Dengue vaccine supplies under endemic and epidemic conditions in three dengue-endemic countries: Colombia,Thailand, and Vietnam

BackgroundDengue fever has been a major public health concern in Colombia, Thailand, and Vietnam. Unlike other infectious diseases, dengue vaccines had not been available for a long time, causing difficulties to control the disease. However, the first live attenuated, tetravalent dengue vaccine (CYD-TDV) became available in 2016 and has been already licensed in some dengue-endemic countries. Because several second-generation dengue vaccines are also in the pipeline, it is critical to understand the efficient allocation of dengue vaccines considering the geographical variation of the disease.MethodsThe Climate Risk Factor (CRF) index was created using the climate and non-climate factors in the three countries. A random-coefficient negative binomial model was chosen to validate the relationship between the CRF index and dengue incidence proxy. Given the statistical significance of the CRF index, high risk areas for dengue fever were identified at the 5 km by 5 km resolution and used to estimate vaccination coverage rates and the number of doses required for various types of vaccination scenarios by country.Results and conclusionsBased upon a three-dose scheme, the estimated number of vaccines required for routine vaccination targeting 9 years old ranged from 1 to 2.6 million doses across the countries during the first year of introduction. A one-off catch-up campaign targeting the age group of 10–17 year olds would require 8 to 18 million additional doses. Routine vaccination (with or without a catch-up campaign) covered 63%, 90%, and 91% of the targeted age group populations in Colombia, Thailand, and Vietnam respectively. Given that many dengue-endemic countries face limited resources and that the costs for mass vaccination campaigns may not be trivial, the findings of this study can guide the decision makers in the three countries regarding the efficient distribution of vaccines by identifying populations at high risk at 5 km by 5 km resolution.     

Effectiveness of a single-dose mass dengue vaccination in Cebu,Philippines: A case-control study

BackgroundDengue fever is an important public health problem in the Philippines. In April 2016, the Department of Health launched a three-dose school based dengue vaccination program of nine- to fourteen-year-old children in three regions with the highest number of dengue cases using CYD-TDV (Dengvaxia, Sanofi Pasteur). In July 2017, a community-based dengue vaccination program was implemented in Cebu province. The program was discontinued in December 2017 amidst public controversy, after the first dose had been administered. We assessed the effectiveness of a single dose of CYD-TDV against hospitalized virologically confirmed dengue (VCD).MethodsWe conducted a case-control study in Cebu province following the dengue mass vaccination. Children who were nine to fourteen years of age during the mass vaccination and subsequently admitted to any of four participating public hospitals with suspected dengue were enrolled in the study as cases. Blood for RT-PCR and clinical and socio-demographic information were obtained. To estimate the level of vaccine protection, vaccination status was compared between children with hospitalized virologically confirmed dengue and controls of the same six-year age-group as the cases, matched on sex, neighborhood and time of occurrence of cases.FindingsWe enrolled 490 cases and 980 controls. Receipt of one dose of CYD-TDV was associated with 26% (95 % CI, −2 to 47%; p = 0 0675) overall protection against hospitalized virologically confirmed dengue and 51% (95 % CI, 23 to 68; p = 0 0016) protection against dengue with warning signs.InterpretationA single dose of CYD-TDV given to nine to fourteen-year-old children through a community-based mass vaccination program conferred protection against dengue with warning signs and severe dengue but we were unable to conclude on protection against milder illness.     

