Dengue vaccine: WHO position paper,July 2016 – recommendations

This article presents the World Health Organization’s (WHO) recommendations on the use of dengue vaccine excerpted from the WHO position paper on dengue vaccine published in the Weekly epidemiological Record in July 2016 (Dengue vaccine: WHO position paper, 2016) [1]. The current document is the first WHO position paper on dengue vaccination and focuses primarily on the available evidence concerning the only dengue vaccine to have been registered by National Regulatory Authorities. The position paper gives consideration to the epidemiological features of the disease and assesses the potential use of the vaccine for public health benefits.Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to-recommendation table. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO’s current position on the use of vaccines in the global context. This paper reflects the recommendations of the WHO’s Strategic Advisory Group of Experts (SAGE) on immunization. Recommendations on the use of this dengue vaccine were discussed by SAGE in April 2016; evidence presented at that SAGE meeting can be accessed at: http://www.who.int/immunization/sage/previous/en/index.html.     

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.     

Estimation of parameters related to vaccine efficacy and dengue transmission from two large phase III studies

BackgroundA tetravalent dengue vaccine was shown to be efficacious against symptomatic dengue in two phase III efficacy studies performed in five Asian and five Latin American countries. The objective here was to estimate key parameters of a dengue transmission model using the data collected during these studies.MethodsParameter estimation was based on a Sequential Monte Carlo approach and used a cohort version of the transmission model. Serotype-specific basic reproduction numbers were derived for each country. Parameters related to serotype interactions included duration of cross-protection and level of cross-enhancement characterized by differences in symptomaticity for primary, secondary and post-secondary infections. We tested several vaccine efficacy profiles and simulated the evolution of vaccine efficacy over time for the scenarios providing the best fit to the data.ResultsTwo reference scenarios were identified. The first included temporary cross-protection and the second combined cross-protection and cross-enhancement upon wild-type infection and following vaccination. Both scenarios were associated with differences in efficacy by serotype, higher efficacy for pre-exposed subjects and against severe dengue, increase in efficacy with doses for naïve subjects and by a more important waning of vaccine protection for subjects when naïve than when pre-exposed. Over 20 years, the median reduction of dengue risk induced by the direct protection conferred by the vaccine ranged from 24% to 47% according to country for the first scenario and from 34% to 54% for the second.ConclusionOur study is an important first step in deriving a general framework that combines disease dynamics and mechanisms of vaccine protection that could be used to assess the impact of vaccination at a population level.     

Systematic review of health economic evaluation studies of dengue vaccines

Objectives

To review the literature on economic evaluation of dengue vaccination to produce evidence to support a local cost-effectiveness study and to subsidize the decision to introduce a dengue vaccine in the Brazilian National Immunization Program. Methods: We systematically searched multiple databases (MEDLINE (via PubMed), EMBASE, SCOPUS, NHS Economic Evaluation Database (NHS EED), HTA Database (via Centre for Reviews and Dissemination – CRD) and LILACS), selecting full HEEs of dengue vaccine. Two independent reviewers screened articles for relevance and extracted the data. The methodology for the quality reporting was assessed using CHEERS checklist. We performed a qualitative narrative synthesis. Results: Thirteen studies conducted in Asian and Latin America countries were reviewed. All studies were favorable to the incorporation of the vaccine. However, the assumptions and values assumed for vaccine efficacy, safety and duration of protection, as well as the choice of the study population and the type of model used in the analyses, associated to an insufficient reporting of the methodological steps, affect the validity of the studies’ results. The quality reporting appraisal showed that the majority (8/13) of the studies reported less than 55% of the CHEERS checklists’ items. Conclusions: This systematic review shows that the economic evaluation of dengue vaccination did not adhere to key recommended general methods for economic evaluation. The presented cost-effectiveness results should not be transferred to other countries. It is recommended to conduct studies with local epidemiological and cost data, as well as assumptions about vaccination that reflect the results observed in clinical trials.     

