Incidence of Respiratory Syncytial Virus in Community-Dwelling Adults Aged 18-64 Years Over 2 Seasons, 2022-2024, in a North American Community.

Background: The incidence of respiratory syncytial virus (RSV)-acute respiratory infection (ARI) in community-dwelling adults after the Omicron variant of the COVID-19 pandemic is unknown. Our aim was to assess the incidence of RSV-ARI in adults aged 18 to 64 years over 2 consecutive RSV seasons (October-April 2022-2024) in 4 US states. Methods: This community-based prospective cohort study comprised 7501 participants in Minnesota, Wisconsin, Florida, and Arizona. We calculated RSV-ARI and RSV-lower respiratory tract disease (LRTD) incidence and attack rates. We reported unadjusted incidence by age group, gender, race and ethnicity, Charlson Comorbidity Index, socioeconomic status, residential state, and rural/urban setting. Results: Seasons 1 and 2 had 2250 and 2377 ARI episodes, respectively, with an RSV-ARI positivity rate of 5.5% for season 1 and 5.8% for season 2 among those tested. In season 1, the overall incidence of RSV-ARI was 27.71 (95% CI, 22.82-33.34) per 1000 person-years (1.49% attack rate). Almost half (49.0%) had RSV-LRTD, with an incidence of 13.53 (95% CI, 10.19-17.61) per 1000 person-years (0.73% attack rate). In season 2, the RSV-ARI and RSV-LRTD incidence rates were 26.39 (95% CI, 21.73-31.75) per 1000 person-years (1.51% attack rate) and 12.43 (95% CI, 9.31-16.26) per 1000 person-years (0.72% attack rate). RSV-ARI incidence peaked in November 2022 and December 2023. Conclusions: Our observations suggest that RSV-ARI incidence and seasonal pattern are shifting to prepandemic RSV epidemiology.

Burden of respiratory syncytial virus infections in older adults with acute respiratory infection in Japan: An epidemiological study among outpatients.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory illness, with severe outcomes in older adults. Information on the prevalence, hospitalization rate, and impact on the health-related quality of life (HRQoL) of RSV in older adults with acute respiratory infections (ARI) in outpatient settings in Japan is limited. METHODS: This multi-center epidemiological study included outpatients aged ≥60 years presenting with ARI between August 2021 and February 2023. Nasal and throat swabs were collected and tested by reverse transcription polymerase chain reaction (RT-PCR). The prevalence of RT-PCR-confirmed RSV (cRSV)-ARI, cRSV-lower respiratory tract disease (LRTD), and other respiratory viruses was calculated by season, region, age group, and RSV subtype. HRQoL was assessed via patient-reported outcomes. RESULTS: The study included 923 ARI episodes (cRSV-ARI: N = 24; non-cRSV-ARI: N = 899). In years 1 and 2 (August 2021-July 2022 and August 2022-February 2023), the prevalence of cRSV-ARI was 2.5% and 2.8%, respectively. There was a predominance of RSV-B and RSV-A subtypes in years 1 and 2, respectively. In years 1 and 2 combined, 37.5% of cRSV-ARI cases had lower respiratory tract infection; all cRSV-LRTD cases occurred in those aged 60-74 years. RSV-ARI cases reported throat, chest, and respiratory symptoms, leading to impaired functioning and HRQoL. CONCLUSIONS: During the observed study period, RSV was circulating among older adults in Japan. RSV was a leading cause of ARI and LRTD. More data are needed to fully clarify the burden of RSV among older adults in Japan.

Enhanced Safety Surveillance of GSK's Inactivated Quadrivalent Seasonal Influenza Vaccine in Belgium, Germany, and Spain During the 2022/2023 Influenza Season.

BACKGROUND: Seasonal influenza is prevented through annual vaccination, especially in children and older adults. These vaccines are annually updated based on World Health Organization recommendations and require continuous safety monitoring. OBJECTIVE: We assessed the frequency and severity of adverse events within 7 days of administering GSK's inactivated quadrivalent seasonal influenza vaccine (IIV4) in Belgium, Germany, and Spain during the 2022/2023 influenza season. METHODS: In this enhanced safety surveillance study, adults who received GSK's IIV4 and parents/guardians/legally acceptable representatives of vaccinated children (aged 6 months-17 years) were invited to complete adverse drug reaction cards reporting adverse events within 7 days post-vaccination. RESULTS: In total, 1332 participants (53.6% female) received at least one dose of GSK's IIV4, including 43 children who received two doses. Overall, 97.8% of adverse drug reaction cards were completed and returned in the study. All participants in Belgium were adults, while 54.7% and 7.4% in Spain and Germany, respectively, were pediatric participants aged 6 months-17 years. After Dose 1, across all age groups, 49.8% of participants reported at least one adverse event. The most common adverse events (cumulative frequency >5%) following Dose 1 were injection-site pain (37.6%), fatigue (15.0%), headache (13.2%), injection-site swelling (9.3%), myalgia (7.6%), and injection-site erythema (7.4%). Across all countries, adverse events were most common in adults aged 18-65 years (59.7%), followed by those aged 3-17 years (47.0%), >65 years (35.7%), and 6-35 months (23.5%). After Dose 2, 18.6% of participants reported at least one adverse event, with general disorders and administration site conditions again being the most frequent. CONCLUSIONS: Across all age and risk groups for serious disease, no serious adverse events related to GSK's IIV4 were reported within 7 days post-vaccination. This study supports and confirms the acceptable safety profile of GSK's IIV4 across all recommended age groups. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov number: not applicable.

