2006/02/09 by Heather B. Jaspan, Stephen D Lawn, Jeffrey T. Safrit +1 · 1 citation
Immunology and Microbiology · Social Sciences · Medicine · #HIV Research and Treatment #Vaccine Coverage and Hesitancy #Hepatitis B Virus Studies
paper · doi:10.1097/01.aids.0000210602.40267.60
openalex publication_date 2006/02/09 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30
Introduction Development of an effective HIV-1 vaccine would greatly advance prospects for control of the AIDS epidemic. To date, development of vaccine candidates has been of limited success, demanding innovative approaches to vaccine technology [1]. Inactivated and live attenuated vaccine technology, so successful in vaccinology of other pathogens, is considered too risky for HIV infection [1,2]. Subunit vaccines have been ineffective, failing to elicit neutralizing antibody responses [3,4]. Therefore sterilizing immunity, which is thought to be critical for prevention of infection, seems an unlikely prospect [5]. Current promising DNA and vector-based vaccine candidates in or about to enter phase I trials (www.iavi.org; http://chi.ucsf.edu/vaccines/) are designed to induce cellular immune responses that prevent persistent infection or disease development rather than acquisition of infection. Even if these problems are overcome, the clinical testing of a successful vaccine is estimated to take at least 10 years with the best collaborative global efforts. In 2005, the devastating impact of the HIV/AIDS pandemic continues unabated. UNAIDS estimates that 3.5 million people were newly infected with HIV in the year 2003 and that 700 000 of these infections occurred in those aged less than 15 years [6], most living in sub-Saharan Africa. Paediatric HIV infections are acquired both vertically and horizontally [7], and HIV vaccines might be developed to combat both modes of transmission. A vaccine administered in the neonatal period would almost certainly not prevent HIV infections due to in utero or intrapartum exposure. However, breast-feeding by infected mothers carries a risk of vertical transmission especially in developing countries where formula milk feeding is either unavailable or unaffordable and may itself be associated with a high risk of morbidity. A vaccine that induced an effective immune response in the newborn could reduce this transmission. Horizontal transmission is predominantly sexual, and in sub-Saharan African countries sexual debut can be as young as 10 years, with much trans-generational sex, putting the pre-adolescent at risk for HIV acquisition [8–12]. Adolescents in the developed world are also at high risk of acquiring HIV-1, with 20 000 new infections in 13–24-year olds annually in the United States alone [13]. Children and adolescents are therefore important targets for a preventative HIV vaccine. HIV vaccine clinical trials to date have been conducted almost exclusively in adults. None of the preventative HIV vaccine trials have included adolescents and only two completed trials targeted HIV-1 exposed neonates (PACTG 326 and PACTG 230) [14–19]. In order to license a vaccine for use in children, data should exist on the safety and immunogenicity or efficacy of the vaccine in this age group. Development of vaccines in children is facilitated where there are specific correlates of immunity. For example, trials in adults demonstrated that hepatitis B surface antibody (HepBsAb) titres of greater than 10 IU/l conferred protection against hepatitis B infection. The use of this surrogate marker enabled testing and approval of the recombinant Hepatitis B vaccine for neonates [20,21]. However, in the absence of correlates of immunity to HIV-1 infection the approval of a vaccine for children will require efficacy data and will thus take longer. Inclusion of children and adolescents in clinical trial research and particularly HIV vaccine trials is difficult [22]. Ethico-legal issues concerning age of informed consent, protection of children, and reporting of illegal sexual activity and sexually transmitted diseases confront researchers. Socio-behavioral issues include assessment of true understanding of the consent form and possible disinhibition of sexual behaviour whilst participating in trials. There is also a lack of experience in recruiting and retaining adolescents and the provision of youth-friendly services. These are thought to be an important prerequisite for adolescent trials, and are non-existent in many HIV trial sites [23]. Yet these problems can and must be addressed. There are physiological and immunological differences between children and adults that may change the safety and efficacy of developed vaccines. The purpose of this review is primarily to highlight the immunological differences between infants, adolescents and adults and to describe some of the reported disparities between these age groups in their responses to licensed as well as other experimental vaccines. Age-dependent immune function Generally, the immune response has two separate although highly integrated and interdependent components, namely the innate and adaptive responses. While novel approaches are being considered to enhance innate responses to vaccination, the adaptive immune system is of