Safety reporting in developing country vaccine clinical trials-a systematic review

With more vaccines becoming available worldwide, vaccine research is on the rise in developing countries. To gain a better understanding of safety reporting from vaccine clinical research in developing countries, we conducted a systematic review in Medline and Embase (1989-2011) of published randomized clinical trials (RCTs) reporting safety outcomes with ≥50% developing country participation (PROSPERO systematic review registration number: CRD42012002025). Developing country vaccine RCTs were analyzed with respect to the number of participants, age groups studied, inclusion of safety information, number of reported adverse events following immunization (AEFI), type and duration of safety follow-up, use of standardized AEFI case definitions, grading of AEFI severity, and the reporting of levels of diagnostic certainty for AEFI. The systematic search yielded a total number of 50 randomized vaccine clinical trials investigating 12 different vaccines, most commonly rotavirus and malaria vaccines. In these trials, 94,459 AEFI were reported from 446,908 participants receiving 735,920 vaccine doses. All 50 RCTs mentioned safety outcomes with 70% using definitions for at least one AEFI. The most commonly defined AEFI was fever (27), followed by local (16) and systemic reactions (14). Logistic regression analysis revealed a positive correlation between the implementation of a fever case definition and the reporting rate for fever as an AEFI (p=0.027). Overall, 16 different definitions for fever and 7 different definitions for erythema were applied. Predefined AEFI case definitions by the Brighton Collaboration were used in only two out of 50 RCTs. The search was limited to RCTs published in English or German and may be missing studies published locally. The reported systematic review suggests room for improvement with respect to the harmonization of safety reporting from developing country vaccine clinical trials and the implementation of standardized case definitions.     

Heterogeneity of case definitions used in vaccine effectiveness studies--and its impact on meta-analysis

In the literature, different definitions of clinical illness cases and observation period are used to assess influenza vaccine effectiveness, usually without addressing their actual specificity and sensitivity. These properties, however, have large implications on influenza vaccine effectiveness estimates in single trials and meta-analyses of trials. Re-arranging 30 trials (in 17 publications) with a total of 29,265 subjects according to specificity and sensitivity of their case definitions and observation periods, resulted in large differences between vaccine effectiveness estimates for various levels of specificity and sensitivity. For highly specific definitions the combined vaccine effectiveness estimate was 54%, but for highly sensible definitions only 11%. Such findings call for a cautious interpretation of combined vaccine effectiveness estimates. Internationally agreed case and observation period definitions would be desirable to facilitate future meta-analyses.     

A grading system for local skin reactions developed for clinical trials of an intradermal and transcutaneous ETEC vaccine

BackgroundTrials assessing the safety of novel vaccine candidates are essential in the evaluation and development of candidate vaccines. Immunogenicity and dose-sparing features of vaccination approaches which target skin and associated tissues have garnered increased interest; for enteric vaccines, cutaneous vaccination has been of particular interest. Cutaneous vaccine site reactions are among the most common and visible vaccine related adverse events (AEs) when skin routes are used. Regulatory guidelines governing classification of severity focus on functional impact but are insufficient to characterize a spectrum of skin reaction and allow for comparisons of routes, doses and products with similar local cutaneous AEs.ObjectivesOur group developed a grading scale to evaluate and compare cutaneous vaccine site reactions ahead of early-phase clinical trials of intradermal (ID) and transcutaneous immunization (TCI) with enterotoxigenic E.coli (ETEC) vaccine candidates (adhesin-based vaccine co-administered with LTR192G). We reviewed existing methods for characterizing the appearance and severity of local vaccine site reactions following TCI and ID vaccination and devised a standardized vaccine site appearance grading scale (VSAGS) for use in the clinical development of novel ETEC vaccine candidates which focused on pathophysiologic manifestation of skin findings.ResultsAvailable data from published reports revealed erythematous papules and pruritus were the most common local AEs associated with TCI. Frequency of reactions varied notably across studies as did TCI vaccination methodologies and products. ID vaccination commonly results in erythema and induration at the vaccine site as well as pigmentation changes. There was no published methodology to characterize the spectrum of dermatologic findings.ConclusionID and TCI vaccination are associated with a largely predictable range of cutaneous AEs. A grading scale focused on the appearance of cutaneous changes was useful in comparing cutaneous AEs. A standardized grading scale will facilitate documentation and comparison of cutaneous AEs.     