Leveraging Influenza Virus Surveillance From 2012 to 2015 to Characterize the Burden of Respiratory Syncytial Virus Disease in Canadian Adults ≥50 Years of Age Hospitalized With Acute Respiratory Illness.

Background: Respiratory syncytial virus (RSV) disease in older adults is undercharacterized. To help inform future immunization policies, this study aimed to describe the disease burden in Canadian adults aged ≥50 years hospitalized with RSV. Methods: Using administrative data and nasopharyngeal swabs collected from active surveillance among adults aged ≥50 years hospitalized with an acute respiratory illness (ARI) during the 2012-2013, 2013-2014, and 2014-2015 influenza seasons, RSV was identified using a respiratory virus multiplex polymerase chain reaction test to describe the associated disease burden, incidence, and healthcare costs. Results: Of 7797 patients tested, 371 (4.8%) were RSV positive (2.2% RSV-A and 2.6% RSV-B). RSV prevalence varied by season from 4.2% to 6.2%. Respiratory virus coinfection was observed in 11.6% (43/371) of RSV cases, with influenza A being the most common. RSV hospitalization rates varied between seasons and increased with age, from 8-12 per 100 000 population in adults aged 50-59 years to 174-487 per 100 000 in adults aged ≥80 years. The median age of RSV cases was 74.9 years, 63.7% were female, and 98.1% of cases had ≥1 comorbidity. Among RSV cases, the mean length of hospital stay was 10.6 days, 13.7% were admitted to the intensive care unit, 6.4% required mechanical ventilation, and 6.1% died. The mean cost per RSV case was $13 602 (Canadian dollars) but varied by age and Canadian province. Conclusions: This study adds to the growing literature on adult RSV burden by showing considerable morbidity, mortality, and healthcare costs in hospitalized adults aged ≥50 years with ARIs such as influenza.

Respiratory Syncytial Virus Disease Burden in Community-Dwelling and Long-Term Care Facility Older Adults in Europe and the United States: A Prospective Study.

Background: Data on respiratory syncytial virus (RSV) disease burden in adults remain scarce. We assessed the burden of confirmed RSV-acute respiratory infections (cRSV-ARIs) in community-dwelling (CD) adults and those in long-term care facilities (LTCFs). Methods: In this prospective cohort study covering 2 RSV seasons (October 2019-March 2020 and October 2020-June 2021), RSV-ARIs were identified through active surveillance, in medically stable CD-adults ≥50 years (Europe) or adults ≥65 years in LTCFs (Europe and the United States). RSV infection was confirmed by polymerase chain reaction from combined nasal and throat swabs. Results: Of 1981 adults enrolled, 1251 adults in CD and 664 LTCFs (season 1) and 1223 adults in CD and 494 LTCFs (season 2) were included in the analyses. During season 1, overall incidence rates ([IRs] cases/1000 person-years) and attack rates (ARs) for cRSV-ARIs were 37.25 (95% confidence interval [CI], 22.62-61.35) and 1.84% in adults in CD and 47.85 (CI, 22.58-101.4) and 2.26% in adults in LTCFs. Complications occurred for 17.4% (CD) and 13.3% (LTCFs) of cRSV-ARIs. One cRSV-ARI occurred in season 2 (IR = 2.91 [CI, 0.40-20.97]; AR = 0.20%), without complications. No cRSV-ARIs led to hospitalization or death. Viral pathogens were codetected in ≤17.4% of cRSV-ARIs. Conclusions: RSV is an important cause of disease burden in adults in CD and LTCFs. Despite the observed low severity of cRSV-ARI, our results support the need for RSV prevention strategies among adults ≥50 years old.

Incidence of Respiratory Syncytial Virus Infection in Older Adults Before and During the COVID-19 Pandemic.