Public health impact and cost-effectiveness of implementing a ‘pre-vaccination screening' strategy with the dengue vaccine in Puerto Rico

BackgroundThe World Health Organization (WHO) recommended ‘pre-vaccination screening’ as its preferred implementation strategy when using the licensed dengue vaccine (CYD-TDV; Dengvaxia, Sanofi), so that only individuals with previous dengue infection are vaccinated. The US Centers for Disease Control and Prevention (CDC) recommended use of CYD-TDV to prevent dengue in children with previous laboratory-confirmed dengue infection in regions where dengue is endemic. Here, we evaluate the public health impact and cost-effectiveness of a ‘pre-vaccination screening’ strategy in Puerto Rico.MethodsThe current analysis builds upon a previously published transmission model used to assess the benefits/risks associated with dengue vaccination. For ‘pre-vaccination screening’, three alternative testing methods were assessed: one using an immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) dengue serotest, another with dengue serotesting using a rapid diagnostic test (RDT), and one using both sequentially (as recommended in Puerto Rico). The time horizon considered was 10 years.ResultsIn Puerto Rico, the disability-adjusted life years (DALYs) averted for ‘pre-vaccination screening’ with an ELISA-based program, RDT-based program, and both sequentially would be a median 1,192 (95% CI: 716–2,232), 2,812 (95% CI: 1,579–5,019), and 1,017 (95% CI: 561–1,738), respectively. These benefits would arise from the reduction in cases: median 24,961 (95% CI: 17,480–36,782), 58,273 (95% CI: 40,729–84,796), 20,775 (95% CI: 14,637–30,374) fewer cases, respectively. The cost per DALY averted from a payer perspective would be US$12,518 (95 %CI: US$4,749–26,922), US$10,047 (95% CI: US$3,350–23,852), and US$12,334 (95% CI: US$4,965–26,444), respectively. All three strategies would be cost saving from a societal perspective.ConclusionsOur study supports the WHO and CDC ‘pre-vaccination screening’ guidance for CYD-TDV implementation. In Puerto Rico, regardless of the testing strategy and even with a relatively low rate of testing, it would be cost-effective from a payer perspective and cost saving from a societal perspective.     

Next generation dengue vaccines: a review of candidates in preclinical development

Dengue represents a major public health problem of growing global importance. In the absence of specific dengue therapeutics, strategies for disease control have increasingly focused on the development of dengue vaccines. While a licensed dengue vaccine is not yet available, several vaccine candidates are currently being evaluated in clinical trials and are described in detail in accompanying articles. In addition, there are a large variety of candidates in preclinical development, which are based on diverse technologies, ensuring a continued influx of innovation into the development pipeline. Potentially, some of the current preclinical candidates may become next generation dengue vaccines with superior product profiles. This review provides an overview of the various technological approaches to dengue vaccine development and specifically focuses on candidates in preclinical development.     

Economic evaluation of vaccination programme of 13-valent pneumococcal conjugate vaccine to the birth cohort in Japan

Japan is now preparing to incorporate PCV-7 into the national childhood immunisation programme. Our recently published economic evaluation of using PCV-7 to the birth cohort suggests that the cost to gain one QALY is lower than the WHO's cost-effectiveness criterion for intervention. However, many countries have started to introduce PCV-13 into their national immunisation schedule replacing PCV-7 for preventing pneumococcal diseases among young children. These raise the need to appraise the ‘value for money’ of replacing PCV-7 with PCV-13 vaccination programme in Japan.     

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.     

贵州省脑膜炎球菌多糖疫苗不同免疫策略的成本-效果比较分析

目的 比较分析贵州省脑膜炎球菌多糖疫苗（meningococcal polysaccharide vaccine,MPV）推广使用和纳入免疫规划策略的成本-效果。方法 根据贵州省MPV接种、流脑发病情况,采用成本-效果分析法,计算贵州省不同阶段推广使用MPV和将MPV纳入免疫规划策略的成本-效果比值（cost-effectiveness ratio,CER）。结果 1999—2015年,贵州省共接种6 285.73万剂次MPV,共减少流脑发病94 069例,减少致残13 170例,减少死亡10 710例;推广使用MPV、将MPV纳入免疫规划免疫策略总投入成本8.20亿元,26年间,接种MPV每减少1例流脑病例投入的成本为6 952元,其中,1990—2005年推广使用MPV 、2006—2015年纳入免疫规划策略每减少1例流脑病例投入的成本分别为4 915.64、614.59元。结论 接种MPV对降低贵州省流脑发病水平具有良好的成本-效果,2006—2015年将MPV纳入免疫规划策略的成本-效果明显优于1990—2005年推广使用MPV策略。     

Evaluation of protection induced by a dengue virus serotype 2 envelope domain III protein scaffold/DNA vaccine in non-human primates