Comparing vaccines: A systematic review of the use of the non-inferiority margin in vaccine trials

BackgroundNon-inferiority (NI) randomized controlled trials (RCTs) aim to demonstrate that a new treatment is no worse than a comparator that has already shown its efficacy over placebo within a pre-specified margin. However, clear guidelines on how the NI margin should be determined are lacking for vaccine trials. A difference (seroprevalence/risk) of 10% or a geometric mean titre/concentration (GMT) ratio of 1.5 or 2.0 in antibody levels is implicitly recommended for vaccine trials. We aimed to explore which NI margins were used in vaccine RCTs and how they were determined.MethodsA systematic search for NI vaccine RCTs yielded 177 eligible articles. Data were extracted from these articles using a standardized form and included general characteristics and characteristics specific for NI trials. Relations between the study characteristics and the NI margin used were explored.ResultsAmong the 143 studies using an NI margin based on difference (n = 136 on immunogenicity, n = 2 on efficacy and n = 5 on safety), 66% used a margin of 10%, 23% used margins lower than 10% (range 1–7.5%) and 11% used margins larger than 10% (range 11.5–25%). Of the 103 studies using a NI margin based on the GMT ratio, 50% used a margin of 0.67/1.5 and 49% used 0.5/2.0. As observed, 85% of the studies did not discuss the method of margin determination; and 19% of the studies lacked a confidence interval or p-value for non-inferiority.ConclusionMost NI vaccine RCTs used an NI margin of 10% for difference or a GMT ratio of 1.5 or 2.0 without a clear rationale. Most articles presented enough information for the reader to make a judgement about the NI margin used and the conclusions. The reporting on the design, margins used and results of NI vaccine trials could be improved; more explicit guidelines may help to achieve this end.     

Validación de escalas abreviadas de zarit para la medición de síndrome del cuidador primario del adulto mayor en Medellín

ObjectiveTo determine which abbreviated Zarit Scale (ZS) better evaluates the burden of the caregiver of an elderly patient in Medellin, Colombia.DesignValidation study.SettingPrimary Care setting in the city of Medellin.ParticipantsPrimary caregiver of dependent elderly patients over 65 years old.Principal measurementsSensitivity, specificity, positive predictive value, and negative predictive value for the different abbreviated Zarit scales, plus performing a reliability analysis using the Cronbach Alpha coefficient.ResultsThe abbreviated scales obtained a sensitivity of between 36.84 and 81.58%, specificity between 95.99 and 100%, positive predictive values between 71.05 and 100%, and negative predictive values of between 91.64 and 97.42%.ConclusionsThe scale that better determined caregiver burden in Primary Care was the Bedard Screening scale, with a sensitivity of 81.58%, a specificity of 96.35% and positive and negative predictive values of 75.61% and 97.42%, respectively.     

Caregiver recall in childhood vaccination surveys: Systematic review of recall quality and use in low- and middle-income settings

IntroductionHigh population coverage is key to the impact of vaccines. However, vaccine coverage estimates in low- and middle-income countries (LMICs) have repeatedly been shown to be of poor quality. LMICs often rely on ‘caregiver recall’ of vaccination, the validity and collection method of which remains uncertain. We aimed to critique the quality of caregiver recall and make recommendations for its collection and use.MethodsWe performed a systematic review for methods assessing childhood vaccination coverage in LMICs. We searched Medline using variations of the key terms: (child) AND (vaccinat¹) AND (survey OR recall OR coverage) AND (reliab¹ OR valid¹). We selected articles assessing the quality of recall in LMICs and extracted reported validity, reliability and completeness. We synthesised recommendations on collecting, analysing and presenting caregiver recall for varying resource availabilities.ResultsOf 1268 articles, 134 full texts were screened and eight were included for review. There was heterogeneity in study designs, ways of incorporating recall data and outcomes measured. Sensitivity of recall was 41–98%; specificity was 12–80%. There was a dearth of reliability measures and no consistent method for dealing with data incompleteness.ConclusionThere are quality concerns with caregiver recall and difficulty in assessing it given the lack of a ‘gold standard’ for vaccine status. To improve coverage estimates and the impact of vaccines, caregiver recall should be used. Other recommendations include: recall is included for those presenting vaccine records; missing data is imputed; recall and record quality are assessed in a sub-sample; and sensitivity analyses are performed.     

