Epidemiology of Escherichia coli Bacteremia: A Systematic Literature Review.

BACKGROUND: Escherichia coli is the most common cause of bacteremia in high-income countries. To enable the development and implementation of effective prevention strategies, a better understanding of the current epidemiology of invasive E. coli infections is needed. METHODS: A systematic review of literature published between 1 January 2007 and 31 March 2018 on the burden and epidemiology of E. coli bacteremia in populations that include adults in high-income countries was conducted. Meta-analysis was performed for descriptive purposes. RESULTS: During the studied time interval, the estimated incidence rate of E. coli bacteremia was 48 per 100 000 person-years, but this increased considerably with age: rates per 100 000 person-years were >100 in 55-to-75-year-olds and >300 in 75-to-85-year-olds. Overall, E. coli accounted for 27% of documented bacteremia episodes: 18% if hospital acquired, 32% if community-onset healthcare associated, and 33% if community acquired. The estimated case fatality rate was 12%. Approximately 44% of episodes were community acquired, 27% community-onset healthcare associated, and 27% hospital acquired. Urinary tract infection (UTI) was the primary source for 53% of episodes. CONCLUSIONS: This systematic review confirms the substantial burden of E. coli bacteremia in older adults and justifies the implementation of community-level programs to prevent E. coli bacteremia and ideally UTI in this age group.

Model estimates of hospitalization discharge rates for norovirus gastroenteritis in Europe, 2004-2015.

BACKGROUND: Norovirus is an important cause of acute gastroenteritis globally. However, norovirus is rarely laboratory confirmed or recorded explicitly as a cause of hospitalization. In recent years, there has been an interest in using medical databases and indirect modelling methods to estimate the incidence of norovirus gastroenteritis. The objective of this study was to estimate the incidence of hospitalizations for norovirus gastroenteritis in Europe (2004-2015) using nationwide in-patient discharge records from different European countries. METHODS: National hospital discharge registers in all 28 European Union countries (at that time) and all 4 European Free Trade Association countries were contacted and invited to participate in the study. Discharges with ICD9/ICD10 codes for acute gastroenteritis (AGE) as first-listed (principal) diagnosis were extracted to assess hospitalization rates for AGE and norovirus gastroenteritis (NGE), overall, by age group, country, month, and seasonal year. The number of cause-unspecified episodes was regressed against pathogen-specific AGE episodes: Rotavirus, Clostridium difficile, Other Bacterial, Other Viral and Parasitic separately. NGE hospital discharges were estimated for each month by calculating the difference between observed cause-unspecified and model-predicted counts, assuming that any remaining seasonality not otherwise captured in the model was due to norovirus, and adding those to the coded NGE episodes to get the total number of norovirus-associated episodes. RESULTS: Data were available from 15 countries, representing 68% of the total population in Europe. Only 24.4% of all AGE discharges were coded as cause-specified. We estimated that between 2004 and 2015, the overall rate of NGE hospital discharges in Europe was 3.9 per 10,000 person-years, ranging from 1.2 (Portugal) to 10.7 (Lithuania). Norovirus was predicted to be responsible for 17% of all AGE hospital discharges in Europe in this period. Norovirus affects individuals of all ages, but NGE discharge rates were highest in children < 5 years (24.8 per 10,000 person-years), and adults aged ≥80 years (10.7 per 10,000 person-years). CONCLUSION: We estimated that 1 in 400 hospitalizations in Europe can be attributed to Norovirus. In the absence of routine norovirus testing and recording in hospital settings, modelling methods are useful resources to estimate the incidence of norovirus gastroenteritis.

Incorporating patient generated health data into pharmacoepidemiological research.

Epidemiology and pharmacoepidemiology frequently employ Real-World Data (RWD) from healthcare teams to inform research. These data sources usually include signs, symptoms, tests, and treatments, but may lack important information such as the patient's diet or adherence or quality of life. By harnessing digital tools a new fount of evidence, Patient (or Citizen/Person) Generated Health Data (PGHD), is becoming more readily available. This review focusses on the advantages and considerations in using PGHD for pharmacoepidemiological research. New and corroborative types of data can be collected directly from patients using digital devices, both passively and actively. Practical issues such as patient engagement, data linking, validation, and analysis are among important considerations in the use of PGHD. In our ever increasingly patient-centric world, PGHD incorporated into more traditional Real-Word data sources offers innovative opportunities to expand our understanding of the complex factors involved in health and the safety and effectiveness of disease treatments. Pharmacoepidemiologists have a unique role in realizing the potential of PGHD by ensuring that robust methodology, governance, and analytical techniques underpin its use to generate meaningful research results.

