A comparison of the test-negative and traditional case-control study designs with respect to the bias of estimates of rotavirus vaccine effectiveness

Estimation of the effectiveness of rotavirus vaccines via the test-negative control study design has gained popularity over the past few years. In this study design, children with severe diarrhea who test positive for rotavirus infection are considered as cases, while children who test negative serve as controls. We use a simple probability model to evaluate and compare the test-negative control and the traditional case-control designs with respect to the bias of resulting estimates of rotavirus vaccine effectiveness (VE). Comparisons are performed under two scenarios, corresponding to studies performed in high-income and low-income countries. We consider two potential sources of bias: (a) misclassification bias resulting from imperfect sensitivity and specificity of the test used to diagnose rotavirus infection, and (b) selection bias associated with possible effect of rotavirus vaccination on the probability of contracting severe non-rotavirus diarrhea.Our results suggest that both sources of bias may produce VE estimates with substantial bias. Particularly, lack of perfect specificity is associated with severe negative bias. For example, if the specificity of the diagnostic test is 90% then VE estimates from both types of case-control studies may under-estimate the true VE by more than 20%. If the vaccine protects children against non-rotavirus diarrhea then VE estimates from test-negative control studies may be close to zero even though the true VE is 50%. However, the sensitivity and specificity of the enzyme immunoassay test currently used to diagnose rotavirus infections are both over 99%, and there is no solid evidence that the existing rotavirus vaccines affect the rates of non-rotavirus diarrhea. We therefore conclude that the test-negative control study design is a convenient and reliable alternative for estimation of rotavirus VE.     

Impact of Rotavirus Vaccines on Gastroenteritis Hospitalizations in Western Australia: A Time-series Analysis

BackgroundRotavirus vaccination was introduced into the Australian National Immunisation Program in mid-2007. We aimed to assess the impact of the rotavirus vaccination program on the burden of hospitalizations associated with all-cause acute gastroenteritis (including rotavirus gastroenteritis and non-rotavirus gastroenteritis) in the Aboriginal and non-Aboriginal population in Western Australia.MethodsWe identified all hospital records, between July 2004 and June 2012, with a discharge diagnosis code for all-cause gastroenteritis. Age-specific hospitalization rates for rotavirus and non-rotavirus acute gastroenteritis before and after the introduction of the rotavirus vaccination program were compared. Interrupted time-series models were used to examine differences in the annual trends of all-cause gastroenteritis hospitalization between the two periods.ResultsBetween July 2004 and June 2012, there were a total of 106,974 all-cause gastroenteritis-coded hospitalizations (1,381 rotavirus-coded [15% among Aboriginal] and 105,593 non-rotavirus gastroenteritis-coded [7% among Aboriginal]). Following rotavirus vaccination introduction, significant reductions in rotavirus-coded hospitalization rates were observed in all children aged <5 years (up to 79% among non-Aboriginal and up to 66% among Aboriginal). Among adults aged ≥65 years, rotavirus-coded hospitalizations were 89% (95% confidence interval, 16–187%) higher in the rotavirus vaccination program period. The time-series analysis suggested reductions in all-cause gastroenteritis hospitalizations in the post-vaccination period among both vaccinated and unvaccinated (age-ineligible) children, with increases observed in adults aged ≥45 years.ConclusionsRotavirus vaccination has been associated with a significant decline in gastroenteritis hospitalizations among children. The increase in the elderly requires further evaluation, including assessment of the cost-benefits of rotavirus vaccination in this population.Key words: rotavirus vaccine, acute gastroenteritis, vaccine impact, hospitalizations, time-series     

Evaluating the first introduction of rotavirus vaccine in Thailand: Moving from evidence to policy

