic countries: Vietnam, Thailand, and Colombia.MethodsThe vaccination impacts of CYD-TDV and NVC were derived by fitting the empirical seroprevalence rates of 9 year olds into an individual-based meta-population transmission model, previously used for the WHO-SAGE working group. The disability-adjusted life years were estimated by applying country-specific parametric values. The cost-effectiveness analyses of four intervention strategies in combination with routine and catch-up campaigns were compared for both vaccines to inform decision makers regarding the most suitable immunization program in each of the three countries.Results and conclusionBoth CYD-TDV and NVC could be cost-effective at the DALY threshold cost of $2000 depending upon vaccination costs. With CYD-TDV, targeting 9 year olds in routine vaccination programs and 10–29 year olds as a one-off catch-up campaign was the most cost-effective strategy in all three countries. With NVC, while the most cost-effective strategy was to vaccinate 9–29 and 9–18 year olds in Vietnam and Thailand respectively, vaccinating younger age cohorts between 1 and 5 years old in Colombia was more cost-effective than other strategies. Given that three countries will soon face decisions regarding whether and how to incorporate CYD-TDV or future dengue vaccines into their budget-constrained national immunization programs, the current study outcomes can be used to help decision makers understand the expected impacts and cost-effectiveness of such vaccines.     

Development of the Sanofi Pasteur tetravalent dengue vaccine: One more step forward

Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this dengue vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naïve and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies.     

Next generation dengue vaccines: A review of the preclinical development pipeline

Dengue represents a significant and growing public health problem across the globe, with approximately half of the world's population at risk. The increasing and expanding burden of dengue has highlighted the need for new tools to prevent dengue, including development of dengue vaccines. Recently, the first dengue vaccine candidate was evaluated in Phase 3 clinical trials, and other vaccine candidates are under clinical evaluation. There are also a number of candidates in preclinical development, based on diverse technologies, with promising results in animal models and likely to move into clinical trials and could eventually be next-generation dengue vaccines. This review provides an overview of the various technological approaches to dengue vaccine development with specific focus on candidates in preclinical development and with evaluation in non-human primates.     

NIAID meeting report: Improving malaria vaccine strategies through the application of immunological principles

A highly efficacious vaccine to prevent malaria infection or clinical disease is still far from reality despite several decades of intensive effort and a growing global commitment in malaria vaccine development. Further understanding of the mechanisms required for induction of effective host immune responses and maintenance of long-term protective immunity is needed to facilitate rational approaches for vaccine design and evaluation. The National Institute of Allergy and Infectious Diseases (NIAID) conducted a workshop on June 18–19, 2012 with experts in the fields of malaria vaccine development, malaria immunology, and basic immunology to address issues associated with improving our current understanding of malaria vaccine immunity. This report summarizes the discussion and major recommendations generated by the workshop participants regarding the application of recent advances in basic immunology and state-of-the-art immunological tools to improve progress and help address current challenges and knowledge gaps in malaria vaccine development.     

Live-attenuated, tetravalent dengue vaccine in children, adolescents and adults in a dengue endemic country: randomized controlled phase I trial in the Philippines

A recombinant live attenuated tetravalent dengue vaccine (TDV) is safe and immunogenic in adults and children in dengue-naïve populations. Data are needed in dengue endemic populations. In a phase I, randomized, controlled, blind-observer study in the Philippines, groups of participants aged 2-5, 6-11, 12-17, and 18-45 years received either three TDV vaccinations at months 0, 3.5, and 12 (TDV-TDV-TDV group) or licensed typhoid vaccination at month 0 and TDV at months 3.5 and 12 (TyVi-TDV-TDV group) and were followed for safety (including biological safety and vaccine virus viremia) and immunogenicity. No serious adverse vaccine related events and no significant trends in biological safety parameters were reported. Injection site pain, headache, malaise, myalgia, fever, and asthenia were reported most frequently, as mild to moderate in most cases and transient. Reactogenicity did not increase with successive vaccinations and was no higher in children than in adults and adolescents. Low levels of vaccinal viremia were detected in both groups after each TDV vaccination. After three TDV vaccinations, the seropositivity rates against serotypes 1-4 were: 91%, 100%, 96%, 100%, respectively, in 2-5 year-olds; 88%, 96% 96%, 92% in 6-11 year-olds; 88%, 83%, 92%, 96% in adolescents; and 100% for all serotypes in adults. A similar response was observed after two doses for the TyVi-TDV-TDV group. The safety profile of TDV in a flavivirus endemic population was consistent with previous reports from flavivirus naïve populations. A vaccine regimen of either three TDV vaccinations administered over a year or two TDV vaccinations given more than 8 months apart resulted in a balanced antibody response to all four dengue serotypes in this flavivirus-exposed population, including children.     

