Exploring the relationship between nutritional status and immunogenicity of routine childhood vaccines

Background Infection and malnutrition remain significant causes of under-five morbidity and mortality in sub-Saharan Africa with a cyclical relationship between infection and malnutrition. Malnourished chil-dren are more prone to infection and would benefit from vaccination which is the most cost-effective tool available against infectious disease. However due to nutrition-induced immune suppression the malnourished child may not respond as well to vaccination. Methods We explored the relationship between undernutrition and immune responses measured by anti-body titres/IgG concentrations following one dose of yellow fever and measles vaccines in two cohorts of African children. Based on findings from our initial analysis we also assessed the lon-gevity of responses to yellow fever vaccine in a third cohort of African children. World Health Organization z-scores for weight for age, weight for height and height for age were used to as-sess nutritional status. Vaccine responses to measles and yellow fever were measured by standard ELISA and sero/micro neutralization respectively. Linear and logistic regression models were built to assess the relationships between the covariates and vaccine responses. In addition, we explored correlation of a known immune modulator which is also a nutritional factor – iron on vaccine response. Results There was significantly higher seroconversion following yellow fever vaccination in Mali com-pared to Ghana (91.0 vs 63.5% (p <0.001), and a trend to better seroconversion at higher height for age scores. Females attained significantly higher post vaccination antibody concentrations than males (p<0.001) following measles vaccination. Five to six years post yellow fever vaccina-tion within routine programmes one quarter of the children no longer had protective titers. Iron metabolism is down regulated in the first week of neonatal life. Conclusions Chronic malnutrition may negatively impact responses to yellow fever vaccines. Five to six years post routine vaccination over 25% of children were no longer protected (defined by anti-body concentrations) from yellow fever suggesting vulnerability to disease. There may be scope for considering differing vaccines doses for boys and girls for measles vaccine

Exploring the relationship between nutritional status and immunogenicity of routine childhood vaccines

Background Infection and malnutrition remain significant causes of under-five morbidity and mortality in sub-Saharan Africa with a cyclical relationship between infection and malnutrition. Malnourished chil-dren are more prone to infection and would benefit from vaccination which is the most cost-effective tool available against infectious disease. However due to nutrition-induced immune suppression the malnourished child may not respond as well to vaccination. Methods We explored the relationship between undernutrition and immune responses measured by anti-body titres/IgG concentrations following one dose of yellow fever and measles vaccines in two cohorts of African children. Based on findings from our initial analysis we also assessed the lon-gevity of responses to yellow fever vaccine in a third cohort of African children. World Health Organization z-scores for weight for age, weight for height and height for age were used to as-sess nutritional status. Vaccine responses to measles and yellow fever were measured by standard ELISA and sero/micro neutralization respectively. Linear and logistic regression models were built to assess the relationships between the covariates and vaccine responses. In addition, we explored correlation of a known immune modulator which is also a nutritional factor – iron on vaccine response. Results There was significantly higher seroconversion following yellow fever vaccination in Mali com-pared to Ghana (91.0 vs 63.5% (p <0.001), and a trend to better seroconversion at higher height for age scores. Females attained significantly higher post vaccination antibody concentrations than males (p<0.001) following measles vaccination. Five to six years post yellow fever vaccina-tion within routine programmes one quarter of the children no longer had protective titers. Iron metabolism is down regulated in the first week of neonatal life. Conclusions Chronic malnutrition may negatively impact responses to yellow fever vaccines. Five to six years post routine vaccination over 25% of children were no longer protected (defined by anti-body concentrations) from yellow fever suggesting vulnerability to disease. There may be scope for considering differing vaccines doses for boys and girls for measles vaccine

The burden of viral respiratory infections in young children in low-resource settings.

No abstract availble

Recall and decay of consent information among parents of infants participating in a randomized controlled clinical trial using an audio-visual tool in The Gambia.

Communicating essential research information to low literacy research participants in Africa is highly challenging, since this population is vulnerable to poor comprehension of consent information. Several supportive materials have been developed to aid participant comprehension in these settings. Within the framework of a pneumococcal vaccine trial in The Gambia, we evaluated the recall and decay of consent information during the trial which used an audio-visual tool called 'Speaking Book', to foster comprehension among parents of participating infants. The Speaking Book was developed in the 2 most widely spoken local languages. Four-hundred and 9 parents of trial infants gave consent to participate in this nested study and were included in the baseline assessment of their knowledge about trial participation. An additional assessment was conducted approximately 90 d later, following completion of the clinical trial protocol. All parents received a Speaking Book at the start of the trial. Trial knowledge was already high at the baseline assessment with no differences related to socio-economic status or education. Knowledge of key trial information was retained at the completion of the study follow-up. The Speaking Book (SB) was well received by the study participants. We hypothesize that the SB may have contributed to the retention of information over the trial follow-up. Further studies evaluating the impact of this innovative tool are thus warranted

Serological Protection 5-6 Years Post Vaccination Against Yellow Fever in African Infants Vaccinated in Routine Programmes.

