New respiratory syncytial virus immunization products in low- and middle-income countries: potential for cost-effective impact on a high burden of disease in young infants.

As new, efficacious respiratory syncytial virus (RSV) immunization products reach the market, affordable pricing as well as improved estimation of disease burden and the full potential and cost effectiveness of RSV prevention in the hardest hit geographies in low- and middle-income countries are critical to inform country adoption and enable maximum impact against infant disease and mortality globally. The data reported in the special issue underscore the enormous burden, and associated cost, of RSV disease in young infants in several LMICs, including Kenya and South Africa, as well as the potential for RSV maternal vaccines or long-acting monoclonal antibodies, to be cost-effective and possibly even cost-saving.

Maternal interventions vigilance harmonization in low- and middle-income countries: Stakeholder meeting report; Amsterdam, May 1-2, 2018.

Although major reductions in maternal and child mortality were achieved in the Millennium Development Goals era, progress must be accelerated to meet Sustainable Development Goals health targets by 2030. An estimated 2.7 million neonatal deaths and 2.6 million stillbirths still occur annually. Over the past several years there has been renewed global interest in innovative approaches to maternal immunization to potentially decrease mortality and severe morbidity in neonates, and in the pregnant woman and her fetus. Several new vaccines are in clinical development for indications in pregnant women, e.g., vaccines against respiratory syncytial virus, and group B streptococcus. Achieving near-concurrent introduction of new maternal vaccines in high-, middle-, and low-income countries requires that mechanisms are in place for appropriate safety monitoring worldwide. The Bill & Melinda Gates Foundation convened a global expert meeting in Amsterdam on May 1-2, 2018, to discuss a framework for appropriate pharmacovigilance for vaccines used during pregnancy based on integrated maternal interventions vigilance (MIV) systems and collection of appropriate data to inform timely decision-making by and for pregnant women. Planning for MIV requires a multi-disciplinary, collaborative approach that fully leverages and builds upon existing resources, and builds new capabilities and capacity where needed. Meeting participants identified priority actions including (1) establishing background rates to better evaluate emerging safety signals and vaccine effectiveness, (2) identifying potential sentinel vaccine surveillance sites, (3) developing data sharing capabilities, (4) creating guidance documents and protocols, and (5) the advanced preparation of culturally-appropriate communication plans and risk management plans. Integrating MIV across the routine obstetric and neonatal health care delivery continuum and all relevant programs and data systems could result in fundamental improvements in maternal, neonatal and child health. Improved pregnancy pharmacovigilance platforms may strengthen other vaccine and drug product safety systems and improve maternal and child research capabilities in LMICs.

Assessing the Evidence for Maternal Pertussis Immunization: A Report From the Bill & Melinda Gates Foundation Symposium on Pertussis Infant Disease Burden in Low- and Lower-Middle-Income Countries.

Implementation of effective interventions has halved maternal and child mortality over the past 2 decades, but less progress has been made in reducing neonatal mortality. Almost 45% of under-5 global mortality now occurs in infants <1 month of age, with approximately 86% of neonatal deaths occurring in low- and lower-middle-income countries (LMICs). As an estimated 23% of neonatal deaths globally are due to infectious causes, maternal immunization (MI) is one intervention that may reduce mortality in the first few months of life, when direct protection often relies on passively transmitted maternal antibodies. Despite all countries including pertussis-containing vaccines in their routine childhood immunization schedules, supported through the Expanded Programme on Immunization, pertussis continues to circulate globally. Although based on limited robust epidemiologic data, current estimates derived from modeling implicate pertussis in 1% of under-5 mortality, with infants too young to be vaccinated at highest risk of death. Pertussis MI programs have proven effective in reducing infant pertussis mortality in high-income countries using tetanus-diphtheria-acellular pertussis (Tdap) vaccines in their maternal and infant programs; however, these vaccines are cost-prohibitive for routine use in LMICs. The reach of antenatal care programs to deliver maternal pertussis vaccines, particularly with respect to infants at greatest risk of pertussis, needs to be further evaluated. Recognizing that decisions on the potential impact of pertussis MI in LMICs need, as a first step, robust contemporary mortality data for early infant pertussis, a symposium of global key experts was held. The symposium reviewed current evidence and identified knowledge gaps with respect to the infant pertussis disease burden in LMICs, and discussed proposed strategies to assess the potential impact of pertussis MI.

