Epidemiological impact and cost-effectiveness analysis of COVID-19 vaccination in Kenya.

BACKGROUND: A few studies have assessed the epidemiological impact and the cost-effectiveness of COVID-19 vaccines in settings where most of the population had been exposed to SARS-CoV-2 infection. METHODS: We conducted a cost-effectiveness analysis of COVID-19 vaccine in Kenya from a societal perspective over a 1.5-year time frame. An age-structured transmission model assumed at least 80% of the population to have prior natural immunity when an immune escape variant was introduced. We examine the effect of slow (18 months) or rapid (6 months) vaccine roll-out with vaccine coverage of 30%, 50% or 70% of the adult (>18 years) population prioritising roll-out in those over 50-years (80% uptake in all scenarios). Cost data were obtained from primary analyses. We assumed vaccine procurement at US$7 per dose and vaccine delivery costs of US$3.90-US$6.11 per dose. The cost-effectiveness threshold was US$919.11. FINDINGS: Slow roll-out at 30% coverage largely targets those over 50 years and resulted in 54% fewer deaths (8132 (7914-8373)) than no vaccination and was cost saving (incremental cost-effectiveness ratio, ICER=US$-1343 (US$-1345 to US$-1341) per disability-adjusted life-year, DALY averted). Increasing coverage to 50% and 70%, further reduced deaths by 12% (810 (757-872) and 5% (282 (251-317) but was not cost-effective, using Kenya's cost-effectiveness threshold (US$919.11). Rapid roll-out with 30% coverage averted 63% more deaths and was more cost-saving (ICER=US$-1607 (US$-1609 to US$-1604) per DALY averted) compared with slow roll-out at the same coverage level, but 50% and 70% coverage scenarios were not cost-effective. INTERPRETATION: With prior exposure partially protecting much of the Kenyan population, vaccination of young adults may no longer be cost-effective.

Postmortem investigations and identification of multiple causes of child deaths: An analysis of findings from the Child Health and Mortality Prevention Surveillance (CHAMPS) network.

BACKGROUND: The current burden of >5 million deaths yearly is the focus of the Sustainable Development Goal (SDG) to end preventable deaths of newborns and children under 5 years old by 2030. To accelerate progression toward this goal, data are needed that accurately quantify the leading causes of death, so that interventions can target the common causes. By adding postmortem pathology and microbiology studies to other available data, the Child Health and Mortality Prevention Surveillance (CHAMPS) network provides comprehensive evaluations of conditions leading to death, in contrast to standard methods that rely on data from medical records and verbal autopsy and report only a single underlying condition. We analyzed CHAMPS data to characterize the value of considering multiple causes of death. METHODS AND FINDINGS: We examined deaths identified from December 2016 through November 2020 from 7 CHAMPS sites (in Bangladesh, Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa), including 741 neonatal, 278 infant, and 241 child <5 years deaths for which results from Determination of Cause of Death (DeCoDe) panels were complete. DeCoDe panelists included all conditions in the causal chain according to the ICD-10 guidelines and assessed if prevention or effective management of the condition would have prevented the death. We analyzed the distribution of all conditions listed as causal, including underlying, antecedent, and immediate causes of death. Among 1,232 deaths with an underlying condition determined, we found a range of 0 to 6 (mean 1.5, IQR 0 to 2) additional conditions in the causal chain leading to death. While pathology provides very helpful clues, we cannot always be certain that conditions identified led to death or occurred in an agonal stage of death. For neonates, preterm birth complications (most commonly respiratory distress syndrome) were the most common underlying condition (n = 282, 38%); among those with preterm birth complications, 256 (91%) had additional conditions in causal chains, including 184 (65%) with a different preterm birth complication, 128 (45%) with neonatal sepsis, 69 (24%) with lower respiratory infection (LRI), 60 (21%) with meningitis, and 25 (9%) with perinatal asphyxia/hypoxia. Of the 278 infant deaths, 212 (79%) had ≥1 additional cause of death (CoD) beyond the underlying cause. The 2 most common underlying conditions in infants were malnutrition and congenital birth defects; LRI and sepsis were the most common additional conditions in causal chains, each accounting for approximately half of deaths with either underlying condition. Of the 241 child deaths, 178 (75%) had ≥1 additional condition. Among 46 child deaths with malnutrition as the underlying condition, all had ≥1 other condition in the causal chain, most commonly sepsis, followed by LRI, malaria, and diarrheal disease. Including all positions in the causal chain for neonatal deaths resulted in 19-fold and 11-fold increases in attributable roles for meningitis and LRI, respectively. For infant deaths, the proportion caused by meningitis and sepsis increased by 16-fold and 11-fold, respectively; for child deaths, sepsis and LRI are increased 12-fold and 10-fold, respectively. While comprehensive CoD determinations were done for a substantial number of deaths, there is potential for bias regarding which deaths in surveillance areas underwent minimally invasive tissue sampling (MITS), potentially reducing representativeness of findings. CONCLUSIONS: Including conditions that appear anywhere in the causal chain, rather than considering underlying condition alone, markedly changed the proportion of deaths attributed to various diagnoses, especially LRI, sepsis, and meningitis. While CHAMPS methods cannot determine when 2 conditions cause death independently or may be synergistic, our findings suggest that considering the chain of events leading to death can better guide research and prevention priorities aimed at reducing child deaths.

Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study.

BACKGROUND: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years. METHODS: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus-associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths. FINDINGS: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries. INTERPRETATION: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries. FUNDING: Bill & Melinda Gates Foundation.

The allocation of USdollar;105 billion in global funding from G20 countries for infectious disease research between 2000 and 2017: a content analysis of investments.

BACKGROUND: Each year, billions of US$ are spent globally on infectious disease research and development. However, there is little systematic tracking of global research and development. We present research on investments into infectious diseases research from funders in the G20 countries across an 18-year time period spanning 2000-17, comparing amounts invested for different conditions and considering the global burden of disease to identify potential areas of relative underfunding. METHODS: The study examined research awards made between 2000 and 2017 for infectious disease research from G20-based public and philanthropic funders. We searched research databases using a range of keywords, and open access data were extracted from funder websites. Awards were categorised by type of science, specialty, and disease or pathogen. Data collected included study title, abstract, award amount, funder, and year. We used descriptive statistics and Spearman's correlation coefficient to investigate the association between research investment and disease burden, using Global Burden of Disease 2017 study data. FINDINGS: The final 2000-17 dataset included 94 074 awards for infectious disease research, with a sum investment of $104·9 billion (annual range 4·1 billion to 8·4 billion) and a median award size of $257 176 (IQR 62 562-770 661). Pre-clinical research received $61·1 billion (58·2%) across 70 337 (74·8%) awards and public health research received $29·5 billion (28·1%) from 19 197 (20·4%) awards. HIV/AIDS received $42·1 billion (40·1%), tuberculosis received $7·0 billion (6·7%), malaria received $5·6 billion (5·3%), and pneumonia received $3·5 billion (3·3%). Funding for Ebola virus ($1·2 billion), Zika virus ($0·3 billion), influenza ($4·4 billion), and coronavirus ($0·5 billion) was typically highest soon after a high-profile outbreak. There was a general increase in year-on-year investment in infectious disease research between 2000 and 2006, with a decline between 2007 and 2017. Funders based in the USA provided $81·6 billion (77·8%). Based on funding per 2017 disability-adjusted life years (DALYs), HIV/AIDS received the greatest relative investment ($772 per DALY), compared with tuberculosis ($156 per DALY), malaria ($125 per DALY), and pneumonia ($33 per DALY). Syphilis and scabies received the least relative investment (both $9 per DALY). We observed weak positive correlation (r=0·30) between investment and 2017 disease burden. INTERPRETATION: HIV research received the highest amount of investment relative to DALY burden. Scabies and syphilis received the lowest relative funding. Investments for high-threat pathogens (eg, Ebola virus and coronavirus) were often reactive and followed outbreaks. We found little evidence that funding is proactively guided by global burden or pandemic risk. Our findings show how research investments are allocated and how this relates to disease burden and diseases with pandemic potential. FUNDING: Bill & Melinda Gates Foundation.

