Comparison of test-negative and syndrome-negative controls in SARS-CoV-2 vaccine effectiveness evaluations for preventing COVID-19 hospitalizations in the United States

BackgroundTest-negative design (TND) studies have produced validated estimates of vaccine effectiveness (VE) for influenza vaccine studies. However, syndrome-negative controls have been proposed for differentiating bias and true estimates in VE evaluations for COVID-19. To understand the use of alternative control groups, we compared characteristics and VE estimates of syndrome-negative and test-negative VE controls.MethodsAdults hospitalized at 21 medical centers in 18 states March 11–August 31, 2021 were eligible for analysis. Case patients had symptomatic acute respiratory infection (ARI) and tested positive for SARS-CoV-2. Control groups were test-negative patients with ARI but negative SARS-CoV-2 testing, and syndrome-negative controls were without ARI and negative SARS-CoV-2 testing. Chi square and Wilcoxon rank sum tests were used to detect differences in baseline characteristics. VE against COVID-19 hospitalization was calculated using logistic regression comparing adjusted odds of prior mRNA vaccination between cases hospitalized with COVID-19 and each control group.Results5811 adults (2726 cases, 1696 test-negative controls, and 1389 syndrome-negative controls) were included. Control groups differed across characteristics including age, race/ethnicity, employment, previous hospitalizations, medical conditions, and immunosuppression. However, control-group-specific VE estimates were very similar. Among immunocompetent patients aged 18–64 years, VE was 93 % (95 % CI: 90–94) using syndrome-negative controls and 91 % (95 % CI: 88–93) using test-negative controls.ConclusionsDespite demographic and clinical differences between control groups, the use of either control group produced similar VE estimates across age groups and immunosuppression status. These findings support the use of test-negative controls and increase confidence in COVID-19 VE estimates produced by test-negative design studies.     

Evaluating the case-positive,control test-negative study design for influenza vaccine effectiveness for the frailty bias

IntroductionPrevious influenza vaccine effectiveness studies were criticized for their failure to control for frailty. This study was designed to see if the test-negative study design overcomes this bias.MethodsAdults ≥ 50 years of age with respiratory symptoms were enrolled from November 2006 through May 2012 during the influenza season (excluding the 2009–2010 H1N1 pandemic season) to perform yearly test-negative control influenza vaccine effectiveness studies in Nashville, TN. At enrollment, both a nasal and throat swab sample were obtained and tested for influenza by RT-PCR. Frailty was calculated using a modified Rockwood Index that included 60 variables ascertained in a retrospective chart review giving a score of 0 to 1. Subjects were divided into three strata: non frail (≤0.08), pre-frail (>0.08 to <0.25), and frail (≥0.25). Vaccine effectiveness was calculated using the formula [1-adjusted odds ratio (OR)] × 100%. Adjusted ORs for individual years and all years combined were estimated by penalized multivariable logistic regression.ResultsOf 1023 hospitalized adults enrolled, 866 (84.7%) participants had complete immunization status, molecular influenza testing and covariates to calculate frailty. There were 83 influenza-positive cases and 783 test-negative controls overall, who were 74% white, 25% black, and 59% female. The median frailty index was 0.167 (Interquartile: 0.117, 0.267). The frailty index was 0.167 (0.100, 0.233) for the influenza positive cases compared to 0.183 (0.133, 0.267) for influenza negative controls (p = 0.07). Vaccine effectiveness estimates were 55.2% (95%CI: 30.5, 74.2), 60.4% (95%CI: 29.5, 74.4), and 54.3% (95%CI: 28.8, 74.0) without the frailty variable, including frailty as a continuous variable, and including frailty as a categorical variable, respectively.ConclusionsUsing the case positive test negative study design to assess vaccine effectiveness, our measure of frailty was not a significant confounder as inclusion of this measure did not significantly change vaccine effectiveness estimates.     

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.     