BackgroundWe assessed the effectiveness and possible impact of introducing rotavirus vaccine into the routine immunization program.MethodsTwo provinces were selected for an observational study, one where vaccine was introduced and another where vaccine was not available. In these areas, two sub-studies were linked. The prospective cohort study enrolled children 2 month old and followed them to the age of 18 months to detect all diarrhea episodes. The hospital surveillance study enrolled all children up to age 5 hospitalized with diarrhea whose fecal samples were tested for rotavirus. Rates of rotavirus hospitalizations in older children who had not been vaccinated in both settings provided data to determine whether immunization had an indirect herd effect. The key endpoints for the study were both vaccine effectiveness (VE) based upon hospitalized rotavirus diarrhea and herd protection.FindingsFrom the cohort study, the overall VE for hospitalized rotavirus diarrhea was 88% (95%CI 76–94). Data from hospital surveillance indicated that for 2 consecutive years, the seasonal peak of rotavirus admissions was no longer present in the vaccinated area. Herd protection was observed among older children born before the rotavirus vaccine program was introduced, who experienced a 40–69% reduction in admission for rotavirus.ConclusionsRotavirus vaccine was highly effective in preventing diarrheal hospitalizations and in conferring herd protection among older children who had not been vaccinated.     

Effectiveness of monovalent rotavirus vaccine against hospitalizations due to all rotavirus and equine-like G3P[8] genotypes in Haiti 2014–2019

BackgroundRotavirus vaccines are effective in preventing severe rotavirus. Haiti introduced 2-dose monovalent (G1P[8]) rotavirus vaccine recommended for infants at 6 and 10 weeks of age in 2014. We calculated the effectiveness of rotavirus vaccine against hospitalization for acute gastroenteritis in Haiti.MethodsWe enrolled children 6–59 months old admitted May 2014-September 2019 for acute watery diarrhea at any sentinel surveillance hospital. Stool was tested for rotavirus using enzyme immunoassay (EIA) and genotyped with multiplex one-step RT-PCR assay and Sanger sequencing for stratification by genotype. We used a case-negative design where cases were children positive for rotavirus and controls were negative for rotavirus. Only children eligible for vaccination were included and a child was considered vaccinated if vaccine was given ≥ 14 days before enrollment. We used unconditional logistic regression to calculate odds ratios and calculated 2-dose and 1-dose vaccine effectiveness (VE) as (1 - odds ratio) * 100.ResultsWe included 129 (19%) positive cases and 543 (81%) negative controls. Among cases, 77 (60%) were positive for equine-like G3P[8]. Two doses of rotavirus vaccine were 66% (95% CI: 44, 80) effective against hospitalizations due to any strain of rotavirus and 64% (95% CI: 33, 81) effective against hospitalizations due to the equine-like G3P[8] genotype.ConclusionsThese findings are comparable to other countries in the Americas region. To the best of our knowledge, this is the first VE estimate both against the equine-like G3P[8] genotype and from a Caribbean country. Overall, these results support rotavirus vaccine use and demonstrate the importance of complete vaccination.     

Role of rotavirus vaccination on an emerging G8P[8] rotavirus strain causing an outbreak in central Japan