Sustaining pneumococcal vaccination after transitioning from Gavi support: a modelling and cost-effectiveness study in Kenya.

BACKGROUND: In 2009, Gavi, the World Bank, and donors launched the pneumococcal Advance Market Commitment, which helped countries access more affordable pneumococcal vaccines. As many low-income countries begin to reach the threshold at which countries transition from Gavi support to self-financing (3-year average gross national income per capita of US$1580), they will need to consider whether to continue pneumococcal conjugate vaccine (PCV) use at full cost or to discontinue PCV in their childhood immunisation programmes. Using Kenya as a case study, we assessed the incremental cost-effectiveness of continuing PCV use. METHODS: In this modelling and cost-effectiveness study, we fitted a dynamic compartmental model of pneumococcal carriage to annual carriage prevalence surveys and invasive pneumococcal disease (IPD) incidence in Kilifi, Kenya. We predicted disease incidence and related mortality for either continuing PCV use beyond 2022, the start of Kenya's transition from Gavi support, or its discontinuation. We calculated the costs per disability-adjusted life-year (DALY) averted and associated 95% prediction intervals (PI). FINDINGS: We predicted that if PCV use is discontinued in Kenya in 2022, overall IPD incidence will increase from 8·5 per 100 000 in 2022, to 16·2 per 100 000 per year in 2032. Continuing vaccination would prevent 14 329 (95% PI 6130-25 256) deaths and 101 513 (4386-196 674) disease cases during that time. Continuing PCV after 2022 will require an estimated additional US$15·8 million annually compared with discontinuing vaccination. We predicted that the incremental cost per DALY averted of continuing PCV would be $153 (95% PI 70-411) in 2032. INTERPRETATION: Continuing PCV use is essential to sustain its health gains. Based on the Kenyan GDP per capita of $1445, and in comparison to other vaccines, continued PCV use at full costs is cost-effective (on the basis of the assumption that any reduction in disease will translate to a reduction in mortality). Although affordability is likely to be a concern, our findings support an expansion of the vaccine budget in Kenya. FUNDING: Wellcome Trust and Gavi, the Vaccine Alliance.

Global funding trends for malaria research in sub-Saharan Africa: a systematic analysis.

BACKGROUND: Total domestic and international funding for malaria is inadequate to achieve WHO global targets in burden reduction by 2030. We describe the trends of investments in malaria-related research in sub-Saharan Africa and compare investment with national disease burden to identify areas of funding strength and potentially neglected populations. We also considered funding for malaria control. METHODS: Research funding data related to malaria for 1997-2013 were sourced from existing datasets, from 13 major public and philanthropic global health funders, and from funding databases. Investments (reported in US$) were considered by geographical area and compared with data on parasite prevalence and populations at risk in sub-Saharan Africa. 45 sub-Saharan African countries were ranked by amount of research funding received. FINDINGS: We found 333 research awards totalling US$814·4 million. Public health research covered $308·1 million (37·8%) and clinical trials covered $275·2 million (33·8%). Tanzania ($107·8 million [13·2%]), Uganda ($97·9 million [12·0%]), and Kenya ($92·9 million [11·4%]) received the highest sum of research investment and the most research awards. Malawi, Tanzania, and Uganda remained highly ranked after adjusting for national gross domestic product. Countries with a reasonably high malaria burden that received little research investment or funding for malaria control included Central African Republic (ranked 40th) and Sierra Leone (ranked 35th). Congo (Brazzaville) and Guinea had reasonably high malaria mortality, yet Congo (Brazzaville) ranked 38th and Guinea ranked 25th, thus receiving little investment. INTERPRETATION: Some countries receive reasonably large investments in malaria-related research (Tanzania, Kenya, Uganda), whereas others receive little or no investments (Sierra Leone, Central African Republic). Research investments are typically highest in countries where funding for malaria control is also high. Investment strategies should consider more equitable research and operational investments across countries to include currently neglected and susceptible populations. FUNDING: Royal Society of Tropical Medicine and Hygiene and Bill & Melinda Gates Foundation.