Influenza vaccine effectiveness against hospitalization with laboratory-confirmed influenza in Greece: A pooled analysis across six seasons, 2013–2014 to 2018–2019

BackgroundMonitoring seasonal influenza Vaccine Effectiveness (VE) is key to inform vaccination strategies and sustain uptake. Pooling data across multiple seasons increases precision and allows for subgroup analyses, providing more conclusive evidence. Our aim was to assess VE against hospitalization with laboratory-confirmed influenza in Greece over six seasons, from 2013 to 2014 to 2018–2019, using routinely collected surveillance data.MethodsSwab samples from hospitalized patients across the country were tested for influenza by RT-PCR. We used the test-negative design, with patients testing positive for influenza serving as cases and those testing negative serving as controls. VE was calculated as one minus the Odds Ratio (OR) for influenza vaccination, estimated by mixed-effects logistic regression and adjusted for age, sex, hospitalization type (being in intensive care or not), time from symptom onset to swabbing, and calendar time. Stratified estimates by age and hospitalization type were obtained, and also subgroup estimates by influenza type/subtype and season. Antigenic and genetic characterization of a subset of circulating influenza strains was performed.ResultsA total of 3,882 test-positive cases and 5,895 test-negative controls were analyzed. Across all seasons, adjusted VE was 45.5% (95% CI: 31.6–56.6) against all influenza, 62.8% against A(H1N1)pdm09 (95% CI: 40.7–76.7), 28.2% against A(H3N2) (95% CI: 12.0–41.3) and 45.5% against influenza B (95% CI: 29.1–58.1). VE was slightly lower for patients aged 60 years and over, and similar between patients hospitalized inside or outside intensive care. Circulating A(H1N1)pdm09 and B strains were antigenically similar to the vaccine strains, whereas A(H3N2) were not.ConclusionOur results confirm the public health benefits from seasonal influenza vaccination, despite the suboptimal effectiveness against A(H3N2) strains. Continued monitoring of VE is essential, and routinely collected surveillance data can be valuable in this regard.     

Effectiveness of four doses of pertussis vaccine during infancy diminished in elementary school age: A test-negative case-control study in Japan

ObjectiveThe Japanese national immunization program recommends that children receive 4 doses of acellular pertussis vaccine between 3 months and 2 years of age. Nevertheless, the number of pertussis cases is increasing in elementary school children aged 6–12 years. Therefore, a test-negative case-control study was conducted to assess the effectiveness of the pertussis vaccine program.MethodsSubjects included children aged ≥3 months who visited a collaborating hospital due to pertussis-specific cough between October 2017 and November 2019. All subjects underwent diagnostic tests for pertussis, and those diagnosed as positive were regarded as cases. Subjects diagnosed as pertussis-negative were classified as controls. Vaccination history was collected using a questionnaire administered to parents with reference to immunization records. Logistic regression models were employed to calculate the odds ratio (OR) and 95% confidence interval for laboratory-confirmed pertussis.ResultsOf 187 recruited subjects (120 cases and 67 controls), questionnaire responses were obtained for 145 subjects (95 cases and 50 controls). Compared with unvaccinated subjects, the vaccine effectiveness (VE) of 4 doses was 70% among all subjects and reached to 90% with marginal significance among subjects under 6 years of age. However, among school-aged subjects, the VE was not suggestive of protection against pertussis (VE: 8%). For vaccinees given 4 doses, the OR for developing pertussis increased significantly with longer duration since the fourth dose (compared with <4.5 years, OR of 6.0–8.2 years = 5.74; OR of ≥8.3 years = 3.88; P for trend by duration < 0.01).ConclusionEffectiveness of administering 4 doses of pertussis vaccine during infancy decreases with time passed since the fourth dose. This regimen does not protect school-aged children against pertussis.     