Efficacy and safety of high-dose influenza vaccine in elderly adults: A systematic review and meta-analysis

IntroductionOlder adults are prioritized for influenza vaccination but also have lowered antibody responses to the vaccine. Higher-doses of influenza antigen may increase immune response and thus be more effective. Our objectives were to compare the efficacy and safety of the high-dose influenza vaccine to the standard-dose influenza vaccine in the elderly (age > 65).MethodsData sources: Randomized trials (RCTs) from Medline (Ovid), EMBASE (Ovid), Cochrane Library (Wiley), ClinicalTrials.gov, reference lists of relevant articles, and gray literature.Study selection: Two reviewers independently identified RCTs comparing high-dose influenza vaccine (60 μg of hemagglutinin per strain) to standard-dose influenza vaccine (15 μg of hemagglutinin per strain) in adults over the age of 65 years.Data extraction: Two reviewers independently extracted trial-level data including population characteristics, interventions, outcomes, and funding sources. Risk of bias was assessed using the Cochrane Risk of Bias tool.ResultsWe included seven eligible trials; all were categorized as having a low (n = 3) or unclear (n = 4) risk of bias. Patients receiving the high-dose vaccine had significantly less risk of developing laboratory-confirmed influenza infections (Relative Risk 0.76, 95%CI 0.65 to 0.90; I² 0%, 2 trials, 41,141 patients). Post-vaccination geometric mean titres and seroprotection rates were also higher in high-dose vaccine recipients. There were no protocol-defined serious adverse events in the included trials in either group.ConclusionsIn elderly adults, the high-dose influenza vaccine was well-tolerated, more immunogenic, and more efficacious in preventing influenza infections than the standard-dose vaccine. Further pragmatic trials are needed to determine if the higher efficacy translates into higher vaccine effectiveness in adults over the age of 65.     

So much at stake: Ethical tradeoffs in accelerating SARSCoV-2 vaccine development

BackgroundA sense of urgency exists to develop vaccines against SARS CoV-2, responsible for numerous global cases and deaths, as well as widespread social and economic disruption. Multiple approaches have been proposed to speed up vaccine development, including accelerated randomized controlled trials (RCT), controlled human challenge trials (CHI), and wide distribution through an emergency use authorization after collecting initial data. There is a need to examine how best to accelerate vaccine development in the setting of a pandemic, without compromising ethical and scientific norms.MethodsTrade-offs in scientific and social value between generating reliable evidence about safety and efficacy while promoting rapid vaccine availability are examined along five ethically relevant dimensions: (1) confidence in and generalizability of data, (2) feasibility, (3) speed and cost, (4) participant risks, and (5) social risks.ResultsAccelerated individually randomized RCTs permit expeditious evaluation of vaccine candidates using established methods, expertise, and infrastructure. RCTs are more likely than other approaches to be feasible, increase speed and reduce cost, and generate reliable data about safety and efficacy without significantly increasing risks to participants or undermining societal trust.ConclusionEthical analysis suggests that accelerated RCTs are the best approach to accelerating vaccine development in a pandemic, and more likely than other approaches to enhance social value without compromising ethics or science. RCTs can expeditiously collect rigorous data about vaccine safety and efficacy. Innovative and flexible designs and implementation strategies to respond to shifting incidence and test vaccine candidates in parallel or sequentially would add value, as will coordinated data sharing across vaccine trials. CHI studies may be an important complementary strategy when more is known. Widely disseminating a vaccine candidate without efficacy data will not serve the public health nor achieve the goal of identifying safe and effective SARS Co-V-2 vaccines.     

Inadequate statistical power to detect clinically significant differences in adverse event rates in randomized controlled trials

ObjectiveTo determine the statistical power to detect potentially clinically significant differences in serious adverse events between drug therapies reported in a sample of randomized controlled trials (RCTs).Study Design and SettingSystematic review of RCTs with positive efficacy endpoint and at least a twofold difference in the proportion of patients with serious adverse events between treatment groups from six major journals. The power of each study to detect statistically significant differences in serious adverse events was calculated.ResultsOf the six included trials, all performed statistical analysis on adverse events without disclosure of the statistical power for detecting the reported differences between groups. The power of each study to detect the reported differences in adverse events was calculated and yielded values ranging from 0.07 to 0.37 among trials with non–statistically significant differences.ConclusionStatistical testing for differences in the proportion of patients experiencing an adverse event is common in RCTs; non–statistically significant differences are associated with low statistical power. A high probability of type II error may lead to erroneous clinical inference resulting in harm. The statistical power for nonsignificant tests should be considered in the interpretation of results.     