Potential impact of dengue vaccination: Insights from two large-scale phase III trials with a tetravalent dengue vaccine

BackgroundA tetravalent dengue vaccine demonstrated its protective efficacy in two phase III efficacy studies. Results from these studies were used to derive vaccination impact in the five Asian (Indonesia, Malaysia, Philippines, Thailand, Vietnam) and the five Latin American countries (Brazil, Colombia, Honduras, Mexico and Puerto Rico) participating in these trials.MethodsVaccination impact was investigated with an age-structured, host-vector, serotype-specific compartmental model. Parameters related to vaccine efficacy and levels of dengue transmission were estimated using data collected during the phase III efficacy studies. Several vaccination programs, including routine vaccination at different ages with and without large catch-up campaigns, were investigated.ResultsAll vaccination programs explored translated into significant reductions in dengue cases at the population level over the first 10 years following vaccine introduction and beyond. The most efficient age for vaccination varied according to transmission intensity and 9 years was close to the most efficient age across all settings. The combination of routine vaccination and large catch-up campaigns was found to enable a rapid reduction of dengue burden after vaccine introduction.ConclusionOur analysis suggests that dengue vaccination can significantly reduce the public health impact of dengue in countries where the disease is endemic.     

The potential impact of dengue vaccination with,and without,pre-vaccination screening

BackgroundThe World Health Organization defined a ‘screen and vaccinate’ strategy as its recommended policy for the licensed dengue vaccine (Dengvaxia, Sanofi Pasteur), so that only individuals with previous dengue infection are vaccinated. The objectives of the present study were to build upon a recently published analysis of the benefits and risks associated with dengue vaccination to evaluate the public health impact and cost-effectiveness of a screen and vaccinate strategy.MethodsThe current analysis was based on a previously reported transmission model and added, for the screening part, three rapid diagnostic tests with identical specificity (99%) but alternative sensitivities (50-70-90%) in the detection of prior dengue infection. The impact of a screen-and-vaccinate strategy considered nine settings representing different levels of transmission intensity. Outcomes (dengue-related hospitalizations, severe dengue, and symptomatic dengue) were assessed according to the level of transmission setting. The cost-effectiveness of vaccination in 10 endemic countries was also assessed.ResultsAlthough associated, in most cases, with a lower population impact than a ‘no-screening’ approach, a screen and vaccinate strategy is more effective in reducing the number of hospitalized and severe cases prevented per vaccination performed and generates positive health benefits for individuals screened and subsequently vaccinated. As a result, this intervention is cost-effective in all countries considered except for very low transmission settings. The overall population impact of a screen and vaccinate approach is also likely to be improved by the use of several rounds of screening (up to 48% reduction in dengue hospitalization over 10 years with 5 rounds).ConclusionsWHO recommended option of a screen and vaccinate policy is likely to have a positive impact both at the individual and population level across a wide range of transmission settings and has the potential to be as, if not more, cost-effective than a no screening strategy.     

Cost-utility analysis of dengue vaccination in a country with heterogeneous risk of dengue transmission

BackgroundDengue is one of the most important vector-borne diseases worldwide, and annually, nearly 390 million people are infected and 500,000 patients are hospitalized for severe dengue. Argentina has great variability in the risk of dengue transmission due to eco-climatic reasons. Currently no vaccines are available for dengue even though several vaccines are under development.ObjectiveThe aim of this study was to estimate the cost-effectiveness of a dengue vaccine in a country with heterogeneous risk of dengue transmission like Argentina.MethodsThe analysis was carried out from a societal perspective using a Markov model that included both vaccine and disease parameters. Utility was measured as disability adjusted life years (DALYs) averted, and the incremental cost-effectiveness ratio (ICER) of the vaccination was expressed in 2014 American dollars (US$) per DALY averted. One-way and probabilistic sensitivity analyses were performed to evaluate uncertainty in model outcomes, and a threshold analysis was conducted to estimate the highest possible price of the vaccine.ResultsThe ICER of the vaccination program was found to be US$ 5714 per DALY averted. This value is lower than 3 times the per capita GDP of Argentina (US$ 38,619 in 2014); 54.9% of the simulations were below this value. If a vaccination program would be implemented the maximum vaccine price per dose has to be US$1.49 for a vaccination at national level or US$28.72 for a targeted vaccination in high transmission areas.ConclusionsThese results demonstrate that vaccination against dengue would be cost-effective in Argentina, especially if carried out in predetermined regions at high risk of dengue transmission. However, these results should be interpreted with caution because the probabilistic sensitivity analysis showed that there was considerable uncertainty around the ICER value. The influence of variations in vaccine efficacy, cost and other important parameters are discussed in the text.     