Norovirus Gastroenteritis among Hospitalized Patients, Germany, 2007-2012.

We estimated numbers of hospitalizations for norovirus gastroenteritis (NGE) and associated medical costs in Germany, where norovirus testing is high because reimbursement is affected. We extracted aggregate data for patients hospitalized with a primary or secondary code from the International Classification of Diseases, 10th Revision (ICD-10), NGE diagnosis during 2007-2012 from the German Federal Statistics Office. We assessed reliability of the coding system in patient records from a large academic hospital. Approximately 53,000-90,000 NGE hospitalizations occurred annually in Germany (21,000-33,000 with primary and 32,000-57,000 with secondary ICD-10-coded NGE diagnoses). Rates of hospitalization with NGE as primary diagnosis were highest in children <2 years of age; rates of hospitalization with NGE as secondary diagnosis were highest in adults >85 years of age. The average annual reimbursed direct medical cost of NGE hospitalizations was €31-43 million. Among patients with a NGE ICD-10 code, 87.6% had positive norovirus laboratory results.

Estimating the incidence of norovirus acute gastroenteritis among US and European international travelers to areas of moderate to high risk of traveler's diarrhea: a prospective cohort study protocol.

BACKGROUND: Acute gastroenteritis (AGE) is the leading cause of illness among returning travelers seeking medical care. Multiple types of enteric pathogens can cause travel-acquired AGE and, while bacterial pathogens have a predominant role, the importance of viruses, such as norovirus, is increasingly recognized. There is a lack of information on travel-acquired norovirus incidence among symptomatic and asymptomatic individuals irrespective of healthcare-seeking behavior. Our aim is to estimate the incidence of travel-acquired AGE due to norovirus and to characterize the burden of disease among international travelers from the United States and Europe. METHODS: We describe a prospective cohort study implemented in five US and European sites to estimate the role of AGE due to norovirus among adult international travelers. We enrolled individuals aged 18 years and older who are traveling to regions of moderate-high risk of AGE, or via cruise ship with an international port stop, with a trip duration of 3-15 days. The study will generate a wide range of health and travel-related data for pre-, during, and up to 6-months post-travel. We will identify laboratory-confirmed travel-acquired norovirus infections among both symptomatic and asymptomatic individuals from self-collected whole stool samples tested via quantitative RT-PCR. Coinfections will be identified in a subset of travelers with AGE using a multiplex molecular-based assay. DISCUSSION: This study is unique in design and breadth of data collected. The prospective collection of health and behavioral data, as well as biologic samples from travelers irrespective of symptoms, will provide useful data to better understand the importance of norovirus AGE among international travelers. This study will provide data to estimate the incidence of norovirus infections and AGE and the risk of post-infectious sequelae in the 6-month post-travel period serving as a baseline for future norovirus AGE vaccination studies. This study will contribute valuable information to better understand the role of norovirus in travel-acquired AGE risk and the impact of these infections on a broad set of outcomes.

Estimating the Burden of Medically Attended Norovirus Gastroenteritis: Modeling Linked Primary Care and Hospitalization Datasets.

Background: Norovirus is the leading cause of community-acquired and nosocomial acute gastroenteritis. Routine testing for norovirus is seldom undertaken, and diagnosis is mainly based on presenting symptoms. This makes understanding the burden of medically attended norovirus-attributable gastroenteritis (MA-NGE) and targeting care and prevention strategies challenging. Methods: We used linked population-based healthcare datasets (Clinical Practice Research Datalink General Practice OnLine Database linked with Hospital Episode Statistics Admitted Patient Care) to model the incidence of MA-NGE associated with primary care consultations or hospitalizations according to age groups in England in the period July 2007-June 2013. Results: Mean annual incidence rates of MA-NGE were 4.9/1000 person-years and 0.7/1000 person-years for episodes involving primary care or hospitalizations, respectively. Incidence rates were highest in children aged <5 years: 34.0 consultations/1000 person-years and 3.3 hospitalizations/1000 person-years. Medically attended norovirus-attributable gastroenteritis hospitalization rates were second highest in adults aged >65 years (1.7/1000 person-years). Conclusions: In this particular study, the burden of MA-NGE estimated from healthcare datasets was higher than previously estimated in small cohort studies in England. Routinely collected primary care and hospitalization datasets are useful resources to estimate and monitor the burden of MA-NGE in a population over time.