BackgroundIn this study, we examined the effectiveness of RV1 and RV5 vaccines during an outbreak of G8P[8] rotavirus group A strain (G8P[8]-RVA). These vaccines were originally designed to provide protection against severe diseases caused by common circulating strains, whereas G8P[8]-RVA remains emerging strain and partially heterotypic to the vaccines. It is imperative to investigate vaccine effectiveness (VE) against G8P[8]-RVA because this strain appears to be predominant in recent years, particularly, in post-vaccine era.MethodsRVA infection and genotypes were confirmed by polymerase chain reaction (PCR) followed by sequence-based genotyping. VE was determined during an outbreak of G8P[8]-RVA in Shizuoka Prefecture, Japan, in February-July 2017, retrospectively, by comparing vaccination status of children suffering from acute gastroenteritis (AGE) between ‘PCR-positive’ and ‘PCR-negative’ cases using conditional logistic regression adjusted for age.ResultsAmong 80 AGE children, RVA was detected in 58 (73%), of which 53 (66%) was G8P[8]-RVA. The clinical characteristics of G8P[8]-RVA and other RVA strains were identically severe. Notably, the attack rates of G8P[8]-RVA in vaccinated (61.1%) and unvaccinated (65.5%) children were almost similar. Indeed, no substantial effectiveness were found against G8P[8]-RVA (VE, 14% [95% CI: −140% to 70%]) or other RVA strains (VE, 58% [95% CI: −20% to 90%]) for mild infections. However, these vaccines remained strongly effective against moderate (VE, 75% [95% CI: 1% to 40%]) and severe (VE, 92% [95% CI: 60% to 98%]) RVA infections. The disease severity including Vesikari score, duration and frequency of diarrhea, and body temperature were significantly lower in vaccinated children.ConclusionsThis study demonstrates the effectiveness of current RV vaccines against moderate and severe, but not against the mild infections during an outbreak caused by unusual G8P[8]-RVA, which was virtually not targeted in the vaccines.     

Evaluation of non-specific effects of human rotavirus vaccination in medical risk infants

BackgroundThe WHO recommends research into non-specific effects of vaccination. For rotavirus vaccines, these have not yet been well established. We studied non-specific effects up to 18 months of age using data from a quasi-experimental before-after study comparing cohorts of rotavirus vaccinated and unvaccinated infants with medical risk conditions.MethodsInfants were enrolled at six weeks of age before and after a stepped-wedge implementation of a hospital-based risk-group rotavirus vaccination program. Other infant vaccinations were administered according to the Dutch National Immunization Program and similar in both cohorts. Non-specific effect outcomes were prospectively collected using monthly questionnaires and included acute hospitalization (excluding for acute gastroenteritis), monthly incidence of acute respiratory illness and eczema. We used time-to-event analysis and negative binomial regression to assess the effect of at least one dose of rotavirus vaccination for each of these outcomes.FindingsThe analysis included 496 rotavirus unvaccinated and 719 vaccinated medical risk infants. In total, 1067 (88%) were premature, 373 (31%) small for gestational age and 201 (17%) had a congenital pathology. The adjusted hazard ratio for first acute hospitalization was 0·91 (95 %CI 0·76;1·16) for rotavirus vaccinated versus unvaccinated infants. Adjusted incidence rate ratio for acute respiratory illness was 1·05 (95 %CI 0·96;1·15) and for eczema 0·89 (95 %CI 0·69;1·15).ConclusionThe results suggest no, or minimal non-specific effects from rotavirus vaccination on acute hospitalization, acute respiratory illness or eczema in medical risk infants.Trial registration: as NTR5361 in the Dutch trial registry, www.trialregister.nl.     

Effectiveness of Lanzhou lamb rotavirus vaccine in preventing gastroenteritis among children younger than 5 years of age

BackgroundLanzhou Lamb rotavirus (LLR) vaccine was licensed in China in 2000. It was the only vaccine available in private market before 2018. However, the data about the post-marketing effectiveness is very limited. To assess the vaccine effectiveness (VE), we conducted a case-control study based on the hospital surveillance system in Beijing from 2015 to 2017.MethodsSeven hospitals located in seven districts in Beijing, from October 1, 2015, to March 31, 2017, were included. The VE of LLR vaccine was assessed in laboratory-confirmed rotavirus infection among children younger than five years old through a case-control design, using rotavirus-negative cases as controls. LLR vaccination was documented from a vaccination registry. VE was estimated adjusting for age group, gender, study site, the month of illness onset and interval days between illness onset to sampling through a logistic regression model.ResultsA total of 598 cases and 1766 controls were included in this study. The vaccine average coverage rate during 2015–2017 among children younger than five years old was 10.8% in Beijing. The adjusted VE for LLR vaccine of 1 dose versus 0 dose was 34.9% (95%CI, 5.3–55.3). We also obtained the adjusted VE of 87.7% (95%CI, 32.7–97.8) for patients with the severity score ≥11, 36.2% (95%CI, 4.7–57.3) for children of 2–35 months age group and 40.8% (95%CI, 7.8–61.9) against G9 rotavirus infection. Vaccinated cases were less likely to have watery stool (OR = 0.42) and have diarrhea longer than 5 days (OR = 0.47) than unvaccinated cases.DiscussionLLR vaccine conferred protection against rotavirus disease. Children who were vaccinated presented with less severe clinical manifestations. An immunization schedule of receiving all three doses in the first year should be preferred.     