Incidence rates of neurotropic-like and viscerotropic-like disease in three dengue-endemic countries: Mexico,Brazil, and Malaysia

Background

The background incidence of viscerotropic- (VLD) and neurotropic-like disease (NLD) unrelated to immunization in dengue-endemic countries is currently unknown.

Estimation of expected dengue seroprevalence from passive epidemiological surveillance systems in selected areas of Argentina: A proxy to evaluate the applicability of dengue vaccination

BackgroundCurrent recommendations about dengue vaccination by the World Health Organization depend on seroprevalence levels and serological status in populations and individuals. However, seroprevalence estimation may be difficult due to a diversity of factors. Thus, estimation through models using data from epidemiological surveillance systems could be an alternative procedure to achieve this goal.ObjectiveTo estimate the expected dengue seroprevalence in children of selected areas in Argentina, using a simple model based on data from passive epidemiological surveillance systems.MethodsA Markov model using a simulated cohort of individuals from age 0 to 9 years was developed. Parameters regarding the reported annual incidence of dengue, proportion of inapparent cases, and expansion factors for outpatient and hospitalized cases were considered as transition probabilities. The proportion of immune population at 9 years of age was taken as a proxy of the expected seroprevalence, considering this age as targeted for vaccination. The model was used to evaluate the expected seroprevalence in Misiones and Salta provinces and in Buenos Aires city, three settings showing different climatic favorability for dengue.ResultsThe estimates of the seroprevalence for the group of 9-year-old children for Misiones was 79% (95%CI:46–100%), and for Salta 22% (95%CI:14–30%), both located in northeastern and northwestern Argentina, respectively. Buenos Aires city, from central Argentina, showed a likely seroprevalence of 7% (95%CI: 3–11%). According to the deterministic sensitivity analyses, the parameter showing the highest influence on these results was the probability of inapparent cases.ConclusionsThis model allowed the estimation of dengue seroprevalence in settings where this information is not available. Particularly for Misiones, the expected seroprevalence was higher than 70% in a wide range of scenarios, thus in this province a vaccination strategy directed to seropositive children of >9 years should be analyzed, including further considerations as safety, cost-effectiveness, and budget impact.     

Re-evaluating the cost and cost-effectiveness of rotavirus vaccination in Bangladesh,Ghana, and Malawi: A comparison of three rotavirus vaccines

IntroductionDiarrhea is a leading cause of mortality worldwide and rotavirus accounts for many of these deaths. As of August 2018, 96 countries have introduced rotavirus vaccines into their immunization programs. Two rotavirus vaccines, Rotarix® and RotaTeq®, have been WHO-prequalified since 2009, with Rotarix® being the preferred product of most Gavi-supported countries. ROTAVAC® and ROTASIIL® have both been prequalified recently.Materials and methodsWe reevaluated the costs and cost-effectiveness of rotavirus vaccination in Bangladesh, Ghana, and Malawi and compared Rotarix®, ROTAVAC®, and ROTASIIL® in each country. For consistency with previously published analyses in these countries, we used the same Excel-based cohort model and much of the same data as the original analyses. We varied the expected price (with and without Gavi subsidy), wastage, and incremental health system costs associated with each vaccine. We assumed the same efficacy and waning assumptions following administration of two or three doses for the respective product.ResultsThe discounted cost per DALY averted compared to no vaccination ranged from 0.3 to 1.3 times GNI per capita for each vaccine. With the Gavi subsidy, the average cost-effectiveness ratios were below 0.3 times GNI per capita in all three countries. Though critical empirical cost data are not yet available, Rotarix® is the least costly and most cost-effective product in the countries examined in this modelling study. However, small decreases in the incremental health system cost for other products could result in cost and cost-effectiveness outcomes that match or surpass those of Rotarix®.ConclusionCountries may wish to consider new rotavirus vaccines entering the market. Countries should carefully examine multiple product attributes including price and the incremental health system costs associated with each vaccine. These costs will vary by country and may be a defining factor in determining the least costly and most cost-effective product for the population.     