Estimation of the burden of varicella in Europe before the introduction of universal childhood immunization.

BACKGROUND: Varicella is generally considered a mild disease. Disease burden is not well known and country-level estimation is challenging. As varicella disease is not notifiable, notification criteria and rates vary between countries. In general, existing surveillance systems do not capture cases that do not seek medical care, and most are affected by underreporting and underascertainment. We aimed to estimate the overall varicella disease burden in Europe to provide critical information to support decision-making regarding varicella vaccination. METHODS: We conducted a systematic literature review to identify all available epidemiological data on varicella IgG antibody seroprevalence, primary care and hospitalisation incidence, and mortality. We then developed methods to estimate age-specific varicella incidence and annual number of cases by different levels of severity (cases in the community, health care seekers in primary care and hospitals, and deaths) for all countries belonging to the European Medicines Agency (EMA) region and Switzerland. RESULTS: In the absence of universal varicella immunization, the burden of varicella would be substantial with a total of 5.5 million (95% CI: 4.7-6.4) varicella cases occurring annually across Europe. Variation exists between countries but overall the majority of cases (3 million; 95% CI: 2.7-3.3) would occur in children <5 years. Annually, 3-3.9 million patients would consult a primary care physician, 18,200-23,500 patients would be hospitalised, and 80 varicella-related deaths would occur (95% CI: 19-822). CONCLUSIONS: Varicella disease burden is substantial. Most cases occur in children <5 years old but adults require hospitalisation more often and are at higher risk of death. This information should be considered when planning and evaluating varicella control strategies. A better understanding of the driving factors of country-specific differences in varicella transmission and health care utilization is needed. Improving and standardizing varicella surveillance in Europe, as initiated by the European Centre for Disease Prevention and Control (ECDC), is important to improve data quality to facilitate inter-country comparison.

A decade of norovirus disease risk among older adults in upper-middle and high income countries: a systematic review.

BACKGROUND: Noroviruses (NoVs) are the most common cause of acute gastroenteritis (AGE) causing both sporadic and outbreak-associated illness. Norovirus (NoV) infections occur across all ages but certain sub-groups are considered at increased risk due to heightened transmission and/or symptom severity. Older adults are potentially at high risk of NoV-associated illness due to frequent outbreaks in long-term care facilities (LTCFs) and severe health outcomes following infection. Elucidation of NoV risk among older adults will support prevention, treatment and control efforts. METHODS: We conducted a systematic literature review to summarize the published risk estimates of NoV-associated illness, hospitalization and death among individuals aged 65 years and older. A structured search using defined NoV and gastroenteritis (GE) terms was performed in the PubMed and EMBASE databases of human studies published between January 1, 2003 and May 16, 2013. RESULTS: We identified 39 studies from high income (HI) and upper-middle income (UMI) countries. Thirty-six percent of publications provided risk estimates based on laboratory-confirmed or epidemiologically-linked population-based surveillance data using molecular diagnostic methods. Over the study period, estimated annual NoV rates and extrapolated number of cases among older adults in HI and UMI countries were: 29-120/10,000 or 1.2-4.8 million NoV-associated illnesses; 18-54/10,000 or 723,000-2.2 million NoV-associated outpatient visits; 1-19/10,000 or 40,00-763,000 NoV-associated inpatient visits; 0.04-0.32/10,000 or 2000-13,000 NoV-associated deaths. NoV was responsible for approximately 10-20 % of GE hospitalizations and 10-15 % of all-cause GE deaths among older adults. Older adults experienced a heightened risk of nosocomial infections. Those in LTCFs experience frequent NoV outbreaks and the range in attack rates was 3-45 %, case hospitalization rates 0.5-6 % and case fatality rates 0.3-1.6 %. CONCLUSIONS: Older adults are at increased risk of severe NoV-associated health outcomes. NoV-associated hospitalization rates were higher, more severe, resulted in longer stays and incurred greater costs than for younger patients. NoV-associated mortality rates were approximately 200 % higher among individuals 65 years and older compared to <5 years. The burden of NoV among older adults is expected to rise along with societal aging and increased need for institutionalized care. NoV prevention in older adults, including potential vaccination, may significantly impact risk of severe illness.