Surveillance of the impact of pneumococcal conjugate vaccines in developing countries.

Infection due to Streptococcus pneumoniae is a leading cause of morbidity and mortality in young children, especially in developing countries. With the support of Gavi, the Vaccine Alliance, the majority of these countries have introduced pneumococcal conjugate vaccines (PCV) into their national immunization programs and early data demonstrate a high degree of effectiveness, translating to enormous public health benefit through both direct and indirect (herd) effects. Future vaccination strategy may be focused on maintaining herd effects rather than individual protection. Evaluation of vaccine-type carriage, particularly in pneumonia cases, may be an easy, feasible way of measuring continued vaccine impact.

Defining the estimated core genome of bacterial populations using a Bayesian decision model.

The bacterial core genome is of intense interest and the volume of whole genome sequence data in the public domain available to investigate it has increased dramatically. The aim of our study was to develop a model to estimate the bacterial core genome from next-generation whole genome sequencing data and use this model to identify novel genes associated with important biological functions. Five bacterial datasets were analysed, comprising 2096 genomes in total. We developed a Bayesian decision model to estimate the number of core genes, calculated pairwise evolutionary distances (p-distances) based on nucleotide sequence diversity, and plotted the median p-distance for each core gene relative to its genome location. We designed visually-informative genome diagrams to depict areas of interest in genomes. Case studies demonstrated how the model could identify areas for further study, e.g. 25% of the core genes with higher sequence diversity in the Campylobacter jejuni and Neisseria meningitidis genomes encoded hypothetical proteins. The core gene with the highest p-distance value in C. jejuni was annotated in the reference genome as a putative hydrolase, but further work revealed that it shared sequence homology with beta-lactamase/metallo-beta-lactamases (enzymes that provide resistance to a range of broad-spectrum antibiotics) and thioredoxin reductase genes (which reduce oxidative stress and are essential for DNA replication) in other C. jejuni genomes. Our Bayesian model of estimating the core genome is principled, easy to use and can be applied to large genome datasets. This study also highlighted the lack of knowledge currently available for many core genes in bacterial genomes of significant global public health importance.

Use of near-real-time medical claims data to generate timely vaccine coverage estimates in the US: the dynamics of PCV13 vaccine uptake.

BACKGROUND: Vaccine coverage estimates lag by years in the US. Commercially available medical claims databases contain timely records of childhood vaccinations given in physician offices. We used such data to track the replacement of the 7-valent pneumococcal conjugate vaccine (PCV7) by PCV13, a new vaccine active against 6 additional serotypes, starting in March 2010. METHODS: We developed an age cohort model to compute vaccination coverage over time. We used age-stratified, national projections of monthly PCV7 and PCV13 doses administered to children <5 years based on physicians' office claims, January 2008-May 2012. We assumed doses were given on schedule, and tracked cumulative numbers of doses given to aging monthly cohorts to estimate the percentage of children fully PCV13-immunized. To account for children uninsured or in the Vaccines for Children program, estimates were projected using National Immunization Survey coverage data. RESULTS: PCV7 was phased out by June 2010. By March 2012, 82% of children 6-23 months were fully immunized with PCV13 and 42% of toddlers aged 15-59 months had received a catch-up PCV13 dose. For children aged 6-59 months, protective PCV13 coverage levels reached 33% and 56% by March 2011 and 2012, respectively, and were projected to reach 88% by March 2014. Our estimates for children aged 0-59 and 24-59 months are consistent with CDC's Immunization Information System sentinel sites data for 2011-2012. CONCLUSIONS: By using a simple analytic approach to compute vaccine coverage in aging cohorts from claims data, we show that PCV13 coverage rose rapidly as the PCV7 program was replaced. These estimates, validated against a CDC sentinel surveillance system in 8 states, should enable early documentation of the PCV13 impact on pneumococcal disease in the US. Moreover, they demonstrate the feasibility of tracking uptake patterns in near real-time even with simple summary counts of medical claims data.