principal importance in vaccinology due to its specificity and memory. Neutralizing antibodies block viral entry into cells and therefore can prevent infection. However, neutralizing antibodies to HIV primary isolates have proven difficult to elicit. Cytotoxic T lymphocytes (CTL) are thought to be very important in the initial control of HIV-infection by killing infected cells expressing viral antigens [24]. HIV specific CTL responses are therefore of great interest to vaccine developers. However, as different approaches to HIV vaccine development are explored, age-related differences in immunological responses should be considered (Table 1).Table 1: Differences in the infant and adolescent immune systems as compared with the adult immune system.Neonatal immunity Immaturity of the newborn immune system leads to a ‘physiological immunodeficiency’ that encompasses all arms of the host response as reflected by the increased susceptibility of young children to infections by both viral and bacterial pathogens. Differences in innate immunity have been described, including neutrophil, toll-like receptor (TLR)-dependant, and dentritic cell (DC) immune function (Table 1). The humoral immune system remains relatively underdeveloped, with the neonate initially being almost entirely dependent upon passively acquired maternal antibody (Table 1). Maternal immunoglobulin (Ig)-G is actively transported across the placenta during gestation, predominantly during the third trimester, and is present at levels as high as those in adults. Maternal IgA is acquired from breast milk [25]. Passively acquired antibodies can alter the humoral and antibody-dependant response to immunogens for up to 18 months in infants of infected or immunized mothers; in contrast, cellular immune responses appear unaffected by maternal antibody (Fig. 1) [26,27].Fig. 1: The effects of maternity antibody on vaccine responses in the neonate. Reproduced with permission from Lambert et al. [62].In addition to quantitative differences in antibody production during early life versus adulthood, there are also qualitative differences. IgG and IgA responses to pathogens, although inducible, are relatively weak during the first year of life, being short-lived and of low avidity [25]. Immunogens have been described as thymus-dependant (TD) versus thymus-independent (TI) [28]. TI antigens include high molecular weight polymers, including polysaccharides and polynucleotides. Immune responses to TI antigens develop late in infancy by about 18 months [28]. This has important implications when developing vaccines that include highly glycosylated proteins such as those that are present in the HIV envelope. The T-cell repertoire of the developing immune system is less obviously impaired. However, neonates have fewer antigen-specific T-cell precursors than adults [29] and quantitative differences in most T-cell subsets are detectable throughout childhood and adolescence [30]. Qualitative differences in cytokine profiles also exist (Table 1). Neonates and children produce less interleukin (IL)-2, IL-4, IL-6 and IL-10 in response to mitogens [20,21,31–33]. In the presence of endogenous antigen presenting cells (APC), human cord-blood T cells proliferate poorly and are poor producers of certain cytokines. Overall, the neonatal cytokine profile is thought to be polarized towards a T-helper type 2 (TH2) response to antigen [34–36]. However, an overall deficiency of certain cytokines may also explain why neonatal CD4 cells nevertheless have diminished capacity to provide help for Ig synthesis [37,38]. Induction of CTL is age-dependant and is impaired in infants (Table 1). For example, fewer infants under 5 months develop CTL responses to respiratory syncytial virus (RSV) compared to those 6–24 months of age [39]. Conversely, promising evidence suggests that it may be possible to induce very early cytotoxic responses in infancy as demonstrated by CD8 cell interferon (IFN)-γ responses to autologous envelope (Env) peptides in infants vertically infected with HIV [40]. High frequencies of cytomegalovirus (CMV)-specific CD8 T cells have been detected as early as 28 weeks of gestation [41]. These findings raise the prospect that it may be possible to induce immune responses to HIV immunogens by vaccination immediately post-partum. Little is known about neonatal gut mucosal immunology. The mucosal surface is exposed to a huge antigenic challenge and the immature mucosal immune system must learn to distinguish when a tolerogenic versus an immunogenic response is most appropriate [42]. The neonatal gut is an important portal of entry for HIV, the mechanisms of which have not been elucidated. Adolescent immunity An increase in gonadotropic hormones that promote the secretion of androgens and oestrogens in both boys and girls characterize puberty. Both Leydig cells and ovaries produce testosterone and 17-β-oestradiol (17-β-E2). In normal children, testosterone levels begin to rise at a bone age of about 12 years in boys and at 10 years in girls. However, dihydroepiandrosterone (DHEA) levels begin to rise earlier, at about 7 years of age in boys and 8 years of age in girls. Both 17-β-oestradiol (17-β-E2) and testosterone levels increase substantially