A case-control study of risk factors for intussusception among infants in eastern France after the introduction of the rotavirus vaccine

ObjectiveThe objective of the present study was to investigate the risk factors for intussusception (IS) among infants, including vaccination against rotavirus.MethodsCase-control study with systematic inclusion of all infants aged <1 year with suspected IS admitted to emergency departments in the eastern region of France between 1 April 2008 and 31 March 2012. All cases classed level 1 according to the Brighton classification were matched to 4 hospital controls. Two exposure windows were examined; exposure to the first dose of rotavirus vaccine in the 7 and in the 14 days prior to the occurrence of IS.ResultsA total of 115 cases were matched with 457 controls. The average vaccination coverage rate over the 4 years of study was 8.6%. Rotavirus vaccine was not found to be significantly associated with the occurrence of IS in the 7 days (odds ratio (OR) not calculated; p = 0.99) and in the 14 days after administration of one dose vaccine (OR 1.33, 95% confidence interval (CI) 0.14–12.82). Infant formula alone or combined with breastfeeding was associated with an excess risk of IS (OR 2.74, 95% CI 1.10–6.79). A history of gastroenteritis within 2 weeks prior to hospitalisation was also associated with an increased risk (OR 2.24, 95% CI 1.07–4.67).ConclusionOur study indicates that infant formula alone or combined with breastfeeding is a risk factor for IS. A small, non-significant increase in the risk of IS was observed after rotavirus vaccination, although the low vaccine coverage rate likely precluded detection of a significant increase in risk.     

Comparison of two control groups for estimation of oral cholera vaccine effectiveness using a case-control study design

BackgroundCase-control studies to quantify oral cholera vaccine effectiveness (VE) often rely on neighbors without diarrhea as community controls. Test-negative controls can be easily recruited and may minimize bias due to differential health-seeking behavior and recall. We compared VE estimates derived from community and test-negative controls and conducted bias-indicator analyses to assess potential bias with community controls.MethodsFrom October 2012 through November 2016, patients with acute watery diarrhea were recruited from cholera treatment centers in rural Haiti. Cholera cases had a positive stool culture. Non-cholera diarrhea cases (test-negative controls and non-cholera diarrhea cases for bias-indicator analyses) had a negative culture and rapid test. Up to four community controls were matched to diarrhea cases by age group, time, and neighborhood.ResultsPrimary analyses included 181 cholera cases, 157 non-cholera diarrhea cases, 716 VE community controls and 625 bias-indicator community controls. VE for self-reported vaccination with two doses was consistent across the two control groups, with statistically significant VE estimates ranging from 72 to 74%. Sensitivity analyses revealed similar, though somewhat attenuated estimates for self-reported two dose VE. Bias-indicator estimates were consistently less than one, with VE estimates ranging from 19 to 43%, some of which were statistically significant.ConclusionsOCV estimates from case-control analyses using community and test-negative controls were similar. While bias-indicator analyses suggested possible over-estimation of VE estimates using community controls, test-negative analyses suggested this bias, if present, was minimal. Test-negative controls can be a valid low-cost and time-efficient alternative to community controls for OCV effectiveness estimation and may be especially relevant in emergency situations.     

Effectiveness of Covishield vaccine in preventing Covid-19 – A test-negative case-control study

IntroductionThis study aimed at assessing the vaccine effectiveness (VE) of Covishield, which is identical to AstraZeneca vaccine, in preventing laboratory-confirmed Covid-19.MethodsUsing test-negative case-control design, information on vaccination status of cases with Covid-19 among healthcare workers in our institution in Puducherry, India, and an equal number of controls matched for age and date of testing, was obtained. The groups were compared using multivariable conditional logistic regression to calculate odds ratios (OR). VE was calculated as 100*(1–adjusted odds ratio)%.ResultsUsing data from 360 case-control pairs, VE of one dose and of two doses, in providing protection against Covid-19 was 49% (95% CI: 17%-68%) and 54% (27%-71%), respectively. Among cases with moderately severe disease that required oxygen therapy, VE following any number of vaccine doses was 95% (44%-100%).ConclusionCovishield vaccine protected significantly against Covid-19, with a higher protection rate against severe forms of disease.     