Economic evaluation and budget impact analysis of dengue vaccination following pre-vaccination serological screening in India

ObjectivesTo evaluate the budget impact and cost-effectiveness of dengue vaccination following pre-vaccination serological screening in India.MethodsWe used a static cohort model (combination of decision tree and Markov model) to compare dengue disease and cost burden with and without dengue vaccination program with serological screening for a hypothetical cohort of 10-year-old adolescents. Budget impact was expressed in terms of total budget required for implementation of vaccination programme. Program impact was expressed in terms of disability-adjusted life-years (DALYs) averted. Cost effectiveness was expressed as costs per DALY averted. All costs are expressed in 2018 US dollars. Sensitivity analysis was performed for ICERs in different vaccination scenarios.ResultsThe total budget for implementation of dengue vaccination programme is approximately around US$ 530 million (INR 3620 crores). Our model results suggest dengue vaccination result in a net gain of almost 86,000 DALYS. We found the Dengue vaccine to be a cost-effective intervention with an ICER of $3364 (INR 2,30,098) which is less than three-times GDP per capita of India ($6047; INR 413,601). One-way sensitivity analysis shows that the ICER is most affected by the overall incidence of dengue infections followed by vaccine price. Probabilistic sensitivity analysis shows that ICER for dengue vaccination varied from $1182 (INR 80,837) to $6367 (INR 435,439).ConclusionOur study shows that dengue vaccine with pre-vaccination serological screening programme is a cost-effective intervention with the conservative estimates.     

Age,revaccination, and tolerance effects on pneumococcal vaccination strategies in the elderly: A cost-effectiveness analysis

Optimal pneumococcal polysaccharide vaccination (PPV) policy is unknown for cohorts aged ≥65 years. Using a Markov model, we estimated the cost-effectiveness of single- and multiple-dose PPV strategies in 65-, 75-, and 80-year-old cohorts. PPV at age 65 cost $26,100 per QALY (quality adjusted life years) gained. Vaccination at ages 75 and 80 cost $71,300–75,800 per QALY; revaccination strategies cost more. When prior vaccination and loss of vaccine effectiveness due to tolerance are assumed, cost-effectiveness ratios increase substantially. Single-dose PPV is worth considering in patients aged 65–80 from clinical and economic standpoints. Revaccination strategies for the elderly are less cost-effective, particularly when prior vaccination and vaccine tolerance are considered.     

The cost-effectiveness of rotavirus vaccination: Comparative analyses for five European countries and transferability in Europe

Cost-effectiveness analyses are usually not directly comparable between countries because of differences in analytical and modelling assumptions. We investigated the cost-effectiveness of rotavirus vaccination in five European Union countries (Belgium, England and Wales, Finland, France and the Netherlands) using a single model, burden of disease estimates supplied by national public health agencies and a subset of common assumptions. Under base case assumptions (vaccination with Rotarix^®, 3% discount rate, health care provider perspective, no herd immunity and quality of life of one caregiver affected by a rotavirus episode) and a cost-effectiveness threshold of €30,000, vaccination is likely to be cost effective in Finland only. However, single changes to assumptions may make it cost effective in Belgium and the Netherlands. The estimated threshold price per dose for Rotarix^® (excluding administration costs) to be cost effective was €41 in Belgium, €28 in England and Wales, €51 in Finland, €36 in France and €46 in the Netherlands.     

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,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.     