Importance: Little is known about the burden and outcomes of respiratory syncytial virus (RSV)-positive acute respiratory infection (ARI) in community-dwelling older adults. Objective: To assess the incidence of RSV-positive ARI before and during the COVID-19 pandemic, and to assess outcomes for RSV-positive ARI in older adults. Design, Setting, and Participants: This was a community-based cohort study of adults residing in southeast Minnesota that followed up with 2325 adults aged 50 years or older for 2 RSV seasons (2019-2021) to assess the incidence of RSV-positive ARI. The study assessed outcomes at 2 to 4 weeks, 6 to 7 months, and 12 to 13 months after RSV-positive ARI. Exposure: RSV-positive and -negative ARI. Main Outcomes and Measures: RSV status was the main study outcome. Incidence and attack rates of RSV-positive ARI were calculated during each RSV season, including before (October 2019 to April 2020) and during (October 2020 to April 2021) COVID-19 pandemic, and further calculated during non-RSV season (May to September 2021) for assessing impact of COVID-19. The self-reported quality of life (QOL) by Short-Form Health Survey-36 (SF-36) and physical functional measures (eg, 6-minute walk and spirometry) at each time point was assessed. Results: In this study of 2325 participants, the median (range) age of study participants was 67 (50-98) years, 1380 (59%) were female, and 2240 (96%) were non-Hispanic White individuals. The prepandemic incidence rate of RSV-positive ARI was 48.6 (95% CI, 36.9-62.9) per 1000 person-years with a 2.50% (95% CI, 1.90%-3.21%) attack rate. No RSV-positive ARI case was identified during the COVID-19 pandemic RSV season. Incidence of 10.2 (95% CI, 4.1-21.1) per 1000 person-years and attack rate of 0.42%; (95% CI, 0.17%-0.86%) were observed during the summer of 2021. Based on prepandemic RSV season results, participants with RSV-positive ARI (vs matched RSV-negative ARI) reported significantly lower QOL adjusted mean difference (limitations due to physical health, -16.7 [95% CI, -31.8 to -1.8]; fatigue, -8.4 [95% CI, -14.3 to -2.4]; and difficulty in social functioning, -11.9 [95% CI, -19.8 to -4.0] within 2 to 4 weeks after RSV-positive ARI [ie, short-term outcome]). Compared with participants with RSV-negative ARI, those with RSV-positive ARI also had lower QOL (fatigue: -4.0 [95% CI, -8.5 to -1.3]; difficulty in social functioning, -5.8 [95% CI, -10.3 to -1.3]; and limitation due to emotional problem, -7.0 [95% CI, -12.7 to -1.3] at 6 to 7 months after RSV-positive ARI [intermediate-term outcome]; fatigue, -4.4 [95% CI, -7.3 to -1.5]; difficulty in social functioning, -5.2 [95% CI, -8.7 to -1.7] and limitation due to emotional problem, -5.7 [95% CI, -10.7 to -0.6] at 12-13 months after RSV-positive ARI [ie, long-term outcomes]) independent of age, sex, race and/or ethnicity, socioeconomic status, and high-risk comorbidities. Conclusions and Relevance: In this cohort study, the burden of RSV-positive ARI in older adults during the pre-COVID-19 period was substantial. After a reduction of RSV-positive ARI incidence from October 2020 to April 2021, RSV-positive ARI re-emerged during the summer of 2021. RSV-positive ARI was associated with significant long-term lower QOL beyond the short-term lower QOL in older adults.

Respiratory syncytial virus disease burden in adults aged 60 years and older in high-income countries: A systematic literature review and meta-analysis.

BACKGROUND: Respiratory syncytial virus (RSV)-associated acute respiratory infection (ARI) is an underrecognized cause of illness in older adults. We conducted a systematic literature review and meta-analysis to estimate the RSV disease burden in adults ≥60 years in high-income countries. METHODS: Data on RSV-ARI and hospitalization attack rates and in-hospital case fatality rates (hCFR) in adults ≥60 years from the United States, Canada, European countries, Japan, and South Korea were collected based on a systematic literature search (January 1, 2000-November 3, 2021) or via other methods (citation search, unpublished studies cited by a previous meta-analysis, gray literature, and an RSV-specific abstract booklet). A random effects meta-analysis was performed on estimates from the included studies. RESULTS: Twenty-one studies were included in the meta-analysis. The pooled estimates were 1.62% (95% confidence interval [CI]: 0.84-3.08) for RSV-ARI attack rate, 0.15% (95% CI: 0.09-0.22) for hospitalization attack rate, and 7.13% (95% CI: 5.40-9.36) for hCFR. In 2019, this would translate into approximately 5.2 million cases, 470,000 hospitalizations, and 33,000 in-hospital deaths in ≥60-year-old adults in high-income countries. CONCLUSIONS: RSV disease burden in adults aged ≥60 years in high-income countries is higher than previously estimated, highlighting the need for RSV prophylaxis in this age group.