Effectiveness of trivalent influenza vaccines against hospitalizations due to laboratory-confirmed influenza a in the elderly: Comparison of test-negative design with register-based designs

IntroductionMeasuring influenza vaccine effectiveness (IVE) seasonally is important and has been conducted utilizing several observational study designs. The active test-negative design has been most widely used and the validity of passive register-based studies has been debated. We aimed to explore the potential differences, advantages, and weaknesses of different study designs in estimating influenza vaccine effectiveness.MethodsWe compared three study designs in estimating IVE against hospitalization in the elderly aged 65 years or more over three influenza seasons 2015/16, 2016/17 and 2017/18. Designs compared were active test-negative design (TND), register-based cohort design and register-based case-control design with different selection criteria for cases and controls.ResultsAdjusted IVE estimates for the three consecutive seasons 2015–18 in active test-negative design were 82% (95% confidence interval 26, 96), 21% (-179, 77), 15% (-113, 66). For case-control design, estimates from different analyses ranged in 2015/16 from 47% (-16, 76) to 52% (-48, 84), in 2016/17 from 10% (-42, 43) to 29% (-20, 58), and in 2017/18 from ?27% (-91, 15) to 1% (-40, 30). In the cohort design, the adjusted IVE estimates were 48% (-9, 75), 29% (1, 49), 13% (-21, 37) for the three seasons.ConclusionsThe register-based cohort design produced results more concordant with the active test-negative design than the case-control design. Furthermore, the register-based cohort design yielded most precise estimates with narrower confidence intervals. In Finland with the availability of near real-time nationwide register data, the register-based cohort design is the method of choice to continue the annual surveillance of influenza vaccine effectiveness.     

Are unexplained adverse health events following HPV vaccination associated with infectious mononucleosis? – A Danish nationwide matched case-control study

BackgroundIn Denmark, the acceptance of the HPV vaccination program has been threatened by reports of suspected adverse events. Epstein Barr Virus (EBV) infection is associated with symptoms of long-lasting tiredness and may be misinterpreted as HPV vaccine adverse events. The main aim of this study was to examine if EBV infection around time of HPV vaccination was a risk factor for later suspected vaccine adverse events.MethodsThe study was a nationwide register-based matched case-control study. Cases were females vaccinated against HPV in the period 2011 throughout 2017 with suspected adverse events. For each case, five HPV vaccinated females without suspected adverse events were selected. Information about EBV infection was obtained from the Danish Microbiology Database and assessed for three time periods: (1) before first HPV vaccination, (2) around time of HPV vaccination, and (3) any time during the study period 2010–2017. Multiple logistic regression was used to estimate the association between EBV and suspected adverse events.ResultsWe identified 1217 cases, matched to 6085 controls. A higher proportion of cases (38; 3.1%) than controls (31; 0.5%) were tested for EBV around time of HPV vaccination and cases had elevated odds for testing both EBV positive (OR 4.52, 95% CI 2.68–7.63) and EBV negative (OR 20.99, 95% CI 5.81–75.79). Only five females were classified with acute/recent EVB infection in this period.ConclusionMisinterpretation of EBV infection late symptoms is not a leading explanation for Danish females experiencing suspected adverse events after HPV vaccination. Although EBV cannot be excluded as an explanatory factor for a very small proportion of suspected adverse events, the findings are more likely explained by protopathic bias, i.e. the fact that a larger proportion of females suspecting adverse events are tested for EBV.     

The impact of new universal child influenza programs in Australia: Vaccine coverage,effectiveness and disease epidemiology in hospitalised children in 2018

