Comparison of measles IgG enzyme immunoassays (EIA) versus plaque reduction neutralization test (PRNT) for measuring measles serostatus: a systematic review of head-to-head analyses of measles IgG EIA and PRNT.

BACKGROUND: As countries move towards or achieve measles elimination status, serosurveillance is an important public health tool. However, a major challenge of serosurveillance is finding a feasible, accurate, cost-effective, and high throughput assay to measure measles antibody concentrations and estimate susceptibility in a population. We conducted a systematic review to assess, characterize, and - to the extent possible - quantify the performance of measles IgG enzyme-linked assays (EIAs) compared to the gold standard, plaque reduction neutralization tests (PRNT). METHODS: We followed the PRISMA statement for a systematic literature search and methods for conducting and reporting systematic reviews and meta-analyses recommended by the Cochrane Screening and Diagnostic Tests Methods Group. We identified studies through PubMed and Embase electronic databases and included serologic studies detecting measles virus IgG antibodies among participants of any age from the same source population that reported an index (any EIA or multiple bead-based assays, MBA) and reference test (PRNT) using sera, whole blood, or plasma. Measures of diagnostic accuracy with 95% confidence intervals (CI) were abstracted for each study result, where reported. RESULTS: We identified 550 unique publications and identified 36 eligible studies for analysis. We classified studies as high, medium, or low quality; results from high quality studies are reported. Because most high quality studies used the Siemens Enzygnost EIA kit, we generate individual and pooled diagnostic accuracy estimates for this assay separately. Median sensitivity of the Enzygnost EIA was 92.1% [IQR = 82.3, 95.7]; median specificity was 96.9 [93.0, 100.0]. Pooled sensitivity and specificity from studies using the Enzygnost kit were 91.6 (95%CI: 80.7,96.6) and 96.0 (95%CI: 90.9,98.3), respectively. The sensitivity of all other EIA kits across high quality studies ranged from 0% to 98.9% with median (IQR) = 90.6 [86.6, 95.2]; specificity ranged from 58.8% to 100.0% with median (IQR) = 100.0 [88.7, 100.0]. CONCLUSIONS: Evidence on the diagnostic accuracy of currently available measles IgG EIAs is variable, insufficient, and may not be fit for purpose for serosurveillance goals. Additional studies evaluating the diagnostic accuracy of measles EIAs, including MBAs, should be conducted among diverse populations and settings (e.g., vaccination status, elimination/endemic status, age groups).

Plasma concentrations of leptin at mid-pregnancy are associated with gestational weight gain among pregnant women in Tanzania: a prospective cohort study.

BACKGROUND: Gestational weight gain (GWG) has critical implications for maternal and child health. Inflammation and angiogenesis are implicated in various aspects of maternal metabolism that may play a role in gestational weight gain. The associations of inflammatory, angiogenic, and metabolic pathways with GWG are yet to be elucidated. This study evaluated associations between a panel of inflammatory, angiogenic, and metabolic proteins measured in mid-pregnancy and gestational weight gain. METHODS: Pregnant women were enrolled from Dar es Salaam, Tanzania, between 2001 and 2004. The participants were enrolled at mid-pregnancy (12 to 27 weeks of gestation) and followed up until delivery. This analysis focused on a cohort of 1002 women who were primigravid, had singleton live births, had longitudinal measures of gestational weight, and whose mid-pregnancy plasma samples underwent analysis for 18 proteins. RESULTS: Higher plasma concentrations of leptin (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 10.24; 95% CI 3.31, 17.16; p-trend = 0.003) and chitinase-3-like protein-1 (CH3L1) (mean difference in GWG percent adequacy comparing highest with lowest quartiles: 7.02; 95% CI 0.31, 13.72; p-trend = 0.007) were associated with greater GWG in a dose-response pattern. Higher leptin concentrations were associated with a lower risk of inadequate GWG (risk ratio comparing highest with lowest quartiles: 0.77; 95% CI 0.65, 0.91; p-trend = 0.001) and a higher risk of excessive GWG (risk ratio comparing highest with lowest quartiles: 1.57; 95% CI 1.03, 2.39; p-trend = 0.03). Higher CH3L1 concentrations were associated with a higher risk of excessive GWG (p-trend = 0.007). The associations of leptin and CH3L1 with inadequate GWG were stronger during the second than the third trimester. The other 16 proteins examined were not significantly associated with GWG. CONCLUSIONS: Mid-pregnancy plasma leptin concentrations may be associated with GWG and have clinical predictive utility in identifying women at a higher risk of inadequate or excessive gestational weight gain.

Using Serosurvey Data Triangulation for More Accurate Estimates of Vaccine Coverage: Measured and Modeled Coverage From Pakistan Household Surveys.