Cost-effectiveness of rotavirus vaccination in the Philippines: A modeling study

IntroductionRotavirus gastroenteritis (RVGE) remains a leading cause of hospitalization and death in children under five years of age in the Philippines. Rotavirus (RV) vaccination was introduced into the national immunization program (NIP) in 2012 but has since been limited to one region due to cost considerations and conflicting local cost-effectiveness estimates. Updated estimates of the cost-effectiveness of RV vaccination are required to inform prioritization of national immunization activities.MethodsWe calculated the potential costs and benefits of rotavirus vaccination over a 10-year-period (2021–2031) from a government and societal perspective, comparing four alternative rotavirus vaccines: Rotavac, Rotasiil, Rotarix and Rotateq. For each vaccine, a proportionate outcomes model was used to calculate the expected number of disease events, DALYs, vaccination program costs, and healthcare costs, with and without vaccination. The primary outcome measure was the cost per DALY averted. Assuming each product would generate similar benefits, the dominant (lowest cost) product was identified. We then calculated the cost-effectiveness (US$ per Disability Adjusted Life Year [DALY] averted) of the least costly product and compared it to willingness-to-pay thresholds of 0.5 and 1 times the national GDP per capita ($3,485), and ran deterministic and probabilistic sensitivity analyses.ResultsIntroducing any of the four rotavirus vaccines would avert around 40% of RVGE visits, hospitalizations, and deaths over the period 2021–2031. Over the same ten-year period, the incremental cost of vaccination from a government perspective was estimated to be around $104, $105, $220, and $277 million for Rotavac, Rotasiil, Rotarix and Rotateq, respectively. The equivalent cost from a societal perspective was $58, $60, $178 and $231 million. The cost-effectiveness of the least costly product (Rotavac) was $1,148 ($830–$1682) from a government perspective and $646 ($233–1277) from a societal perspective. All other products offered similar benefits but at a higher cost. There is a >99% probability that Rotavac would be cost-effective at a willingness-to-pay threshold set at 0.5 times the national GDP per capita.ConclusionBoth Rotavac and Rotasiil are likely to be cost-effective options in the Philippines, but it is not possible to say definitively which product should be preferred. Rotarix and Rotateq are expected to offer similar benefits at more cost, so would need to be priced far more competitively to be considered for introduction.     

A Phase 1, double-blind,randomized, placebo-controlled study to evaluate the safety and immunogenicity of a tetravalent live attenuated dengue vaccine in adults

BackgroundDengue fever is an important public health problem, especially in Asia and South America. A tetravalent live attenuated dengue vaccine was manufactured in India after receipt of vaccine strains from NIAID, NIH, USA.MethodsThis was a Phase 1, double-blind, randomized, placebo-controlled study performed in 60 healthy adults of 18 to 45 years. Participants were randomized 2:1 to receive a single subcutaneous injection of either a tetravalent live attenuated dengue vaccine or placebo. Safety was assessed by unsolicited adverse events (AEs) and solicited reactions through 21 days after vaccination and serious adverse events (SAEs) through the entire study period of 180 days. Dengue viremia was assessed at baseline and on day 9, 11 and 13 post-vaccination using a plaque assay. Immunogenicity was assessed using the plaque reduction neutralization test (PRNT) assay using vaccine-matched wild virus serotypes (DENV 1, DENV 2, DENV 3 and DENV 4) at baseline and on 56-, 84- and 180-days post-vaccination. PRNT assay using circulating wild type DENV 1, DENV 2, DENV 3 and DENV 4 were done on day 1 and day 85 for a subset of 31 participants.Results60 participants were randomized to receive dengue vaccine (n = 40) or placebo (n = 20). 23 participants (59 %) showed DENV vaccine viremia post- vaccination for any of the four serotypes with majority on day 9 and day 11. At baseline, all participants were naïve by dengue PRNT₅₀ for all four serotypes in both the study groups except for four in the dengue vaccine group and two in the placebo group. On day 57, the GMTs of neutralizing antibodies ranged from 66.76 (95 % CI 36.63, 121.69) to 293.84 (95 % CI 192.25, 449.11) for all four serotypes in the dengue vaccine group. On day 181 though the titers declined, they still remained much higher than the baseline. The titers in the placebo group did not change after vaccination. Seroconversion through day 85 ranged from 79.5 % for DENV 1 to 100 % for DENV2 while in the placebo group, no participant showed seroconversion through day 85. Similar trends were noted when PRNT was done using wild DENV serotypes in both vaccine and placebo groups.Among solicited reactions, injection site erythema, rash, headache, fatigue, myalgia and arthralgia were reported more frequently in the vaccine group than placebo group. All solicited reactions were of grade 1 or grade 2 severity and completely resolved. One unrelated serious adverse event was reported in the vaccine group.ConclusionA single dose of dengue vaccine was safe and well tolerated in adults. The vaccine was highly immunogenic with trivalent or tetravalent seroconversion and seropositivity in most of the participants.The study was funded by Serum Institute of India Pvt. Ltd., Pune, India. ClinicalTrials.gov: NCT04035278.     

