Gonorrhoea is one of the most common bacterial sexually transmitted infections in England. Over 41,000 cases were recorded in 2015, more than half of which occurred in men who have sex with men ...(MSM). As the bacterium has developed resistance to each first-line antibiotic in turn, we need an improved understanding of fitness benefits and costs of antibiotic resistance to inform control policy and planning. Cefixime was recommended as a single-dose treatment for gonorrhoea from 2005 to 2010, during which time resistance increased, and subsequently declined.
We developed a stochastic compartmental model representing the natural history and transmission of cefixime-sensitive and cefixime-resistant strains of Neisseria gonorrhoeae in MSM in England, which was applied to data on diagnoses and prescriptions between 2008 and 2015. We estimated that asymptomatic carriers play a crucial role in overall transmission dynamics, with 37% (95% credible interval CrI 24%-52%) of infections remaining asymptomatic and untreated, accounting for 89% (95% CrI 82%-93%) of onward transmission. The fitness cost of cefixime resistance in the absence of cefixime usage was estimated to be such that the number of secondary infections caused by resistant strains is only about half as much as for the susceptible strains, which is insufficient to maintain persistence. However, we estimated that treatment of cefixime-resistant strains with cefixime was unsuccessful in 83% (95% CrI 53%-99%) of cases, representing a fitness benefit of resistance. This benefit was large enough to counterbalance the fitness cost when 31% (95% CrI 26%-36%) of cases were treated with cefixime, and when more than 55% (95% CrI 44%-66%) of cases were treated with cefixime, the resistant strain had a net fitness advantage over the susceptible strain. Limitations include sparse data leading to large intervals on key model parameters and necessary assumptions in the modelling of a complex epidemiological process.
Our study provides, to our knowledge, the first estimates of the fitness cost and benefit associated with resistance of the gonococcus to a clinically relevant antibiotic. Our findings have important implications for antibiotic stewardship and public health policies and, in particular, suggest that a previously abandoned antibiotic could be used again to treat a minority of gonorrhoea cases without raising resistance levels.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Plague, caused by the bacterium Yersinia pestis, is one of the deadliest infectious diseases in human history, and still causes worrying outbreaks in Africa and South America. Despite the historical ...and current importance of plague, several questions remain unanswered concerning its transmission routes and infection risk factors. The plague outbreak that started in September 1665 in the Derbyshire village of Eyam claimed 257 lives over 14 months, wiping out entire families. Since previous attempts at modelling the Eyam plague, new data have been unearthed from parish records revealing a much more complete record of the disease. Using a stochastic compartmental model and Bayesian analytical methods, we found that both rodent-to-human and human-to-human transmission played an important role in spreading the infection, and that they accounted, respectively, for a quarter and three-quarters of all infections, with a statistically significant seasonality effect. We also found that the force of infection was stronger for infectious individuals living in the same household compared with the rest of the village. Poverty significantly increased the risk of disease, whereas adulthood decreased the risk. These results on the Eyam outbreak contribute to the current debate on the relative importance of plague transmission routes.
Gonorrhoea is a rapidly growing public health threat, with rising incidence and increasing drug resistance. Evidence that the MeNZB and four-component serogroup B meningococcal (4CMenB) vaccines, ...designed against Neisseria meningitidis, can also offer protection against gonorrhoea has created interest in using 4CMenB for this purpose and for developing gonorrhoea-specific vaccines. However, cost-effectiveness, and how the efficacy and duration of protection affect a gonorrhoea vaccine's value, have not been assessed.
We developed an integrated transmission-dynamic health-economic model, calibrated using Bayesian methods to surveillance data (from the Genitourinary Medicine Clinic Activity Dataset and the Gonococcal Resistance to Antimicrobials Surveillance Programme) on men who have sex with men (MSM) in England. We considered vaccination of MSM from the perspective of sexual health clinics, with and without vaccination offered to all adolescents in schools (vaccination before entry VbE), comparing three realistic approaches to targeting: vaccination on attendance (VoA) for testing; vaccination on diagnosis (VoD) with gonorrhoea; or vaccination according to risk (VaR), offered to patients diagnosed with gonorrhoea plus individuals who test negative but report having more than five sexual partners per year. For the primary analysis, vaccine impact was assessed relative to no vaccination in a conservative baseline scenario wherein time-varying behavioural parameters (sexual risk behaviour and screening rates) stabilise. To calculate the value of vaccination per dose administered, the value of vaccination was calculated by summing the averted costs of testing and treatment, and the monetary value of quality-adjusted life-year (QALY) gains with a QALY valued at £20 000. Costs were in 2018–19 GB£, and both costs and QALYs were discounted at 3·5% per year. We analysed the effects of varying vaccine uptake (0·5, 1, or 2 times HPV vaccine uptake by MSM in sexual health clinics in England), vaccine efficacy (1–100%) and duration of protection (1–20 years), and the time-horizon considered (10 years and 20 years). In addition, we calculated incremental cost-effectiveness ratios for the use of 4CMenB using assumed vaccine prices.
