Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria ...develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only 'adaptive' but also 'innate' lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO(+) CD62L(-) effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ(+)IL-2(+)) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field.
Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infections and hospitalisations among young children and is globally responsible for many deaths in young ...children, especially in infants aged <6 months. Furthermore, RSV is a common cause of severe respiratory disease and hospitalisation among older adults. The development of new candidate vaccines and monoclonal antibodies highlights the need for reliable surveillance of RSV. In the European Union (EU), no up-to-date general recommendations on RSV surveillance are currently available. Based on outcomes of a workshop with 29 European experts in the field of RSV virology, epidemiology and public health, we provide recommendations for developing a feasible and sustainable national surveillance strategy for RSV that will enable harmonisation and data comparison at the European level. We discuss three surveillance components: active sentinel community surveillance, active sentinel hospital surveillance and passive laboratory surveillance, using the EU acute respiratory infection and World Health Organization (WHO) extended severe acute respiratory infection case definitions. Furthermore, we recommend the use of quantitative reverse transcriptase PCR-based assays as the standard detection method for RSV and virus genetic characterisation, if possible, to monitor genetic evolution. These guidelines provide a basis for good quality, feasible and affordable surveillance of RSV. Harmonisation of surveillance standards at the European and global level will contribute to the wider availability of national level RSV surveillance data for regional and global analysis, and for estimation of RSV burden and the impact of future immunisation programmes.
Abstract
Background
Respiratory syncytial virus (RSV) is a leading cause of respiratory tract infection (RTI) in young children. Registries provide opportunities to explore RSV epidemiology and ...burden.
Methods
We explored routinely collected hospital data on RSV in children aged < 5 years in 7 European countries. We compare RSV-associated admission rates, age, seasonality, and time trends between countries.
Results
We found similar age distributions of RSV-associated hospital admissions in each country, with the highest burden in children < 1 years old and peak at age 1 month. Average annual rates of RTI admission were 41.3–112.0 per 1000 children aged < 1 year and 8.6–22.3 per 1000 children aged < 1 year. In children aged < 5 years, 57%–72% of RTI admissions with specified causal pathogen were coded as RSV, with 62%–87% of pathogen-coded admissions in children < 1 year coded as RSV.
Conclusions
Our results demonstrate the benefits and limitations of using linked routinely collected data to explore epidemiology and burden of RSV. Our future work will use these data to generate estimates of RSV burden using time-series modelling methodology, to inform policymaking and regulatory decisions regarding RSV immunization strategy and monitor the impact of future vaccines.
Volunteers immunized under chloroquine chemoprophylaxis with Plasmodium falciparum sporozoites (CPS) develop complete, long-lasting protection against homologous sporozoite challenge. Chloroquine ...affects neither sporozoites nor liver-stages, but kills only asexual forms in erythrocytes once released from the liver into the circulation. Consequently, CPS immunization exposes the host to antigens from both preerythrocytic and blood stages, and induced immunity might target either of these stages. We therefore explored the life cycle stage specificity of CPS-induced protection. Twenty-five malaria-naïve volunteers were enrolled in a clinical trial, 15 of whom received CPS immunization. Five immunized subjects and five controls received a sporozoite challenge by mosquito bites, whereas nine immunized and five control subjects received an i.v. challenge with P. falciparum- infected erythrocytes. The latter approach completely bypasses preerythrocytic stages, enabling a direct comparison of protection against either life cycle stage. CPS-immunized subjects (13 of 14) developed anticircumsporozoite antibodies, whereas only one volunteer generated minimal titers against typical blood-stage antigens. IgG from CPS-immunized volunteers did not inhibit asexual blood-stage growth in vitro. All CPS-immunized subjects (5 of 5) were protected against sporozoite challenge. In contrast, nine of nine CPS-immunized subjects developed parasitemia after blood-stage challenge, with identical prepatent periods and blood-stage multiplication rates compared with controls. Intravenously challenged CPS-immunized subjects showed earlier fever and increased plasma concentrations of inflammatory markers D-dimer, IFN-γ, and monokine induced by IFN-γ than i.v. challenged controls. The complete lack of protection against blood-stage challenge indicates that CPS-induced protection is mediated by immunity against preerythrocytic stages. However, evidence is presented for immune recognition of P. falciparum -infected erythrocytes, suggesting memory responses unable to generate functional immunity.
Decline of RSV-specific antibodies during the COVID-19 pandemic den Hartog, Gerco; van Kasteren, Puck B; Schepp, Rutger M ...
Lancet. Infectious diseases/The Lancet. Infectious diseases,
January 2023, 2023-01-00, 20230101, Volume:
23, Issue:
1
Journal Article
Peer reviewed
Open access
Lifting these measures resulted in out-of-season RSV activity, sometimes exceeding the incidence of hospitalisations observed in regular seasons.1–3 Declining immunity due to reduced exposure to the ...virus may contribute to this altered epidemiology.1,4,5 Bardsley and colleagues1 showed that the combination of laboratory, clinical, and syndromic data capture the impact of RSV activity, yet did not provide insight into the proposed decline in immunity. The repeated-measures general linear model (SPSS version 28; IBM, Armonk, NY, USA) was used to compare antibody concentrations between sampling timepoints of the same subjects and between age groups. p values, adjusted to Bonferroni and Benjamini-Hochberg procedures, are reported for timepoints and age-group differences respectively. ...monitoring changes in antibody concentrations could identify populations susceptible to RSV infection.
Abstract
Background
Respiratory syncytial virus (RSV) is a leading cause of respiratory tract illness in young children and a major cause of hospital admissions globally.