We describe the preclinical development of a dengue virus vaccine targeting the dengue virus serotype 2 (DENV2) envelope domain III (EDIII). This study provides proof-of-principle that a dengue EDIII protein scaffold/DNA vaccine can protect against dengue challenge. The dengue vaccine (EDIII-E2) is composed of both a protein particle and a DNA expression plasmid delivered simultaneously via intramuscular injection (protein) and gene gun (DNA) into rhesus macaques. The protein component can contain a maximum of 60 copies of EDIII presented on a multimeric scaffold of Geobacillus stearothermophilus E2 proteins. The DNA component is composed of the EDIII portion of the envelope gene cloned into an expression plasmid. The EDIII-E2 vaccine elicited robust antibody responses to DENV2, with neutralizing antibody responses detectable following the first boost and reaching titers of greater than 1:100,000 following the second and final boost. Vaccinated and naïve groups of macaques were challenged with DENV2. All vaccinated macaques were protected from detectable viremia by infectious assay, while naïve animals had detectable viremia for 2–7 days post-challenge. All naïve macaques had detectable viral RNA from day 2–10 post-challenge. In the EDIII-E2 group, three macaques were negative for viral RNA and three were found to have detectable viral RNA post challenge. Viremia onset was delayed and the duration was shortened relative to naïve controls. The presence of viral RNA post-challenge corresponded to a 10–30-fold boost in neutralization titers 28 days post challenge, whereas no boost was observed in the fully protected animals. Based on these results, we determine that pre-challenge 50% neutralization titers of >1:6000 correlated with sterilizing protection against DENV2 challenge in EDIII-E2 vaccinated macaques. Identification of the critical correlate of protection for the EDIII-E2 platform in the robust non-human primate model lays the groundwork for further development of a tetravalent EDIII-E2 dengue vaccine.     

An adenovirus type 5 (AdV5) vector encoding an envelope domain III-based tetravalent antigen elicits immune responses against all four dengue viruses in the presence of prior AdV5 immunity

Dengue is a mosquito-borne viral disease caused by four antigenically distinct serotypes of dengue viruses (DENVs). This disease, which is prevalent in over a hundred tropical and sub-tropical countries of the world, represents a significant global public health problem. A tetravalent dengue vaccine capable of protecting against all four DENV serotypes has been elusive so far. Current efforts are focused on producing a tetravalent vaccine by mixing four monovalent vaccine components. In this work, we have utilized a discrete carboxy-terminal region of the major DENV envelope (E) protein, known as domain III (EDIII), which mediates virus entry into target cells and contains multiple serotype-specific neutralizing epitopes, to create a chimeric tetravalent antigen. This antigen derived by in-frame fusion of the EDIII-encoding sequences of the four DENV serotypes was expressed using a replication-defective recombinant human adenovirus type 5 (rAdV5) vaccine vector. This rAdV5 vector induced cell-mediated immune responses and virus-neutralizing antibodies specific to each of the four DENVs in mice. Interestingly, anti-AdV5 antibodies did not suppress the induction of DENV-specific neutralizing antibodies. We observed that anti-AdV5 antibodies in the sera of immunized mice could promote uptake of a rAdV5-derived reporter vector into U937 cells, suggesting that pre-existing immunity to AdV5 may in fact facilitate the uptake of rAdV5 vectored vaccines into antigen presenting cells. This work presents an alternative approach to developing a single component tetravalent vaccine that bypasses the complexities inherent in the currently adopted four-in-one physical mixture approach.     

Clinical Manifestations and Trend of Dengue Cases Admitted in a Tertiary Care Hospital, Udupi District, Karnataka

Background:

India is one of the seven identified countries in the South-East Asia region regularly reporting dengue fever (DF)/dengue hemorrhagic fever (DHF) outbreaks and may soon transform into a major niche for dengue infection in the future with more and more new areas being struck by dengue epidemics

Objective:

To study the clinical manifestations, trend and outcome of all confirmed dengue cases admitted in a tertiary care hospital.

Study Design:

Record-based study conducted in a coastal district of Karnataka. Required data from all the laboratory confirmed cases from 2002 to 2008 were collected from Medical Records Department (MRD) and analyzed using SPSS 13.5 version.

Results:

Study included 466 patients. Majority were males, 301(64.6%) and in the and in the age group of 15-44 years, 267 (57.5%). Maximum number of cases were seen in 2007, 219 (47%) and in the month of September, 89 (19.1%). The most common presentation was fever 462 (99.1%), followed by myalgia 301 (64.6%), vomiting 222 (47.6%), headache 222 (47.6%) and abdominal pain 175 (37.6%). The most common hemorrhagic manifestation was petechiae 84 (67.2%). 391 (83.9%) cases presented with dengue fever, 41 (8.8%) dengue hemorrhagic fever, and 34 (7.3%) with dengue shock syndrome. Out of 66 (14.1%) patients who developed clinical complications, 22 (33.3%) had ARDS and 20 (30.3%) had pleural effusion. Deaths reported were 11(2.4%).