Assessing the efficiency of catch-up campaigns for the introduction of pneumococcal conjugate vaccine: a modelling study based on data from PCV10 introduction in Kilifi, Kenya.

BACKGROUND: The World Health Organisation recommends the use of catch-up campaigns as part of the introduction of pneumococcal conjugate vaccines (PCVs) to accelerate herd protection and hence PCV impact. The value of a catch-up campaign is a trade-off between the costs of vaccinating additional age groups and the benefit of additional direct and indirect protection. There is a paucity of observational data, particularly from low- and middle-income countries, to quantify the optimal breadth of such catch-up campaigns. METHODS: In Kilifi, Kenya, PCV10 was introduced in 2011 using the three-dose Expanded Programme on Immunisation infant schedule and a catch-up campaign in children <5 years old. We fitted a transmission dynamic model to detailed local data, including nasopharyngeal carriage and invasive pneumococcal disease (IPD), to infer the marginal impact of the PCV catch-up campaign over hypothetical routine cohort vaccination in that setting and to estimate the likely impact of alternative campaigns and their dose efficiency. RESULTS: We estimated that, within 10 years of introduction, the catch-up campaign among children <5 years old prevents an additional 65 (48-84) IPD cases across age groups, compared to PCV cohort introduction alone. Vaccination without any catch-up campaign prevented 155 (121-193) IPD cases and used 1321 (1058-1698) PCV doses per IPD case prevented. In the years after implementation, the PCV programme gradually accrues herd protection, and hence its dose efficiency increases: 10 years after the start of cohort vaccination alone the programme used 910 (732-1184) doses per IPD case averted. We estimated that a two-dose catch-up among children <1 year old uses an additional 910 (732-1184) doses per additional IPD case averted. Furthermore, by extending a single-dose catch-up campaign to children aged 1 to <2 years and subsequently to those aged 2 to <5 years, the campaign uses an additional 412 (296-606) and 543 (403-763) doses per additional IPD case averted. These results were not sensitive to vaccine coverage, serotype competition, the duration of vaccine protection or the relative protection of infants. CONCLUSIONS: We find that catch-up campaigns are a highly dose-efficient way to accelerate population protection against pneumococcal disease.

Standardization of Clinical Assessment and Sample Collection Across All PERCH Study Sites.

BACKGROUND.: Variable adherence to standardized case definitions, clinical procedures, specimen collection techniques, and laboratory methods has complicated the interpretation of previous multicenter pneumonia etiology studies. To circumvent these problems, a program of clinical standardization was embedded in the Pneumonia Etiology Research for Child Health (PERCH) study. METHODS.: Between March 2011 and August 2013, standardized training on the PERCH case definition, clinical procedures, and collection of laboratory specimens was delivered to 331 clinical staff at 9 study sites in 7 countries (The Gambia, Kenya, Mali, South Africa, Zambia, Thailand, and Bangladesh), through 32 on-site courses and a training website. Staff competency was assessed throughout 24 months of enrollment with multiple-choice question (MCQ) examinations, a video quiz, and checklist evaluations of practical skills. RESULTS.: MCQ evaluation was confined to 158 clinical staff members who enrolled PERCH cases and controls, with scores obtained for >86% of eligible staff at each time-point. Median scores after baseline training were ≥80%, and improved by 10 percentage points with refresher training, with no significant intersite differences. Percentage agreement with the clinical trainer on the presence or absence of clinical signs on video clips was high (≥89%), with interobserver concordance being substantial to high (AC1 statistic, 0.62-0.82) for 5 of 6 signs assessed. Staff attained median scores of >90% in checklist evaluations of practical skills. CONCLUSIONS.: Satisfactory clinical standardization was achieved within and across all PERCH sites, providing reassurance that any etiological or clinical differences observed across the study sites are true differences, and not attributable to differences in application of the clinical case definition, interpretation of clinical signs, or in techniques used for clinical measurements or specimen collection.