Household surveys remain an essential method for estimating vaccine coverage in developing countries. However, the resulting estimates have inevitable and currently unmeasurable information biases due to inaccuracies in recall, low retention of home-based records (HBRs; i.e., vaccination cards), and inaccurate recording of vaccination on HBRs. We developed an innovative method with which to overcome these biases, enhance the validity of survey results, and estimate true vaccine coverage using nested serological assessments of immune markers. We enrolled children aged 12-23 months in vaccine coverage surveys in Karachi, Pakistan, from January to December 2016. Vaccination history was collected through verbal recall by the caregiver and, when available, by HBR. One-third of survey participants were randomly enrolled for serological testing for anti-measles virus immunoglobulin G antibody. We applied Bayesian latent class models to evaluate the misalignment among measles vaccination histories derived by recall, HBRs, and measles serology and estimated true measles vaccine coverage. The model-based estimate of true measles vaccine coverage was 61.1% (95% credible interval: 53.5, 69.4) among all survey participants. The standard estimate of 73.2% (95% confidence interval: 71.3, 75.1) defined by positive recall or HBR documentation substantially overestimated the vaccine coverage. Researchers can correct for information biases using serological assessments in a subsample of survey participants and latent class analytical approaches.

Benefits and Challenges in Using Seroprevalence Data to Inform Models for Measles and Rubella Elimination.

Background: Control efforts for measles and rubella are intensifying globally. It becomes increasingly important to identify and reach remaining susceptible populations as elimination is approached. Methods: Serological surveys for measles and rubella can potentially measure susceptibility directly, but their use remains rare. In this study, using simulations, we outline key subtleties in interpretation associated with the dynamic context of age-specific immunity, highlighting how the patterns of immunity predicted from disease surveillance and vaccination coverage data may be misleading. Results: High-quality representative serosurveys could provide a more accurate assessment of immunity if challenges of conducting, analyzing, and interpreting them are overcome. We frame the core disease control and elimination questions that could be addressed by improved serological tools, discussing challenges and suggesting approaches to increase the feasibility and sustainability of the tool. Conclusions: Accounting for the dynamical context, serosurveys could play a key role in efforts to achieve and sustain elimination.

Biomarkers of endothelial dysfunction predict sepsis mortality in young infants: a matched case-control study.

BACKGROUND: Reducing death due to neonatal sepsis is a global health priority, however there are limited tools to facilitate early recognition and treatment. We hypothesized that measuring circulating biomarkers of endothelial function and integrity (i.e. Angiopoietin-Tie2 axis) would identify young infants with sepsis and predict their clinical outcome. METHODS: We conducted a matched case-control (1:3) study of 98 young infants aged 0-59 days of life presenting to a referral hospital in Bangladesh with suspected sepsis. Plasma levels of Ang-1, Ang-2, sICAM-1, and sVCAM-1 concentrations were measured at admission. The primary outcome was mortality (n = 18); the secondary outcome was bacteremia (n = 10). RESULTS: Ang-2 concentrations at presentation were higher among infants who subsequently died of sepsis compared to survivors (aOR 2.50, p = 0.024). Compared to surviving control infants, the Ang-2:Ang-1 ratio was higher among infants who died (aOR 2.29, p = 0.016) and in infants with bacteremia (aOR 5.72, p = 0.041), and there was an increased odds of death across Ang-2:Ang-1 ratio tertiles (aOR 4.82, p = 0.013). CONCLUSIONS: This study provides new evidence linking the Angiopoietin-Tie2 pathway with mortality and bacteremia in young infants with suspected sepsis. If validated in additional studies, markers of the angiopoietin-Tie2 axis may have clinical utility in risk stratification of infants with suspected sepsis.

Methemoglobin and nitric oxide therapy in Ugandan children hospitalized for febrile illness: results from a prospective cohort study and randomized double-blind placebo-controlled trial.