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

BackgroundEarly 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).MethodsSubjects 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.ResultsOf 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.ConclusionsThese 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.     

Preparing for introduction of a dengue vaccine: recommendations from the 1st Dengue v2V Asia-Pacific Meeting

Infection with dengue virus is a major public health problem in the Asia-Pacific region and throughout tropical and sub-tropical regions of the world. Vaccination represents a major opportunity to control dengue and several candidate vaccines are in development. Experts in dengue and in vaccine introduction gathered for a two day meeting during which they examined the challenges inherent to the introduction of a dengue vaccine into the national immunisation programmes of countries of the Asia-Pacific. The aim was to develop a series of recommendations to reduce the delay between vaccine licensure and vaccine introduction. Major recommendations arising from the meeting included: ascertaining and publicising the full burden and cost of dengue; changing the perception of dengue in non-endemic countries to help generate global support for dengue vaccination; ensuring high quality active surveillance systems and diagnostics; and identifying sustainable sources of funding, both to support vaccine introduction and to maintain the vaccination programme. The attendees at the meeting were in agreement that with the introduction of an effective vaccine, dengue is a disease that could be controlled, and that in order to ensure a vaccine is introduced as rapidly as possible, there is a need to start preparing now.     

Use of circulating cathodic antigen strips for the diagnosis of urinary schistosomiasis

Rapid diagnostic tests are needed for the implementation and monitoring of national schistosomiasis control programmes. The field applicability of the circulating cathodic antigen (CCA) urine reagent strip for the diagnosis of Schistosoma haematobium infection was evaluated among 265 pre- and primary schoolchildren aged 2-19 years in a rural area of Zimbabwe. The CCA strip was compared with egg detection before and six weeks after treatment with praziquantel. Pre-treatment prevalence (overall 40.4%) and intensity of infection, as determined by egg counts, increased with age. CCA and parasitological results were significantly correlated (P<0.001), although concordance was slight (kappa=0.21). Discordant results were mainly attributable to CCA-positive, egg-negative individuals. Correlations and levels of agreement improved significantly with age (P<0.001, kappa=0.40) and intensity of infection (P<0.001). Praziquantel treatment led to 'cure' in 90.9% and 70.5% of children as measured by the egg detection and CCA methods, respectively. An arbitrary gold standard was constructed that included both CCA and egg detection results. Using this standard, the sensitivities of the CCA test were 88.2% and 95.8%, respectively, for pre- and post-treatment results. The improved version that is field applicable now has an acceptable role in the field diagnosis of S. haematobium.     

从公众对大数据平台脊髓灰质炎疫苗和麻腮风联合减毒活疫苗的信息搜索探讨疫苗知识的健康传播策略

目的分析公众对脊髓灰质炎(脊灰)疫苗和麻腮风联合减毒活疫苗(麻腮风疫苗)的信息搜索,探讨疫苗知识的健康传播策略。方法通过"百度搜索"和"宝宝知道"数据平台,收集2019年4月上旬公众对脊灰疫苗和麻腮风疫苗的搜索信息,采用文本挖掘和聚类算法,分析公众关注信息的频次和排序。结果公众对脊灰疫苗内容的关注度由高到低依次为疫苗不良反应、疫苗基本信息、疫苗接种方式和接种疫苗后注意事项;对麻腮风疫苗内容的关注度依次为疫苗基本信息、不良反应和接种方式。在疫苗安全性方面,公众同时关注疫苗接种后不良反应的类型和处理方式。结论公众对疫苗的搜索信息随疫苗不同而不同,疫苗知识的健康传播策略需精准化。     

Effect of Tdap when administered before,with or after the 13-valent pneumococcal conjugate vaccine (coadministered with the quadrivalent meningococcal conjugate vaccine) in adults: A randomised controlled trial

