More than 2 million newborns and infants under the age of 6 months die from infection worldwide each year—that's more than 200 every hour. In this context, vaccines are second only to clean drinking water as a cost-effective measure to reduce infant morbidity and mortality. The global eradication of smallpox and the hopefully forthcoming eradication of polio demonstrate the potential power of immunization programs. But despite a suite of vaccinations recommended by the World Health Organization (WHO), including those for tuberculosis, diphtheria, tetanus, pertussis, hepatitis B, and measles, neonates and infants continue to fall victim to such infections each year, highlighting early-life susceptibility and an unmet global need for improved immunization.

Immunization of pregnant mothers, with the consequent, passive trans-placental transmission of antibodies to the fetus, is one potential option to protect neonates. However, this promising strategy might be limited by safety and...

Furthermore, even those vaccines approved for neonate use are based on ad hoc evaluations of vaccinations originally developed for use in older individuals. Optimal development of novel vaccine formulations should take into account a growing body of research characterizing age-dependent development of immunity. White blood cells (leukocytes), in particular antigen-presenting cells, demonstrate impaired immune responses to many stimuli in the first months of life, including reduced production of certain immune signaling proteins (cytokines) required for robust cell-mediated immunity. Adjuvants, molecules that enhance responses to vaccine antigens, can be added to vaccine formulations and represent an important strategy to boost immune responses, but neonatal leukocytes demonstrate distinct responses to different adjuvants when compared to adult leukocytes.

To consider these differences when developing novel vaccines for infants, researchers can use human neonatal and infant primary leukocytes cultured with the relevant human humoral components, including autologous blood plasma that contains distinct components that modulate early-life immunity. Results from such in vitro studies should inform the selection of appropriate preclinical animal models that most closely mimic the neonatal and infant immune responses. Follow up clinical trials should ensure that rigorous biomarker evaluation, including genome-wide transcriptional and proteomic approaches, are used to further refine age-specific markers of safety and efficacy, and should be designed to test earlier ages of initial immunization.

Optimizing neonatal and infant vaccine formulations will also entail evaluation of distinct routes of administration, combination vaccines, live vector vaccines, and the possibility of genetic immunization. Finally, post-approval phase IV clinical evaluations can ultimately verify that immune responses known to be protective in adults or older children are also protective against disease in neonates and young infants.

Although there are several challenges in developing vaccines for newborns and infants, proof-of-concept exists that this approach can be safe and effective and represents a promising strategy to reduce infant mortality. The time for change is now. More than 3 newborns and young infants die each minute from infection worldwide, but improved vaccination programs can go a long way to mitigating this terrible loss.

Ofer Levy, MD, PhD, is a staff physician in the Division of Infectious Diseases at Children’s Hospital Boston and an Assistant Professor at Harvard Medical School. His laboratory studies immunity in immunocompromised hosts. He can be reached at For more on Levy’s views on infant vaccinations, see his recent perspective in Science Translational Medicine.

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