BACKGROUND: Exposure of red blood cells to oxidants increases production of methemoglobin (MHb) resulting in impaired oxygen delivery to tissues. There are no reliable estimates of methemoglobinemia in low resource clinical settings. Our objectives were to: i) evaluate risk factors for methemoglobinemia in Ugandan children hospitalized with fever (study 1); and ii) investigate MHb responses in critically ill Ugandan children with severe malaria treated with inhaled nitric oxide (iNO), an oxidant that induces MHb in a dose-dependent manner (study 2). METHODS: Two prospective studies were conducted at Jinja Regional Referral Hospital in Uganda between 2011 and 2013. Study 1, a prospective cohort study of children admitted to hospital with fever (fever cohort, n = 2089 children 2 months to 5 years). Study 2, a randomized double-blind placebo-controlled parallel arm trial of room air placebo vs. 80 ppm iNO as an adjunctive therapy for children with severe malaria (RCT, n = 180 children 1-10 years receiving intravenous artesunate and 72 h of study gas). The primary outcomes were: i) masimo pulse co-oximetry elevated MHb levels at admission (>2 %, fever cohort); ii) four hourly MHb levels in the RCT. RESULTS: In the fever cohort, 34 % of children admitted with fever had elevated MHb at admission. Children with a history of vomiting, delayed capillary refill, elevated lactate, severe anemia, malaria, or hemoglobinopathies had increased odds of methemoglobinemia (p < 0.05 in a multivariate model). MHb levels at admission were higher in children who died (n = 89) compared to those who survived (n = 1964), p = 0.008. Among children enrolled in the iNO RCT, MHb levels typically plateaued within 12-24 h of starting study gas. MHb levels were higher in children receiving iNO compared to placebo, and MHb > 10 % occurred in 5.7 % of children receiving iNO. There were no differences in rates of study gas discontinuation between trial arms. CONCLUSIONS: Hospitalized children with evidence of impaired oxygen delivery, metabolic acidosis, anemia, or malaria were at risk of methemoglobinemia. However, we demonstrated high-dose iNO could be safely administered to critically ill children with severe malaria with appropriate MHb monitoring. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01255215 (Date registered: December 5, 2010).

Prospective validation of pediatric disease severity scores to predict mortality in Ugandan children presenting with malaria and non-malaria febrile illness.

INTRODUCTION: The development of simple clinical tools to identify children at risk of death would enable rapid and rational implementation of lifesaving measures to reduce childhood mortality globally. METHODS: We evaluated the ability of three clinical scoring systems to predict in-hospital mortality in a prospective observational study of Ugandan children with fever. We computed the Lambaréné Organ Dysfunction Score (LODS), Signs of Inflammation in Children that Kill (SICK), and the Pediatric Early Death Index for Africa (PEDIA). Model discrimination was evaluated by comparing areas under receiver operating characteristic curves (AUCs) and calibration was assessed using the Hosmer-Lemeshow goodness-of-fit test. Sub-analyses were performed in malaria versus non-malaria febrile illness (NMFI), and in early (≤48 hours) versus late (>48 hours) deaths. RESULTS: In total, 2089 children with known outcomes were included in the study (99 deaths, 4.7% mortality). All three scoring systems yielded good discrimination (AUCs, 95% confidence interval (CI): LODS, 0.90, 0.88 to 0.91; SICK, 0.85, 0.83 to 0.86; PEDIA, 0.90, 0.88 to 0.91). Using the Youden index to identify the best cut-offs, LODS had the highest positive likelihood ratio (+LR, 95% CI: LODS, 6.5, 5.6 to 7.6; SICK, 4.4, 3.9 to 5.0; PEDIA, 4.4, 3.9 to 5.0), whereas PEDIA had the lowest negative likelihood ratio (-LR, 95% CI: LODS, 0.21, 0.1 to 0.3; SICK, 0.22, 0.1 to 0.3; PEDIA, 0.16, 0.1 to 0.3), LODS and PEDIA were well calibrated (P = 0.79 and P = 0.21 respectively), and had higher AUCs than SICK in discriminating between survivors and non-survivors in malaria (AUCs, 95% CI: LODS, 0.92, 0.90 to 0.93; SICK, 0.86, 0.84 to 0.87; PEDIA, 0.92, 0.90 to 0.93), but comparable AUCs in NMFI (AUCs, 95% CI: LODS, 0.86, 0.83 to 0.89; SICK, 0.82, 0.79 to 0.86; PEDIA, 0.87, 0.83 to 0.893). The majority of deaths in the study occurred early (n = 85, 85.9%) where LODS and PEDIA had good discrimination. CONCLUSIONS: All three scoring systems predicted outcome, but LODS holds the most promise as a clinical prognostic score based on its simplicity to compute, requirement for no equipment, and good discrimination.

Angiogenic and inflammatory biomarkers in midpregnancy and small-for-gestational-age outcomes in Tanzania.