Assessing the safety, impact and effectiveness of RTS,S/AS01E malaria vaccine following its introduction in three sub-Saharan African countries: methodological approaches and study set-up.

BACKGROUND: Following a 30-year development process, RTS,S/AS01E (GSK, Belgium) is the first malaria vaccine to reach Phase IV assessments. The World Health Organization-commissioned Malaria Vaccine Implementation Programme (MVIP) is coordinating the delivery of RTS,S/AS01E through routine national immunization programmes in areas of 3 countries in sub-Saharan Africa. The first doses were given in the participating MVIP areas in Malawi on 23 April, Ghana on 30 April, and Kenya on 13 September 2019. The countries participating in the MVIP have little or no baseline incidence data on rare diseases, some of which may be associated with immunization, a deficit that could compromise the interpretation of possible adverse events reported following the introduction of a new vaccine in the paediatric population. Further, effects of vaccination on malaria transmission, existing malaria control strategies, and possible vaccine-mediated selective pressure on Plasmodium falciparum variants, could also impact long-term malaria control. To address this data gap and as part of its post-approval commitments, GSK has developed a post-approval plan comprising of 4 complementary Phase IV studies that will evaluate safety, effectiveness and impact of RTS,S/AS01E through active participant follow-up in the context of its real-life implementation. METHODS: EPI-MAL-002 (NCT02374450) is a pre-implementation safety surveillance study that is establishing the background incidence rates of protocol-defined adverse events of special interest. EPI-MAL-003 (NCT03855995) is an identically designed post-implementation safety and vaccine impact study. EPI-MAL-005 (NCT02251704) is a cross-sectional pre- and post-implementation study to measure malaria transmission intensity and monitor the use of other malaria control interventions in the study areas, and EPI-MAL-010 (EUPAS42948) will evaluate the P. falciparum genetic diversity in the periods before and after vaccine implementation. CONCLUSION: GSK's post-approval plan has been designed to address important knowledge gaps in RTS,S/AS01E vaccine safety, effectiveness and impact. The studies are currently being conducted in the MVIP areas. Their implementation has provided opportunities and posed challenges linked to conducting large studies in regions where healthcare infrastructure is limited. The results from these studies will support ongoing evaluation of RTS,S/AS01E's benefit-risk and inform decision-making for its potential wider implementation across sub-Saharan Africa.

Contact With Young Children Increases the Risk of Respiratory Infection in Older Adults in Europe-the RESCEU Study.

BACKGROUND: Knowledge about how older adults get a respiratory infection is crucial for planning preventive strategies. We aimed to determine how contact with young children living outside of the household affects the risk of acute respiratory tract infections (ARTI) in community-dwelling older adults. METHODS: This study is part of the European RESCEU older adult study. Weekly surveillance was performed to detect ARTI throughout 2 winter seasons (2017-2018, 2018-2019). Child exposure, defined as having regular contact with children under 5 living outside of the subject's household, was assessed at baseline. The average attributable fraction was calculated to determine the fraction of ARTI explained by exposure to these children. RESULTS: We prospectively established that 597/1006 (59%) participants experienced at least 1 ARTI. Child exposure increased the risk of all-cause ARTI (adjusted odds ratio [aOR], 1.58; 95% confidence interval [CI], 1.21 -2.08; P = .001). This risk was highest in those with the most frequent contact (aOR, 1.80; 95% CI, 1.23-2.63; P = .003). The average attributable fraction of child exposure explaining ARTI was 10% (95% CI, 5%-15%). CONCLUSIONS: One of 10 ARTI in community-dwelling older adults is attributable to exposure to preschool children living outside of the household. CLINICAL TRIALS REGISTRATION: NCT03621930.

Respiratory syncytial virus acute respiratory infections in ≥ 65-year-old adults in long-term care facilities in the Czech Republic.