Microscopic Analysis and Quality Assessment of Induced Sputum From Children With Pneumonia in the PERCH Study.

BACKGROUND.: It is standard practice for laboratories to assess the cellular quality of expectorated sputum specimens to check that they originated from the lower respiratory tract. The presence of low numbers of squamous epithelial cells (SECs) and high numbers of polymorphonuclear (PMN) cells are regarded as indicative of a lower respiratory tract specimen. However, these quality ratings have never been evaluated for induced sputum specimens from children with suspected pneumonia. METHODS.: We evaluated induced sputum Gram stain smears and cultures from hospitalized children aged 1-59 months enrolled in a large study of community-acquired pneumonia. We hypothesized that a specimen representative of the lower respiratory tract will contain smaller quantities of oropharyngeal flora and be more likely to have a predominance of potential pathogens compared to a specimen containing mainly saliva. The prevalence of potential pathogens cultured from induced sputum specimens and quantity of oropharyngeal flora were compared for different quantities of SECs and PMNs. RESULTS.: Of 3772 induced sputum specimens, 2608 (69%) had <10 SECs per low-power field (LPF) and 2350 (62%) had >25 PMNs per LPF, measures traditionally associated with specimens from the lower respiratory tract in adults. Using isolation of low quantities of oropharyngeal flora and higher prevalence of potential pathogens as markers of higher quality, <10 SECs per LPF (but not >25 PMNs per LPF) was the microscopic variable most associated with high quality of induced sputum. CONCLUSIONS.: Quantity of SECs may be a useful quality measure of induced sputum from young children with pneumonia.

Mapping pneumonia research: A systematic analysis of UK investments and published outputs 1997-2013.

BACKGROUND: The burden of pneumonia continues to be substantial, particularly among the poorest in global society. We describe here the trends for UK pneumonia R&D investment and published outputs, and correlate with 2013 global mortality. METHODS: Data related to awards to UK institutions for pneumonia research from 1997 to 2013 were systematically sourced and categorised by disease area and type of science. Investment was compared to mortality figures in 2010 and 2013 for pneumonia, tuberculosis and influenza. Investment was also compared to publication data. RESULTS: Of all infectious disease research between 2011 and 2013 (£917.0 million), £28.8 million (3.1%) was for pneumonia. This was an absolute and proportionate increase from previous time periods. Translational pneumonia research (33.3%) received increased funding compared with 1997-2010 where funding was almost entirely preclinical (87.5%, here 30.9%), but high-burden areas such as paediatrics, elderly care and antimicrobial resistance received little investment. Annual investment remains volatile; publication temporal trends show a consistent increase. When comparing investment to global burden with a novel 'investment by mortality observed' metric, tuberculosis (£48.36) and influenza (£484.21) receive relatively more funding than pneumonia (£43.08), despite investment for pneumonia greatly increasing in 2013 compared to 2010 (£7.39). Limitations include a lack of private sector data and the need for careful interpretation of the comparisons with burden, plus categorisation is subjective. CONCLUSIONS: There has been a welcome increase for pneumonia funding awarded to UK institutions in 2011-2013 compared with 1997-2010, along with increases for more translational research. Published outputs relating to pneumonia rose steadily from 1997 to 2013. Investment relative to mortality for pneumonia has increased, but it remains low compared to other respiratory infections and clear inequities remain. Analyses that measure investments in pneumonia can provide an insight into funding trends and research gaps. RESEARCH IN CONTEXT: Pneumonia continues to be a high-burden illness around the globe. This paper shows that although research funding is increasing in the UK (between 1997 and 2013), it remains poorly funded compared to other important respiratory infectious diseases such as tuberculosis and influenza. Publications about pneumonia have been steadily increasing over time, indicating continuing academic and clinical interest in the topic. Though global mortality of pneumonia is declining, it should still be an area of high priority for funders, policymakers and researchers.