OBJECTIVE: We sought to investigate the relationship between a panel of angiogenic and inflammatory biomarkers measured in midpregnancy and small-for-gestational-age (SGA) outcomes in sub-Saharan Africa. STUDY DESIGN: Concentrations of 18 angiogenic and inflammatory biomarkers were determined in 432 pregnant women in Dar es Salaam, Tanzania, who participated in a trial examining the effect of multivitamins on pregnancy outcomes. Infants falling below the 10th percentile of birthweight for gestational age relative to the applied growth standards were considered SGA. Multivariate binomial regression models with the log link function were used to determine the relative risk of SGA associated with increasing quartiles of each biomarker. Restricted cubic splines were used to test for nonlinearity of these associations. RESULTS: A total of 60 participants (13.9%) gave birth to SGA infants. Compared to those in the first quartile, the risk of SGA was reduced among those in the fourth quartiles of vascular endothelial growth factor-A (adjusted risk ratio [RR], 0.38; 95% confidence interval [CI], 0.19-0.74), placental growth factor (adjusted RR, 0.28; 95% CI, 0.12-0.61), soluble fms-like tyrosine kinase-1 (adjusted RR, 0.48; 95% CI, 0.23-1.01), monocyte chemoattractant protein-1 (adjusted RR, 0.48; 95% CI, 0.25-0.92), and leptin (adjusted RR, 0.46; 95% CI, 0.22-0.96). CONCLUSION: Our findings provide evidence of altered angiogenic and inflammatory mediators, at midpregnancy, in women who went on to deliver SGA infants.

Characterization of Streptococcus pneumoniae isolates obtained from the middle ear fluid of US children, 2011-2021.

Introduction: Pneumococcal conjugate vaccines (PCVs), including higher valency vaccines such as PCV20, have the potential to reduce pediatric otitis media. We assessed serotype distribution, potential PCV coverage, and antimicrobial susceptibility of Streptococcus pneumoniae isolates cultured from middle ear fluid (MEF) of US children age ≤5 years. Methods: S. pneumoniae isolates identified from US hospitals participating in the SENTRY Antimicrobial Surveillance program from 2011 to 2021 were included. Serotypes were determined by in silico analysis based on Pneumococcal Capsular Typing methodology. The percentage of isolates belonging to serotypes included in PCV13 (serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, 23F), PCV15 (PCV13 plus 22F, 33F), and PCV20 (PCV13 plus, 8, 10A, 11A, 12F, 15B, 22F and 33F) was calculated. Antimicrobial susceptibility testing was performed by broth microdilution and interpreted using CLSI criteria. Nonsusceptibility was defined as isolates that were intermediate or resistant to a selected antimicrobial. Results: Among the 199 S. pneumoniae isolates that were identified, 56.8% were from children age <2 years. Six serotypes accounted for around 60% of isolates: 35B (16.6%), 15B (14.6%), 15A (7.5%), 19A (7.5%), 19F (7.5%), and 3 (7.0%). Serotypes included in PCV13, PCV15, and PCV20 accounted for 23.1%, 30.2%, and 54.8% of isolates, respectively. Overall, 45.2% of isolates were penicillin non-susceptible, and 13.6% were MDR, of which 48% were serotype 19A. Seven serotypes (19A, 15A, 15B, 15C, 23A, 33F, and 35B) accounted for the majority of non-susceptible isolates. Discussion: PCVs, particularly PCV20, may prevent a substantial fraction of S. pneumoniae otitis media (OM), including OM due to non-susceptible serotypes. The addition of serotypes 15A, 23A, and 35B would improve coverage against susceptible and non-susceptible pneumococcal OM.

Non-pharmaceutical interventions for COVID-19 transiently reduced pneumococcal and Haemophilus influenzae carriage in a cross-sectional pediatric cohort in Southampton, UK.

The Southampton pneumococcal carriage study of children under 5 years old continued during the coronavirus disease 2019 (COVID-19) pandemic. Here, we present data from October 2018 to March 2023 describing prevalence of pneumococci and other pathobionts during the winter seasons before, during, and after the introduction of non-pharmaceutical interventions (NPIs) to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. Nasopharyngeal swabs were collected from children attending outpatient clinics at a secondary care hospital and community healthcare sites. Pre-NPIs, in 2019/2020, the carriage prevalence of pneumococci at the hospital site was 32% (n = 161 positive/499 participants). During NPIs, this fell to 19% (n = 12/64), although based on fewer participants compared to previous years due to COVID-19 restrictions on health-care attendance. In 2021/2022, after NPIs had eased, prevalence rebounded to 33% (n = 15/46) [compared to NPIs period, χ2 (1, N = 110) =2.78, P = 0.09]. Carriage prevalence at community healthcare sites fell significantly from 27% (n = 127/470) in 2019/2020 to 19% during the NPI period (n = 44/228) in 2020/2021 [χ2 (1, N = 698) =4.95, P = 0.026]. No rebound was observed in 2021/2022 [19% (n = 56/288)]. However, in a multivariate logistic regression model, neither site had a significantly lower carriage prevalence during the NPI period compared to the post NPI period. A reduction in serotype diversity was observed in 2020/2021. Carriage of Haemophilus influenzae was particularly affected by NPIs with a significant reduction observed. In conclusion, among children under 5 years of age, transient, modest, and statistically non-significant alterations in carriage of both Streptococcus pneumoniae and H. influenzae were associated with SARS-CoV-2 NPIs.IMPORTANCEStreptococcus pneumoniae (the pneumococcus) continues to be a major contributor to global morbidity and mortality. Using our long-running pediatric study, we examined changes in pneumococcal carriage prevalence in nearly 3,000 children under the age of 5 years between the winters of 2018/2019 and 2022/2023. This period coincided with the severe acute respiratory syndrome coronavirus 2 pandemic and, in particular, the implementation of national strategies to limit disease transmission in the UK. We observed a transient reduction of both Streptococcus pneumoniae and Haemophilus influenzae in these populations during this period of non-pharmaceutical interventions. This aligned with the reduction in invasive pneumococcal disease seen in the UK and is therefore a likely contributor to this phenomenon.