BackgroundNew jurisdictionally-based vaccination programs were established providing free quadrivalent influenza vaccine (QIV) for preschool Australian children in 2018. This was in addition to the National Immunisation Program (NIP) funded QIV for Indigenous children and children with comorbid medical conditions. We assessed the impact of this policy change on influenza disease burden and vaccine coverage, as well as report on 2018 vaccine effectiveness in a hospital-based surveillance system.MethodsSubjects were recruited prospectively from twelve PAEDS-FluCAN sentinel hospital sites (April until October 2018). Children aged ≤16 years hospitalised with an acute respiratory illness (ARI) and laboratory-confirmed influenza were considered cases. Hospitalised children with ARI who tested negative for influenza were considered controls. VE estimates were calculated from the adjusted odds ratio of vaccination in cases and controls.ResultsA total of 458 children were hospitalised with influenza: 31.7% were <2 years, 5.0% were Indigenous, and 40.6% had medical comorbidities predisposing to severe influenza. Influenza A was detected in 90.6% of children (A/H1N1: 38.0%; A/H3N2: 3.1%; A/unsubtyped 48.6%). The median length of stay was 2 days (IQR: 1,3) and 8.1% were admitted to ICU. Oseltamivir use was infrequent (16.6%). Two in-hospital deaths occurred (0.45%). 12.0% of influenza cases were vaccinated compared with 36.0% of test-negative controls. Vaccine effectiveness of QIV for preventing influenza hospitalisation was estimated at 78.8% (95%CI: 66.9; 86.4).ConclusionsCompared with 2017 (n = 1268 cases), a significant reduction in severe influenza was observed in Australian children, possibly contributed to by improved vaccine coverage and high vaccine effectiveness. Despite introduction of jurisdictionally-funded preschool programs and NIP-funded vaccine for children with risk factors for severe disease, improved coverage is required to ensure adequate protection against paediatric influenza morbidity and mortality.     

Risk Factors of Dengue Fever in Urban Areas of Rawalpindi District in Pakistan During 2017: A Case Control Study

BackgroundDuring August 2017, increased numbers of suspected dengue fever cases were reported in the hospitals of Rawalpindi district. A case control study was conducted to determine the risk factors among urban areas, dengue serotype, and recommend preventive measures.ObjectiveThe objective of the investigation was to determine the risk factors among urban areas, dengue serotype, and recommend preventive measures.MethodsA case was defined as having acute febrile illness with one or more of the following symptoms: retro-orbital pain, headache, rash, myalgia, arthralgia, and hemorrhage. The cases were residents of Rawalpindi and were confirmed for dengue fever from August 30, 2017, to October 30, 2017. All NS1 confirmed cases from urban areas of Rawalpindi were recruited from tertiary care hospitals. Age- and sex-matched controls were selected from the same community with a 1:1 ratio. Frequency, univariate, and multivariate analyses were performed at 95% CI with P<.05 considered statistically significant.ResultsTotally 373 cases were recruited. The mean age was 36 (SD 2.9) years (range 10-69 years), and 280 cases (75%) were male. The most affected age group was 21-30 years (n=151, attack rate [AR] 40%), followed by 31-40 years (n=66, AR 23%). Further, 2 deaths were reported (case fatality rate of 0.53%). The most frequent signs or symptoms were fever (n=373, 100%), myalgia and headache (n=320, 86%), and retro-orbital pain (n=272, 73%). Serotype identification was carried out in 322 cases, and DEN-2 was the dominant serotype (n=126, 34%). Contact with a confirmed dengue case (odds ratio [OR] 4.27; 95% CI 3.14-5.81; P<.001), stored water in open containers at home (OR 2.04; 95% CI 1.53-2.73; P<.001), and travel to a dengue outbreak area (OR 2.88; 95% CI 2.12-3.92; P<.001) were the main reasons for the outbreak, whereas use of mosquito repellents (OR 0.12; 95% CI 0.09-0.18; P<.001) and regular water supply at home (OR 0.03; 95% CI 0.02-0.04; P<.001) showed protective effects. The geographical distribution of cases was limited to densely populated areas and all the 5 randomly collected water samples tested positive for dengue larvae.ConclusionsStored water in containers inside houses and subsequent mosquito breeding were the most probable causes of this outbreak. Based on the study findings, undertaking activities to improve the use of mosquito repellents and removing sources of breeding (uncovered water stored indoors) are some recommendations for preventing dengue outbreaks.     

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.     

