REVIEWS B-cell responses to vaccination at the extremes of age Claire-Anne Siegrist* and Richard Aspinall‡ Abstract | Infants and the elderly share a high vulnerability to infections and therefore have specific immunization requirements. Inducing potent and sustained B‑cell responses is as challenging in infants as it is in older subjects. Several mechanisms to explain the decreased B‑cell responses at the extremes of age apply to both infants and the elderly. These include intrinsic B‑cell limitations as well as numerous microenvironmental factors in lymphoid organs and the bone marrow. This Review describes the mechanisms that shape B‑cell responses at the extremes of age and how they could be taken into account to design more effective immunization strategies for these high‑risk age groups. Infant Respiratory and diarrhoeal diseases caused by some have previously overcome, from which they can suffer A ≤ 12-month-old human pathogens — respiratory syncytial virus (RSV), mea- increasingly severe symptoms. Numerous infections baby or a ≤ 3-week-old mouse sles virus, Bordetella pertussis, Streptococcus pneumo- have a higher incidence in the elderly and have a higher (experimental definition). niae, Haemophilus influenzae type b (Hib), rotavirus mortality rate than in younger adults4,5. For example, in or Salmonella spp. —claim the lives of more than 1.6 the United States, the yearly return of influenza and RSV Neonate 1 A ≤ 28-day-old human infant million young children each year , and the global infant infections between 1990 and 1999 was responsible for 6 or a ≤7-day-old mouse. mortality rate still amounts to 49 deaths per 1,000 live 51,203 and 17,358 deaths, respectively . In an average year, births (see the World Health Organization (WHO) influenza, invasive pneumococcal disease and hepatitis B health statistics website). The abrupt transition at birth account for more than 50,000 deaths in the United States, from a sterile intra-uterine environment to a foreign with older individuals being 1,000 times more likely to environment places neonates in a challenging situation. die of these vaccine-preventable diseases than children Innate immune responses can be readily elicited at birth, living in developed countries7. although with specific characteristics (reviewed in REF. 2), Current vaccines mediate their protective efficacy but they are transient and insufficient for immune pro- through the generation of neutralizing antibodies. tection. Furthermore, early immune protection initially Decades of studies have shown that antigen exposure relies on IgG antibodies of maternal origin3, the levels of in early life results in blunted, delayed or undetectable which decline after birth with a half-life of 21–30 days. antibody responses to infections and immunizations. Therefore, infants would become vulnerable to infec- Historically, the neonatal immune system has been con- tions within a short time frame without the development sidered to be poorly competent in generating immune *WHO Collaborative Center of adaptive immunity to confer sustained protection. responses and instead to be polarized towards the for Neonatal Vaccinology, As adaptive immunity in infants is readily amenable induction of immune tolerance8. A conceptual switch Departments of Pathology– Immunology and Pediatrics, to enhancement through vaccination, great efforts and occurred in the late 1990s through numerous demon- Medical Faculty of the resources have been dedicated to infant immunization, strations that adult-like B- and T-cell responses could be University of Geneva, which has had a notable impact on morbidity and mor- achieved in early life under specific conditions of stim- Centre Medical Universitaire, tality. However, early-life immune responses are weaker ulation (reviewed in REFS 9,10). However, as early-life 1 rue Michel Servet, 1211 Geneva 4, Switzerland. and of shorter duration than those that are elicited in antibody responses markedly differ from those elicited ‡Translational Medicine, immunologically mature hosts. Consequently, vaccine in mature hosts, great challenges remain to be encoun- Cranfield Health, Vincent efficacy in this vulnerable population is limited. tered during vaccine development. At the other extreme Building, Cranfield University, This susceptibility to infection at the start of life is of age, the capacity to induce protective antibody at a Bedfordshire MK43 0AL, UK. mirrored in those who approach the end of the nor- sufficient titre to prevent infection declines significantly Correspondence to C.