Cost-effectiveness of 20-valent pneumococcal conjugate vaccine in US infants.

BACKGROUND: As of June 2023, two pneumococcal conjugate vaccines, 20- (PCV20) and 15- (PCV15) valent formulations, are recommended for US infants under a 3 + 1 schedule. This study evaluated the health and economic impact of vaccinating US infants with a new expanded valency PCV20 formulation. METHODS: A population-based, multi cohort, decision-analytic Markov model was developed to estimate the public health impact and cost-effectiveness of PCV20 from both societal and healthcare system perspectives over 10 years. Epidemiological data were based on published studies and unpublished Active Bacterial Core Surveillance System (ABCs) data. Vaccine effectiveness was based on PCV13 effectiveness and PCV7 efficacy studies. Indirect impact was based on observational studies. Costs and disutilities were based on published data. PCV20 was compared to both PCV13 and PCV15 in separate scenarios. RESULTS: Replacing PCV13 with PCV20 in infants has the potential to avert over 55,000 invasive pneumococcal disease (IPD) cases, 2.5 million pneumonia cases, 5.4 million otitis media (OM) cases, and 19,000 deaths across all ages over a 10-year time horizon, corresponding to net gains of 515,000 life years and 271,000 QALYs. Acquisition costs of PCV20 were offset by monetary savings from averted cases resulting in net savings of $20.6 billion. The same trend was observed when comparing PCV20 versus PCV15, with a net gain of 146,000 QALYs and $9.9 billion in net savings. A large proportion of the avoided costs and cases were attributable to indirect effects in unvaccinated adults and elderly. From a health-care perspective, PCV20 was also the dominant strategy compared to both PCV13 and PCV15. CONCLUSIONS: Infant vaccination with PCV20 is estimated to further reduce pneumococcal disease and associated healthcare system and societal costs compared to both PCV13 and PCV15.

Post-campaign coverage evaluation of a measles and rubella supplementary immunization activity in five districts in India, 2019-2020.

BACKGROUND: In alignment with the Measles and Rubella (MR) Strategic Elimination plan, India conducted a mass measles and rubella vaccination campaign across the country between 2017 and 2020 to provide a dose of MR containing vaccine to all children aged 9 months to 15 years. We estimated campaign vaccination coverage in five districts in India and assessed campaign awareness and factors associated with vaccination during the campaign to better understand reasons for not receiving the dose. METHODS AND FINDINGS: Community-based cross-sectional serosurveys were conducted in five districts of India among children aged 9 months to 15 years after the vaccination campaign. Campaign coverage was estimated based on home-based immunization record or caregiver recall. Campaign coverage was stratified by child- and household-level risk factors and descriptive analyses were performed to assess reasons for not receiving the campaign dose. Three thousand three hundred and fifty-seven children aged 9 months to 15 years at the time of the campaign were enrolled. Campaign coverage among children aged 9 months to 5 years documented or by recall ranged from 74.2% in Kanpur Nagar District to 90.4% in Dibrugarh District, Assam. Similar coverage was observed for older children. Caregiver awareness of the campaign varied from 88.3% in Hoshiarpur District, Punjab to 97.6% in Dibrugarh District, Assam, although 8% of children whose caregivers were aware of the campaign were not vaccinated during the campaign. Failure to receive the campaign dose was associated with urban settings, low maternal education, and lack of school attendance although the associations varied by district. CONCLUSION: Awareness of the MR vaccination campaign was high; however, campaign coverage varied by district and did not reach the elimination target of 95% coverage in any of the districts studied. Areas with lower coverage among younger children must be prioritized by strengthening the routine immunization programme and implementing strategies to identify and reach under-vaccinated children.

Measles vaccination coverage estimates from surveys, clinic records, and immune markers in oral fluid and blood: a population-based cross-sectional study.