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.     

Direct and possible indirect effects of vaccination on rotavirus hospitalisations among children in Malawi four years after programmatic introduction

IntroductionDespite increased use of vaccine in routine immunisation, rotavirus remains a major cause of acute gastroenteritis (AGE) in low-income countries. We describe rotavirus prevalence and hospitalisation in Malawi pre and four years post vaccine introduction; provide updated vaccine effectiveness (VE) estimates; and assess rotavirus vaccine indirect effects.MethodsChildren under five years of age presenting to a referral hospital in Blantyre with AGE were recruited. Stool samples were tested for rotavirus using Enzyme Immunoassay. The change in rotavirus prevalence was evaluated using Poisson regression. Time series analysis was used to further investigate trends in prevalence over time. VE against rotavirus diarrhoea of any severity was estimated using logistic regression. Indirect effects were estimated by evaluating rotavirus prevalence in unvaccinated children over time, and by comparing observed reductions in incidence of rotavirus hospitalisation to those expected based on vaccine coverage and trial efficacy estimates.Results2320 children were included. Prevalence of rotavirus in hospitalised infants (<12 months) with AGE decreased from 69/139(49.64%) prior to vaccine introduction to 197/607(32.45%) post-vaccine introduction (adjusted RR 0.67[95% CI 0.55, 0.82]). Prevalence in children aged 12–23 months demonstrated a less substantial decline: 15/37(40.54%) pre- and 122/352(34.66%) post-vaccine introduction (adjusted RR 0.85, 95% CI 0.57, 1.28). Adjusted VE was 61.89%(95% CI 28.04–79.82), but lower in children aged 12–23 months (31.69% [95% CI −139.03 to 80.48]). In hospitalised infants with rotavirus disease, the observed overall effect of the vaccine was 9% greater than expected according to vaccine coverage and efficacy estimates. Rotavirus prevalence among unvaccinated infants declined post-vaccine introduction (RR 0.70[95% CI 0.55–0.80]).ConclusionsFollowing rotavirus vaccine introduction in Malawi, prevalence of rotavirus in hospitalised children with AGE has declined significantly, with some evidence of an indirect effect in infants. Despite this, rotavirus remains an important cause of severe diarrhoea in Malawian children, particularly in the second year of life.     

Evaluation of rotavirus vaccine effectiveness in a pediatric group practice

Vaccines are traditionally tested under the optimal conditions of clinical trials (efficacy). However, their public health impact is better assessed under the real conditions of a clinical practice (effectiveness). The authors aimed to estimate the effectiveness of a rotavirus vaccine (rhesus rotavirus vaccine-tetravalent (RRV-TV)) to prevent rotavirus-related hospitalization among children 相似文献   