Immunogenicity and protective efficacy of a psoralen-inactivated dengue-1 virus vaccine candidate in Aotus nancymaae monkeys

Psoralens are photoreactive compounds that cross-link pyrimidines after exposure to UVA radiation. In this experiment, we tested the protective efficacy of a psoralen-inactivated dengue vaccine candidate in non-human primates. Two groups of 7 Aotus nancymaae monkeys received either 10 ng per dose of inactivated DENV1 plus alum adjuvant or alum alone (controls). Doses were injected intradermally on days 0, 14, and 28. Monkeys then received a challenge inoculation of 1.1 × 10⁴ PFUs of WestPac 74 DENV-1 on day 132. At 62 days, only 1/7 vaccinated monkeys had detectable IgM, but IgG and neutralizing antibody remained detectable in 7/7. No IgM, IgG, or neutralizing antibody was detectable in control monkeys. DENV-1 viremia was detected after challenge in 3/7 vaccinated monkeys and 5/6 control monkeys (with one removed due to pregnancy) (p = 0.27), but days of viremia were reduced from 3.67 days/animal among controls to 0.71 days/animal among vaccinated monkeys (p = 0.051). Psoralen-inactivated DENV1 is immunogenic in Aotus nancymaae with a trend towards a reduction in days of viremia following experimental challenge.     

Detection of dengue cases by serological testing in a dengue vaccine efficacy trial: Utility for efficacy evaluation and impact of future vaccine introduction

BackgroundDengue diagnosis confirmation and surveillance are widely based on serological assays to detect anti-dengue IgM or IgG antibodies since such tests are affordable/user-friendly. The World Health Organization identified serological based diagnosis as a potential tool to define probable dengue cases in the context of vaccine trials, while acknowledging that this may have to be interpreted with caution.MethodsIn a phase IIb randomized, placebo-controlled trial assessing the efficacy of a tetravalent dengue vaccine (CYD-TDV) in Thai schoolchildren, case definition was based on virological confirmation by either serotype-specific RT-PCRs or by NS1-antigen ELISA (Clinicaltrials.gov NCT00842530). Here, we characterized suspected dengue cases using IgM and IgG ELISA to assess their utility in evaluating probable dengue cases in the context of vaccine efficacy trials, comparing virologically-confirmed and serologically diagnosed dengue in the vaccine and placebo groups. Serologically probable cases were defined as: (1) IgM positive acute- or convalescent-phase samples, or (2) IgG positive acute-phase sample and ≥4-fold IgG increase between acute and convalescent-phase samples.ResultsSerological diagnosis had good sensitivity (97.1%), but low specificity (85.1%) compared to virological confirmation. A high level of false positivity through serology diagnosis particularly in the 2 months post-vaccination was observed, and is most likely related to detection of the immune response to the dengue vaccine. This lack of specificity and bias with vaccination demonstrates the limitation of using IgM and IgG antibody responses to explore vaccine efficacy.ConclusionReliance on serological assessments would lead to a significant number of false positives during routine clinical practice and surveillance following the introduction of the dengue vaccine.     