BACKGROUND: Recent outbreaks of measles and polio in low-income countries illustrate that conventional methods for estimating vaccination coverage do not adequately identify susceptible children. Immune markers of protection against vaccine-preventable diseases in oral fluid (OF) or blood may generate more accurate measures of effective vaccination history, but questions remain about whether antibody surveys are feasible and informative tools for monitoring immunization program performance compared to conventional vaccination coverage indicators. This study compares six indicators of measles vaccination status, including immune markers in oral fluid and blood, from children in rural Bangladesh and evaluates the implications of using each indicator to estimate measles vaccination coverage. METHODS: A cross-sectional population-based study of children ages 12-16 months in Mirzapur, Bangladesh, ascertained measles vaccination (MCV1) history from conventional indicators: maternal report, vaccination card records, 'card+history' and EPI clinic records. Oral fluid from all participants (n=1226) and blood from a subset (n=342) were tested for measles IgG antibodies as indicators of MCV1 history and compared to conventional MCV1 coverage indicators. RESULTS: Maternal report yielded the highest MCV1 coverage estimates (90.8%), followed by EPI records (88.6%), and card+history (84.2%). Seroprotection against measles by OF (57.3%) was significantly lower than other indicators, even after adjusting for incomplete seroconversion and assay performance (71.5%). Among children with blood results, 88.6% were seroprotected, which was significantly higher than coverage by card+history and OF serostatus but consistent with coverage by maternal report and EPI records. Children with vaccination cards or EPI records were more likely to have a history of receiving MCV1 than those without cards or records. Despite similar MCV1 coverage estimates across most indicators, within-child agreement was poor for all indicators. CONCLUSIONS: Measles IgG antibodies in OF was not a suitable immune marker for monitoring measles vaccination coverage in this setting. Because agreement between conventional MCV1 indicators was mediocre, immune marker surveillance with blood samples could be used to validate conventional MCV1 indicators and generate adjusted results that can be compared across indicators.

Acceptability of serosurveys in southern Zambia: data collector and caregiver perspectives.

Background: Factors associated with whether individuals choose to participate in serosurveys are not well understood. Understanding perceptions from multiple perspectives, including the perspectives of both data collectors and participants, through a holistic model such as the socio-ecological model contextualizes individual, interpersonal, and structural level influences on survey research participation. We used a multiple methods approach to characterize reasons for serosurvey participation in communities in Southern Province, Zambia where a serosurvey was conducted in 2016. Methods: The first phase conducted focus group discussions and in-depth interviews with 24 data collectors who participated in a measles-rubella serosurvey in 2016. The second phase surveyed 34 caregivers at health facilities to identify barriers and facilitators to serosurvey participation. Emergent themes were then classified into a socio-ecological model using individual, interpersonal, and structural level constructs. Results: Common themes emerged from data collectors as well as caregivers surveyed. At the individual level, providing incentives was a facilitator, and some religious beliefs were described as a barrier to serosurvey participation. At the interpersonal level, family dynamics and community peer influences could help or hinder serosurvey participation. Community health workers were consistently named as facilitators of participation. At the structural level, concerns about specimen collection, who was selected for serosurveys, and not receiving test results arose as potential barriers. The most frequently reported facilitator was provision of information about the purpose of the serosurvey (85% of respondents). The most frequently reported barrier was lack of clarity regarding use of their blood specimen (53% of respondents). For specimen collection type, caregivers consistently preferred finger prick blood collection over both venous blood draw and oral swabs. Conclusion: Serosurvey participation was deemed acceptable to most study participants. The socio-ecological model revealed barriers and facilitators for participation to guide strategies to improve participation which can be applied to ongoing serosurveys for SARS-CoV-2. Serosurveys should continue to develop engagement plans to provide information about blood collection ahead of the serosurvey and communicate the objectives of such studies through trusted sources such as community health workers and traditional leaders.

An evaluation of the early impact of the COVID-19 pandemic on Zambia's routine immunization program.

Implications of the COVID-19 pandemic for both populations and healthcare systems are vast. In addition to morbidity and mortality from COVID-19, the pandemic also disrupted local health systems, including reductions or delays in routine vaccination services and catch-up vaccination campaigns. These disruptions could lead to outbreaks of other infectious diseases that result in an additional burden of disease and strain on the healthcare system. We evaluated the impact of the COVID-19 pandemic on Zambia's routine childhood immunization program in 2020 using multiple sources of data. We relied on administrative vaccination data and Zambia's 2018 Demographic and Health Survey to project national disruptions to district-specific routine childhood vaccination coverage within the pandemic year 2020. Next, we leveraged a 2016 population-based serological survey to predict age-specific measles seroprevalence and assessed the impact of changes in vaccination coverage on measles outbreak risk in each district. We found minor disruptions to routine administration of measles-rubella and pentavalent vaccines in 2020. This was in part due to Zambia's Child Health Week held in June of 2020 which helped to reach children missed during the first six months of the year. We estimated that the two-month delay in a measles-rubella vaccination campaign, originally planned for September of 2020 but conducted in November of 2020 as a result of the pandemic, had little impact on modeled district-specific measles outbreak risks. This study estimated minimal increases in the number of children missed by vaccination services in Zambia during 2020. However, the ongoing SARS-CoV-2 transmission since our analysis concluded means efforts to maintain routine immunization services and minimize the risk of measles outbreaks will continue to be critical. The methodological framework developed in this analysis relied on routinely collected data to estimate disruptions of the COVID-19 pandemic to national routine vaccination program performance and its impact on children missed at the subnational level can be deployed in other countries or for other vaccines.