Effects of Unstructured Mobility Programs in Older Hospitalized General Medicine Patients: A Systematic Review and Meta-Analysis

ObjectiveMobility interventions have been shown to mitigate functional decline in various clinical populations; however, the effects of mobility programs in older hospitalized patients are unclear. The objective of this study was to determine the effects of unstructured mobility programs on physical activity, physical function, length of stay (LOS), and quality of life (QOL) in older (≥60 years) general medicine inpatients.DesignIn this systematic review and meta-analysis, we systematically searched MEDLINE, Embase, CINAHL, and AMED databases from inception to March 2020, plus hand screening references of relevant studies.Setting and ParticipantsWe included randomized controlled trials (RCTs) and quasi-experimental studies assessing the effects of mobility programs compared to usual care in older adults admitted to general medicine units.MeasuresTeams of 2 reviewers independently extracted data, assessed risk of bias, and evaluated quality of evidence. Where study population, intervention, and outcomes were similar, results from RCTs were combined by meta-analysis.ResultsThree RCTs and 10 quasi-experimental studies met eligibility criteria. Interventions mainly included ambulation and staff, patient, or caregiver education. Meta-analyses showed that mobility interventions had a moderate effect on physical activity [step count standardized mean difference 0.60, 95% confidence interval (CI) 0.23-0.97] and a nonsignificant effect on LOS (mean difference –0.36, 95% CI –1.92 to 1.21), both favoring mobility. Narrative synthesis showed consistent evidence for improvement in physical function, potential decrease in LOS, and no increase in adverse events with mobility interventions.Conclusions and ImplicationsUnstructured mobility interventions in general medicine units may improve older hospitalized patients’ physical activity and physical function; however, the quality of evidence was low. More RCTs are needed to evaluate the effectiveness of mobility interventions, particularly on LOS and QOL.     

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.     

The effectiveness of influenza vaccination in pregnancy in relation to child health outcomes: Systematic review and meta-analysis

ObjectivesTo determine the effectiveness of influenza vaccination during pregnancy on child health outcomes.DesignSystematic review/meta-analysis.Data sourcesClinical Trials.gov, Cochrane Library, EMBASE, Medline, Medline in process, PubMed and Web of Science, from 1st January 1996 to 29th June 2018. An updated Medline search was performed 30th June 2018 to 31st October 2019.MethodsRandomised controlled trials (RCTs) and observational studies reporting health outcomes of infants and children born to women who received inactivated influenza vaccine during pregnancy. The primary outcome was infant laboratory confirmed influenza (LCI). Secondary outcomes included influenza-like illness (ILI), other respiratory illnesses, primary care, clinic visit or hospitalisations due to influenza illness and long-term respiratory childhood outcomes.Results19 studies were included; 15 observational studies and 4 primary RCTs with an additional 3 papers reporting secondary outcomes of these RCTs. In a random effects meta-analysis of 2 RCTs including 5742 participants, maternal influenza vaccination was associated with an overall reduction of LCI in infants of 34% (95% confidence interval 15–50%). However, there was no effect of maternal influenza vaccination on ILI in infants ≤6 months old. Two RCTs were excluded from the meta-analysis for the outcome of LCI in infants (different controls used). Both of these studies showed a protective effect for infants from LCI, with a vaccine efficacy of up to 70%.Overall observational studies showed an inverse (protective) association between maternal influenza vaccination and infant LCI, hospitalisation and clinic visits due to LCI or ILI in infants and other respiratory illness in infants ≤6 months old.ConclusionsThis systematic review supports maternal influenza vaccination as a strategy to reduce LCI and influenza-related hospitalisations in young infants. Communicating these benefits to pregnant women may support their decision to accept influenza vaccination in pregnancy and increase vaccine coverage in pregnant women.RegistrationPROSPERO CRD42018102776.     