Sequential or co-administration of vaccines has potential to alter the immune response to any of the antigens. Existing literature suggests that prior immunisation of tetanus/diphtheria-containing vaccines can either enhance or suppress immune response to conjugate pneumococcal or meningococcal vaccines. We examined this interaction among adult Australian travellers before attending the Hajj pilgrimage 2014. We also investigated tolerability of these vaccines separately and concomitantly. We randomly assigned each participant to one of three vaccination schedules. Group A received adult tetanus, diphtheria and acellular pertussis vaccine (Tdap) 3–4 weeks before receiving CRM197-conjugated 13-valent pneumococcal vaccine (PCV13) and CRM197-conjugated quadrivalent meningococcal vaccine (MCV4). Group B received all three vaccines on one day. Group C received PCV13 and MCV4 3–4 weeks before Tdap. Blood samples collected at baseline, each vaccination visit and 3–4 weeks after vaccination were tested using the pneumococcal opsonophagocytic assay (OPA) and by ELISA for diphtheria and tetanus antibodies. Funding for meningococcal serology was not available. Participants completed symptom diaries after each vaccination. A total of 111 participants aged 18–64 (median 40) years were recruited. No statistically significant difference was detected across the three groups in achieving OPA titre ⩾1:8 post vaccination. However, compared to other groups, Group A had a statistically significant lower number of subjects achieving ⩾4-fold rise in serotype 3, and also significantly lower geometric mean titres (GMTs) to six (of 13) pneumococcal serotypes (3, 5, 18C, 4, 19A and 9V). Group C (given prior PCV13 and MVC4) had statistically significant higher pre-Tdap geometric mean concentration (GMC) of anti-diphtheria IgG; however, there was no difference across the three groups following Tdap. Anti-tetanus IgG GMCs were similar across the groups before and after Tdap. No serious adverse events were reported. In conclusion, Tdap vaccination 3–4 weeks before concomitant administration of PCV13 and MCV4 significantly reduced the antibody response to six of the 13 pneumococcal serotypes in adults.The trial is registered at the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000536763.     

A continuous-scale measure of child development for population-based epidemiological surveys: a preliminary study using Item Response Theory for the Denver Test

A method for translating research data from the Denver Test into individual scores of developmental status measured in a continuous scale is presented. It was devised using the Denver Developmental Screening Test (DDST) but can be used for Denver II. The DDST was applied in a community-based survey of 3389 under-5-year-olds in Porto Alegre, Brazil. The items of success were standardised by logistic regression on log chronological age. Each child's ability age was then estimated by maximum likelihood as the age in this reference population corresponding to the child's success and failures in the test. The score of developmental status is the natural logarithm of this ability age divided by chronological age and thus measures the delay or advance in the child's ability age compared with chronological age. This method estimates development status using both difficulty and discriminating power of each item in the reference population, an advantage over scores based on total number of items correctly performed or failed, which depend on difficulty only. The score corresponds with maternal opinion of child developmental status and with the 3-category scale of the DDST. It shows good construct validity, indicated by symmetrical and homogeneous variability from 3 months upwards, and reasonable results in describing gender differences in development by age, the mean score increasing with socio-economic conditions and diminishing among low-birthweight children. If a standardised measure of development status (z-scores) is required, this can be obtained by dividing the score by its standard deviation. Concurrent and discriminant validity of the score must be examined in further studies.     

Vaccination willingness,vaccine hesitancy,and estimated coverage at the first round of COVID-19 vaccination in China: A national cross-sectional study

BackgroundVaccination against coronavirus disease 2019 (COVID-19) has become an important public health solution. To date, there has been a lack of data on COVID-19 vaccination willingness, vaccine hesitancy, and vaccination coverage in China since the vaccine has become available.MethodsWe designed and implemented a cross-sectional, population-based online survey to evaluate the willingness, hesitancy, and coverage of the COVID-19 vaccine among the Chinese population. 8742 valid samples were recruited and classified as the vaccine-priority group (n = 3902; 44.6%) and the non-priority group (n = 4840; 55.4%).ResultsThe proportion of people’s trust in the vaccine, delivery system, and government were 69.0%, 78.0% and 81.3%, respectively. 67.1% of the participants were reportedly willing to accept the COVID-19 vaccination, while 9.0% refused it. 834 (35.5%) reported vaccine hesitancy, including acceptors with doubts (48.8%), refusers (39.4%), and delayers (11.8%). The current coverage was 34.4%, far from reaching the requirements of herd immunity. The predicted rate of COVID-19 vaccination was 64.9%, 68.9% and 81.1% based on the rates of vaccine hesitancy, willingness, and refusal, respectively.ConclusionsThe COVID-19 vaccine rate is far from reaching the requirements of herd immunity, which will require more flexible and comprehensive efforts to improve the population’s confidence and willingness to vaccinate. It should be highlighted that vaccination alone is insufficient to stop the pandemic; further efforts are needed not only to increase vaccination coverage but also to maintain non-specific prevention strategies.