Seasonal variation in the non-specific effects of BCG vaccination on neonatal mortality: three randomised controlled trials in Guinea-Bissau

Abstract

The BCG vaccine protects non-specifically against other diseases than tuberculosis. Three randomised controlled trials of early BCG in Guinea-Bissau found a 38% reduction in all-cause neonatal mortality. Little is known about the underlying mechanisms. In Guinea-Bissau, prevalent infectious diseases display distinct seasonality. Revisiting the three trials (>6500 infants) comparing early BCG versus no early BCG in low weight infants on all-cause neonatal mortality over 12 consecutive years, we explored the seasonal variation in BCG’s effect on mortality. In a subgroup of participants, adaptive and innate cytokine responses were measured 4 weeks after randomisation. Consistently over the course of the three trials and 12 years, the effect of BCG on all-cause neonatal mortality was particularly beneficial when administered in November to January, coincident with peaking malaria infections. During these months, BCG was also associated with stronger proinflammatory responses to heterologous challenge. Recent studies have suggested a protective effect of BCG against malaria. BCG may also ameliorate immune-compromising fatal effects of placental malaria in the newborn.

Iron Deficiency Anemia at Time of Vaccination Predicts Decreased Vaccine Response and Iron Supplementation at Time of Vaccination Increases Humoral Vaccine Response: A Birth Cohort Study and a Randomized Trial Follow-Up Study in Kenyan Infants

“…As our main outcomes, we assessed antibody concentrations and seroprotection, but these are only surrogates of disease protection induced by vaccination. The Bacillus-Calmette-Guérin (BCG) vaccine may provide protection against other infectious diseases than tuberculosis ( 41 ) but we did not record BCG administration nor measure BCG vaccine response. In the randomized trial, we compared the MV response in infants receiving a MNP with iron to infants receiving the same MNP without iron.…”

COVID-19: A model correlating BCG vaccination to protection from mortality implicates trained immunity

“…Neonatal BCG vaccination has been shown to be associated with lower mortality rates among both TB-exposed and TB-unexposed children (Thysen et al, 2020). Three randomized controlled trials of early BCG vaccination in Guinea-Bissau found a 38% reduction in all-cause neonatal mortality (Jensen et al, 2020). These effects do not only benefit infants, as a recent clinical trial revealed that revaccinating at-risk teenagers with the BCG vaccine they first got as infants could significantly reduce the threat of these patients becoming carriers of TB infection (Nemes et al, NEJM 2018).…”

Lessons from Bacillus Calmette-Guérin: Harnessing Trained Immunity for Vaccine Development

“…Furthermore, trained immunity is affected by the timing of BCG administration. In clinical trials in Guinea-Bissau, BCG immunization to low-weight infants administered between November and January, during peak malaria infections, both beneficially reduced all-cause neonatal mortality and resulted in stronger responses to heterologous stimulation in whole blood assays, suggesting that there may be seasonal considerations for BCG immunization [ 51 ]. Trained immunity effects, as well as specific adaptive responses, were stronger when BCG was administered to adult volunteers in the early morning versus later in the morning, while evening vaccination produced almost no enhancement in specific and nonspecific effects [ 52 ].…”