In general, live attenuated vaccines stimulate potent neutralizing antibody and CTL responses. However, humoral responses may be abrogated in the presence of maternal antibody. Measles, mumps, bacille Calmette–Guerin (BCG) and varicella vaccines are all live-attenuated. Infants have equivalent cellular immune responses to measles and mumps vaccines independent of maternal antibody as measured by T-cell proliferation and IFN-γ production; and cellular responses are also equal to those of adults . Responses to BCG vaccination as indicated by tuberculin skin test are affected by pubertal stage and testicular volume. Responses during puberty are greater than post-pubertal responses and correlate with serum concentrations of DHEA sulphate and AED . Age affects the immune response to varicella vaccination to the extent that age-dependent dose adjustments are necessary, particularly around adolescence. When administered to children under 13 years of age, varicella vaccine induces protective antibodies in > 95% of recipients after a single dose whereas susceptible persons > 13 years of age require two doses separated by 4–8 weeks .
The concept of paediatric live-attenuated preventative HIV-1 vaccines has been tested in the animal model. Van Rompay et al. immunized groups of infant macaques at birth and 3 weeks of age with live-attenuated SIVmac1A11 and then challenged them orally at 4 weeks of age with SIVmac251. All animals became infected, but the immunized animals had lower viraemia and longer disease-free survival than unvaccinated controls . However, since another study found that macaques immunized with live attenuated, nef-deleted SIV eventually succumbed to AIDS  the strategy of a live-attenuated HIV vaccine has been suspended. Therefore no data exists in humans for this type of HIV vaccine.
Examples of killed vaccines in use or in trials for children to date include hepatitis A, whole cell pertussis, and tick-borne encephalitis. The dosage of both forms of inactivated hepatitis A vaccines licensed in the US are half of the adult dose in those 2–18 years of age . Infants with passively acquired maternal antibody to hepatitis A virus responded to highly purified, formalin-inactivated hepatitis A vaccine with lower antibody titres after vaccination; responses to booster doses at 6 years of age also remain persistently lower . Although humoral responses to hepatitis A vaccine are strong throughout adolescence, seroconversion rates after one dose of vaccine decrease with increasing age . Tick-borne encephalitis vaccine also demonstrates an age-dependant antibody response in children aged 6 months to 12 years  that is likewise affected by maternal antibody titres.
Inactivated vaccines against HIV raise concerns of poor immunogenicity as well as safety. So far, only trials using inactivated gp120 depleted virus in HIV-1-infected adults and children as therapeutic vaccination have been conducted . In the animal model, macaques immunized with formalin-inactivated SIV were protected against challenge with pathogenic SIV . However, it was later found that the protective effect was mediated by antigens from the human cells used to grow the viral strain . Rats immunized at birth with inactivated, gp120-depleted HIV-1 developed strong IFN-γ-producing cell-mediated immune responses . Immunization of pregnant rats followed by neonatal immunization resulted in a mixed cell-mediated and humoral response in the neonatal animal. However, this inactivated HIV did contain immunostimulatory CpG DNA as an adjuvant .
The immune response to polysaccharide vaccines is relevant to HIV vaccinology in that HIV gp120 is highly glycosylated and is therefore a TI immunogen. The ability to respond to polysaccharide antigen develops late in embryonic development  and age-dependant responses to various polysaccharide vaccines are well documented . Of further importance, the immunogenicity of polysaccharide vaccines in infants is enhanced by techniques such as conjugation and the immunogenicity of different conjugates is age-dependent . For example, conjugation of the poorly immunogenic Haemophilis influenzae type b (Hib) capsular polysaccharide, PRP, to various haptens, renders them far more immunogenic in infants than unconjugated polysaccharide vaccine . However, PRP-D (diptheria toxoid) elicits weaker responses in those less than 6 months of age, whereas Haemophilus B oligosaccharide conjugate vaccine, HbOC, produces a weak response at 2 months but a significant response to the 4-month booster [80,85].
Recombinant hepatitis B vaccines are the most well-known example of a subunit vaccine, and age-related responses to this and other vaccines are well-documented (Table 2). Multiple HIV-1 recombinant protein vaccines have now been evaluated in phase I trials in humans and a phase III trial has been completed . The first phase I preventative HIV-1 vaccine trial in neonates born to HIV-1 infected mothers employed recombinant gp120 . The infants were administered recombinant gp120 with adjuvant MF59 using various schedules. Infants were able to mount lymphoproliferative and antibody responses [14,18]. An important finding was that high levels of anti-HIV maternal antibody found at earlier ages did not affect the antibody response in infants receiving the accelerated schedule. Such HIV envelope candidate vaccines elicit high antibody titres to gp120, but their neutralizing capacity is mostly for in vitro T-cell line adapted virus and not primary isolates . However, new evidence suggests that it may be possible to mimic the critical structure of gp120 or gp140 necessary to stimulate production of neutralizing antibodies .