Conclusion:

Community awareness, early diagnosis and management and vector control measures need to be strengthened, during peri-monsoon period, in order to curb the increasing number of dengue cases.     

Economic evaluation of vaccination programme of 7-valent pneumococcal conjugate vaccine to the birth cohort in Japan

Aiming to introduce 7-valent pneumococcal conjugate vaccine (PVC-7) into routine vaccination schedule, the government of Japan gives a temporary budget to encourage municipalities in launching public vaccination programme which started on November 26, 2010 and ends on March 31, 2012. This study aims to appraise the 'value for money' of PCV-7 vaccination programme from the societal perspective and the budget impact from the perspective of municipalities, which is responsible for providing routine vaccination. We conducted a cost-effectiveness analysis with Markov modelling and calculated incremental cost-effectiveness ratio (ICER) value of launching such programme with two levels of co-payment, ￥1000 (US$13) or ￥0, and two scenarios of the uptake of vaccine (vaccinated-alone or co-vaccinated with other vaccines). We found that when vaccinated-alone, ICERs in QALY were ￥7,441,000 (US$93,013) or ￥9,065,000 (US$113,313), and when co-vaccinated ￥7,441,000 (US$93,013) or ￥5,489,000 (US$68,613), without or with productivity loss, respectively, regardless of co-payment level of the programme. Co-vaccinated programmes had lower ICER than vaccinated-alone programmes due to the savings in productivity loss. By adopting WHO's classification that an intervention is 'cost-effective' if ICER (in QALY) is between 1 and 3 times of GDP as a criterion, PCV-7 vaccination programme in Japan is concluded as "cost-effective" from the perspective of society. The introduction of either no co-payment or ￥1000 (US$13) co-payment vaccination programme appears to be not budget saving for the first 6 years, whereas the level of budget impact are less than ￥11,000,000 (US$137,500) or ￥8,500,000 (US$106,250), respectively, for a municipality with 1000 birth cohort in the 1st year and 2nd to 5th year birth cohort proportional to the birth cohort population of estimated future population.     

Influenza vaccination type,live, attenuated influenza vaccine (LAIV) versus inactivated influenza vaccine (IIV), received by children,United States, 2011−12 through 2013−14 influenza seasons

BackgroundInfluenza vaccines available for children in the United States include inactivated influenza vaccine (IIV) and live, attenuated influenza vaccine (LAIV). Objectives of this study were to quantify proportions of IIV and LAIV received by vaccinated children, and examine associations between vaccine type received and demographic characteristics.MethodsNational Immunization Survey-Flu (NIS-Flu) parental reported data for the 2011−12 through 2013−14 influenza seasons were used to estimate proportions of vaccinated children 2−17 years who received IIV and LAIV. Tests of association between vaccination type and demographic variables were conducted using Wald chi-square tests and pair-wise comparison t-tests. Multivariable logistic regression was used to determine variables independently associated with receipt of LAIV versus IIV.ResultsIn the 2013−14 season, 33.3% of vaccinated children received LAIV, similar to the proportion in the 2011−12 (32.2%) and 2012−13 (32.1%) seasons. Across all seasons studied, the strongest observed association was between vaccination type and child's age, with children 2−8 years (Adjusted Prevalence Ratio (95% confidence interval) [APR(95% CI)] 1.41(1.27−1.56), 1.46(1.34−1.59), and 1.50(1.38−1.63) for 2011−12, 2012−13, and 2013−14) and 9−12 years (APR(95% CI) 1.37(1.23−1.54), 1.38(1.26−1.51), and 1.50(1.38−1.63) for 2011−12, 2012−13, and 2013−14) being more likely to have received LAIV than children 13−17 years. Among those vaccinated, whites were more likely to have received LAIV compared with blacks (APR(95% CI) 1.19(1.05−1.35), 1.24(1.10−1.39), and 1.22(1.11−1.34) for 2011−12, 2012−13, and 2013−14), and children living above poverty (annual income >$75,000) were more likely to have received LAIV than those living at or below poverty (APR(95% CI) 1.43(1.23−1.67), 1.13(1.02−1.26), and 1.16(1.06−1.28) for 2011−12, 2012−13, and 2013−14).ConclusionsThis study provides a baseline of the extent and patterns of LAIV uptake that can be used to measure the impact of relevant public health policy. Additional research is needed to investigate parental and provider preferences and barriers regarding LAIV.