Impact and effectiveness of monovalent rotavirus vaccine in Tajik children

BackgroundIn 2015, Tajikistan became the second country in Central Asia to introduce rotavirus vaccine into its national immunization program. Before vaccine introduction, rotavirus was estimated to cause > 40% of pediatric diarrhea hospitalizations in Tajikistan. We aimed to assess the impact of rotavirus vaccine introduction on rotavirus disease burden and estimate rotavirus vaccine effectiveness (VE).MethodsUsing surveillance data from 2013 through 2019, we examined trends in monthly hospital admissions among children < 5 years old, before and after rotavirus vaccine introduction. Poisson regression was used to quantify decreases. VE was estimated using a test-negative case control design, with data from admissions during 2017 – 2019. Immunization records were obtained from clinics.ResultsAmong enrolled children, rotavirus positivity declined from 42% to 25% in the post-vaccine introduction period, a decrease of 41% (95% Confidence Interval [CI]: 36 – 45%). Declines were greatest in children < 12 months of age. Estimated VE of a complete course of rotavirus vaccine was 55% (95% CI: 21 – 73%) among children 5 – 59 months of age and 64% (95% CI: 36 – 80%) among children 5 – 23 months of age. VE point estimates were higher among children receiving both doses of rotavirus vaccine non-concurrently with OPV and among children receiving their first dose of rotavirus vaccine at 4 – 11 months of age, but CIs were wide and overlapping.ConclusionsOur data demonstrate that rotavirus vaccine introduction was associated with a substantial reduction in pediatric rotavirus hospitalization burden in Tajikistan, and that rotavirus vaccination is effective in Tajik children.     

Dose-dependent effectiveness of acellular pertussis vaccine in infants: A population-based case-control study

BackgroundPertussis is a vaccine-preventable disease which is most severe in young infants. More than two decades after the introduction of acelluar pertussis vaccines (aPV) in national immunization programs in many countries worldwide, a resurgence of pertussis has been recognized. Suboptimal effectiveness of aPV has been blamed as one major reason but only few studies have evaluated dose-dependent vaccine effectiveness (VE) provided by aPV in current practice.MethodsWe performed a population-based retrospective case-control study by comparing pertussis immunization data of children 2.5 months to 2 years of age hospitalized for pertussis and residing in Switzerland with immunization data of a random control sample of children aged 2 years and residing in Switzerland. VE was defined as the percentage of hospitalizations avoided by number of aPV doses. It was calculated as 1-infection rate ratio (IRR)*100. IRR was calculated by dividing infection rates of vaccinated children and infection rates of unvaccinated children. To get dose specific VE, infection rates were stratified by number doses received.ResultsVE against hospitalization due to pertussis increased significantly with each consecutive aPV dose in a “3 + 1” primary course in infants: 42.1% (95% CI: 11.3–62.6), 83.9% (70.2–92.1), 98.2% (96.1–99.3), and 100% (97.9–100) after the 1st, 2nd, 3rd, and 4th dose, respectively.ConclusionAcellular pertussis vaccines continue to demonstrate protection against hospitalization due to pertussis in infants and young children. Therefore, together with advancing immunization of pregnant women and household contacts, better control of severe pertussis in young infants can be achieved by timely initiation of immunization.     

Rotavirus vaccine effectiveness in low-income settings: An evaluation of the test-negative design

BackgroundThe test-negative design (TND), an epidemiologic method currently used to measure rotavirus vaccine (RV) effectiveness, compares the vaccination status of rotavirus-positive cases and rotavirus-negative controls meeting a pre-defined case definition for acute gastroenteritis. Despite the use of this study design in low-income settings, the TND has not been evaluated to measure rotavirus vaccine effectiveness.MethodsThis study builds upon prior methods to evaluate the use of the TND for influenza vaccine using a randomized controlled clinical trial database. Test-negative vaccine effectiveness (VE-TND) estimates were derived from three large randomized placebo-controlled trials (RCTs) of monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in sub-Saharan Africa and Asia. Derived VE-TND estimates were compared to the original RCT vaccine efficacy estimates (VE-RCTs). The core assumption of the TND (i.e., rotavirus vaccine has no effect on rotavirus-negative diarrhea) was also assessed.ResultsTND vaccine effectiveness estimates were nearly equivalent to original RCT vaccine efficacy estimates. Neither RV had a substantial effect on rotavirus-negative diarrhea.ConclusionsThis study supports the TND as an appropriate epidemiologic study design to measure rotavirus vaccine effectiveness in low-income settings.     

