10.5061/DRYAD.0GB5MKM1S
Siegers, Kris E.
0000-0003-3540-1747
University Medical Center Utrecht
van Herwaarden, Antonius E.
Radboud University Nijmegen Medical Centre
de Waard, Jacobus H.
Central University of Venezuela
del Nogal, Berenice
Children's Hospital "Dr. J. M. de los Ríos"
Hermans, Peter W.M.
University Medical Center Utrecht
van Tienoven, Doorlène
Radboud University Nijmegen
Berbers, Guy A.M.
Radboud University Nijmegen
de Jonge, Marien I.
University Medical Center Utrecht
Verhagen, Lilly M.
University Medical Center Utrecht
The metabolic hormone adiponectin affects the correlation between
nutritional status and pneumococcal vaccine response in vulnerable
indigenous children
Dryad
dataset
2021
13-valent pneumococcal conjugate vaccination
Indigenous children
chronic malnutrition
Metabolic hormones
Adiponectin
Venezuela
FOS: Other medical sciences
Pfizer Venezuela*
Clinical Research Talent fellowship UMC Utrecht*
2022-06-26T00:00:00Z
2022-06-26T00:00:00Z
en
80407 bytes
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CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
Background: Almost 200 million children worldwide are either
undernourished or overweight. Only a few studies have addressed the effect
of variation in nutritional status on vaccine response. We previously
demonstrated an association between stunting and an increased
post-vaccination 13-valent pneumococcal conjugate vaccine (PCV13)
response. In this prospective study, we assessed to what extent metabolic
hormones may be a modifier in the association between nutritional status
and PCV13 response. Methods: Venezuelan children aged 6 weeks to 59 months
were vaccinated with a primary series of PCV13. Nutritional status and
serum levels of leptin, adiponectin and ghrelin were measured upon
vaccination and their combined effect on serum post-vaccination antibody
concentrations was assessed by generalized estimating equations
multivariable regression analysis. Results: A total of 210 children were
included, of whom 80 were stunted, 81 had a normal weight and 49 were
overweight. Overweight children had lower post-vaccination antibody
concentrations than normal weight children (regression coefficient -1.15,
95% CI -2.22 – -0.072). Additionally, there was a significant
adiponectin-nutritional status interaction. In stunted children, higher
adiponectin serum concentrations were associated with lower post-PCV13
antibody concentrations (regression coefficient -0.19, 95% CI -0.24 –
-0.14) while the opposite was seen in overweight children (regression
coefficient 0.14, 95% CI 0.049 – 0.22). Conclusion: Metabolic hormones,
in particular adiponectin, may modify the effect of nutritional status on
pneumococcal vaccine response. These findings emphasize the importance of
further research to better understand the immunometabolic pathways
underlying vaccine response and enable a future of optimal personalized
vaccination schedules.
Study population and setting The Warao Amerindians live in Antonio Díaz, a
municipality located in the Orinoco River Delta in Venezuela that can only
be reached by boat. This study included Warao children aged 6 weeks to 59
months from the following nine indigenous communities in Antonio Díaz:
Araguabisi, Araguaimujo, Arature, Bonoina, Guayaboroina, Ibaruma, Jobure
de Curiapo, Merejina, and Winikina. Door-to-door visits were made to
inform all parents of age-eligible children present in these communities
during study visits. Children were included between May and November 2012.
The original study was registered in a primary registry of the World
Health Organization (ICTRP / RPCEC) with identifier number RPCEC00000158.
This study included a subset of the original cohort as described in
Verhagen et al. 2016 (14), i.e., all children who were stunted or
overweight with a serum sample available and an equally large control
group of normal weight children. Children who met multiple definitions,
i.e. being overweight and stunted, were not included in the subset. Other
exclusion criteria were known immunosuppression/deficiency, previous
vaccination with any pneumococcal vaccine and major congenital
malformations. Vaccination schedule Children aged 6 weeks to 6 months, 7
to 23 months and 24 to 59 months received a primary series of PCV13
including respectively 3, 2 and 1 dose(s) following CDC guidelines (30).