Changes to registration elements and results in a cohort of Clinicaltrials.gov trials were not reflected in published articles

ObjectivesTo assess effectiveness of legislative initiatives to stimulate public registration of trial results, we assessed adherence to protocol and results reporting, changes to registry, and publication data for randomized controlled trials (RCTs) after introduction of Food and Drug Administration Amendment Act (FDAAA).Study Design and SettingObservational study of a cohort of ClinicalTrials.gov registered FDAAA-covered RCTs found through ClinicalTrials.gov between 2009 and 2012 and data from corresponding publications. WHO Minimum Data Set items were abstracted by one author and verified by the other author.ResultsAmong 81 eligible trials, most were industry-funded, with a drug intervention in parallel assignment. Secondary outcomes at the initial and last registration were omitted for 17% and 19.7% of RCTs, respectively. RCT registration changes mostly involved scientific title (18.8%). Inclusion criteria omission was most common (88%) in publications. Inferential statistical methods for primary and secondary outcomes matched between registry and publication for 53.4% and 28.6% of RCTs, respectively. Serious and other adverse events (AEs) that were absent for 23.8% and 4.8% of RCTs, respectively, were published as nonoccurring.ConclusionDiscrepancies remain relatively high between registered and published outcomes, particularly regarding registered omissions in publications and concomitant reporting, nature of statistical method used, and reporting of AEs. This seriously undermines transparency of clinical trials and needs immediate attention of all stakeholders in health research.     

Urban land-use and respiratory symptoms in infants

Background

Children's respiratory health has been linked to many factors, including air pollution. The impacts of urban land-use on health are not fully understood, although these relationships are of key importance given the growing populations living in urban environments.

Objectives

We investigated whether the degree of urban land-use near a family's residence is associated with severity of respiratory symptoms like wheeze among infants.

Methods

Wheeze occurrence was recorded for the first year of life for 680 infants in Connecticut for 1996–1998 from a cohort at risk for asthma development. Land-use categories were obtained from the National Land Cover Database. The fraction of urban land-use near each subject's home was related to severity of wheeze symptoms using ordered logistic regression, adjusting for individual-level data including smoking in the household, race, gender, and socio-economic status. Nitrogen dioxide (NO₂) exposure was estimated using integrated traffic exposure modeling. Different levels of urban land-use intensity were included in separate models to explore intensity-response relationships. A buffer distance was selected based on the log-likelihood value of models with buffers of 100–2000 m by 10 m increments.

Results

A 10% increase in urban land-use within the selected 1540 m buffer of each infant's residence was associated with 1.09-fold increased risk of wheeze severity (95% confidence interval, 1.02–1.16). Results were robust to alternate buffer sizes. When NO₂, representing traffic pollution, was added to the model, results for urban land-use were no longer statistically significant, but had similar central estimates. Higher urban intensity showed higher risk of prevalence and severity of wheeze symptoms.

Conclusions

Urban land-use was associated with severity of wheeze symptoms in infants. Findings indicate that health effect estimates for urbanicity incorporate some effects of traffic-related emissions, but also involve other factors. These may include differences in housing characteristics or baseline healthcare status.     

Primary school interventions to promote fruit and vegetable consumption: a systematic review and meta-analysis

ObjectiveThe consumption of fruits and vegetables (FV) may contribute to the prevention of many diseases. However, children at school age do not eat an enough amount of those foods. We have systematically reviewed the literature to assess the effectiveness of school interventions for promoting the consumption of FV.MethodsWe performed a search in MEDLINE, EMBASE, CINAHL and CENTRAL. We pooled results and stratified the analysis according to type of intervention and study design.ResultsNineteen cluster studies were included. Most studies did not describe randomization method and did not take the cluster's effect into account. Pooled results of two randomized controlled trials (RCTs) of computer-based interventions showed effectiveness in improving consumption of FV [Standardized Mean Difference (SMD) 0.33 (95% CI 0.16, 0.50)]. No significant differences were found in pooled analysis of seven RCTs of multicomponent interventions or pooling results of two RCTs evaluating free/subsidized FV interventions.ConclusionsMeta-analysis shows that computer-based interventions were effective in increasing FV consumption. Multicomponent interventions and free/subsidized FV interventions were not effective. Improvements in methodology are needed in future cluster studies. Although these results are preliminary, computer-based interventions could be considered in schools, given that they are effective and cheaper than other alternatives.     