Cost-effectiveness of Rotavirus vaccination in Vietnam

Background  

Rotavirus is the most common cause of severe diarrhea leading to hospitalization or disease-specific death among young children. New rotavirus vaccines have recently been approved. Some previous studies have provided broad qualitative insights into the health and economic consequences of introducing the vaccines into low-income countries, representing several features of rotavirus infection, such as varying degrees of severity and age-dependency of clinical manifestation, in their model-based analyses. We extend this work to reflect additional features of rotavirus (e.g., the possibility of reinfection and varying degrees of partial immunity conferred by natural infection), and assess the influence of the features on the cost-effectiveness of rotavirus vaccination.     

Long-term effectiveness of pentavalent and monovalent rotavirus vaccines against hospitalization in Taiwan children

BackgroundTwo rotavirus vaccines (RV1 and RV5) are available on the private market in Taiwan, not included in national immunization program. Scanty reports evaluated the rotavirus vaccine effectiveness (VE) in Asian countries.MethodsFrom February 2014-July 2017, we conducted a prospective case-control study in ten hospitals in Taiwan. Case-patients included children aged 8–59 months, and hospitalized with laboratory-confirmed rotavirus acute gastroenteritis (AGE). For each case patient, up to four controls, rotavirus-negative AGE or non-AGE illnesses, respectively, were matched by gender, age and enrolled date. Vaccination history was confirmed through vaccination card or hospital record. VE was calculated as (1 − odds ratio of vaccination) × 100%.ResultsTotally 4248 AGE patients and 2242 non-AGE controls were enrolled. A total of 330 case-patients with rotavirus AGE, 1226 rotavirus-negative AGE controls and 1122 non-AGE controls were included for analysis. Unvaccinated rate was 85.15% for rotavirus-positive cases, 42.9% for rotavirus-negative controls, and 34.31% for non-AGE controls. VE of two-dose RV1 was 84.9% (95% confidence interval [CI]:77.7%, 90.1%) for rotavirus-negative AGE and 88.9% (95% CI: 83.4%, 92.8%) for non-AGE controls, while VE of three-dose RV5 was 92.5% (95% CI: 85.1%, 96.7%) and 96.4% (95% CI: 91.9%, 98.6%), respectively. For respective vaccine, VEs were not significantly different in term of rotavirus genotypes. VEs of both vaccines declined <80% in children aged three years by combined controls.ConclusionsBoth vaccines provided excellent and sustained protection against rotavirus AGE hospitalization in children in Taiwan, but the effectiveness declined slightly in children aged three years.     

The effectiveness of influenza vaccination among nursery school children in China during the 2016/17 influenza season

BackgroundThe effectiveness of influenza vaccine among nursery school children has not been systematically studied. We conducted a cohort study of children from 13 nursery schools in Suzhou, China, to estimate the effectiveness of influenza vaccine against laboratory-confirmed influenza during 2016–17.MethodsChildren aged 36–72 months were chosen from 13 nursery schools from 3 District in Suzhou. The surveillance started 2 weeks after vaccination during October 2016–February 2017. Class teachers reported the names of students with ILI (influenza-like illness) to study clinicians on each school day. Further, local physicians collected the student’s nasopharyngeal swab or throat swab, either at a study clinic or at the child’s home. The swabs were sent to the National Influenza Network Laboratory in Suzhou Center for Disease Control and Prevention for influenza testing by RT-PCR.ResultA total of 4614 children were enrolled, of which 15 children (vaccinated: 2; unvaccinated: 13) were lost to follow-up. Of the remaining 4599 children, 558 swabs were collected. Among these swabs, 70 samples tested positive for influenza virus; 17 in the vaccinated group (B Victoria: 2; H3N2: 15) and 53 in the unvaccinated group (B Victoria: 14; A(H1N1)pdm09: 1; H3N2: 38). The overall influenza vaccine effectiveness (VE) during the influenza season of 2016–2017 was 20.6%. The incidence of developing ILI symptoms and healthcare seeking behavior through clinical visits was significantly lower in vaccinated children than in the unvaccinated group.ConclusionInfluenza vaccine protection in vaccinated and unvaccinated children showed no statistical difference and the VE percentage varied for different virus subtypes. However, the incidence rate of developing ILI and healthcare seeking behavior was significant lower in the vaccinated group than in the unvaccinated children. Larger studies are required to estimate the VE according to the influenza type, subtype, and lineage during influenza seasons in China in the future.     