OBJECTIVES: Due to immunosenescence and presence of comorbidities, respiratory syncytial virus (RSV) disease burden is a major health concern in older adults, which is expected to increase with the life expectancy rise. Data on RSV burden are scarce in older adults residing in long-term care facilities, a vulnerable population living in crowded settings. Therefore, two independent prospective studies were conducted during the 2003-2004 and 2004-2005 RSV seasons to assess RSV acute respiratory illnesses (ARIs) and lower respiratory tract infections (LRTIs) in ≥ 65-year-old adults residing in long-term care facilities in the Czech Republic. METHODS: RSV ARI episodes were confirmed by polymerase chain reaction in nasal swabs collected within 3 days of symptoms onset. The mortality and morbidity of RSV-confirmed ARIs, as well as the risk factors associated with RSV-confirmed ARIs were evaluated. RESULTS: Among 1,251 participants in the 2003-2004 season (ARI surveillance between October and March), there were no RSV-positive cases in 255 ARI and 105 LRTI episodes. Among 1,280 participants in the 2004-2005 season (ARI surveillance between October and April), there were 39 and 26 RSV-positive cases in 335 ARI and 217 LRTI episodes, respectively, and RSV-positive ARI and LRTI episode incidence rates were 45.82 and 30.40 per 1,000 person-years. Among 290 RSV-negative and 39 RSV-positive ARI cases in the 2004-2005 season, 15 and 4 hospitalizations, 188 and 26 LRTIs, and 11 and 3 deaths were reported. Risk factors associated with RSV-positive ARI were female gender (odds ratio: 4.98), chronic heart failure class II (odds ratio: 2.31) and diabetes requiring insulin treatment (odds ratio: 9.82). CONCLUSIONS: These studies showed that RSV was an important cause of ARI in older adults living in long-term care facilities in the 2004-2005 season, with fluctuating yearly incidences.

Adherence to Public Health Measures Mitigates the Risk of COVID-19 Infection in Older Adults: A Community-Based Study.

OBJECTIVE: To assess the prevalence and characteristics of coronavirus disease 2019 (COVID-19) cases during the reopening period in older adults, given that little is known about the prevalence of COVID-19 after the stay-at-home order was lifted in the United States, nor the actual effects of adherence to recommended public health measures (RPHM) on the risk of COVID-19. PATIENTS AND METHODS: This was a cross-sectional study nested in a parent prospective cohort study, which followed a population-based sample of 2325 adults 50 years and older residing in southeast Minnesota to assess the incidence of viral infections. Participants were instructed to self-collect both nasal and oropharyngeal swabs, which were tested by reverse transcription polymerase chain reaction-based severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) assay between May 8, 2020, and June, 30, 2020. We assessed the prevalence of COVID-19 cases and characteristics of study subjects. RESULTS: A total of 1505 eligible subjects participated in the study whose mean age was 68 years, with 885 (59%) women, 32 (2%) racial/ethnic minorities, and 906 (60%) with high-risk conditions for influenza. The prevalence of other Coronaviridae (human coronavirus [HCoV]-229E, HCoV-NL63, and HCoV-OC43) during the 2019 to 2020 flu season was 109 (7%), and none tested positive for SARS-CoV-2. Almost all participants reported adhering to the RPHM (1,488 [99%] for social distancing, 1,438 [96%] for wearing mask in a public space, 1,476 [98%] for hand hygiene, and 1,441 (96%) for staying home mostly). Eighty-six percent of participants resided in a single-family home. CONCLUSION: We did not identify SARS-COV-2 infection in our study cohort. The combination of participants' behavior in following the RPHM and their living environment may considerably mitigate the risk of COVID-19.

Burden of respiratory syncytial virus infection in community-dwelling older adults in Europe (RESCEU): an international prospective cohort study.

BACKGROUND: Respiratory syncytial virus (RSV) infection in older adults is recognised as an important health issue. We aimed to assess the community burden of RSV in Europe in older adults aged ≥60 years. METHODS: This international, prospective, observational cohort study is part of work by the REspiratory Syncytial virus Consortium in EUrope (RESCEU). Participants were recruited through general practitioners' (GPs) offices before two independent RSV seasons. Participants reported weekly about symptoms of acute respiratory tract infection (ARTI) during one RSV season. ARTI patients were tested for RSV during home visits and completed a daily symptom diary. RSV illness included PCR-confirmed ARTI and those showing seroconversion over the season. RSV ARTI was based on PCR alone (ClinicalTrials.gov, NCT03621930). RESULTS: We recruited 1040 participants (527 in season 2017-2018 and 513 in season 2018-2019) with a median age of 75 years (range 60-100 years). Of these, 1023 (99%) lived independently at home at baseline. RSV illness incidence was 22 out of 527 (4.2%) and 37 out of 513 (7.2%) in the respective seasons. RSV illness did not affect frailty or cardiopulmonary status during the course of the study. No patients were hospitalised or died from RSV illness. In the 36 patients with PCR confirmed RSV ARTI, symptom duration averaged 19 days, while a doctor's visit took place in 11 out of 36 cases (31%). RSV ARTI could not be differentiated clinically from all other ARTIs based on symptoms. CONCLUSION: This European study showed that RSV is prevalent in community-dwelling older adults and rarely causes severe disease. This suggests that watchful waiting, using a continuity of care approach to identify those who do need more intensive care, is often justified when RSV is suspected in family practice.