Introduction: Although effective live attenuated yellow fever (YF) vaccines have been available for over 9 decades sporadic outbreaks continue to occur in endemic regions. These may be linked to several factors including epidemiological factors such as vector and intermediate host distribution or vaccine coverage and efficacy. The World Health Organization's research priorities include gathering systematic evidence around the potential need for booster vaccination with YF vaccine whether this follows full or fractional doses in children. Knowledge on the longevity of response to YF vaccine and the implications of this response needs to be consolidated to guide future vaccination policy. Methods: We measured anti-YF IgG by microneutralization assay in a group of 481 African infants who had received YF vaccine as part of routine EPI programmes, to explore serological protection from YF 5-6 years post YF vaccination, as well as the effect of co variates. Findings: Notably, 22.2% of the cohort had undetectable antibody concentrations, with another 7.5% revealing concentrations below the threshold of seropositivity of 0.5 IU/mL. Sex, season, country and time since vaccination did not affect the longevity of antibody concentration or having antibody concentrations above a defined threshold. Conclusion: Roughly 30% of children in this cohort did not demonstrate anti-yellow fever antibody concentrations above the defined threshold of protection, with 20% having no demonstrable antibody. Knowledge on the longevity of response to YF vaccine and the implications needs to be consolidated to guide future vaccination policy

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) in Africa: Current Considerations and Future Projections.

The burden of severe Covid-19 has been relatively low in sib-Saharan Africa compared to Europe and the Americas. However, SARS-CoV-2 sero-prevalence data has demonstrated that there has been more widespread transmission than can be deduced from reported cases. This could be attributed to under reporting due to low testing capacity or high numbers of asymptomatic SARS-CoV-2 infection in communities. Recent data indicates that prior SARS-CoV-2 exposure is protective against reinfection and that vaccination of previously SARS-CoV-2 infected individuals induces robust cross-reactive antibody responses. Considering these data, calls for a need for a re-think of the COVID-19 vaccination strategy in sub-Saharan African settings with high SARSCoV-2 population exposure but limited available vaccine doses. A potential recommendation would be to prioritize rapid and widespread vaccination of the first dose, while waiting for more vaccines to become available

Tracking coverage, dropout and multidimensional equity gaps in immunisation systems in West Africa, 2000-2017.

BACKGROUND: Several West African countries are unlikely to achieve the recommended Global Vaccine Action Plan (GVAP) immunisation coverage and dropout targets in a landscape beset with entrenched intra-country equity gaps in immunisation. Our aim was to assess and compare the immunisation coverage, dropout and equity gaps across 15 West African countries between 2000 and 2017. METHODS: We compared Bacille Calmette Guerin (BCG) and the third dose of diphtheria-tetanus-pertussis (DTP3) containing vaccine coverage between 2000 and 2017 using the WHO and Unicef Estimates of National Immunisation Coverage for 15 West African countries. Estimated subregional median and weighted average coverages, and dropout (DTP1-DTP3) were tracked against the GVAP targets of ≥90% coverage (BCG and DTP3), and ≤10% dropouts. Equity gaps in immunisation were assessed using the latest disaggregated national health survey immunisation data. RESULTS: The weighted average subregional BCG coverage was 60.7% in 2000, peaked at 83.2% in 2009 and was 65.7% in 2017. The weighted average DTP3 coverage was 42.3% in 2000, peaked at 70.3% in 2009 and was 61.5% in 2017. As of 2017, 46.7% of countries (7/15) had met the GVAP targets on DTP3 coverage. Average weighted subregional immunisation dropouts consistently reduced from 16.4% in 2000 to 7.4% in 2017, meeting the GVAP target in 2008. In most countries, inequalities in BCG, and DTP3 coverage and dropouts were mainly related to equity gaps of more than 20% points between the wealthiest and the poorest, high coverage regions and low coverage regions, and between children of mothers with at least secondary education and those with no formal education. A child's sex and place of residence (urban or rural) minimally determined equity gaps. CONCLUSIONS: The West African subregion made progress between 2000 and 2017 in ensuring that its children utilised immunisation services, however, wide equity gaps persist

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) formulated with 2-phenoxyethanol in multidose vials given with routine vaccination in healthy infants: An open-label randomized controlled trial.