A prospective cohort study of SARS-CoV-2 infection-induced seroconversion and disease incidence in German healthcare workers before and during the rollout of COVID-19 vaccines.

We assessed the seroepidemiology of SARS-CoV-2 infection and the incidence of coronavirus disease 2019 (COVID-19) before and during the rollout of COVID-19 vaccines, in a prospective observational cohort study on healthcare workers (HCWs) in a large tertiary hospital in Mainz, Germany. Antibody status was assessed during six visits between September 2020 and February 2022. Self-reported symptoms were collected using a smartphone application; symptomatic HCWs were tested using real-time polymerase chain reaction (RT-PCR) assays for SARS-CoV-2. Rates of virologically confirmed and severe COVID-19 were estimated using the U.S. Food and Drug Administration (FDA) and Coalition for Epidemic Preparedness Innovations (CEPI) case definitions, respectively, and were contrasted to background community transmission and circulating SARS-CoV-2 variants. A total of 3665 HCWs were enrolled (mean follow-up time: 18 months); 97 met the FDA definition of virologically confirmed COVID-19 (incidence rate (IR) 2.3/1000 person-months (PMs), one severe case). Most cases reported ≥2 symptoms, commonly, cough and anosmia or ageusia. Overall, 263 individuals seroconverted (IR 6.6/1000 PMs-2.9 times the estimated IR of COVID-19), indicating many cases were missed, either due to asymptomatic infections or to an atypical presentation of symptoms. A triphasic trend in anti-SARS-CoV-2 seroprevalence and seroconversion was observed, with an initial increase following the rollout of COVID-19 vaccines, a two-fold decline six months later, and finally a six-fold increase by the end of the study when Omicron was the dominant circulating variant. Despite the increase in infection rates at the end of the study due to the circulation of the Omicron variant, the infection and disease rates observed were lower than the published estimates in HCWs and rates in the general local population. Preferential vaccination of HCWs and the strict monitoring program for SARS-CoV-2 infection are the most likely reasons for the successful control of COVID-19 in this high-risk population.

A multi-country study of intussusception in children under 2 years of age in Latin America: analysis of prospective surveillance data.

BACKGROUND: Intussusception (IS) is a form of acute intestinal obstruction that occurs mainly in infants and is usually of unknown cause. An association between IS and the first licensed rotavirus vaccine, a reassortant-tetravalent, rhesus-based rotavirus vaccine (RRV-TV), led to the withdrawal of the vaccine. New rotavirus vaccines have now been developed and extensively studied for their potential association with IS. This study aimed to describe the epidemiology and to estimate the incidence of IS in Latin American infants prior to new vaccine introduction. METHODS: Children under 2 years of age representing potential IS cases were enrolled in 16 centers in 11 Latin American countries from January 2003 to May 2005. IS cases were classified as definite, probable, possible or suspected as stated on the Brighton Collaboration Working Group guidelines. RESULTS: From 517 potential cases identified, 476 (92%) cases were classified as definite, 21 probable, 10 possible and 10 suspected for intussusception. Among the 476 definite IS cases, the median age at presentation was 6.4 months with 89% of cases aged <1 year. The male to female ratio was 1.5:1. The incidence of definite IS per 100,000 subject-years ranged from 1.9 in Brazil to 62.4 in Argentina for children <2 years of age, and from 3.8 in Brazil to 105.3 in Argentina for children aged <1 year. Median hospital stay was 4 days with a high prevalence of surgery as the primary treatment (65%). Most cases (88%) made a complete recovery, but 13 (3%) died. No clear seasonal pattern of IS cases emerged. CONCLUSIONS: This study describes the epidemiology and estimates the incidence of IS in Latin American infants prior to the introduction of new rotavirus vaccines. The incidence of IS was found to vary between different countries, as observed in previous studies. TRIAL REGISTRATION: Clinical study identifier 999910/204 (SERO-EPI-IS-204).

Norovirus acute gastroenteritis among US and European travellers to areas of moderate to high risk of travellers' diarrhoea: a prospective cohort study.