Burden of disease in adults admitted to hospital in a rural region of coastal Kenya: an analysis of data from linked clinical and demographic surveillance systems.

BACKGROUND: Estimates of the burden of disease in adults in sub-Saharan Africa largely rely on models of sparse data. We aimed to measure the burden of disease in adults living in a rural area of coastal Kenya with use of linked clinical and demographic surveillance data. METHODS: We used data from 18,712 adults admitted to Kilifi District Hospital (Kilifi, Kenya) between Jan 1, 2007, and Dec 31, 2012, linked to 790,635 person-years of observation within the Kilifi Health and Demographic Surveillance System, to establish the rates and major causes of admission to hospital. These data were also used to model disease-specific disability-adjusted life-years lost in the population. We used geographical mapping software to calculate admission rates stratified by distance from the hospital. FINDINGS: The main causes of admission to hospital in women living within 5 km of the hospital were infectious and parasitic diseases (303 per 100,000 person-years of observation), pregnancy-related disorders (239 per 100,000 person-years of observation), and circulatory illnesses (105 per 100,000 person-years of observation). Leading causes of hospital admission in men living within 5 km of the hospital were infectious and parasitic diseases (169 per 100,000 person-years of observation), injuries (135 per 100,000 person-years of observation), and digestive system disorders (112 per 100,000 person-years of observation). HIV-related diseases were the leading cause of disability-adjusted life-years lost (2050 per 100,000 person-years of observation), followed by non-communicable diseases (741 per 100,000 person-years of observation). For every 5 km increase in distance from the hospital, all-cause admission rates decreased by 11% (95% CI 7­14) in men and 20% (17­23) in women. The magnitude of this decline was highest for endocrine disorders in women (35%; 95% CI 22­46) and neoplasms in men (30%; 9­45). INTERPRETATION: Adults in rural Kenya face a combined burden of infectious diseases, pregnancy-related disorders, cardiovascular illnesses, and injuries. Disease burden estimates based on hospital data are affected by distance from the hospital, and the amount of underestimation of disease burden differs by both disease and sex. FUNDING: The Wellcome Trust, GAVI Alliance.

Use of vaccines as probes to define disease burden.

Vaccine probe studies have emerged in the past 15 years as a useful way to characterise disease. By contrast, traditional studies of vaccines focus on defining the vaccine effectiveness or efficacy. The underlying basis for the vaccine probe approach is that the difference in disease burden between vaccinated and unvaccinated individuals can be ascribed to the vaccine-specific pathogen. Vaccine probe studies can increase understanding of a vaccine's public health value. For instance, even when a vaccine has a seemingly low efficacy, a high baseline disease incidence can lead to a large vaccine-preventable disease burden and thus that population-based vaccine introduction would be justified. So far, vaccines have been used as probes to characterise disease syndromes caused by Haemophilus influenzae type b, pneumococcus, rotavirus, and early infant influenza. However, vaccine probe studies have enormous potential and could be used more widely in epidemiology, for example, to define the vaccine-preventable burden of malaria, typhoid, paediatric influenza, and dengue, and to identify causal interactions between different pathogens.

Assessment of health benefits and cost-effectiveness of 10-valent and 13-valent pneumococcal conjugate vaccination in Kenyan children.