BACKGROUND: This open-label randomized controlled trial in infants compared safety, tolerability, and immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) formulated with the preservative 2-phenoxyethanol (2-PE) in a multidose vial (MDV) to the current PCV13 without 2-PE in a single-dose syringe (SDS). METHODS: Gambian infants were randomized 1:1 to receive PCV13 as either MDV or SDS at ages 2, 3, and 4months. Serotype-specific antipneumococcal antibody responses and opsonophagocytic activity ([OPA]; subset) were measured at age 5months. Noninferiority was declared if the lower bound of the 97.5% CI for the difference (MDV-SDS) in proportions of subjects achieving IgG concentrations ≥0.35μg/mL (primary endpoint) was greater than -10%. IgG geometric mean concentrations (GMCs) were noninferior if the lower limit of the two-sided 97.5% CI of the geometric mean ratio (MDV vs SDS) was greater than 0.5. Reactogenicity and other adverse events were collected. RESULTS: 500 participants were randomized and vaccinated; 489 (MDV: n=245; SDS: n=244) completed the trial. Noninferiority of MDV was demonstrated for all serotypes as measured by percentage of subjects achieving antibody responses above ≥0.35μg/mL. IgG GMCs (coprimary endpoint) also demonstrated noninferiority of MDV; OPA results supported these findings. Safety and tolerability were comparable between groups. CONCLUSIONS: PCV13 in MDV was safe and immunogenic when administered according to the routine schedule to infants. MDV was noninferior to SDS for all 13 pneumococcal serotypes. Comparable immunogenicity and safety profiles of PCV13 MDV and SDS suggest PCV13 MDV can help optimize vaccination in resource-limited settings. ClinicalTrials.gov NCT01964716 https://clinicaltrials.gov/ct2/show/NCT01964716

Plasma Adenosine Deaminase (ADA)-1 and -2 Demonstrate Robust Ontogeny Across the First Four Months of Human Life.

Background: Human adenosine deaminases (ADAs) modulate the immune response: ADA1 via metabolizing adenosine, a purine metabolite that inhibits pro-inflammatory and Th1 cytokine production, and the multi-functional ADA2, by enhancing T-cell proliferation and monocyte differentiation. Newborns are relatively deficient in ADA1 resulting in elevated plasma adenosine concentrations and a Th2/anti-inflammatory bias compared to adults. Despite the growing recognition of the role of ADAs in immune regulation, little is known about the ontogeny of ADA concentrations. Methods: In a subgroup of the EPIC002-study, clinical data and plasma samples were collected from 540 Gambian infants at four time-points: day of birth; first week of life; one month of age; and four months of age. Concentrations of total extracellular ADA, ADA1, and ADA2 were measured by chromogenic assay and evaluated in relation to clinical data. Plasma cytokines/chemokine were measured across the first week of life and correlated to ADA concentrations. Results: ADA2 demonstrated a steady rise across the first months of life, while ADA1 concentration significantly decreased 0.79-fold across the first week then increased 1.4-fold by four months of life. Males demonstrated significantly higher concentrations of ADA2 (1.1-fold) than females at four months; newborns with early-term (37 to <39 weeks) and late-term (≥41 weeks) gestational age demonstrated significantly higher ADA1 at birth (1.1-fold), and those born to mothers with advanced maternal age (≥35 years) had lower plasma concentrations of ADA2 at one month (0.93-fold). Plasma ADA1 concentrations were positively correlated with plasma CXCL8 during the first week of life, while ADA2 concentrations correlated positively with TNFα, IFNγ and CXCL10, and negatively with IL-6 and CXCL8. Conclusions: The ratio of plasma ADA2/ADA1 concentration increased during the first week of life, after which both ADA1 and ADA2 increased across the first four months of life suggesting a gradual development of Th1/Th2 balanced immunity. Furthermore, ADA1 and ADA2 were positively correlated with cytokines/chemokines during the first week of life. Overall, ADA isoforms demonstrate robust ontogeny in newborns and infants but further mechanistic studies are needed to clarify their roles in early life immune development and the correlations with sex, gestational age, and maternal age that were observed

Community Perspectives Associated With the African PsA-TT (MenAfriVac) Vaccine Trials.

BACKGROUND: The Meningitis Vaccine Project (MVP) was established to address epidemic meningitis as a public health problem in sub-Saharan Africa and, to that end, worked to develop a group A meningococcal conjugate vaccine, PsA-TT. METHODS: Experiences in 4 clinical trial sites are described. Culturally sensitive collaborative strategies were adopted to manage acceptable communication methods, peculiarities with the consent process, participant medical issues, community care, and death. RESULTS: The clinical trials were completed successfully through community acceptance and active community collaboration. The trials also strengthened the capacities in the participating communities, and actively worked to resolve community problems. CONCLUSIONS: The understanding and integration of sociocultural realities of communities were major assets in the conduct and acceptance of these trials. MVP succeeded in these sites and provided a sound example for future clinical studies in Africa. CLINICAL TRIALS REGISTRATION: ISRTCN78147026 (PsA-TT 002); ISRCTN87739946 (PsA-TT 003); ISRCTN82484612 (PsA-TT 004); PACTR ATMR2010030001913177 (PsA-TT 006); and PACTR201110000328305 (PsA-TT 007)