Peptide vaccines can potentially deliver specific epitopes using systems such as lipopeptides that enable utilization of the MHC class I pathway. SPf66 malaria vaccine is a synthetic protein with amino acid sequences derived from pre-erythrocytic and asexual blood-stage proteins of Plasmodium falciparum. Responses to this vaccine are strongly age-related; no efficacy of this vaccine was found in Gambian children aged 6–11 months  whereas a 31% efficacy rate was found in 1–5-year-old children in Tanzania . A lack of a sustained anti-SPf66 IgG response was also found in infants compared to older children in this trial. Efficacy trials of the same vaccine in Brazil showed a significant level of protection in those older than 20 years with no intercurrent malaria during vaccinations, but no protection among those less than 20 years of age . At present, HIV-1 lipopeptide vaccines have only been tested in phase I trials in adults .
DNA vaccination at birth can prime both CTL and antibody responses in animals even when the recipient carries maternal antibody, providing long-term protection in mice . In contrast to the strong IgG2a skewing of the humoral immune response after conventional vaccination in neonates, DNA vaccines expressing the same antigen may induce similar IgG1 and IgG2a levels in neonate and adult animals . Therefore, DNA technology holds promise for use as neonatal HIV-1 vaccines. To date, there is far less experience with DNA vaccination for other pathogens than for HIV. While responses to DNA vaccines in macaques have been detectable, the naked DNA HIV vaccines that have been evaluated in phase I human clinical trials stimulate only transient weak cellular immune responses in adults . No HIV-1 DNA vaccine has been tested thus far in children. The response to DNA vaccination can be enhanced by boosting with a viral vector .
HIV vaccine development has greatly advanced vector vaccine technology. Multiple viral and bacterial vector-based HIV vaccines are currently in human trials or in development. Safety concerns regarding the use of vaccinia vectors have spurred the development of HIV vaccines based on other viral vectors, including other poxviruses which infect but cannot replicate in human cells, and adenoviruses. Viral vectors provide an excellent means to deliver foreign DNA in a form that utilizes the class I antigen presentation pathway. However, pre-existing antibody titres to the vector delivery system can affect the response to the immunogen and therefore can be affected by age . Toddlers, for example, may have higher adenoviral titres due to exposure in day-care.
In the paediatric macaque model, recombinant pox vaccines expressing Gag, Pol and Env proteins were able to protect neonatal monkeys exposed to mucosal challenge . Vaccination using MVA-SIVgagpolenv and ALVAC-SIVgagpolenv (which employs a canarypox-based antigen delivery system) both gave partial protection against infection: 11 of the 17 MVA-SIVgagpolenv immunized macaques and only six of the 16 ALVAC-SIVgpe immunized infants became persistently viraemic compared to all of the unimmunized animals . Infant macaques immunized at birth and 3 weeks of age with modified vaccinia virus Ankara (MVA) expressing SIV Gag, Pol, and Env (MVASIVgpe) all became infected after SIVmac239 challenge but lived longer than infected unimmunized controls. Maternal antibodies did not significantly reduce the efficacy of the MVA-SIVgpe vaccine .
Human trials have employed poxvirus vectors in HIV-exposed neonates. PACTG 326 part I evaluated the safety and immunogenicity of ALVAC vCP205 (high-dose versus low dose) . ALVAC vCP205 contains HIV-1 subtype B gp120 gene linked to the transmembrane portion of gp41, plus gag and pol from HIV-1 LAI strain. Lymphoproliferative responses to p24 and gp160 were present in approximately 44% and 33% of vaccine recipients, respectively. CTL responses to Gag and Env were detected in 35% and 24% of vaccines and many of these were detectable as early as 6 weeks . In another arm of PACTG 326, a phase I/II study of ALVAC-HIV vCP1452, a modified recombinant canarypox expressing env, gag, nef and pol genes alone or with subunit gp120 vaccine (AIDSVAX B/B), also showed lymphoproliferative and CTL responses in a few infants at preliminary analysis .
Progressive physiological maturation of the immune system results in age-dependent differences in immune function and responses to vaccines. We have reviewed how humoral and cell-mediated immune function changes from the neonatal period through infancy, puberty and into adulthood. There are many changing influences on immune responses such as maternal antibody in the neonate and the immuno-modulatory effects of sex steroid hormones in adolescence. As a result, vaccine efficacy is often not uniform across these age groups.
The development of an effective HIV vaccine is a major global health priority. In younger age groups, vaccines are greatly needed to prevent horizontal HIV transmission in adolescents and acquisition of HIV infection from breast-feeding in infants. However, to date, no preventive HIV vaccine trials have included adolescents and only two have included neonates born to HIV-infected mothers. The process of development and conduct of clinical efficacy trials in these age groups is constrained by many ethical and legal issues. However, there is also a compelling argument that such vaccines are needed and that a moral imperative exists to develop and test candidate vaccines in these age groups. Potential ways in which the process of vaccine development and testing might take into account the immunological characteristics of the developing immune system are listed in Table 4. Current efforts to develop an HIV vaccine should not be shortsighted but should consider the age-specific functional responses of the maturing immune system.
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