Economic burden of acute lower respiratory tract infection in South African children.

BACKGROUND: Acute lower respiratory tract infections (ALRTI) are a leading cause of childhood mortality, but there are few data on disease costs in developing countries. OBJECTIVES: This study's purpose was to analyse ALRTI's costs-of-illness and economic burden in urban South African children. METHODS: ALRTI costs-of-illness (expressed in US$ 2010) at a tertiary hospital were measured using a micro-costing approach nested within a clinical trial. Demographic, epidemiological and data on use of health resources were integrated with costs-of-illness to estimate the economic burden of ALRTI in urban South African children aged <5 years. RESULTS: 745 children experiencing 858 ALRTI episodes were studied. 338 (39.4%), 513 (59.8%) and 7 (0.8%) episodes were managed in short-stay, paediatric ward and intensive care settings, respectively. Mean lengths of stay in short-stay, paediatric ward and intensive care (ICU) were 1.4, 8.1 and 14.4 days, respectively. The societal costs-of-illness per ALRTI episode managed in short-stay and paediatric ward settings, respectively, were US$266 (95% CI 245-286) and 1287 (95% CI 1174-1401) in HIV-infected patients, and US$257 (95% CI 247-267) and 1032 (95% CI 931-1133) in HIV-uninfected patients. Family costs were not collected in ICUs. ICU direct medical costs were US$5968 (95% CI 4025-8056) in HIV-uninfected patients and US$7849 in one HIV-infected patient. Under-5 children experienced an estimated 424,220 episodes annually of ALRTI. ALRTI treatment cost the public health system an estimated US$28,975,000 while an additional US$539,000 of costs were borne by families. CONCLUSION: ALRTIs in children <5 years impose a heavy economic burden on families and the South African public health-care system.

Persistent high burden of invasive pneumococcal disease in South African HIV-infected adults in the era of an antiretroviral treatment program.

BACKGROUND: Highly active antiretroviral treatment (HAART) programs have been associated with declines in the burden of invasive pneumococcal disease (IPD) in industrialized countries. The aim of this study was to evaluate trends in IPD hospitalizations in HIV-infected adults in Soweto, South Africa, associated with up-scaling of the HAART program from 2003 to 2008. METHODS: Laboratory-confirmed IPD cases were identified from 2003 through 2008 through an existing surveillance program. The period 2003-04 was designated as the early-HAART era, 2005-06 as the intermediate-HAART era and 2007-08 as the established-HAART era. The incidence of IPD was compared between the early-HAART and established-HAART eras in HIV-infected and-uninfected individuals. RESULTS: A total of 2,567 IPD cases among individuals older than 18 years were reported from 2003 through 2008. Overall incidence of IPD (per 100,000) did not change during the study period in HIV-infected adults (207.4 cases in the early-HAART and 214.0 cases in the established-HAART era; p = 0.55). IPD incidence, actually increased 1.16-fold (95% CI: 1.01; 1.62) in HIV-infected females between the early-and established-HAART eras (212.1 cases and 246.2 cases, respectively; p = 0.03). The incidence of IPD remained unchanged in HIV-uninfected adults across the three time periods. CONCLUSION: Despite a stable prevalence of HIV and the increased roll-out of HAART for treatment of AIDS patients in our setting, the burden of IPD has not decreased among HIV-infected adults. The study indicates a need for ongoing monitoring of disease and HAART program effectiveness to reduce opportunistic infections in African adults with HIV/AIDS, as well as the need to consider alternate strategies including pneumococcal conjugate vaccine immunization for the prevention of IPD in HIV-infected adults.

A framework for global surveillance of antibiotic resistance.