Omega-3, Omega-6, and Polyunsaturated Fat for Cognition: Systematic Review and Meta-analysis of Randomized Trials

ObjectivesNeurocognitive function may be influenced by polyunsaturated fat intake. Many older adults consume omega-3 supplements hoping to prevent cognitive decline. We assessed effects of increasing omega-3, omega-6, or total polyunsaturated fats on new neurocognitive illness and cognition.Design and inclusion criteriaWe carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) in adults, with duration ≥24 weeks, assessing effects of higher vs lower omega-3, omega-6, or total polyunsaturated fats and outcomes: new neurocognitive illness, newly impaired cognition, and/or continuous measures of cognition.MethodsWe searched MEDLINE, Embase, Cochrane CENTRAL, and trials registers (final update of ongoing trials December 2018). We duplicated screening, data extraction, and risk of bias assessment. Neurocognitive measures were grouped to enable random effects meta-analysis. GRADE assessment, sensitivity analyses, and subgrouping by dose, duration, type of intervention, and replacement were used to interrogate our findings.ResultsSearches generated 37,810 hits, from which we included 38 RCTs (41 comparisons, 49,757 participants). Meta-analysis suggested no or very little effect of long-chain omega-3 on new neurocognitive illness [risk ratio (RR) 0.98, 95% confidence interval (CI) 0.87-1.10, 6 RCTs, 33,496 participants, I² 36%), new cognitive impairment (RR 0.99, 95% CI 0.92-1.06, 5 RCTs, 33,296 participants, I² 0%) or global cognition assessed using the Mini-Mental State Examination (MD 0.10, 95% CI 0.03-0.16, 13 RCTs, 14,851 participants, I² 0%), all moderate-quality evidence. Effects did not differ with sensitivity analyses, and we found no differential effects by dose, duration, intervention type, or replacement. Effects of increasing α-linolenic acid, omega-6, or total PUFA were unclear.ConclusionsThis extensive trial data set enabled assessment of effects on neurocognitive illness and cognitive decline not previously adequately assessed. Long-chain omega-3 probably has little or no effect on new neurocognitive outcomes or cognitive impairment.ImplicationsLong-chain omega-3 supplements do not help older adults protect against cognitive decline.     

Immunogenicity,duration of protection,effectiveness and safety of rubella containing vaccines: A systematic literature review and meta-analysis

BackgroundRubella containing vaccines (RCV) prevent rubella virus infection and subsequent congenital rubella syndrome (CRS). To update the evidence on immunogenicity, duration of protection, effectiveness and safety of RCV, we conducted a systematic literature review.MethodsWe searched EMBASE and SCOPUS, using keywords for rubella vaccine in combination with immunogenicity (seroconversion and seropositivity), duration of protection, efficacy/effectiveness, and safety. Original research papers involving at least one dose of RCV (at any age), published between 1-1-2010 and 17-5-2019 were included. Where appropriate, meta-analyses were performed. Quality of included studies was assessed using GRADE methodology.ResultsWe included 36 papers (32 randomized controlled trials (RCTs) and 4 observational studies) on immunogenicity (RA27/3 strain) in children and adolescent girls, 14 papers (5 RCTs and 9 observational studies) on duration of protection, one paper on vaccine effectiveness (VE) (BRDII strain), and 74 studies on safety, including three on safety in pregnancy.Meta-analysis of immunogenicity data showed 99% seroconversion (95% CI: 98–99%) after a single dose of RCV in children, independent of co-administration with other vaccines. Seroconversion after RCV1 below 9 months of age (BRDII strain, at 8 months) was 93% (95% CI: 92–95%). For duration of protection, the included studies showed a seropositivity of 88%-100% measured 1–20 years after one or two RCV doses. The single study on VE of BRDII strain, reported 100% VE after one and two doses. Among 34,332 individuals participating in the RCTs, 140 severe adverse events (SAEs) were reported as possibly related to RCV. Among the case reports on SAEs, the association with RCV was confirmed in one report (on fulminant encephalitis). Among 3,000 pregnant women who were inadvertently vaccinated, no SAEs were reported.ConclusionsOne and two doses of RCV are highly immunogenic for a long period of time, effective in preventing rubella and CRS, and safe.     