Historical Population-Level Impact of Infant 13-Valent Pneumococcal Conjugate Vaccine (PCV13) National Immunization Programs on Invasive Pneumococcal Disease in Australia, Canada, England and Wales, Israel, and the United States.

INTRODUCTION: This study estimates the annual population-level impact of 13-valent pneumococcal conjugate vaccine (PCV13) infant national immunization programs (NIPs) on vaccine-type and non-vaccine type invasive pneumococcal disease (IPD) incidence across all ages using national surveillance data. METHODS: We identified countries (Australia, Canada, England and Wales, Israel, and the US) with national IPD active surveillance data that introduced the seven-valent PCV (PCV7) followed by PCV13, which also reported annual serotype- and age group-specific incidence. We extracted IPD incidence by serotype groupings [PCV13 minus PCV7 (PCV13-7) serotypes; PCV13-7 serotypes excluding serotype 3; non-PCV13 serotypes; and the 20-valent (PCV20) minus PCV13 (PCV20-13) serotypes] and by age groups (< 2 years, 2-4 years, 5-17 years, 18-34 years, 35-49 years, 50-64 years, and ≥ 65 years). For each country, we calculated the annual relative change in IPD incidence (percent change), and the corresponding incidence rate ratio (IRR), for 7 years post introduction compared to the year prior to PCV13 program initiation. RESULTS: PCV13-7 vaccine-type IPD incidence consistently decreased over time following introduction of PCV13 across countries, reaching an approximate steady state after 3-4 years in ages < 5 years, with roughly 60-90% decrease (IRRs = 0.1-0.4) and after 4-5 years in ages ≥ 65 years with approximately 60-80% decrease (IRRs = 0.2-0.4). Incidence declines were more substantial for the PCV13-7 grouping when excluding serotype 3. Non-PCV13 serotype incidence was variable by country and age group, ranging from virtually no serotype replacement compared to the PCV7 period across ages in the US to increases for other countries ranging from 10 to 204% (IRRs = 1.10-3.04) in children < 5 years and 41% to 123% (IRRs = 1.41-2.23) in ages ≥ 65 years. CONCLUSIONS: Countries with longstanding PCV13 infant NIPs have observed substantial direct and indirect benefits, which are demonstrated in this study by the reduction in PCV13-7 IPD incidence compared to PCV7 period in all age groups. Over time, non-PCV13 serotypes have emerged in response to the reduction of incidence of PCV13-unique serotypes. Higher-valent PCVs are needed to address this emerging pneumococcal disease burden as well as the direct vaccination of both pediatric and adult populations against the most prevalent circulating serotypes.

Systematic Literature Review of the Epidemiological Characteristics of Pneumococcal Disease Caused by the Additional Serotypes Covered by the 20-Valent Pneumococcal Conjugate Vaccine.

Higher valency pneumococcal conjugate vaccines (PCV15 and PCV20) have been developed to address the disease burden of current non-vaccine serotypes. This review describes the epidemiological characteristics of serotypes beyond PCV13 (serotypes 8, 10A, 11A, 12F, 15B/C, 22F, and 33F; PCV20nonPCV13 serotypes). Peer-reviewed studies published between 1 January 2010 (the year PCV13 became available) and 18 August 2020 were systematically reviewed (PROSPERO number: CRD42021212875). Data describing serotype-specific outcomes on disease proportions, incidence, severity, and antimicrobial non-susceptibility were summarized for individual and aggregate PCV20nonPCV13 serotypes by age group and by type and duration of pediatric PCV immunization program. Of 1168 studies, 127 (11%) were included in the analysis. PCV20nonPCV13 serotypes accounted for 28% of invasive pneumococcal disease (IPD), although the most frequent serotypes differed between children (10A, 15B/C) and adults (8, 12F, 22F). In children, serotype 15B/C tended to be more frequently associated with pneumococcal meningitis and acute otitis media; in adults, serotype 8 was more frequently associated with pneumonia and serotype 12F with meningitis. Serotypes 10A and 15B/C in children and 11A and 15B/C in adults were often associated with severe IPD. Serotype 15B/C was also among the most frequently identified penicillin/macrolide non-susceptible PCV20nonPCV13 serotypes. These results could inform decision making about higher valency PCV choice and use.