BACKGROUND: Acute gastroenteritis (AGE) is a major medical condition for travellers worldwide, particularly travellers to low- and middle-income countries. Norovirus (NoV) is the most common cause of viral AGE in older children and adults, but data on prevalence and impact among travellers is limited. METHODS: Prospective, multi-site, observational cohort study conducted 2015-2017, among adult international travellers from the US and Europe to areas of moderate to high risk of travel-acquired AGE. Participants provided self-collected pre-travel stool samples and self-reported AGE symptoms while travelling. Post-travel stool samples were requested from symptomatic subjects and a sample of asymptomatic travellers within 14days of return. Samples were tested for NoV by RT-qPCR, genotyped if positive, and tested for other common enteric pathogens by Luminex xTAG GPP. RESULTS: Of the 1109 participants included, 437 (39.4%) developed AGE symptoms resulting in an overall AGE incidence of 24.7 per 100 person-weeks (95% CI: 22.4; 27.1). Twenty NoV-positive AGE cases (5.2% of those tested) were identified at an incidence of 1.1 per 100 person-weeks (95% CI: 0.7; 1.7). NoV-positive samples belonged mostly to genogroup GII (18, 85.7%); None of the 13 samples sequenced belonged to genotype GII.4. Clinical severity of AGE was higher for NoV-positive than for NoV-negative cases (mean modified Vesikari Score 6.8 vs 4.9) with more cases classified as severe or moderate (25% vs 6.8%). Eighty percent of NoV-positive participants (vs. 38.9% in NoV-negative) reported at least moderate impact on travel plans. CONCLUSIONS: AGE is a prevalent disease among travellers with a small proportion associated with NoV. Post-travel stool sample collection timing might have influenced the low number of NoV cases detected; however, NoV infections resulted in high clinical severity and impact on travel plans. These results may contribute to targeted vaccine development and the design of future studies on NoV epidemiology.

A prospective, multi-site, cohort study to estimate incidence of infection and disease due to Lassa fever virus in West African countries (the Enable Lassa research programme)-Study protocol.

BACKGROUND: Lassa fever (LF), a haemorrhagic illness caused by the Lassa fever virus (LASV), is endemic in West Africa and causes 5000 fatalities every year. The true prevalence and incidence rates of LF are unknown as infections are often asymptomatic, clinical presentations are varied, and surveillance systems are not robust. The aim of the Enable Lassa research programme is to estimate the incidences of LASV infection and LF disease in five West African countries. The core protocol described here harmonises key study components, such as eligibility criteria, case definitions, outcome measures, and laboratory tests, which will maximise the comparability of data for between-country analyses. METHOD: We are conducting a prospective cohort study in Benin, Guinea, Liberia, Nigeria (three sites), and Sierra Leone from 2020 to 2023, with 24 months of follow-up. Each site will assess the incidence of LASV infection, LF disease, or both. When both incidences are assessed the LASV cohort (nmin = 1000 per site) will be drawn from the LF cohort (nmin = 5000 per site). During recruitment participants will complete questionnaires on household composition, socioeconomic status, demographic characteristics, and LF history, and blood samples will be collected to determine IgG LASV serostatus. LF disease cohort participants will be contacted biweekly to identify acute febrile cases, from whom blood samples will be drawn to test for active LASV infection using RT-PCR. Symptom and treatment data will be abstracted from medical records of LF cases. LF survivors will be followed up after four months to assess sequelae, specifically sensorineural hearing loss. LASV infection cohort participants will be asked for a blood sample every six months to assess LASV serostatus (IgG and IgM). DISCUSSION: Data on LASV infection and LF disease incidence in West Africa from this research programme will determine the feasibility of future Phase IIb or III clinical trials for LF vaccine candidates.

Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study.

OBJECTIVE: The 2009-2010 A/H1N1 pandemic provided a unique setting to study the safety of MF59-adjuvanted vaccination in pregnancy. STUDY DESIGN: This was an observational cohort study of the safety of an MF59-adjuvanted A/H1N1 vaccine (Focetria) conducted among 4508 pregnant women (2295 vaccinated vs 2213 unvaccinated), with 3 month follow-up of neonates. RESULTS: No maternal deaths or abortions occurred among the vaccinated women. No differences between the vaccinated and unvaccinated cohorts were observed for gestational diabetes, preeclampsia, stillbirth, low birthweight, neonatal deaths, or congenital malformations. The risk of premature birth was significantly decreased among the vaccinated women (adjusted proportional hazard, 0.69; 95% confidence interval, 0.51-0.92). No differences were observed in rates of congenital malformations after vaccination in the first (2.1%), second (2.7%), or third (2.1%) trimesters. CONCLUSION: There was no evidence of a safety risk for MF59-adjuvanted A/H1N1 vaccination in pregnant women; protection was observed against premature birth.

