Research Article: Impact of nutritional supplementation during pregnancy on antibody responses to diphtheria-tetanus-pertussis vaccination in infants: A randomised trial in The Gambia

Date Published: August 6, 2019

Publisher: Public Library of Science

Author(s): Sandra G. Okala, Momodou K. Darboe, Fatou Sosseh, Bakary Sonko, Tisbeh Faye-Joof, Andrew M. Prentice, Sophie E. Moore, Lars Åke Persson

Abstract: BackgroundExposure to a nutritionally deficient environment during fetal life and early infancy may adversely alter the ontogeny of the immune system and affect an infant’s ability to mount an optimal immune response to vaccination. We examined the effects of maternal nutritional supplementation during pregnancy on infants’ antibody responses to the diphtheria-tetanus-pertussis (DTP) vaccine included in the Expanded Programme on Immunisation (EPI).Methods and findingsThe Early Nutrition and Immune Development (ENID) trial was a randomised, partially blinded trial conducted between April 2010 and February 2015 in the rural West Kiang region of The Gambia, a resource-poor region affected by chronic undernutrition. Pregnant women (<20 weeks’ gestation) with a singleton pregnancy (n = 875) were randomised to receive one of four supplements: iron-folic acid (FeFol; standard of care), multiple micronutrient (MMN), protein-energy (PE), or PE + MMN daily from enrolment (mean [SD] 13.7 [3.3] weeks’ gestation) until delivery. Infants were administered the DTP vaccine at 8, 12, and 16 weeks of age according to the Gambian Government protocol. Results for the primary outcome of the trial (infant thymic size) were described previously; here, we report on a secondary outcome, infant antibody response to vaccination. The effects of supplementation on mean DTP antibody titres measured in blood samples collected from infants at 12 weeks (n = 710) and 24 weeks (n = 662) were analysed with adjustment for confounders including maternal age, compliance to supplement, and infant sex and season. At 12 weeks, following a single dose of the vaccine, compared with FeFol (mean 95% confidence interval [CI]; 0.11 IU/mL, 0.09–0.12), antenatal supplementation with MMN or MMN + PE resulted in 42.4% (95% CI 20.1–64.6; p < 0.001) and 29.4% (6.4–52.5; p = 0.012) higher mean anti-diphtheria titres, respectively. Mean anti-tetanus titres were higher by 9.0% (5.5–12.5), 7.8% (4.3–11.4), and 7.3% (4.0–10.7) in MMN, PE, and PE + MMN groups (all, p < 0.001), respectively, than in the FeFol group (0.55 IU/mL, 0.52–0.58). Mean anti-pertussis titres were not significantly different in the FeFol, MMN, and PE + MNN groups but were all higher than in the PE group (all, p < 0.001). At 24 weeks, following all three doses, no significant differences in mean anti-diphtheria titres were detected across the supplement groups. Mean anti-tetanus titres were 3.4% (0.19–6.5; p = 0.038) higher in the PE + MMN group than in the FeFol group (3.47 IU/mL, 3.29–3.66). Mean anti-pertussis titres were higher by 9.4% (3.3–15.5; p = 0.004) and 15.4% (9.6–21.2; p < 0.001) in PE and PE + MMN groups, compared with the FeFol group (74.9 IU/mL, 67.8–82.8). Limitations of the study included the lack of maternal antibody status (breast milk or plasma) or prevaccination antibody measurements in the infants.ConclusionAccording to our results from rural Gambia, maternal supplementation with MMN combined with PE during pregnancy enhanced antibody responses to the DTP vaccine in early infancy. Provision of nutritional supplements to pregnant women in food insecure settings may improve infant immune development and responses to EPI vaccines.Trial registrationISRCTN49285450.

Partial Text: The Expanded Programme on Immunisation (EPI), introduced in 1974 by WHO, established a standardised vaccination schedule for all children globally, initially including diphtheria-tetanus-pertussis (DTP), Bacillus Calmette-Guérin (BCG), oral polio, and measles vaccines [1]. This programme has been implemented widely and is estimated to prevent between 2 and 3 million deaths in children annually. However, despite this, there remains a heavy burden of childhood deaths globally, largely from infection-related causes and especially during the first year of life, when the immune system is most vulnerable [2,3]. In tandem, undernutrition during fetal life and early childhood has been estimated to contribute to 45% of all deaths in children globally [4,5]. Through a vicious circle, undernutrition heightens the risk of infections, while infections predispose to undernutrition [5]. In settings such as sub-Saharan Africa, where supplementary nutrition and routine childhood vaccinations are lifesaving [6], novel interventions are required to break this cycle of infection and undernutrition.

A total of 2,798 participants were recruited for monthly surveillance of pregnancy between January 2010 and June 2013, and 1,195 participants were assessed for eligibility (Fig 1). Of these, 875 (73.2%) participants confirmed pregnant with singleton infants and with GA <20 weeks were randomised to enter the antenatal supplementation phase of the trial. Of the 800 live births, 710 (88.8%) infants had DTP antibody measurements at 12 weeks and 662 (82.9%) at 24 weeks and were included in the ITT analyses. There were no differences in participant characteristics between those remaining in the trial and those lost to follow-up, either from baseline to delivery, or from live births to infants included in the current analysis of antibody responses (S1 Table; S2 Table). In a food insecure environment, in rural sub-Saharan Africa, infants born to women who received nutritional supplementation during pregnancy containing a combination of MMN and PE had measurably better responses to routine vaccines given in early infancy compared with the standard of care (daily FeFol). To our knowledge, this is the first randomised trial to examine the impact of a comprehensive package of nutritional supplements given during pregnancy on antibody responses to vaccinations within the first 6 months of life. This corroborates previous findings indicating a direct role of maternal nutritional status and supplementation on the infant’s immune development and function. Source:


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