Effectiveness of H1N1/09 monovalent and trivalent influenza vaccines against hospitalization with laboratory-confirmed H1N1/09 influenza in Australia: a test-negative case control study

We aimed to estimate the effectiveness of H1N1/09 containing influenza vaccines against hospitalization from influenza in Australia. We performed a test-negative case control study in patients hospitalized in 15 sentinel Australian hospitals between March and November 2010, comparing influenza vaccination (H1N1/09 monovalent or 2010 seasonal trivalent) in hospitalized patients with PCR-confirmed influenza compared to PCR-negative controls. Between March and November 2010, 1169 hospitalized patients were tested for suspected influenza, of which influenza vaccine status was ascertained in 165/238 patients with H1N1/09 influenza, 40/64 with seasonal influenza and 558/867 test negative controls; 24% of H1N1/09 cases, 43% of seasonal influenza cases and 54% of controls were vaccinated. VE against hospitalisation with H1N1/09 influenza after adjusting for age, medical comorbidities and pregnancy status was estimated at 49% (95% CI: 13%, 70%). Influenza vaccination was associated with a reduction in hospitalisation caused by H1N1/09 influenza in the 2010 southern hemisphere winter season.     

Data quality of dengue epidemiological surveillance in Belo Horizonte, Southeastern Brazil

OBJECTIVE: To evaluate the quality of data from the Brazilian information system for mandatory reporting diseases, for the detection of cases notified as suspected dengue fever and hospitalized in the public and private hospitals associated to the Public Health System. METHODS: The study was carried out in Belo Horizonte, Southeastern Brazil, during the years of 1996 to June 2002. The criterion of evaluation used were those recommended by the Guidelines for Evaluating Public Health Surveillance Systems. As a reference standard, medical charts recorded in the Unified System hospitalized discharge database system were revised and validated. A total of 266 (90%) of 294 medical charts were selected; 230 (86.5%) filled the suspect dengue fever criterion. To verify possible association between underreporting and selected variables, was used the odds ratio, with 95% of confidence interval in a logistic regression model. The sensitivity was defined as the proportion of hospitalized dengue cases registered in both systems. Predictive value positive was calculated as the proportion of confirmed cases and those recorded in the reporting system. RESULTS: Underreporting of suspected dengue fever was of 37% cases during 1997 to 2002, it was five times higher during the first three years (OR=5.93; 95% CI: 2.50-14.04) and eight times higher for patients hospitalized in private hospitals than in the public ones (OR=8.42; 95% CI: 2.26-31.27). Underreport was also associated to cases with no haemorrhagic episodes (OR=2.81; 95% CI: 1.28-6.15) and without dengue-specific laboratory exams in medical charts (OR=4.07; 95% CI:1.00-16.52). Sensitivity was 63% and predictive value positive was 43%. CONCLUSIONS: Cases recorded in the reporting system were those more severe and did not represent the total of cases hospitalized in Unified Health System, thus the case fatality rate may be overestimated. The results indicate the necessity of changes in the evaluated surveillance model and in the implementation of the qualification of the health professionals, mainly those working in the private hospitals associated to Unified Health System.     

Effectiveness of typhoid conjugate vaccine in Zimbabwe used in response to an outbreak among children and young adults: A matched case control study

BackgroundZimbabwe suffers from regular outbreaks of typhoid fever (TF), worse since 2017. Most cases were in Harare and a vaccination campaign with Typhoid Conjugate Vaccine (TCV) was conducted in March 2019. The vaccine effectiveness (VE) was assessed against culture-confirmed S. Typhi in children six months to 15 years and in individuals six months to 45 years in Harare.MethodsA matched case-control study was conducted in three urban suburbs of Harare targeted by the TCV vaccination campaign. Suspected TF cases were enrolled prospectively in four health facilities and were matched to facility (1:1) and community (1:5) controls.FindingsOf 504 suspected cases from July 2019 to March 2020, 148 laboratory-confirmed TF cases and 153 controls confirmed-negative were identified. One hundred and five (47 aged six months to 15 years) cases were age, sex, and residence matched with 105 facility-based controls while 96 cases were matched 1:5 by age, sex, and immediate-neighbour with 229 community controls.The adjusted VE against confirmed TF was 75% (95%CI: 1–94, p = 0.049) compared to facility controls, and 84% (95%CI: 57–94, p < 0.001) compared to community controls in individuals six months to 15 years. The adjusted VE against confirmed TF was 46% (95%CI: 26–77, p = 0.153) compared to facility controls, and 67% (95%CI: 35–83, p = 0.002) compared to community controls six months to 45 years old.InterpretationThis study confirms that one vaccine dose of TCV is effective to control TF in children between six months and 15 years old in an African setting.     