Economic analysis for evidence-based policy-making on a national immunization program: a case of rotavirus vaccine in Thailand

Severe diarrhea caused by rotavirus is a health problem worldwide, including Thailand. The World Health Organization has recommended incorporating rotavirus vaccination into national immunization programs. This policy has been implemented in several countries, but not in Thailand where the mortality rate is not high. This leads to the question of whether it would be cost-effective to implement such a policy. The Thai National Vaccine Committee, through the Immunization Practice Subcommittee, has conducted an economic analysis. Their study aimed to estimate the costs of rotavirus diarrhea and of a rotavirus vaccination program, and the cost-effectiveness of such a program including budget impact analysis. The study was designed as an economic evaluation, employing modeling technique in both provider and societal perspectives. A birth cohort of Thai children in 2009 was used in the analysis, with a 5-year time horizon. Costs were composed of cost of the illness and the vaccination program. Outcomes were measured in the form of lives saved and DALYs averted. Both costs and outcomes were discounted at 3%. The study found the discounted number of deaths to be 7.02 and 20.52 for vaccinated and unvaccinated cohorts, respectively (13.5 deaths averted). Discounted DALYs were 263.33 and 826.57 for vaccinated and unvaccinated cohorts, respectively (563.24 DALYs averted). Costs of rotavirus diarrhea in a societal perspective were US$6.6 million and US$21.0 million for vaccinated and unvaccinated cohorts, respectively. At base case, the costs per additional death averted were US$5.1 million and US$5.7 for 2-dose and 3-dose vaccines, respectively, in a societal perspective. Costs per additional DALYs averted were US$128,063 and US$142,144, respectively. In a societal perspective, with a cost-effectiveness threshold at 1 GDP per capita per DALYs averted, vaccine prices per dose were US$4.98 and US$3.32 for 2-dose and 3-dose vaccines, respectively; in a provider perspective, they were US$2.90 and US$1.93. One-way and probabilistic sensitivity analyses were included. The budget required for vaccine purchase was calculated for all scenarios.     

Success of rotavirus vaccination in Finland,a register based study measuring impact beyond overall effectiveness

IntroductionEven with vaccines available since 2006, rotavirus continues to be a major cause of acute gastroenteritis globally in children under 5 years old. Finland introduced the rotavirus vaccine to its national vaccination programme in 2009. Since then hospitalizations due to gastroenteritis caused by rotavirus (RVGE) and of all causes (AGE) have been reduced significantly in young children.MethodsWe performed a retrospective analysis of data from register databases consisting of over 200 000 children aged 0.5-2 years. Children born before rotavirus vaccines were available (2002, 2003) and after the implementation of rotavirus vaccination programme (2014, 2015) were followed for episodes of acute infectious gastroenteritis. We calculated the incidences of hospital outpatient and inpatient episodes and used individual vaccination records to estimate the overall, total, direct and indirect vaccine effect (VE %).ResultsAmong children born in 2014 and 2015, there was a 96% reduction in inpatient RVGE episodes and a 78% reduction in episodes of inpatient AGE compared to the pre-vaccination era, comprising the overall VE. Direct effectiveness was 96% and 53% for RVGE and AGE respectively. Herd effect i.e. indirect protection was estimated to be 67% against inpatient RVGE and 56% against inpatient AGE. Protection acquired by the vaccinated children when compared to pre vaccination era i.e. the total VE was 99% for inpatient RVGE and 79% for inpatient AGE.ConclusionsAlthough overall incidences for every disease type studied were reduced, rotavirus is still circulating with seasonality and there is a slight shift of disease towards the older age groups. Together with changes observed in the distribution of rotavirus genotypes, our results indicate that continuous monitoring is still necessary.     