Methods
Here we fit ...age-structured transmission models with immunity propagation to data from the Netherlands (2012–2017). Data included nationwide hospitalizations with confirmed RSV, general practitioner (GP) data on attendance for care from acute respiratory infection, and virological testing of acute respiratory infections at the GP. The transmission models, equipped with key parameter estimates, were used to predict the impact of maternal and pediatric vaccination.
Results
Estimates of the basic reproduction number were generally high (R0 > 10 in scenarios with high statistical support), while susceptibility was estimated to be low in nonelderly adults (<10% in persons 20–64 years) and was higher in older adults (≥65 years). Scenario analyses predicted that maternal vaccination reduces the incidence of infection in vulnerable infants (<1 year) and shifts the age of first infection from infants to young children.
Conclusions
Pediatric vaccination is expected to reduce the incidence of infection in infants and young children (0–5 years), slightly increase incidence in 5 to 9-year-old children, and have minor indirect benefits.
Since the 2009 influenza pandemic, the Netherlands has used a weekly death monitoring system to estimate deaths in excess of expectations. We present estimates of excess deaths during the ongoing ...coronavirus disease (COVID-19) epidemic and 10 previous influenza epidemics. Excess deaths per influenza epidemic averaged 4,000. The estimated 9,554 excess deaths (41% in excess) during the COVID-19 epidemic weeks 12-19 of 2020 appeared comparable to the 9,373 excess deaths (18%) during the severe influenza epidemic of 2017-18. However, these deaths occurred in a shorter time, had a higher peak, and were mitigated by nonpharmaceutical control measures. Excess deaths were 1.8-fold higher than reported laboratory-confirmed COVID-19 deaths (5,449). Based on excess deaths and preliminary results from seroepidemiologic studies, we estimated the infection-fatality rate to be 1%. Monitoring of excess deaths is crucial for timely estimates of disease burden for influenza and COVID-19. Our data complement laboratory-confirmed COVID-19 death reports and enable comparisons between epidemics.
Abstract
Background
No overall estimate of respiratory syncytial virus (RSV)-associated hospitalizations in children aged under 5 years has been published for the European Union (EU). We aimed to ...estimate the RSV hospitalization burden in children aged under 5 years in EU countries and Norway, by age group.
Methods
We collated national RSV-associated hospitalization estimates calculated using linear regression models via the RESCEU project for Denmark, England, Finland, Norway, the Netherlands, and Scotland, 2006–2018. Additional estimates were obtained from a systematic review. Using multiple imputation and nearest neighbor matching methods, we estimated overall RSV-associated hospitalizations and rates in the EU.
Results
Additional estimates for 2 countries (France and Spain) were found in the literature. In the EU, an average of 245 244 (95% confidence interval CI, 224 688–265 799) yearly hospital admissions with a respiratory infection per year were associated with RSV in children aged under 5 years, with most cases occurring among children aged under 1 year (75%). Infants aged under 2 months represented the most affected group (71.6 per 1000 children; 95% CI, 66.6–76.6).
Conclusions
Our findings will help support decisions regarding prevention efforts and represent an important benchmark to understand changes in the RSV burden following the introduction of RSV immunization programs in Europe.
The study estimated that an average of 245 244 children aged under 5 years are hospitalized annually due to RSV in the EU, with the highest hospitalization rates in children aged less than 2 months (71.6 per 1000 children).
Controlled human malaria infection with sporozoites is a standardized and powerful tool for evaluation of malaria vaccine and drug efficacy but so far only applied by exposure to bites of Plasmodium ...falciparum (Pf)-infected mosquitoes. We assessed in an open label Phase 1 trial, infection after intradermal injection of respectively 2,500, 10,000, or 25,000 aseptic, purified, vialed, cryopreserved Pf sporozoites (PfSPZ) in three groups (N = 6/group) of healthy Dutch volunteers. Infection was safe and parasitemia developed in 15 of 18 volunteers (84%), 5 of 6 volunteers in each group. There were no differences between groups in time until parasitemia by microscopy or quantitative polymerase chain reaction, parasite kinetics, clinical symptoms, or laboratory values. This is the first successful infection by needle and syringe with PfSPZ manufactured in compliance with regulatory standards. After further optimization, the use of such PfSPZ may facilitate and accelerate clinical development of novel malaria drugs and vaccines.
Introduction
Since the first reports of COVID-19 cases, sex-discrepancies have been reported in COVID-19 mortality. We provide a detailed description of these sex differences in relation to age and ...comorbidities among notified cases as well as in relation to age and sex-specific mortality in the general Dutch population.
Methods
Data on COVID-19 cases and mortality until May 31st 2020 was extracted from the national surveillance database with exclusion of healthcare workers. Association between sex and case fatality was analyzed with multivariable logistic regression. Subsequently, male–female ratio in standardized mortality ratios and population mortality rates relative to all-cause and infectious disease-specific mortality were computed stratified by age.
Results
Male–female odds ratio for case fatality was 1.33 95% CI 1.26–1.41 and among hospitalized cases 1.27 95% CI 1.16–1.40. This remained significant after adjustment for age and comorbidities. The male–female ratio of the standardized mortality ratio was 1.70 95%CI 1.62–1.78. The
population
mortality rate for COVID-19 was 35.1 per 100.000, with a male–female rate ratio of 1.25 (95% CI 1.18–1.31) which was higher than in all-cause population mortality and infectious disease mortality.
Conclusion
Our study confirms male sex is a predisposing factor for severe outcomes of COVID-19, independent of age and comorbidities. In addition to general male–female-differences, COVID-19 specific mechanisms likely contribute to this mortality discrepancy.
PDF