The foreseen decline in antibiotic effectiveness explains the needs for data to inform the global public health agenda about the magnitude and evolution of antibiotic resistance as a serious threat to human health and development. Opportunistic bacterial pathogens are the cause of the majority of community and hospital-acquired infections worldwide. We provide an inventory of pre-existing regional surveillance programs in the six WHO regions which should form the underpinning for the consolidation of a global network infrastructure and we outline the structural components such as an international network of reference laboratories that need to be put in place to address the void of these crucial data. In addition we suggest to make use of existing Health and Demographic Surveillance Sites (HDSS) to obtain crucial information from communities in resource limited settings at household level in low- and middle-income countries in Asia and Africa. For optimising the use of surveillance data for public health action i.e. priority setting for new drug development, comparative quantification of antibiotic effectiveness at local, national, regional and global level and identification of the action gaps can be helpful.

The case for launch of an international DNA-based birth cohort study.

The global health agenda beyond 2015 will inevitably need to broaden its focus from mortality reduction to the social determinants of deaths, growing inequities among children and mothers, and ensuring the sustainability of the progress made against the infectious diseases. New research tools, including technologies that enable high-throughput genetic and '-omics' research, could be deployed for better understanding of the aetiology of maternal and child health problems. The research needed to address those challenges will require conceptually different studies than those used in the past. It should be guided by stringent ethical frameworks related to the emerging collections of biological specimens and other health related information. We will aim to establish an international birth cohort which should assist low- and middle-income countries to use emerging genomic research technologies to address the main problems in maternal and child health, which are still major contributors to the burden of disease globally.

Public health and economic impact of the 13-valent pneumococcal conjugate vaccine (PCV13) in the United States.

The 7-valent pneumococcal conjugate vaccine (PCV7) has dramatically decreased pneumococcal disease incidence, and the 13-valent vaccine (PCV13) protects against 6 additional Streptococcus pneumoniae serotypes. A decision-analytic model was constructed to evaluate the impact of infant vaccination with PCV13 versus PCV7 on pneumococcal disease incidence and mortality as well as the incremental benefit of a serotype catch-up program. PCV13 effectiveness was extrapolated from observed PCV7 data, using assumptions regarding serotype prevalence and PCV13 protection against additional serotypes. The model predicts that PCV13 is more effective and cost saving compared with PCV7, preventing 106,000 invasive pneumococcal disease (IPD) cases and 2.9 million pneumonia cases, and saving $11.6 billion over a 10-year period. The serotype catch-up program would prevent an additional 12,600 IPD cases and 404,000 pneumonia cases, and save an additional $737 million compared with no catch-up program.

Public health and economic impact of vaccination with 7-valent pneumococcal vaccine (PCV7) in the context of the annual influenza epidemic and a severe influenza pandemic.

BACKGROUND: Influenza pandemic outbreaks occurred in the US in 1918, 1957, and 1968. Historical evidence suggests that the majority of influenza-related deaths during the 1918 US pandemic were attributable to bacterial pneumococcal infections. The 2009 novel influenza A (H1N1) outbreak highlights the importance of interventions that may mitigate the impact of a pandemic. METHODS: A decision-analytic model was constructed to evaluate the impact of 7-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal disease incidence and mortality during a typical influenza season (13/100) and a severe influenza pandemic (30/100). Outcomes were compared for current PCV7 vaccination practices vs. no vaccination. The model was estimated using published sources and includes indirect (herd) protection of non-vaccinated persons. RESULTS: The model predicts that PCV7 vaccination in the US is cost saving for a normal influenza season, reducing pneumococcal-related costs by $1.6 billion. In a severe influenza pandemic, vaccination would save $7.3 billion in costs and prevent 512,000 cases of IPD, 719,000 cases of pneumonia, 62,000 IPD deaths, and 47,000 pneumonia deaths; 84% of deaths are prevented due to indirect (herd) protection in the unvaccinated. CONCLUSIONS: PCV7 vaccination is highly effective and cost saving in both normal and severe pandemic influenza seasons. Current infant vaccination practices may prevent >1 million pneumococcal-related deaths in a severe influenza pandemic, primarily due to herd protection.