Estimating Annual Fluctuations in Malaria Transmission Intensity and in the Use of Malaria Control Interventions in Five Sub-Saharan African Countries.

RTS,S/AS01E malaria vaccine safety, effectiveness, and impact will be assessed in pre- and post-vaccine introduction studies, comparing the occurrence of malaria cases and adverse events in vaccinated versus unvaccinated children. Because those comparisons may be confounded by potential year-to-year fluctuations in malaria transmission intensity and malaria control intervention usage, the latter should be carefully monitored to adequately adjust the analyses. This observational cross-sectional study is assessing Plasmodium falciparum parasite prevalence (PfPR) and malaria control intervention usage over nine annual surveys performed at peak parasite transmission. Plasmodium falciparum parasite prevalence was measured by microscopy and nucleic acid amplification test (quantitative PCR) in parallel in all participants, and defined as the proportion of infected participants among participants tested. Results of surveys 1 (S1) and 2 (S2), conducted in five sub-Saharan African countries, including some participating in the Malaria Vaccine Implementation Programme (MVIP), are reported herein; 4,208 and 4,199 children were, respectively, included in the analyses. Plasmodium falciparum parasite prevalence estimated using microscopy varied between study sites in both surveys, with the lowest prevalence in Senegalese sites and the highest in Burkina Faso. In sites located in the MVIP areas (Kintampo and Kombewa), PfPR in children aged 6 months to 4 years ranged from 24.8% to 27.3%, depending on the study site and the survey. Overall, 89.5% and 86.4% of children used a bednet in S1 and S2, of whom 68.7% and 77.9% used impregnated bednets. No major difference was observed between the two surveys in terms of PfPR or use of malaria control interventions.

Safety profile of the RTS,S/AS01 malaria vaccine in infants and children: additional data from a phase III randomized controlled trial in sub-Saharan Africa.

A phase III, double-blind, randomized, controlled trial (NCT00866619) in sub-Saharan Africa showed RTS,S/AS01 vaccine efficacy against malaria. We now present in-depth safety results from this study. 8922 children (enrolled at 5-17 months) and 6537 infants (enrolled at 6-12 weeks) were 1:1:1-randomized to receive 4 doses of RTS,S/AS01 (R3R) or non-malaria control vaccine (C3C), or 3 RTS,S/AS01 doses plus control (R3C). Aggregate safety data were reviewed by a multi-functional team. Severe malaria with Blantyre Coma Score ≤2 (cerebral malaria [CM]) and gender-specific mortality were assessed post-hoc. Serious adverse event (SAE) and fatal SAE incidences throughout the study were 24.2%-28.4% and 1.5%-2.5%, respectively across groups; 0.0%-0.3% of participants reported vaccination-related SAEs. The incidence of febrile convulsions in children was higher during the first 2-3 days post-vaccination with RTS,S/AS01 than with control vaccine, consistent with the time window of post-vaccination febrile reactions in this study (mostly the day after vaccination). A statistically significant numerical imbalance was observed for meningitis cases in children (R3R: 11, R3C: 10, C3C: 1) but not in infants. CM cases were more frequent in RTS,S/AS01-vaccinated children (R3R: 19, R3C: 24, C3C: 10) but not in infants. All-cause mortality was higher in RTS,S/AS01-vaccinated versus control girls (2.4% vs 1.3%, all ages) in our setting with low overall mortality. The observed meningitis and CM signals are considered likely chance findings, that - given their severity - warrant further evaluation in phase IV studies and WHO-led pilot implementation programs to establish the RTS,S/AS01 benefit-risk profile in real-life settings.

The choice of analytical methodology can alter conclusions regarding herd effects of paediatric pneumococcal vaccination programmes.

BACKGROUND: Estimation of the magnitude of the herd effect on invasive pneumococcal disease (IPD) is important when evaluating health benefits and cost-effectiveness of paediatric pneumococcal conjugate vaccine (PCV) programmes and may influence policy makers' decisions on PCV use. Several epidemiological, programmatic, and immunological factors can affect the magnitude of the PCV herd effect. We investigated to what extent the choice of analytical methodology may also influence herd effect estimates. METHODS: To estimate the magnitude of the herd effect from paediatric PCV programmes, we examined overall IPD incidence rates in ≥65-year-olds from Finland, Australia, England/Wales, and the United States under different analytical scenarios. We used two different statistical methods: before/after comparison of average IPD incidence rates and interrupted time series (ITS) analysis accounting for underlying time trends. We also investigated how varying the length of the pre- and post-PCV analysis periods influenced the outcomes. RESULTS: The estimated impact of paediatric PCV programmes on IPD incidence rates in adults ≥65 years varied substantially across the different scenarios within each country. The choice of statistical method and analysis periods contributed to this variation, and their influence varied by setting. For the datasets from England/Wales and the United States, the different scenarios produced relatively minor variation in estimated impact. For the Australian and Finnish datasets, differences were more prominent. In particular, for Finland, opposite conclusions could be drawn depending on the methodology: while no estimated herd effect was seen with the before/after method, a herd effect was evident with the ITS method. CONCLUSIONS: The choice of statistical method and analysis periods can substantially influence the magnitude of estimated herd effects from paediatric PCV programmes. It is important to consider the reliability and presence of pre-PCV patterns in the IPD surveillance data used for analysis, the methodology and associated assumptions used to estimate herd effects.