Using time-to-onset for detecting safety signals in spontaneous reports of adverse events following immunization: a proof of concept study.

PURPOSE: Disproportionality analyses (DPA) are widely used in pharmacovigilance for detecting safety signals from spontaneous reports of adverse events. In these analyses, time-to-onset (TTO; the time between vaccination and the onset of the adverse event) is rarely considered. Our objective is to assess the potential use of TTO to improve signal detection (SD). METHODS: Adverse events were defined as signals for a vaccine if the TTO distribution was significantly different from the distribution of other events for the same vaccine and from the distribution obtained with the same event for other vaccines. Distributions were compared within a time window of 30 days by using the two-sample Kolmogorov-Smirnov statistic. With the use of the product label as a proxy of true positive safety signals, TTO SD was compared with a standard DPA method (based on stratified empirical Bayesian geometric mean) for an oral live pediatric vaccine (Rotarix™) and an inactivated adult vaccine (Fluarix™). RESULTS: With the use of the GlaxoSmithKline spontaneous reports database for Rotarix™, 10 Medical Dictionary for Regulatory Activities preferred terms were identified as signals, and among them, five were listed in the product label. The DPA method identified only three preferred terms from the label, that is, TTO SD showed higher sensitivity and specificity. For Fluarix™, TTO SD also showed higher sensitivity but lower specificity. CONCLUSION: This TTO SD method is complementary, conceptually and practically, to more traditional DPA and does not share the major drawback of DPA known as the masking effect. Higher sensitivity and/or specificity can be achieved using TTO SD.

Economic Evaluation of Universal Varicella Vaccination in Mexico.

BACKGROUND: Universal varicella vaccination has proven to be cost-effective (CE) in countries where implemented. However, this has not been evaluated for Mexico. METHODS: The yearly disease burden (varicella cases/deaths, outpatient visits, and hospitalizations) was derived from Mexican seroprevalence data adjusted to the 2020 population. The yearly economic burden was calculated by combining disease with Mexican unit cost data from both health care and societal perspectives. Four different vaccination strategies were evaluated: (1) 1 dose of varicella vaccine at 1 year old; (2) 2 doses at 1 and 6 years; (3) 1 dose of varicella vaccine at 1 year, and quadrivalent measles-mumps-rubella-varicella vaccine at 6 years; (4) 2 doses of measles-mumps-rubella-varicella vaccine at 1 and 6 years. We developed an economic model for each vaccination strategy where 20 consecutive birth cohorts were simulated. Vaccination impact (number of avoided cases/deaths) was evaluated for a 20-year follow-up period based on vaccine effectiveness (87% and 97.4% for 1 and 2 doses), and assuming a 95% coverage. We estimated annual costs saved, incremental cost-effectiveness ratio, and costs per life year gained. RESULTS: Avoided cases during the 20-year follow-up with 1, and 2 doses were 20,570,722 and 23,029,751, respectively. Strategies 1 and 2 were found to be cost saving, and strategy 3 to be CE. Strategy 4 was not CE. Strategies 1 and 2 would allow saving annually $53.16 and $34.41 million USD, respectively, to the Mexican society. CONCLUSIONS: Universal varicella vaccination, using 1 dose or 2 doses, would result in a cost-beneficial and CE public health intervention in Mexico.

Real-world impact and effectiveness assessment of the quadrivalent HPV vaccine: a systematic review of study designs and data sources.

INTRODUCTION: Vaccine effectiveness and impact studies are typically observational, generating evidence after vaccine launch in a real-world setting. For human papillomavirus (HPV) vaccination studies, the variety of data sources and methods used is pronounced. Careful selection of study design, data capture and analytical methods can mitigate potential bias in such studies. AREAS COVERED: We systematically reviewed the different study designs, methods, and data sources in published evidence (1/2007-3/2020), which assessed the quadrivalent HPV vaccine effectiveness and impact on cervical/cervicovaginal, anal, and oral HPV infections, anogenital warts, lesions in anus, cervix, oropharynx, penis, vagina or vulva, and recurrent respiratory papillomatosis. EXPERT OPINION: The rapid growth in access to real-world data allows global monitoring of effects of different public health interventions, including HPV vaccination programs. But the use of data which are not collected or organized to support research also underscore a need to develop robust methodology that provides insight of vaccine effects and consequences of different health policy decisions. To achieve the WHO elimination goal, we foresee a growing need to evaluate HPV vaccination programs globally. A critical appraisal summary of methodology used will provide timely guidance to researchers who want to initiate research activities in various settings.