Effectiveness of enterovirus A71 vaccine in severe hand,foot, and mouth disease cases in Guangxi,China

BackgroundHand, foot, and mouth disease (HFMD) caused by enterovirus A71 (EV-A71) is a major public health issue in China that poses severe risks to children’s health, especially those under the age of 3. Since 2016, EV71 vaccines developed by three Chinese manufacturers have been approved for use, and clinical trials of these vaccines have demonstrated protection against EV-A71 infection. However, few studies have assessed the effectiveness of these vaccines in real-world settings.MethodsA test-negative design case-control study was used to estimate vaccine effectiveness (VE) in cases of severe HFMD. We obtained information including EV-A71 vaccination status from the Local Center for Disease Control and Prevention (CDC) on all severe HFMD cases under 12 years in age in Guangxi, China, from Jan. 1, 2017, to Dec. 31, 2018. Enterovirus infection was laboratory confirmed by local CDCs. Individuals with a positive EV-A71 nucleic acid test result were assigned to the case group, and those with negative EV-A71 nucleic acid test results were assigned to the control group. We estimated VE using logistic regression.ResultsA total of 2779 severe HFMD cases were enrolled in the study; 838 children were EV-A71 positive cases, and 1941 children were EV-A71 negative controls. The proportion of EV-A71 positive cases aged 6–36 months was lower than that for EV-A71 negative controls. EV-A71 infection was associated with an increased risk of mortality (aOR, 8.8; 95% CI, 1.3–61.6). The adjusted VE was 81.4% and 88.3% for one dose and two doses, respectively.ConclusionOur findings suggest that the rate of EV-A71 has fallen among severe HFMD cases in Guangxi and that the risk for EV-A71 infection in 6–36-month-old children has been reduced by use of the vaccine. Inactivated vaccines performed well in severe HFMD cases in a real-world setting.     

Vaccine effectiveness against COVID-19 related hospital admission in the Netherlands: A test-negative case-control study

IntroductionReal-world vaccine effectiveness (VE) estimates are essential to identify potential groups at higher risk of break-through infections and to guide policy. We assessed the VE of COVID-19 vaccination against COVID-19 hospitalization, while adjusting and stratifying for patient characteristics.MethodsWe performed a test-negative case-control study in six Dutch hospitals. The study population consisted of adults eligible for COVID-19 vaccination hospitalized between May 1 and June 28, 2021 with respiratory symptoms. Cases were defined as patients who tested positive for SARS-CoV-2 by PCR during the first 48 h of admission or within 14 days prior to hospital admission. Controls were patients tested negative at admission and did not have a positive test during the 2 weeks prior to hospitalization. VE was calculated using multivariable logistic regression, adjusting for calendar week, sex, age, comorbidity and nursing home residency. Subgroup analysis was performed for age, sex and different comorbidities. Secondary endpoints were ICU-admission and mortality.Results379 cases and 255 controls were included of whom 157 (18%) were vaccinated prior to admission. Five cases (1%) and 40 controls (16%) were fully vaccinated (VE: 93%; 95% CI: 81 – 98), and 40 cases (11%) and 70 controls (27%) were partially vaccinated (VE: 70%; 95% CI: 50–82). A strongly protective effect of vaccination was found in all comorbidity subgroups. No ICU-admission or mortality were reported among fully vaccinated cases. Of unvaccinated cases, mortality was 10% and 19% was admitted at the ICU.ConclusionCOVID-19 vaccination provides a strong protective effect against COVID-19 related hospital admission, in patients with and without comorbidity.