PCV13 contains capsular polysaccharides of 13 serotypes of Streptococcus
pneumoniae (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F)
conjugated to CRM-197, a non-toxic variant of diphtheria toxin, as carrier
protein (Fig 1A). Data collection Patient characteristics Physical
examination was performed in all included children, including
anthropometric measurements. Pre-vaccination anthropometric measurements
were transformed into weight-for-age Z-scores (WAZ), height-for-age
Z-scores (HAZ) and Body Mass Index (BMI) Z-scores based on WHO standards
(31). Stunting was defined as HAZ <-2 standard deviation (SD).
Overweight was defined as a BMI above +1SD. A normal nutritional status
was defined as a BMI ≤ +1SD and a HAZ ≥ -2SD. Sampling and laboratory
methods Blood samples were taken just before the first vaccination and
again at 1.5 months (median 6.7 weeks (IQR 6.4–6.9 weeks)) after
completion of the primary PCV13 vaccination series (Fig 1B). For a
detailed description of the sampling and storage procedures we refer to
Verhagen et al. 2016 (14). Determination of pneumococcal serotype-specific
serum immunoglobulin G (IgG) concentrations was performed at the National
Institute for Public Health and the Environment in Bilthoven, The
Netherlands, using a fluorescent bead-based multiplex immunoassay (32).
Metabolic hormones were determined in pre-vaccination serum samples. Serum
ghrelin and leptin levels were analysed (in 100 µL) by radioimmunoassay
(GHRT-89HK and HL-81K respectively, EMD Millipore Corp.; Missouri USA) as
specified by the manufacturer’s instructions. Serum adiponectin
concentration (High Molecular Weight (HMW) Adiponectin) was analysed (in
10 µL) by chemiluminescence enzyme immunoassay on a Lumipulse analyser
G600II (234778, FuijRebio, Gent; Belgium) as specified by the
manufacturer’s instructions. Ethical considerations Approval by the
ethical committee of the Instituto de Biomedicina, Caracas, Venezuela, was
granted. In addition, written permission to carry out the study was
obtained from the Delta Amacuro Indigenous Health Office and from
community leaders of each included community. Children were included upon
written informed consent of parents or primary caregivers. Statistical
analyses Categorical variables were analysed using Chi-square or Fisher’s
exact test, as appropriate. For continuous variables, the unpaired
Student’s t test, nonparametric Mann-Whitney U test or Kruskal Wallis test
was used depending on whether the variables were normally distributed
(Kolmogorov-Smirnov’s test, p >0.05). We used the mean of
serotype-specific log-transformed pneumococcal antibody levels as a
read-out for pneumococcal vaccine response. Linear regression was
performed using the log-transformed antibody concentrations. In our
multivariable models we included the following ten covariates of interest
and potential confounders: age (continuous), time from primary series
completion until post-vaccination blood sampling (continuous), leptin
(continuous), adiponectin (continuous) and ghrelin (continuous, per 20
pg/mL) concentration, community (categorical), mean pre-vaccination
antibody response (continuous), BMI (categorical), and HAZ (categorical).
Generalized estimating equations (GEE) were used to fit a multivariable
linear regression model aimed at identifying possible associations between
nutritional status and metabolic hormones and their interactions
(independent variables) and post-vaccination log-transformed antibody
concentrations (dependant variable), while adjusting for the potential
confounders mentioned above. GEEs account for correlation and lack of
independence of responses for individuals in clusters within communities
using an independence working covariance structure and robust variance
estimators. Models were run separately for both stunted vs. non-stunted
(i.e. including normal weight and overweight children) and overweight vs.
non-overweight children (i.e. including normal weight and stunted
children). For all statistical analyses SPSS software version 25 was used.
Statistical significance was set to p-value <0.05.