through the pubertal stages and are highest at pre-menopausal adulthood [43]. Various lines of evidence suggest that immunological responses and sex steroid hormones are linked at physiological and cellular levels. The increased risk of autoimmunity among pubertal and post-pubertal females (and males to a lesser degree) strongly suggests that sex steroids affect immune function [44]. T cells and macrophages express intra- and extracellular receptors for oestrogens and androgens, implying a direct effect of these hormones on the immune system [45]. B cells, however, express only intracellular oestrogen and androgen receptors [46]. As a result, sex steroid hormones have many effects on the innate and adaptive immune system (reviewed in [47] and summarized in Table 1). Oestrogens Oestrogens exert dose-dependant effects on the immune system; physiological levels of 17-β-E2 are immunostimulatory whereas higher levels have been shown to be immunosupressive [48]. Oestrogen stimulates IgG and IgM secretion by human peripheral blood mononuclear cells (PBMC) in vitro[49]. At the vaginal mucosal surface, an important site for prevention of acquisition of HIV infection, a greater drop in IgG, but not IgA, occurs during the follicular phase of the menstrual cycle in adolescent females compared to adults [50]. Monocytes, macrophages and antigen presentation also seem to be affected by oestrogen (Table 1). Oestrogen (E2) has effects on T-cell immunity, causing fluctuations in CTL activity in the human endometrium during the menstrual cycle. CTL activity is high in the pre-ovulatory phase and absent in the post-ovulatory phase [51]. Androgens Androgens secreted at higher levels during male and female puberty may influence immune responses. The most well known, testosterone, may suppress the stress response to infection; evidence supporting this comes from observations that adrenal and immune corticosterone responses to endotoxin in animals are inhibited by testosterone [48]. These stress responses are maximal prior to puberty in both male and female mice [52]. DHEA and its metabolite, androstenediol (AED), appear to have the opposite effect to testosterone; they protect mice from lethal bacterial infections and lipopolysaccharide (LPS) challenge [53]. Specific effects on the immune system are found in Table 1. The pleiotropic immunological effects of sex hormones and the recognized differences in immune function between adolescents and adults suggest that there may be gender-dependent differences in the immunogenicity and efficacy of vaccines. Some evidence supports this supposition. A vaccine against Plasmodium chabaudi malaria is more efficacious in male than female mice; this difference was partially abrogated by pretreatment of the female mice with testosterone [54]. In humans, responses to tetanus toxoid were lower among female adolescents receiving booster immunizations compared to males [55]. Perhaps of greatest relevance is the recent demonstration that glycoprotein-D-adjuvant vaccine for herpes simplex virus-2 (HSV-2) showed some efficacy in HSV-1 and HSV-2 non-immune females but no efficacy at all among males [56]. The numbers of certain subsets of T cells differ in adolescents compared to adults and between the age-matched adolescent sexes [30,57,58]. Serum concentrations of immune activation markers among adolescents have been found to be significantly associated with race and age [59]. An important change that occurs in adolescence is the gradual involution of the thymus [58], which is the source of naive CD45RA T cells. Thymic involution has traditionally been thought to occur prior to adolescence, but in more recent has been demonstrated into adulthood age-related in function may affect immune responses to at different responses to vaccination At immune responses to antigens are much greater than responses to and antigens by months of age for and by months for polysaccharides responses to some are thought to be due to the effects of maternal However, the of antibody influence to vaccine In antibody responses to in the first months of life are by passively acquired maternal but is nevertheless for of B cells and development of responses to vaccine (Fig. 1). Maternal antibody humoral responses to to a greater than T-cell and seems to on the of maternal antibody to vaccine This is an important if HIV vaccines are to be to infants of or immunized T-cell responses to vaccination also differ in early that induce responses in adults not elicit neonatal responses. the overall capacity to both and persistent responses to antigen challenge in during the early period is specific are with the antigen infections the immune profile of many children in developing countries and maternal infections may have effects on the neonate profiles may it difficult to elicit CTL responses to mice with were not to CTL responses against HIV envelope peptides whereas animals could of vaccination is an important in HIV vaccine The vaginal and are the of HIV entry during childhood and adolescence, and are the site of initial viral Therefore of a mucosal immune response is mucosal or infection, antigen-specific T cells not only the to sites but also to In contrast, lymphocytes from the are