BACKGROUND: The GAVI Alliance supported 10-valent pneumococcal conjugate vaccine (PCV10) introduction in Kenya. We estimated the cost-effectiveness of introducing either PCV10 or the 13-valent vaccine (PCV13) from a societal perspective and explored the incremental impact of including indirect vaccine effects. METHODS: The costs and effects of pneumococcal vaccination among infants born in Kenya in 2010 were assessed using a decision analytic model comparing PCV10 or PCV13, in turn, with no vaccination. Direct vaccine effects were estimated as a reduction in the incidence of pneumococcal meningitis, sepsis, bacteraemic pneumonia and non-bacteraemic pneumonia. Pneumococcal disease incidence was extrapolated from a population-based hospital surveillance system in Kilifi and adjustments were made for variable access to care across Kenya. We used vaccine efficacy estimates from a trial in The Gambia and accounted for serotype distribution in Kilifi. We estimated indirect vaccine protection and serotype replacement by extrapolating from the USA. Multivariable sensitivity analysis was conducted using Monte Carlo simulation. We assumed a vaccine price of US$ 3.50 per dose. FINDINGS: The annual cost of delivering PCV10 was approximately US$14 million. We projected a 42.7% reduction in pneumococcal disease episodes leading to a US$1.97 million reduction in treatment costs and a 6.1% reduction in childhood mortality annually. In the base case analysis, costs per discounted DALY and per death averted by PCV10, amounted to US$ 59 (95% CI 26-103) and US$ 1,958 (95% CI 866-3,425), respectively. PCV13 introduction improved the cost-effectiveness ratios by approximately 20% and inclusion of indirect effects improved cost-effectiveness ratios by 43-56%. The break-even prices for introduction of PCV10 and PCV13 are US$ 0.41 and 0.51, respectively. CONCLUSIONS: Introducing either PCV10 or PCV13 in Kenya is highly cost-effective from a societal perspective. Indirect effects, if they occur, would significantly improve the cost-effectiveness.

The definition of pneumonia, the assessment of severity, and clinical standardization in the Pneumonia Etiology Research for Child Health study.

To develop a case definition for the Pneumonia Etiology Research for Child Health (PERCH) project, we sought a widely acceptable classification that was linked to existing pneumonia research and focused on very severe cases. We began with the World Health Organization's classification of severe/very severe pneumonia and refined it through literature reviews and a 2-stage process of expert consultation. PERCH will study hospitalized children, aged 1-59 months, with pneumonia who present with cough or difficulty breathing and have either severe pneumonia (lower chest wall indrawing) or very severe pneumonia (central cyanosis, difficulty breastfeeding/drinking, vomiting everything, convulsions, lethargy, unconsciousness, or head nodding). It will exclude patients with recent hospitalization and children with wheeze whose indrawing resolves after bronchodilator therapy. The PERCH investigators agreed upon standard interpretations of the symptoms and signs. These will be maintained by a clinical standardization monitor who conducts repeated instruction at each site and by recurrent local training and testing.

Specimen collection for the diagnosis of pediatric pneumonia.

Diagnosing the etiologic agent of pneumonia has an essential role in ensuring the most appropriate and effective therapy for individual patients and is critical to guiding the development of treatment and prevention strategies. However, establishing the etiology of pneumonia remains challenging because of the relative inaccessibility of the infected tissue and the difficulty in obtaining samples without contamination by upper respiratory tract secretions. Here, we review the published and unpublished literature on various specimens available for the diagnosis of pediatric pneumonia. We discuss the advantages and limitations of each specimen, and discuss the rationale for the specimens to be collected for the Pneumonia Etiology Research for Child Health study.

Estimating rates of carriage acquisition and clearance and competitive ability for pneumococcal serotypes in Kenya with a Markov transition model.