Longitudinal estimation of Plasmodium falciparum prevalence in relation to malaria prevention measures in six sub-Saharan African countries.

BACKGROUND: Plasmodium falciparum prevalence (PfPR) is a widely used metric for assessing malaria transmission intensity. This study was carried out concurrently with the RTS,S/AS01 candidate malaria vaccine Phase III trial and estimated PfPR over ≤ 4 standardized cross-sectional surveys. METHODS: This epidemiology study (NCT01190202) was conducted in 8 sites from 6 countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, and Tanzania), between March 2011 and December 2013. Participants were enrolled in a 2:1:1 ratio according to age category: 6 months-4 years, 5-19 years, and ≥ 20 years, respectively, per year and per centre. All sites carried out surveys 1-3 while survey 4 was conducted only in 3 sites. Surveys were usually performed during the peak malaria parasite transmission season, in one home visit, when medical history and malaria risk factors/prevention measures were collected, and a blood sample taken for rapid diagnostic test, microscopy, and haemoglobin measurement. PfPR was estimated by site and age category. RESULTS: Overall, 6401 (survey 1), 6411 (survey 2), 6400 (survey 3), and 2399 (survey 4) individuals were included in the analyses. In the 6 months-4 years age group, the lowest prevalence (assessed using microscopy) was observed in 2 Tanzanian centres (4.6% for Korogwe and 9.95% for Bagamoyo) and Lambaréné, Gabon (6.0%), while the highest PfPR was recorded for Nanoro, Burkina Faso (52.5%). PfPR significantly decreased over the 3 years in Agogo (Ghana), Kombewa (Kenya), Lilongwe (Malawi), and Bagamoyo (Tanzania), and a trend for increased PfPR was observed over the 4 surveys for Kintampo, Ghana. Over the 4 surveys, for all sites, PfPR was predominantly higher in the 5-19 years group than in the other age categories. Occurrence of fever and anaemia was associated with high P. falciparum parasitaemia. Univariate analyses showed a significant association of anti-malarial treatment in 4 surveys (odds ratios [ORs]: 0.52, 0.52, 0.68, 0.41) and bed net use in 2 surveys (ORs: 0.63, 0.68, 1.03, 1.78) with lower risk of malaria infection. CONCLUSION: Local PfPR differed substantially between sites and age groups. In children 6 months-4 years old, a significant decrease in prevalence over the 3 years was observed in 4 out of the 8 study sites. Trial registration Clinical Trials.gov identifier: NCT01190202:NCT. GSK Study ID numbers: 114001.

An epidemiological study to assess Plasmodium falciparum parasite prevalence and malaria control measures in Burkina Faso and Senegal.

BACKGROUND: Malariometric information is needed to decide how to introduce malaria vaccines and evaluate their impact in sub-Saharan African countries. METHODS: This cross-sectional study (NCT01954264) was conducted between October and November, 2013, corresponding to the high malaria transmission season, in four sites with Health and Demographic Surveillance Systems (DSS) [two sites with moderate-to-high malaria endemicity in Burkina Faso (Nouna and Saponé) and two sites with low malaria endemicity in Senegal (Keur Socé and Niakhar)]. Children (N = 2421) were randomly selected from the DSS lists of the study sites and were stratified into two age groups (6 months-4 years and 5-9 years). A blood sample was collected from each child to evaluate parasite prevalence of Plasmodium falciparum and other Plasmodium species and gametocyte density by microscopy, and rapid diagnosis test in the event of fever within 24 h. Case report forms were used to evaluate malaria control measures and other factors. RESULTS: Plasmodium falciparum was identified in 707 (29.2%) children, with a higher prevalence in Burkina Faso than Senegal (57.5 vs 0.9% of children). In Burkina Faso, prevalence was 57.7% in Nouna and 41.9% in Saponé in the 6 months-4 years age group, and 75.4% in Nouna and 70.1% in Saponé in the 5-9 years age group. Infections with other Plasmodium species were rare and only detected in Burkina Faso. While mosquito nets were used by 88.6-97.0 and 64.7-80.2% of children in Burkina Faso and Senegal, other malaria control measures evaluated at individual level were uncommon. In Burkina Faso, exploratory analyses suggested that use of malaria treatment or any other medication within 14 days, and use of insecticide spray within 7 days decreased the prevalence of malaria infection; older age, rural residence, natural floor, grass/palm roof, and unavailability of electricity in the house were factors associated with increased malaria occurrence. CONCLUSIONS: Plasmodium falciparum infection prevalence in children younger than 10 years was 57.5% in Burkina Faso and 0.9% in Senegal, and variability was observed, among others, by age, study site and malaria control measures.