VbE has little impact on gonorrhoea diagnoses, with only 1·7% of MSM vaccinated per year. VoA has the largest impact but requires more vaccine doses than any other strategy, whereas VoD has a moderate impact but requires many fewer doses than VoA. VaR has almost the same impact as VoA but with fewer doses administered than VoA. VaR is the most cost-effective strategy for vaccines of moderate efficacy or duration of protection (or both), although VoD is more cost-effective for very protective and long-lasting vaccines. Even under conservative assumptions (efficacy equivalent to that of MeNZB and protection lasting for 18 months after two-dose primary vaccination and 36 months after single-dose booster vaccination), 4CMenB administered under VaR would likely be cost-saving at its current National Health Service price, averting an estimated mean 110 200 cases (95% credible interval 36 500–223 600), gaining a mean 100·3 QALYs (31·0–215·8), and saving a mean £7·9 million (0·0–20·5) over 10 years. A hypothetical gonorrhoea vaccine's value is increased more by improving its efficacy than its duration of protection—eg, 30% protection lasting 2 years has a median value of £48 (22–85) per dose over 10 years; doubling efficacy increases the value to £102 (53–144) whereas doubling the duration of protection increases it to £72 (34–120).
We recommend that vaccination of MSM against gonorrhoea according to risk in sexual health clinics in England with the 4CMenB vaccine be considered. Development of gonorrhoea-specific vaccines should prioritise maximising efficacy over duration of protection.
Medical Research Council (UK), National Institute for Health Research (UK).
Human networks of sexual contacts are dynamic by nature, with partnerships forming and breaking continuously over time. Sexual behaviours are also highly heterogeneous, so that the number of partners ...reported by individuals over a given period of time is typically distributed as a power-law. Both the dynamism and heterogeneity of sexual partnerships are likely to have an effect in the patterns of spread of sexually transmitted diseases. To represent these two fundamental properties of sexual networks, we developed a stochastic process of dynamic partnership formation and dissolution, which results in power-law numbers of partners over time. Model parameters can be set to produce realistic conditions in terms of the exponent of the power-law distribution, of the number of individuals without relationships and of the average duration of relationships. Using an outbreak of antibiotic resistant gonorrhoea amongst men have sex with men as a case study, we show that our realistic dynamic network exhibits different properties compared to the frequently used static networks or homogeneous mixing models. We also consider an approximation to our dynamic network model in terms of a much simpler branching process. We estimate the parameters of the generation time distribution and offspring distribution which can be used for example in the context of outbreak reconstruction based on genomic data. Finally, we investigate the impact of a range of interventions against gonorrhoea, including increased condom use, more frequent screening and immunisation, concluding that the latter shows great promise to reduce the burden of gonorrhoea, even if the vaccine was only partially effective or applied to only a random subset of the population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Gonorrhea incidence is increasing rapidly in many countries, while antibiotic resistance is making treatment more difficult. Combined with evidence that two meningococcal vaccines ...are likely partially protective against gonorrhea, this has renewed interest in a gonococcal vaccine, and several candidates are in development. Key questions are how protective and long-lasting a vaccine needs to be, and how to target it. We assessed vaccination’s potential impact and the feasibility of achieving the World Health Organization’s (WHO) target of reducing gonorrhea incidence by 90% during 2018–2030, by comparing realistic vaccination strategies under a range of scenarios of vaccine efficacy and duration of protection, and emergence of extensively-resistant gonorrhea.
Methods
We developed a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behavior in men who have sex with men (MSM). We used data from England, which has a comprehensive, consistent nationwide surveillance system. Using particle Markov chain Monte Carlo methods, we fitted to gonorrhea incidence in 2008–2017, then used Bayesian forecasting to examine an extensive range of scenarios.
Results
Even in the worst-case scenario of untreatable infection emerging, the WHO target is achievable if all MSM attending sexual health clinics receive a vaccine offering ≥ 52% protection for ≥ 6 years. A vaccine conferring 31% protection (as estimated for MeNZB) for 2–4 years could reduce incidence in 2030 by 45% in the worst-case scenario, and by 75% if > 70% of resistant gonorrhea remains treatable.