-A.S. 11 e-mail: mal life expectancy curve. Indeed, the elderly not only with age: in individuals of 65 years or older, influenza 12 [email protected] have problems in dealing with new pathogens but and hepatitis B vaccines induce protective antibody doi:10.1038/nri2508 also have difficulties in responding to pathogens that they titres in less than half of their recipients. NATURE REVIEWS | IMMUNOLOGY VOLUME 9 | MARCH 2009 | 185 © 2009 Macmillan Publishers Limited. All rights reserved REVIEWS Table 1 | Human B-cell responses at the extremes of age Cell type or site Characteristics in infants Characteristics in the elderly Naive B cells Decreased expression of cell‑surface receptors Limited generation of naive B cells (CD21, CD40, CD80 and CD86) Plasma cells Limited IgG responses to protein antigen under Poor IgG responses to protein antigen 12 months of age Limited IgG responses to most polysaccharide Poor IgG responses to most polysaccharide antigens under 18–24 months of age antigens Limited persistence of IgG antibodies under Decreased persistence of IgG antibodies 12 months of age Memory B cells Effective priming of memory B cells at and Accumulation of memory B cells of restricted before birth diversity Progressive diversified IgG repertoire Limited diversified IgG repertoire Limited affinity maturation under 4–6 months Affinity maturation is not affected by age of age Germinal centres Impaired germinal centre responses* Impaired germinal centre responses* Limited functional FDC network* Limited functional FDC network* Bone marrow Limited access to plasma cell niches* Limited access to plasma cell niches* Responses are compared with healthy adults. *Shown in mice. FDC, follicular dendritic cell. In this Review, we discuss the mechanisms that Induction of a primary response. The mechanisms could account for the limitations of B-cell responses at that shape B-cell responses in early life were identified the extremes of age, which are both interesting biologi- using neonatal mouse immunization models that were cal phenomena and key considerations for the design of developed to reproduce the main limitations of immune more effective immunization strategies. responses to vaccines that are administered at an early age (reviewed in REFS 9,26) (FIG. 1). There are numerous B-cell responses in early life differences (TABLE 1) between neonatal and adult mouse Postnatal maturation of antibody responses. The vulner- splenic B cells (reviewed in REF. 10), although fewer ability of children younger than 18–24 months of age to differences have been identified by comparing human encapsulated bacteria such as pneumococcus, Hib and peripheral B cells. Specifically, human neonatal B cells meningococcus has long been thought to reflect a gen- express lower levels of the co-stimulatory molecules eral failure to generate T-cell-independent B-cell responses CD40, CD80 and CD86, which decreases their responses to most bacterial polysaccharides (reviewed in REF. 13). to CD40 ligand (CD40L) and interleukin-10 (IL-10)27 However, age also has a direct effect on the magnitude expressed by T cells. Splenic marginal zone infant B cells of antibody responses to T-cell-dependent protein anti- express lower levels of CD21 (REF. 28), which limits their gens (TABLE 1). As an example, RSV infection only triggers capacity to respond to polysaccharide–complement limited T-cell-dependent B-cell responses in young infants, complexes29. The expression of TACI (transmembrane which has implications for the development of live- activator and calcium-modulating cyclophilin-ligand attenuated intranasal RSV vaccines14. Infant vaccine stud- interactor; also known as TNFRSF13B), an important ies worldwide have shown that there is an age-dependent co-stimulatory receptor, is also decreased on both neo- T-cell-independent B-cell stepwise increase in the rates of seroconversion and the natal mouse30 and neonatal human B cells, particularly response 27 A B-cell response that is magnitude of antibody responses, regardless of whether those born prematurely . 15,16 elicited without the repeat immunization is administered . In fact, the In addition, B-cell responses in early life are influenced requirement for CD4+ T-cell use of accelerated schedules in which immunizations by numerous extrinsic factors (TABLE 1). Antibodies of co-stimulation, which is a are initiated at 6–8 weeks of age and repeated at 4-week maternal origin bind to vaccine antigens in an epitope- characteristic of responses to intervals increases the proportion of infants who fail to specific manner and therefore prevent infant B cells most polysaccharide antigens. respond to certain immunogens17,18 and might decrease from accessing immunodominant vaccine epitopes31. 32 33 T-cell-dependent B-cell protective efficacy against many important infant patho- Furthermore, human and mouse neonates have low response gens, such as pertussis1,19. Direct evidence of the post- levels of serum complement component