Small babies, big data

The work, published today in Nature Communications, profiled molecular changes in the first week of newborn life, including what genes are turned on, what proteins are being made and what metabolites are changing. It establishes a common developmental pathway for the first week of a newborn's life, providing a baseline to further our understanding of newborn health and, in particular, the impacts of vaccines on newborns.

"Most infections in the world occur early in life, and newborns have the greatest susceptibility and the worst outcomes," says Ofer Levy, MD, PhD, director of the Precision Vaccines Program at Boston Children's Hospital and a senior author on the paper. "This work provides a valuable window into health and disease in the first week of life."

The research team includes members of the Expanded Program on Immunization Consortium (EPIC), an international collaboration to employ a systems biology approach to understanding vaccine action in early life. Levy partnered with Beate Kampmann, MD, PhD, of the London School of Hygiene & Tropical Medicine (LSHTM) and the Medical Research Council (MRC)- The Gambia, and Tobias Kollmann, MD, PhD, University of British Columbia (UBC) to establish the consortium, which has its administrative hub in the Precision Vaccines Program.

Tiny sample, big knowledge

Previous efforts to gather data on newborn development have been limited by the challenge of obtaining a large enough blood sample from a tiny newborn. The team overcame this challenge with new techniques, partnering with Robert Hancock, PhD of UBC, who led an RNA analysis, and Hanno Steen, PhD of Boston Children's, who led a proteomics analysis. Using sophisticated software to analyze complex data derived from less than half a teaspoon of blood, the UBC labs of Hancock and Scott Tebbutt, PhD found thousands of changes over the first week, including changes in gene expression and components of immune defense such as interferons, neutrophil function and complement pathways.

"We demonstrated that it's possible to recruit newborns in a resource-poor setting, obtain small amounts of their blood, process it, ship it, conduct systems biology assays and integrate the results -- turning big data into knowledge," says Levy. "Key to our analysis was comparing each newborn at day 1, day 3 and day 7 to their own baseline condition on the day of birth. That's when we discovered dramatic molecular changes driven by development."

An inter-continental effort

The researchers piloted their systems biology approach with a group of infants from The Gambia in West Africa after first obtaining permission from village elders and informed consent from mothers in local languages such as Mandinka, Fula and Wolof. They then validated their approach with a second group of Australasian newborns recruited by William Pomat, PhD of the Papua New Guinea Institute of Medical Research and Anita van den Biggelaar, PhD of the University of Western Australia.

The two independent cohorts showed a common, highly dynamic developmental trajectory. The findings suggest that the changes do not occur at random, but instead follow an age-specific pathway.

"This common trajectory is exciting as it allows us to ask bigger questions about the differences between different populations and the impact of biomedical interventions such as vaccines on development," says Levy.

Optimizing vaccines in early life

The study establishes a baseline for health and disease in early life that can help measure responses to key medical interventions and the impact of factors such as diet, disease and maternal health. Levy is particularly interested in studying the impact of immunization. Newborns' responses to immunization are distinct from those of older individuals, and much needs to be learned to optimize the use and benefit of vaccines in early life.

"Currently, most vaccines are developed by trial and error," says Levy. "We seek deep molecular insight into vaccine function in early life so we can better develop infant vaccines for the future."

The study was supported in part by the NIH's National Institute of Allergy and Infectious Diseases as part of the Human Immunology Project Consortium (5U19AI118608-02) and by the Precision Vaccines Program. Co-first authors were Amy Lee, Casey Shannon and Nelly Amenyogbe of UBC; Tue Bennike of Aalborg University, Denmark; Joann Diray-Arce of Boston Children's and Olubukola ("Bukky") Idoko of LSHTM/MRC-Gambia. Co-senior authors were van den Biggelaar, Steen, Tebbutt, Kampmann, Levy and Kollmann.