Real-world impact and effectiveness of the quadrivalent HPV vaccine: an updated systematic literature review.

INTRODUCTION: Human papillomavirus (HPV) infection, which poses significant disease burden, is decreasing following implementation of vaccination programs. Synthesized evidence on HPV vaccine real-world benefit was published in 2016. However, long-term impact of vaccination, and how vaccination programs influence infection rates and disease outcomes, requires further examination. AREAS COVERED: We systematically reviewed observational studies on HPV vaccination within MEDLINE, EMBASE, and Google Scholar from 2016 to 2020, involving 14 years of follow-up data. We identified 138 peer-reviewed publications reporting HPV vaccine impact or effectiveness. Outcomes of interest included rates of infection at different anatomical sites and incidence of several HPV-related disease endpoints. EXPERT OPINION: The expansion of HPV vaccination programs worldwide has led to a reduction in genital infection and significant decreases in incidence of HPV-related disease outcomes. Therefore, the WHO has set goals for the elimination of cervical cancer as a public health concern. To track progress toward this requires an understanding of the effectiveness of different vaccination initiatives. However, the impact on males, and potential benefit of gender-neutral vaccination programs have not been fully explored. To present an accurate commentary on the current outlook of vaccination and to help shape policy therefore requires a systematic review of available data.

Effectiveness of the Fiocruz recombinant ChadOx1-nCoV19 against variants of SARS-CoV-2 in the Municipality of Botucatu-SP.

Introduction: As the COVID-19 pandemic progresses, rapidly emerging variants of concern raise fears that currently licensed vaccines may have reduced effectiveness against these new strains. In the municipality of Botucatu, São Paulo State, Brazil, a mass vaccination campaign using ChadOx1-nCoV19 was initiated on 16th of May 2021, targeting people 18-60 years old. Two vaccine doses were offered 12 weeks apart, with the second delivered on 8th of August, 2021. This setting offered a unique opportunity to assess the effectiveness of two ChadOx1-nCoV19 doses in a real-life setting. Materials and methods: Data on testing, hospitalization, symptoms, demographics, and vaccination were obtained from the Hospital das Clínicas da Faculdade de Medicina de Botucatu. A test-negative study design was employed; whereby the odds of being vaccinated among cases vs controls were calculated to estimate vaccine effectiveness (VE; 1-OR). All individuals aged 18-60 who received a PCR test after the 16th of May and were unvaccinated prior to this date were included in the analysis until the study ended in mid-November 2021. Results: 77,683 citizens of Botucatu aged 18-60 received the first dose, and 74,051 received a second ChadOx1-nCoV19 dose 12 weeks later for a vaccination coverage of 84.2 and 80.2%, respectively. Of 7.958 eligible PCR tests, 2.109 were positive and 5.849 negative. The VE against any symptomatic infection was estimated at 39.2%, 21 days after dose 1, and 74.5%, 14 days after dose 2. There were no COVID-19-related hospitalizations or deaths among the 74,051 fully vaccinated individuals. The VE against severe disease was estimated at 70.8 and 100% after doses 1 and 2, respectively. 90.5% of all lineages sequenced between doses 1 and 2 (16th of May-7th of August) were of the Gamma variant, while 83.0% were of the Delta variant during the second period after dose 2 (8th of August-18th of November). Discussion: This observational study found the effectiveness of ChadOx1-nCoV19 to be 74.5% against COVID-19 disease of any severity, comparable to the efficacy observed in clinical trials (81.3% after dose 2), despite the dominance of the Gamma and Delta VoCs. No COVID-19-related hospitalizations or deaths in fully vaccinated individuals were reported.

Efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate in ten countries in Europe and Latin America (HERALD): a randomised, observer-blinded, placebo-controlled, phase 2b/3 trial.

