Editors' ChoiceInfectious Disease

No one is naïve: Young infant’s immunity can dodge Darwinian selection

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Science Translational Medicine  07 Feb 2018:
Vol. 10, Issue 427, eaar7530
DOI: 10.1126/scitranslmed.aar7530

Abstract

Unlike adults, young infant antibody responses against respiratory syncytial virus are biased toward limited antigenic sites, suggesting a blueprint for future infant and age-specific vaccines.

A critically infected infant is every parent's worst nightmare. Respiratory syncytial virus (RSV) infections cause thousands of infant deaths per year globally, yet there are no vaccines. In adults, antibodies against infections are made when a naïve B cell undergoes maturation through a stochastic somatic mutation process followed by a Darwinian selection of high-affinity cells. Infants, however, present numerous challenges that restrict B cell differentiation. Goodwin et al. characterized the immune response to RSV in infants, reasoning that understanding specificity and neutralizing activity of RSV-induced antibodies in infants could facilitate the development of effective vaccines.

Two targets for RSV are known—a metastable prefusion antigen (preF) and a highly stable postfusion antigen (postF). Targeting postF is ineffective because resulting antibodies are nonneutralizing. The authors suggest that postF antigen immunization may also cause vaccine-enhanced disease, possibly related to nonneutralizing antibodies and immune complexes affecting lung pathologies. Using sequencing, structural analysis, and binding affinity analysis on sera isolated from RSV-infected infants, researchers show that the infant responses are focused on antigenic sites I and III of the RSV protein. These sites are not dominant in adults. In addition, this study shows that in young infants (<3 months), responses were dominated by antibodies directed against site III (preF) and exhibited medium-to-high neutralizing activity, whereas in older infants (>6 months), the responses are directed against site I (postF) with nonneutralizing activity. The data highlight the need for considering age groups within the infant population while designing vaccines and therapeutics. These antibodies are present in the naïve B cell repertoire and not differentiated B cells, suggesting that the hallmark affinity maturation is not a requirement in infants. The authors speculate that developing vaccination strategies that elicit preF and antigenic site III antibodies are likely beneficial for young infants. Whether underlying conditions (i.e., premature babies, microbiome), vaccine composition, and activity of preF antibodies could impact the protective response remains unknown. Understanding these trade-offs will be important for developing future age-specific RSV vaccines.

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