Safety and immunogenicity of different doses and schedules of a live attenuated tetravalent dengue vaccine (TDV) in healthy adults: A Phase 1b randomized study

IntroductionA safe, effective dengue vaccine that can simultaneously induce immunity to all four dengue virus serotypes (DENV-1–4) is a public health priority. A chimeric tetravalent dengue vaccine (TDV) based on an attenuated DENV-2 serotype backbone was evaluated in healthy, flavivirus-seronegative adults.MethodsIn this randomized, multicenter, Phase 1b study conducted in the United States, the safety and immunogenicity of TDV were evaluated in 140 participants aged 18–45 years in six dosing regimen study groups. Participants were injected subcutaneously on Days 0 and 90; placebo (saline) was injected where appropriate to maintain double blinding. Three different TDV dosages (TDV, a vaccine in which TDV-4 had been increased three-fold, and a one-tenth TDV dose), and single or double dosing were evaluated in one and/or both arms. Primary endpoints were solicited and unsolicited adverse events (AEs) and seroconversion rates to DENV-1–4 at Day 120.ResultsThe severity of all AEs was generally mild. The most common unsolicited AEs were headache (52%), fatigue (43%) and myalgia (29%). The incidence of injection site pain ranged from 29 to 64% and 5 to 52% among study groups after the first and second doses, respectively. At Day 120, the ranges of seroconversion rates among the groups were DEN-1: 84–100%; DEN-2: 96–100%; DEN-3: 83–100%; and DEN-4: 33–77%. More than 80% of participants in each group seroconverted to at least three dengue serotypes. Substantial GMT increases from baseline were observed for DEN-1–3 at all time points from Day 30 onward; DEN-4 GMT increases were lower. Increasing TDV-4 slightly increased DEN-4 GMT, did not impact DEN-2 and DEN-3 GMT, but reduced DEN-1 GMT. Neither multiple dosing in both arms, nor one-tenth TDV dosing meaningfully impacted GMT increases relative to TDV.ConclusionsAll TDV doses and dosing schedules were well tolerated and immunogenic in healthy flavivirus-naive adults (ClinicalTrials.gov NCT01511250).     

A systematic review of rubella vaccination strategies implemented in the Americas: impact on the incidence and seroprevalence rates of rubella and congenital rubella syndrome

Objective

To evaluate the impact of rubella vaccination strategies on the rates of acquired rubella and congenital rubella syndrome in the Americas.

Methods

We conducted a systematic review of the literature (MEDLINE, PubMed, EMBASE, Cochrane Library, Artemisa Database, LILACS Database, Evidence Portal, VHL-PAHO Portal, Scielo, and Grey-Literature sources) that was published from 1969–2010. We included studies on rubella incidence and seroprevalence rates that were associated with rubella vaccination. The quality of the studies was evaluated according to international guidelines.

Results

A total of 14 studies were identified: 2 clinical trials, 2 cohort studies, 3 transversal studies, 5 ecological studies, and 2 mathematical models. Childhood vaccination reduced the incidence of rubella by 23.6% to 99.6%, increased the occurrence of epidemic cycles in Argentina and in the United States, and shifted the illness to susceptible adults. Vaccination strategies that focused on women and children in Brazil were associated with a 5.5-fold greater incidence of rubella in men leading to new outbreaks and CRS. A combined vaccination strategy with a universal approach that included routine vaccination for boys, girls, women, and men in Mexico and in Costa Rica reduced the incidence of rubella by more than 98% and led to absence of CRS since 2008. A medium and a low risk of bias were found in 3 and 4 articles, respectively.

Conclusion

The results of this review demonstrate that the combined vaccination strategy with a universal approach was the most effective strategy as evidenced by a drastic reduction in the number of cases and the interruption of endemic transmission of rubella in the Americas.