BACKGROUND: Additional safe and efficacious vaccines are needed to control the COVID-19 pandemic. We aimed to analyse the efficacy and safety of the CVnCoV SARS-CoV-2 mRNA vaccine candidate. METHODS: HERALD is a randomised, observer-blinded, placebo-controlled, phase 2b/3 clinical trial conducted in 47 centres in ten countries in Europe and Latin America. By use of an interactive web response system and stratification by country and age group (18-60 years and ≥61 years), adults with no history of virologically confirmed COVID-19 were randomly assigned (1:1) to receive intramuscularly either two 0·6 mL doses of CVnCoV containing 12 µg of mRNA or two 0·6 mL doses of 0·9% NaCl (placebo) on days 1 and 29. The primary efficacy endpoint was the occurrence of a first episode of virologically confirmed symptomatic COVID-19 of any severity and caused by any strain from 15 days after the second dose. For the primary endpoint, the trial was considered successful if the lower limit of the CI was greater than 30%. Key secondary endpoints were the occurrence of a first episode of virologically confirmed moderate-to-severe COVID-19, severe COVID-19, and COVID-19 of any severity by age group. Primary safety outcomes were solicited local and systemic adverse events within 7 days after each dose and unsolicited adverse events within 28 days after each dose in phase 2b participants, and serious adverse events and adverse events of special interest up to 1 year after the second dose in phase 2b and phase 3 participants. Here, we report data up to June 18, 2021. The study is registered at ClinicalTrials.gov, NCT04652102, and EudraCT, 2020-003998-22, and is ongoing. FINDINGS: Between Dec 11, 2020, and April 12, 2021, 39 680 participants were enrolled and randomly assigned to receive either CVnCoV (n=19 846) or placebo (n=19 834), of whom 19 783 received at least one dose of CVnCoV and 19 746 received at least one dose of placebo. After a mean observation period of 48·2 days (SE 0·2), 83 cases of COVID-19 occurred in the CVnCoV group (n=12 851) in 1735·29 person-years and 145 cases occurred in the placebo group (n=12 211) in 1569·87 person-years, resulting in an overall vaccine efficacy against symptomatic COVID-19 of 48·2% (95·826% CI 31·0-61·4; p=0·016). Vaccine efficacy against moderate-to-severe COVID-19 was 70·7% (95% CI 42·5-86·1; CVnCoV 12 cases in 1735·29 person-years, placebo 37 cases in 1569·87 person-years). In participants aged 18-60 years, vaccine efficacy against symptomatic disease was 52·5% (95% CI 36·2-64·8; CVnCoV 71 cases in 1591·47 person-years, placebo, 136 cases in 1449·23 person-years). Too few cases occurred in participants aged 61 years or older (CVnCoV 12, placebo nine) to allow meaningful assessment of vaccine efficacy. Solicited adverse events, which were mostly systemic, were more common in CVnCoV recipients (1933 [96·5%] of 2003) than in placebo recipients (1344 [67·9%] of 1978), with 542 (27·1%) CVnCoV recipients and 61 (3·1%) placebo recipients reporting grade 3 solicited adverse events. The most frequently reported local reaction after any dose in the CVnCoV group was injection-site pain (1678 [83·6%] of 2007), with 22 grade 3 reactions, and the most frequently reported systematic reactions were fatigue (1603 [80·0%] of 2003) and headache (1541 [76·9%] of 2003). 82 (0·4%) of 19 783 CVnCoV recipients reported 100 serious adverse events and 66 (0·3%) of 19 746 placebo recipients reported 76 serious adverse events. Eight serious adverse events in five CVnCoV recipients and two serious adverse events in two placebo recipients were considered vaccination-related. None of the fatal serious adverse events reported (eight in the CVnCoV group and six in the placebo group) were considered to be related to study vaccination. Adverse events of special interest were reported for 38 (0·2%) participants in the CVnCoV group and 31 (0·2%) participants in the placebo group. These events were considered to be related to the trial vaccine for 14 (<0·1%) participants in the CVnCoV group and for five (<0·1%) participants in the placebo group. INTERPRETATION: CVnCoV was efficacious in the prevention of COVID-19 of any severity and had an acceptable safety profile. Taking into account the changing environment, including the emergence of SARS-CoV-2 variants, and timelines for further development, the decision has been made to cease activities on the CVnCoV candidate and to focus efforts on the development of next-generation vaccine candidates. FUNDING: German Federal Ministry of Education and Research and CureVac.