Cost-effectiveness of pneumococcal conjugate vaccine: an update after 7 years of use in the United States.

Seven-valent pneumococcal conjugate vaccine (PCV7) has been in routine use in the United States since 2000 and data have indicated direct and indirect effects of the vaccine. We simulated the effects of PCV7 on children vaccinated during 2000-2006, incorporating direct and indirect effects on incidence of invasive pneumococcal disease (IPD), hospitalized pneumonia and otitis media. Before accounting for indirect effects, PCV7 cost $201,000 per life-year saved. After incorporating indirect effects on IPD, cost per life-year saved was $10,400. The presence of modest additional indirect effects against hospitalized pneumonia and otitis media in children may have resulted in overall cost savings.

HIV and pneumococcal disease.

PURPOSE OF REVIEW: To describe the impact of highly active antiretroviral therapy on the burden of pneumococcal disease and advances in our understanding of the impact of HIV on this disease. RECENT FINDINGS: Although highly active antiretroviral therapy has reduced the burden of pneumococcal disease among HIV-infected adults, these infections remain far more common than in HIV uninfected adults. HIV-infected adults who smoke or have comorbidities are at particular risk. In the absence of highly active antiretroviral therapy, pneumococcal meningitis has emerged in Africa as a major disease burden with a high mortality among HIV-infected children and adults. Conjugate pneumococcal vaccine protects HIV-infected infants from pneumococcal pneumonia. In the United States, where conjugate vaccine is given to children, herd immunity has reduced the burden of invasive pneumococcal disease among HIV-infected adults. SUMMARY: The pneumococcus remains a significant cause of morbidity and mortality among HIV-infected children and adults, both in developed and in developing countries.

World Health Organisation definition of "radiologically-confirmed pneumonia" may under-estimate the true public health value of conjugate pneumococcal vaccines.

The public health benefit of conjugate pneumococcal vaccine (PCV) in preventing pneumonia would only be appreciated if the tool used for measuring "pneumococcal pneumonia" had good sensitivity. Exploratory studies in South Africa indicate that the sensitivity of "radiologically-confirmed pneumonia" (CXR-AC) underestimates the burden of pneumococcal pneumonia prevented by PCV by as much as 63%. The use of alternate markers such as C-reactive protein enhance the ability of measuring the burden of pneumonia preventable by PCV. A broadened definition of "pneumococcal pneumonia" which includes episodes of pneumonia associated with CXR-AC and those associated with an abnormal chest radiograph other than CXR-AC associated with a CRP of > or =40mg/l should be considered an a priori outcome in future PCV efficacy trials.

Fitness costs of fluoroquinolone resistance in Streptococcus pneumoniae.

The fitness cost of the genes responsible for resistance to fluoroquinolones in clinical isolates of Streptococcus pneumoniae were estimated in vitro in a common genetic background. Naturally occurring parC, parE, and gyrA loci containing mutations in the quinolone-resistance-determining regions were introduced by transformation into S. pneumoniae strain R6 individually and in combinations. The fitness of these transformants was estimated by pairwise competition experiments with a common R6 strain. On average, single par and gyr mutants responsible for low-level MIC resistance (first-step resistance) impose a fitness burden of approximately 8%. Some of these mutants engender no measurable cost, while one, a parE mutant, reduces the fitness of these bacteria by more than 40%. Most interestingly, the addition of the second par or gyr mutations required for clinically significant, high-MIC fluoroquinolone resistance does not increase the fitness burden imposed by these single genes and can even reduce it. We discuss the implications of these results for the epidemiology of fluoroquinolone resistance and the evolution of acquired resistance in treated patients.

Implications for antimicrobial prescribing of strategies based on bacterial eradication.