Subgroup analysis in randomized controlled trials appeared to be dependent on whether relative or absolute effect measures were used

ObjectivesTo assess whether relative or absolute effect measures were used in subgroup analyses of randomized controlled trials (RCTs) and study whether conclusions would change if subgroup effects were calculated on a different scale than reported.Study Design and SettingWe studied all 327 RCTs published in 2010 in five major medical journals. For trials with a dichotomous primary outcome, we extracted reported main and subgroup effect measures. If crude subgrouping data were reported, we calculated the subgroup effects on both relative and absolute scales.ResultsOf the 229 RCTs with a dichotomous primary outcome, 120 (52%) performed subgroup analyses. In 106 of these 120 (88%) RCTs, relative effect measures were used for subgroup analyses, whereas an absolute scale was used in 9 (8%) trials. Two (2%) RCTs reported both relative and absolute subgroup effects. Crude data of the subgroups could be extracted in 41 of the 120 (34%) RCTs. Calculating subgroup effects on a different scale than reported lead to a change in conclusion in 17% of the 41 trials.ConclusionAlmost all RCTs used relative effect measures for subgroup analyses. Interpretation of subgroup effects, however, appeared to be dependent on whether relative or absolute effect measures were used.     

Prevalence and predictors of respiratory symptoms among New York farmers and farm residents

BACKGROUND: Data from telephone interviews with New York farmers and farm residents were used to study the prevalence and risk factors of symptoms that could be related to asthma and allergies. METHODS: Participants were asked if they had wheezing or whistling in the chest in the past year and about the occurrence of stuffy, itchy, runny nose or watery, itchy eyes in the past year. RESULTS: The prevalence of wheeze was 18.2% and of stuffy nose/watery eyes was 57.4% (N = 1,620). Significant risk factors for wheeze were cigarette smoking, a systemic reaction to allergy skin testing, immunotherapy, or insect sting, reactivity to a pet, having goats, and more acreage in corn for silage. Significant risk factors of stuffy nose/watery eyes were younger age, having more than a high school education, being a worker on the farm, and having done spraying. CONCLUSIONS: Wheeze may be indicative of existing or latent asthma, a potentially limiting respiratory illness. Stuffy, itchy, runny nose or watery, itchy eyes, which may cause irritation and discomfort, may also indicate an increased sensitivity to respirable dusts and chemicals. This cohort of New York farmers had significant farm-related risk factors for wheeze and stuffy nose/watery eyes.     

Systematic literature review of cross-protective effect of HPV vaccines based on data from randomized clinical trials and real-world evidence

BackgroundThe extent of cross-protection provided by currently licensed bivalent and quadrivalent HPV vaccines versus direct protection against HPV 31-, 33-, 45-, 52-, and 58-related disease is debated. A systematic literature review was conducted to establish the duration and magnitude of cross-protection in interventional and observational studies.MethodsPubMed and Embase databases were searched to identify randomized controlled trials (RCT) and observational studies published between 2008 and 2019 reporting on efficacy and effectiveness of HPV vaccines in women against non-vaccine types 31, 33, 45, 52, 58, and 6 and 11 (non-bivalent types). Key outcomes of interest were vaccine efficacy against 6- and 12-month persistent infection or genital lesions, and type-specific genital HPV prevalence or incidence. RCT data were analyzed for the according-to-protocol (bivalent vaccine) or negative-for-14-HPV-types (quadrivalent vaccine) efficacy cohorts.ResultsData from 23 RCTs and 33 observational studies evaluating cross-protection were extracted. RCTs assessed cross-protection in post-hoc analyses of small size subgroups. Among fully vaccinated, baseline HPV-naïve women, the bivalent vaccine showed statistically significant cross-protective efficacy, although with wide confidence intervals, against 6-month and 12-month persistent cervical infections and CIN2+ only consistently for HPV 31 and 45, with the highest effect observed for HPV 31 (range 64.6% [95% CI: 27.6 to 83.9] to 79.1% [97.7% CI: 27.6 to 95.9] for 6-month persistent infection; maximal follow-up 4.7 years). No cross-protection was shown in extended follow-up. The quadrivalent vaccine efficacy reached statistical significance for HPV 31 (46.2% [15.3–66.4]; follow-up: 3.6 years). Similarly, observational studies found consistently significant effectiveness only against HPV 31 and 45 with both vaccines.ConclusionsRCTs and observational studies show that cross-protection is inconsistent across non-vaccine HPV types and is largely driven by HPV 31 and 45. Furthermore, existing data suggest that it wanes over time; its long-term durability has not been established.