BACKGROUND: There are more than 90 serotypes of Streptococcus pneumoniae, with varying biologic and epidemiologic properties. Animal studies suggest that carriage induces an acquired immune response that reduces duration of colonization in a nonserotype-specific fashion. METHODS: We studied pneumococcal nasopharyngeal carriage longitudinally in Kenyan children 3-59 months of age, following up positive swabs at days 2, 4, 8, 16, and 32 and then monthly thereafter until 2 swabs were negative for the original serotype. As previously reported, 1868/2840 (66%) of children swabbed at baseline were positive. We estimated acquisition, clearance, and competition parameters for 27 serotypes using a Markov transition model. RESULTS: Point estimates of type-specific acquisition rates ranged from 0.00025/d (type 1) to 0.0031/d (type 19F). Point estimates of time to clearance (inverse of type-specific immune clearance rate) ranged from 28 days (type 20) to 124 days (type 6A). For the serotype most resistant to competition (type 19F), acquisition of other serotypes was 52% less likely (95% confidence interval = 37%-63%) than in an uncolonized host. Fitness components (carriage duration, acquisition rate, lack of susceptibility to competition) were positively correlated with each other and with baseline prevalence, and were associated with biologic properties previously shown to associate with serotype. Duration of carriage declined with age for most serotypes. CONCLUSIONS: Common S. pneumoniae serotypes appear superior in many dimensions of fitness. Differences in rate of immune clearance are attenuated as children age and become capable of more rapid clearance of the longest-lived serotypes. These findings provide information for comparison after introduction of pneumococcal conjugate vaccine.

Spatial and socio-demographic predictors of time-to-immunization in a rural area in Kenya: Is equity attainable?

We conducted a vaccine coverage survey in Kilifi District, Kenya in order to identify predictors of childhood immunization. We calculated travel time to vaccine clinics and examined its relationship to immunization coverage and timeliness among the 2169 enrolled children (median age: 12.5 months). 86% had vaccine cards available, >95% had received three doses of DTP-HepB-Hib and polio vaccines and 88% of measles. Travel time did not affect vaccination coverage or timeliness. The Kenyan EPI reaches nearly all children in Kilifi and delays in vaccination are few, suggesting that vaccines will have maximal impact on child morbidity and mortality.

Geographic access to care is not a determinant of child mortality in a rural Kenyan setting with high health facility density.

BACKGROUND: Policy-makers evaluating country progress towards the Millennium Development Goals also examine trends in health inequities. Distance to health facilities is a known determinant of health care utilization and may drive inequalities in health outcomes; we aimed to investigate its effects on childhood mortality. METHODS: The Epidemiological and Demographic Surveillance System in Kilifi District, Kenya, collects data on vital events and migrations in a population of 220,000 people. We used Geographic Information Systems to estimate pedestrian and vehicular travel times to hospitals and vaccine clinics and developed proportional-hazards models to evaluate the effects of travel time on mortality hazard in children less than 5 years of age, accounting for sex, ethnic group, maternal education, migrant status, rainfall and calendar time. RESULTS: In 2004-6, under-5 and under-1 mortality ratios were 65 and 46 per 1,000 live-births, respectively. Median pedestrian and vehicular travel times to hospital were 193 min (inter-quartile range: 125-267) and 49 min (32-72); analogous values for vaccine clinics were 47 (25-73) and 26 min (13-40). Infant and under-5 mortality varied two-fold across geographic locations, ranging from 34.5 to 61.9 per 1000 child-years and 8.8 to 18.1 per 1000, respectively. However, distance to health facilities was not associated with mortality. Hazard Ratios (HR) were 0.99 (95% CI 0.95-1.04) per hour and 1.01 (95% CI 0.95-1.08) per half-hour of pedestrian and vehicular travel to hospital, respectively, and 1.00 (95% CI 0.99-1.04) and 0.97 (95% CI 0.92-1.05) per quarter-hour of pedestrian and vehicular travel to vaccine clinics in children <5 years of age. CONCLUSIONS: Significant spatial variations in mortality were observed across the area, but were not correlated with distance to health facilities. We conclude that given the present density of health facilities in Kenya, geographic access to curative services does not influence population-level mortality.