Antimicrobial prescribing in respiratory tract infection is generally empirical. Agents that do not eradicate the key bacterial respiratory pathogens (Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis) provide suboptimal therapy. A recent paper developed by a multidisciplinary, multinational group presented a consensus on the principles that should underpin appropriate antimicrobial prescribing. In summary, in order to ensure clinical success and minimize the threat of resistance, empirical therapy should avoid unnecessary and inappropriate use of antimicrobials, deliver the right agent at the right dose and duration, and rapidly eradicate the pathogen at the site of infection. Accurate diagnosis is essential to ensure that only bacterial infections are treated with antibacterial agents. The application of pharmacokinetic/pharmacodynamic (PK/PD) principles to both new and existing antimicrobials allows the prediction of bacteriologic efficacy. Applying these principles when prescribing therapy can help in reducing the potential for the selection and spread of resistance. Local resistance patterns and the bacteriologic/clinical impact of resistance should also be considered. The use of antimicrobials with optimal PK/PD characteristics may be more cost-effective than allowing the possibility of resistance-induced failure. Changing prescribing habits without taking all these factors into account may increase the incidence of unfavorable patient outcomes and the cost of treatment, with more referrals and hospitalizations. Changes in prescribing habits should be considered carefully, to avoid unintended negative consequences. It is the responsibility of physicians to ensure that each prescription is necessary and will maximize the potential for clinical cure, but there is also a collective responsibility to sustain the diversity of antimicrobial therapy via appropriate formularies, guidelines and licensing, reduced over-the-counter availability, and continued research and development through academia and industry. To maximize clinical cure and minimize the emergence and spread of resistance, antimicrobial prescribing should maximize bacterial eradication, and clinical drug evaluation needs to be brought into line with this need.

Defining the potential impact of conjugate bacterial polysaccharide-protein vaccines in reducing the burden of pneumonia in human immunodeficiency virus type 1-infected and -uninfected children.

BACKGROUND: The evaluation of bacterial conjugate vaccines in preventing pneumonia requires the definition of suitable outcome measures against which their use can be evaluated. One such possible outcome measure is alveolar consolidation confirmed by chest radiograph (CXR). OBJECTIVE: To define the CXR presentation in relation to identified bacterial and respiratory viral pathogens among HIV-1-infected and -uninfected children. METHODS: The CXRs of 1186 of 1434 children hospitalized with severe lower respiratory tract infection were evaluated for the presence of alveolar consolidation (homogenous airspace infiltrate), bronchopneumonia (patchy airspace consolidation) or other CXR findings. Children were also investigated for bacterial infection by blood culture in 1364 of 1434 episodes and for respiratory viruses in 990 of 1434 episodes by immunofluorescein monoclonal antibody assays. RESULTS: The prevalence of HIV-1 infection among children who had CXRs in the study was 527 (46.2%) of 1142. Alveolar consolidation was more common in HIV-1-infected (63.7%) than in HIV-uninfected children (42.4%, P < 10(-5)) whereas bronchopneumonic changes (29.0% vs. 38.0%, P = 0.001) or a normal CXR occurred in 7.0 vs. 18.2% (P < 10(-5)) of HIV-1-infected and -uninfected children, respectively. Alveolar consolidation was the main CXR presentation in HIV-1-infected (78.6%) and HIV-uninfected children (64.9%, P = 0.14) with all-cause bacteremic pneumonia as well as those with bacteremic Streptococcus pneumoniae pneumonia (76.9% vs. 83.3%, respectively; P = 0.99). Respiratory virus-associated lower respiratory tract infection, however, was more likely to present with alveolar consolidation in HIV-1-infected (55.8%) than in HIV-uninfected (36.1%, P = 0.02) children. CONCLUSION: Although alveolar consolidation may be a useful tool in defining both the efficacy and burden of bacterial pneumonia in HIV-1-uninfected children, this may not be so for HIV-1-infected children. The higher occurrence of respiratory virus-associated alveolar consolidation, possibly coupled with Pneumocystis carinii pneumonia, may be significant confounders in the interpretation of CXR in HIV-1-infected children, limiting the use of alveolar consolidation as an outcome measure when evaluating the efficacy of bacterial conjugate vaccines in HIV-1-infected children.