Mitigating bias in observational vaccine effectiveness studies using simulated comparator populations: Application to rotavirus vaccination in the UK

BackgroundMeasuring vaccine effectiveness (VE) relies on the use of observational study designs. However, achieving robust estimates of direct and indirect VE is frequently compromised by bias, particularly when using syndromic diagnoses of low-specificity.MethodsIn order to mitigate confounding between the measured outcome and vaccine uptake, we developed a method to balance comparator populations using individual-level propensity scoring derived from the vaccine-exposed population, and applied it to the unexposed comparator population. Indirect VE was estimated by comparing the unvaccinated vaccine-exposed group with a propensity score-simulated unvaccinated, unexposed group. Direct VE was derived by removing indirect VE from the overall VE.We applied this method to an evaluation of the effectiveness of infant rotavirus vaccination in the UK. Using a general practice cohort of 45,259 live births between May 2010 and December 2015, we calculated indirect and direct VE against consultations for acute gastroenteritis using conventional and vaccination-propensity adjustment comparator populations.ResultsThe overall VE during the rotavirus-season (January-May) calculated using mixed-effects Cox regression was 30% [95% confidence intervals (95% CI: 25,35%)]. Use of conventional comparator populations resulted in implausible VE estimates −14% (95% CI: −41,7%) for direct and 29% (95% CI: 14,42%) for indirect effects. Applying our alternative method, direct VE was 26% (95% CI: 1,45%) and indirect VE was 8% (95% CI: −19,29%).ConclusionsEstimating VE using propensity score simulated comparator populations, particularly for studies using routine health data with syndromic, low-specificity endpoints will aid accurate measurement of the broader public health impact of a vaccine programme.     

The case test-negative design for studies of the effectiveness of influenza vaccine

Background

A modification to the case–control study design has become popular to assess vaccine effectiveness (VE) against viral infections. Subjects with symptomatic illness seeking medical care are tested by a highly specific polymerase chain reaction (PCR) assay for the detection of the infection of interest. Cases are subjects testing positive for the virus; those testing negative represent the comparison group. Influenza and rotavirus VE studies using this design are often termed “test-negative case-control” studies, but this design has not been formally described or evaluated. We explicitly state several assumptions of the design and examine the conditions under which VE estimates derived with it are valid and unbiased.

Methods

We derived mathematical expressions for VE estimators obtained using this design and examined their statistical properties. We used simulation methods to test the validity of the estimators and illustrate their performance using an influenza VE study as an example.

Results

Because the marginal ratio of cases to non-cases is unknown during enrollment, this design is not a traditional case-control study; we suggest the name “case test-negative” design. Under sets of increasingly general assumptions, we found that the case test-negative design can provide unbiased VE estimates. However, differences in health care-seeking behavior among cases and non-cases by vaccine status, strong viral interference, or modification of the probability of symptomatic illness by vaccine status can bias VE estimates.

Conclusions

Vaccine effectiveness estimates derived from case test-negative studies are valid and unbiased under a wide range of assumptions. However, if vaccinated cases are less severely ill and seek care less frequently than unvaccinated cases, then an appropriate adjustment for illness severity is required to avoid bias in effectiveness estimates. Viral interference will lead to a non-trivial bias in the vaccine effectiveness estimate from case test-negative studies only when incidence of influenza is extremely high and duration of transient non-specific immunity is long.