Conclusions
Even a partially-protective vaccine, delivered through a realistic targeting strategy, could substantially reduce gonorrhea incidence, despite antibiotic resistance.
A gonorrhea vaccine offering partial protection for several years, pragmatically targeted to people testing for gonorrhea due to symptoms or screening due to sexual risk behavior, could substantially reduce gonorrhea incidence, combating increases in antibiotic resistance.
As the SARS-CoV-2 pandemic progressed, distinct variants emerged and dominated in England. These variants, Wildtype, Alpha, Delta, and Omicron were characterized by variations in transmissibility and ...severity. We used a robust mathematical model and Bayesian inference framework to analyse epidemiological surveillance data from England. We quantified the impact of non-pharmaceutical interventions (NPIs), therapeutics, and vaccination on virus transmission and severity. Each successive variant had a higher intrinsic transmissibility. Omicron (BA.1) had the highest basic reproduction number at 8.3 (95% credible interval (CrI) 7.7-8.8). Varying levels of NPIs were crucial in controlling virus transmission until population immunity accumulated. Immune escape properties of Omicron decreased effective levels of immunity in the population by a third. Furthermore, in contrast to previous studies, we found Alpha had the highest basic infection fatality ratio (2.9%, 95% CrI 2.7-3.2), followed by Delta (2.2%, 95% CrI 2.0-2.4), Wildtype (1.2%, 95% CrI 1.1-1.2), and Omicron (0.7%, 95% CrI 0.6-0.8). Our findings highlight the importance of continued surveillance. Long-term strategies for monitoring and maintaining effective immunity against SARS-CoV-2 are critical to inform the role of NPIs to effectively manage future variants with potentially higher intrinsic transmissibility and severe outcomes.
SARS-CoV-2 infections have been reported in all age groups including infants, children, and adolescents. However, the role of children in the COVID-19 pandemic is still uncertain. This systematic ...review of early studies synthesises evidence on the susceptibility of children to SARS-CoV-2 infection, the severity and clinical outcomes in children with SARS-CoV-2 infection, and the transmissibility of SARS-CoV-2 by children in the initial phases of the COVID-19 pandemic. A systematic literature review was conducted in PubMed. Reviewers extracted data from relevant, peer-reviewed studies published up to July 4th 2020 during the first wave of the SARS-CoV-2 outbreak using a standardised form and assessed quality using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. For studies included in the meta-analysis, we used a random effects model to calculate pooled estimates of the proportion of children considered asymptomatic or in a severe or critical state. We identified 2775 potential studies of which 128 studies met our inclusion criteria; data were extracted from 99, which were then quality assessed. Finally, 29 studies were considered for the meta-analysis that included information of symptoms and/or severity, these were further assessed based on patient recruitment. Our pooled estimate of the proportion of test positive children who were asymptomatic was 21.1% (95% CI: 14.0-28.1%), based on 13 included studies, and the proportion of children with severe or critical symptoms was 3.8% (95% CI: 1.5-6.0%), based on 14 included studies. We did not identify any studies designed to assess transmissibility in children and found that susceptibility to infection in children was highly variable across studies. Children's susceptibility to infection and onward transmissibility relative to adults is still unclear and varied widely between studies. However, it is evident that most children experience clinically mild disease or remain asymptomatically infected. More comprehensive contact-tracing studies combined with serosurveys are needed to quantify children's transmissibility relative to adults. With children back in schools, testing regimes and study protocols that will allow us to better understand the role of children in this pandemic are critical.
England's COVID-19 roadmap out of lockdown policy set out the timeline and conditions for the stepwise lifting of non-pharmaceutical interventions (NPIs) as vaccination roll-out continued, with step ...one starting on March 8, 2021. In this study, we assess the roadmap, the impact of the delta (B.1.617.2) variant of SARS-CoV-2, and potential future epidemic trajectories.
This mathematical modelling study was done to assess the UK Government's four-step process to easing lockdown restrictions in England, UK. We extended a previously described model of SARS-CoV-2 transmission to incorporate vaccination and multi-strain dynamics to explicitly capture the emergence of the delta variant. We calibrated the model to English surveillance data, including hospital admissions, hospital occupancy, seroprevalence data, and population-level PCR testing data using a Bayesian evidence synthesis framework, then modelled the potential trajectory of the epidemic for a range of different schedules for relaxing NPIs. We estimated the resulting number of daily infections and hospital admissions, and daily and cumulative deaths. Three scenarios spanning a range of optimistic to pessimistic vaccine effectiveness, waning natural immunity, and cross-protection from previous infections were investigated. We also considered three levels of mixing after the lifting of restrictions.