Healthcare-seeking behaviour of primary caregivers for acute otitis media in children aged 6 months to <30 months in Panama: results of a cross-sectional survey.

BACKGROUND: Acute otitis media (AOM) is the most common bacterial childhood infection. However, caregivers with children having mild episodes often do not seek healthcare services, which may lead to an under-appreciation of the disease experienced by the community. The objectives of this survey were to estimate the proportion of primary caregivers who went to a healthcare facility when they suspected that their child aged 6 to <30 months was having an AOM episode during the past 6 months and to assess what factors influenced their decision. METHODS: This observational, cross-sectional survey of primary caregivers (≥18 years), with at least one child aged 6 to <30 months was performed in 19 healthcare facilities in Panama (March to May 2013). A 28-item paper questionnaire was administered to assess demographic data, AOM symptoms, as well as potential healthcare-seeking behaviour and factors influencing this behaviour. Potential confounding effects were individually assessed using Chi-squared or Cochran-Mantel-Haenszel tests, and all together in logistic regression models. RESULTS: The total number of eligible participants was 1330 (mean age 28.5 ± 8.0 years). Of these, 245 participants had at least one child whom they suspected had an AOM episode during the past 6 months. Of the 245 participants, 213 (86.9%) sought healthcare at a facility. Several factors were associated with healthcare usage: perceived severity of illness (p = 0.001), occupational status of the caregiver (p = 0.002), household income (p = 0.016) and length of time since the last suspected AOM episode (p = 0.032). CONCLUSIONS: When confronted with a child with obvious symptoms of AOM, the majority of caregivers reported seeking healthcare. This behaviour appeared to be associated with factors related to the severity of the illness, the length of time since the last episode, as well as with the income and occupational status of the caregivers themselves. As many episodes of AOM present with non-specific respiratory symptoms, our results apply only to caregivers who were confronted with children with an obvious symptom.

Etiology of Acute Otitis Media in Children Less Than 5 Years of Age: A Pooled Analysis of 10 Similarly Designed Observational Studies.

BACKGROUND: Acute otitis media (AOM) is an important cause of childhood morbidity and antibiotic prescriptions. However, the relative importance of the well-known otopathogens, Streptococcus pneumoniae (Spn) and Haemophilus influenzae (Hflu), remains unclear because of a limited number of tympanocentesis-based studies that vary significantly in populations sampled, case definitions and heptavalent pneumococcal conjugate vaccine use. METHODS: We conducted a pooled analysis of results from 10 AOM etiology studies of similar design, the protocols of which were derived from a common protocol and conducted in children 3 months to 5 years of age in different countries. Generalized estimating equations were used to account for within-study correlations. RESULTS: The majority, 55.5% (95% confidence interval: 47.0%-65.7%) of 1124 AOM episodes, were bacterial pathogen positive: 29.1% (24.8%-34.1%) yielded Hflu and 23.6% (19.0%-29.2%) Spn. Proportions of Hflu and Spn were higher and lower, respectively, in heptavalent pneumococcal conjugate vaccine-vaccinated children. Hflu and Spn were each isolated from 20% to 35% of children in every 1-year age range. Hflu was less likely to be isolated from first (vs. subsequent) episodes [relative risk (RR): 0.71 (0.60-0.84)]. Spn was more often isolated from sporadic (vs. recurrent) cases [RR: 0.76 (0.61-0.97)]; the opposite was true for Hflu [RR: 1.4 (1.00-1.96)]. Spn cases were more likely to present with severe (vs. mild) symptoms [RR: 1.42 (1.01-2.01)] and Hflu cases with severe tympanic membrane inflammation [RR: 1.35 (1.06-1.71)]. CONCLUSIONS: Spn and Hflu remain the leading otopathogens in all populations examined. While associated with overlapping symptoms and severity, they exhibit some differences in their likelihood to cause disease in specific subpopulations.