Measles immunity gaps among children and adolescents with HIV in Zambia despite high measles vaccination and antiretroviral therapy coverage.

OBJECTIVE: The study objective was to identify measles and rubella immunity gaps among people with HIV (PWH) in Zambia despite high measles vaccine coverage and widespread access to antiretroviral therapy. DESIGN: Nationally representative cross-sectional serosurvey using biorepository specimens. METHODS: Blood specimens collected in the Zambia Population HIV Impact Assessment survey (ZAMPHIA) of 2016 were tested for measles and rubella immunoglobulin G (IgG) antibodies by enzyme immunoassay. Hierarchical generalized additive models were fit to characterize age-specific measles and rubella seroprevalence profiles by HIV infection status. Log-binomial regression was performed to identify factors associated with seronegativity. RESULTS: Of the 25 383 specimens, a subsample of 11 500 were selected and 9852 (85%) were successfully tested. Measles seroprevalence was lower among PWH compared with HIV-uninfected individuals until approximately 30 years of age. Among children younger than the age of 10 years, measles seroprevalence was 47.2% [95% confidence interval (CI): 32.7, 61.7] in PWH and 76.4% (95% CI: 74.9, 78.0) in HIV-uninfected children in same age category. In contrast, rubella seroprevalence was higher among PWH than HIV-uninfected individuals, particularly for children younger than 10 years (68.6% vs. 44.3%, P  < 0.001). Having a detectable viral load was associated with being measles seronegative (adjusted prevalence ratio 0.15, 95% CI: 0.06, 0.38). CONCLUSIONS: These results from a nationally representative serosurvey demonstrate persistence of measles immunity gaps among PWH younger than 30 years of age. There is need to implement the World Health Organization's recommendation to revaccinate children living with HIV against measles following immune reconstitution with antiretroviral therapy to protect these children and prevent measles outbreaks.

The broader impacts of otitis media and sequelae for informing economic evaluations of pneumococcal conjugate vaccines.

INTRODUCTION: Otitis media (OM) is a common childhood infection. Pneumococcal conjugate vaccines (PCVs) prevent OM episodes, thereby reducing short- and long-term clinical, economic, humanistic, and societal consequences. Most economic evaluations of PCVs focus on direct health gains and cost savings from prevented acute episodes but do not fully account for the broader societal impacts of OM prevention. AREAS COVERED: This review explores the broader burden of OM on children, caregivers, and society to better inform future economic evaluations of PCVs. EXPERT OPINION: OM causes a substantial burden to society through long-term sequelae, productivity losses, reduced quality of life for children and caregivers, and contribution to antimicrobial resistance from inappropriate antibiotic use. The effect of PCVs on acute OM has been recognized globally, yet the broader impact has not been consistently quantified, studied, or communicated. Economic evaluations of PCVs must evolve to include broader effects for patients, caregivers, and society from OM prevention. Future PCVs with broader coverage may further reduce OM incidence and antimicrobial resistance, but optimal uptake will depend on increasing the recognition and use of novel frameworks that include broader benefits. Communicating the full value of PCVs to decision makers may result in wider access and positive societal returns.

Diagnostic accuracy of dried blood spots for serology of vaccine-preventable diseases: a systematic review.

INTRODUCTION: Venous serum and plasma are optimal specimens for serological testing but may be logistically infeasible. Dried blood spots (DBS) are a feasible alternative, provided results are adequately sensitive and specific. We aimed to assess the diagnostic accuracy of DBS to measure IgG and IgM antibodies for vaccine-preventable diseases and compare test validity of DBS with venous blood. AREAS COVERED: In October 2020, we searched seven databases for peer-reviewed studies assessing the diagnostic accuracy of DBS specimens compared with serum in detecting antibodies to VPDs in humans. We extracted data and assessed risk of bias in all included studies. We calculated sensitivity and specificity with 95% confidence intervals for each index-reference test comparison. We narratively synthesized the identified evidence on diagnostic accuracy and blood collection and processing methods for DBS. Studies on measles and rubella IgG and IgM were the most frequently identified and reported generally high sensitivity and specificity. EXPERT OPINION: Lack of standardization in collection, storage, and testing methods limited systematic comparison across studies. Our findings indicate a need for additional validation studies on the diagnostic accuracy of DBS to expand their use in serological surveillance. We recommend practical considerations to improve standardized reporting for DBS validation studies.