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Protection against infectious diseases is provided to young infants by passive immunity through the transplacental transfer of immunoglobulin G during pregnancy and through immunoglobulin A in breast milk [1–7]. Despite the obvious benefits of these antibodies to the youngest infants, their levels wane over time, necessitating the development of active immunity through vaccination. The timing of primary vaccination is complex, driven by the need to provide protection prior to a time when the infant is likely to be exposed to disease, by the possibility of interference with vaccine-induced immunity by passively acquired maternal antibodies, and, finally, by considerations of the developing infant immune system [7–9]. The titers of transplacentally transferred passive antibodies (PA) provided to infants are, in part, determined by antibody titers present in the mother during pregnancy. These maternal titers are affected by her nutritional and immune status, and evidence demonstrates that antibody titers induced by vaccination are typically lower than titers induced by natural disease [3, 5, 6, 10]. After decades of vaccination against childhood diseases, it is clear that successful vaccine programs have resulted in dramatic decreases in morbidity and mortality. However, the increasing prevalence of vaccine-derived maternal antibodies has also led to unexpected outcomes. This is most evident in the emergence of measles susceptibility in young infants living in highly vaccinated populations where the measles vaccine has been in use for decades [11–14]. Historically, in developed nations protection against measles among infants <12 months of age was provided by a combination of PA and herd immunity, supported by high population immunization rates. However, this barrier has been disrupted, to a certain extent, by global importation of measles and, paradoxically, by the success of the measles vaccine programs, as vaccine-induced PA wanes earlier in infants as compared to PA derived from maternal natural infection [4, 8, 15, 16]. Measles outbreaks in countries with high measles vaccine coverage have demonstrated a shift in measles incidence to children <12 months of age [17–19], before primary measles vaccination commences in most developed countries. Further, the number of susceptible infants aged <12 months is expected to increase among highly vaccinated populations as the majority of women in child bearing years have vaccine-induced immunity to measles, with recent studies showing 99% of infants born to vaccinated mothers lacking detectable antibodies to measles by 6 months [3, 4]. Waaijenborg and colleagues eloquently highlight this phenomenon in this issue of the Journal by comparing titers of antibodies against measles, mumps, and rubella in 2 distinct populations in the Netherlands, one with high vaccination rates and one with opposition to vaccination and, thus, low vaccination rates and presumably higher rates of immunity induced by natural disease. As with previous studies, the authors note significantly lower measles antibody titers in infants born to women from the highly vaccinated populations in comparison to those born to mothers with presumed naturally induced immunity. In addition, the authors also compared mumps and rubella titers in the 2 populations, showing higher rubella titers in mothers from the population with low vaccination rates and low levels of mumps titers in both groups. Varicella was used in this study as a “control” disease because it is caused by a naturally circulating virus in Received and accepted 7 March 2013; electronically published 8 May 2013. Correspondence: Hayley A. Gans, MD, 300 Pasteur Dr, Rm G 312, Stanford University School of Medicine, Stanford, CA 94305-5208 (hagans@stanford.edu). The Journal of Infectious Diseases 2013;208:1–3 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jit144

Loss of Passively Acquired Maternal Antibodies in Highly Vaccinated Populations: An Emerging Need to Define the Ontogeny of Infant Immune Responses