The roadmap policy was successful in offsetting the increased transmission resulting from lifting NPIs starting on March 8, 2021, with increasing population immunity through vaccination. However, because of the emergence of the delta variant, with an estimated transmission advantage of 76% (95% credible interval 95% CrI 69–83) over alpha, fully lifting NPIs on June 21, 2021, as originally planned might have led to 3900 (95% CrI 1500–5700) peak daily hospital admissions under our central parameter scenario. Delaying until July 19, 2021, reduced peak hospital admissions by three fold to 1400 (95% CrI 700–1700) per day. There was substantial uncertainty in the epidemic trajectory, with particular sensitivity to the transmissibility of delta, level of mixing, and estimates of vaccine effectiveness.
Our findings show that the risk of a large wave of COVID-19 hospital admissions resulting from lifting NPIs can be substantially mitigated if the timing of NPI relaxation is carefully balanced against vaccination coverage. However, with the delta variant, it might not be possible to fully lift NPIs without a third wave of hospital admissions and deaths, even if vaccination coverage is high. Variants of concern, their transmissibility, vaccine uptake, and vaccine effectiveness must be carefully monitored as countries relax pandemic control measures.
National Institute for Health Research, UK Medical Research Council, Wellcome Trust, and UK Foreign, Commonwealth and Development Office.
Abstract
Background
Vaccines are needed to reduce the burden of group A Streptococcus (GAS). We assessed the potential health-economic value of GAS vaccines achievable through prevention of invasive ...disease and acute upper respiratory infections in the United States.
Methods
We estimated annual incidence of invasive GAS disease and associated costs incurred from hospitalization and management of long-term sequelae, as well as productivity losses resulting from acute illness, long-term disability, and mortality. We also estimated healthcare and productivity costs associated with GAS pharyngitis, sinusitis, and acute otitis media. We estimated costs averted by prevention of invasive disease and acute upper respiratory infections for vaccines with differing efficacy profiles; our base case considered vaccines meeting the World Health Organization Preferred Product Profile (WHO-PPP) with a 6-year average duration of protection.
Results
Costs of invasive GAS disease and acute upper respiratory infections totaled $6.08 (95% confidence interval CI, $5.33–$6.86) billion annually. Direct effects of vaccines meeting WHO-PPP characteristics and administered at ages 12 and 18 months would avert $609 (95% CI, $558–$663) million in costs annually, primarily by preventing noninvasive disease; with an additional dose at age 5 years, averted costs would total $869 (95% CI, $798–$945) million annually. Adult vaccination at age 65 years would avert $326 (95% CI, $271–$387) million in annual costs associated with invasive GAS disease. Indirect effects of vaccination programs reducing incidence of GAS diseases across all ages by 20% would avert roughly $1 billion in costs each year.
Conclusions
The economic burden of GAS is substantial. Our findings should inform prioritization of GAS vaccine development and evaluation.
Group A Streptococcus causes roughly $5.3–$6.9 billion in healthcare and productivity costs annually in the United States due to acute upper respiratory infections and invasive disease. Prevention of pharyngitis is central to the economic value of pediatric vaccination.
To make the best use of limited public health resources, we need to determine the appropriate groups to be offered gonorrhoea vaccination—eg, men who have sex with men (MSM), female sex workers, and ...heterosexual adolescents and young adults7—noting that, within any broad group selected for vaccination, it is likely to be necessary to devise approaches to focus on individuals at highest risk of infection and onward transmission.3,8 Decisions regarding which groups to vaccinate need to consider gonorrhoea's natural history (which is currently poorly characterised3,8,9) and transmission patterns, the prevalence of antimicrobial resistance (which is usually higher in MSM4), the frequency and severity of sequelae in women and men,8 and the potential effects of vaccination. Women tend to have the most severe sequelae with N gonorrhoeae infection (pelvic inflammatory disease, tubular factor infertility, and ectopic pregnancy), so the health benefits and reduced treatment costs from vaccination of heterosexuals are likely to accrue mostly in women.7 For the heterosexual population, there are two main options: women-only vaccination or gender-neutral vaccination. ...the proportions of incident infections that are symptomatic are important natural history parameters, which are poorly defined;3,8,9 these estimates can be provided by cohort studies that have regular testing for asymptomatic infection (including the placebo groups of vaccine trials),3 and we encourage reporting by sex and anatomical site.
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