more limited in their to to mucosal the mucosal different T-cell of of is also The may provide an important site for the of a more global mucosal and immune response immune responses not only in the but also in and the female certain vaccine systems and have been found to be more at mucosal immunity than in immunized with expressing both humoral and cellular immune responses in gut and blood This the as to the neonatal gut may also have the to produce and mucosal immune responses to vaccines. that affect mucosal responses also to be For example, the human vaccine demonstrated efficacy during and it is possible that the cycle itself may affect vaginal mucosal responses. have the between and immune This the in immune responses to vaccine candidates and in immunological correlates of vaccine This is by data that responses to many vaccines with age (Table from both and human also that responses to HIV vaccine candidates are age-related and are and in Table of age-related responses to vaccines to vaccine of clinical and HIV or vaccine data in young animals and vaccines In live attenuated vaccines neutralizing antibody and CTL responses. However, humoral responses may be abrogated in the presence of maternal and vaccines are all have cellular immune responses to and vaccines of maternal antibody as by T-cell and and cellular responses are also to those of adults to vaccination as by are affected by pubertal and during puberty are greater than post-pubertal responses and with concentrations of DHEA and the immune response to vaccination to the that are particularly administered to children under years of vaccine antibodies in of a whereas years of age require two by weeks The of preventative HIV-1 vaccines has been in the et al. immunized groups of infant at and weeks of age with and at weeks of age with animals but the immunized animals lower and than However, found that immunized with live to AIDS the of a HIV vaccine has been Therefore no data in for this type of HIV vaccine. Inactivated vaccines of vaccines in use or in trials for children to date include hepatitis cell and The of both of hepatitis A vaccines licensed in the are of the adult in those years of age with passively acquired maternal antibody to hepatitis A virus to highly hepatitis A vaccine with lower antibody titres responses to booster at years of age also lower humoral responses to hepatitis A vaccine are throughout adolescence, of vaccine with age vaccine also an age-dependant antibody response in children aged months to 12 years that is affected by maternal antibody Inactivated vaccines against HIV raise of poor immunogenicity as well as only trials virus in adults and children as vaccination have been conducted In the immunized with were against challenge with However, it was found that the effect was by antigens from the human cells to the viral immunized at with HIV-1 developed immune responses of by neonatal in a and humoral response in the neonatal However, this HIV immunostimulatory DNA as an vaccines The immune response to vaccines is to HIV vaccinology in that HIV is highly glycosylated and is therefore a TI The to to antigen late in development and age-dependant responses to vaccines are well the immunogenicity of vaccines in infants is by such as and the immunogenicity of different is For example, of the poorly immunogenic type to more immunogenic in infants than vaccine However, responses in those less than months of whereas B a weak response at 2 months but a response to the booster Subunit and vaccines hepatitis B vaccines are the most of a and age-related responses to this and other vaccines are (Table HIV-1 recombinant vaccines have been in phase I trials in and a phase trial has been completed The first phase I preventative HIV-1 vaccine trial in neonates to HIV-1 infected mothers recombinant The infants were administered recombinant with were to and antibody responses An important was that high levels of maternal antibody found at not affect the antibody response in infants receiving the HIV envelope vaccines elicit high antibody titres to but their neutralizing capacity is for in T-cell virus and not primary isolates However, new evidence suggests that it may be possible to the critical of or to production of neutralizing antibodies vaccines can specific systems such as that of the I malaria vaccine is a with from and proteins of Plasmodium to this vaccine are strongly no efficacy of this vaccine was found in children aged months whereas a efficacy was found in children in A lack of a IgG response was also found in infants compared to children in this trials of the vaccine in showed a of protection in those than 20 years with no malaria during but no protection among those less than 20 years of age At HIV-1 vaccines have only been in phase I trials in adults DNA vaccines DNA vaccination at can both CTL and antibody responses in animals when the carries maternal protection in mice In to the of the humoral immune response vaccination in DNA vaccines expressing the antigen may induce and levels in neonate and adult animals DNA technology for use as neonatal HIV-1 vaccines. To date, there is less experience with DNA vaccination for other than for While responses to DNA vaccines in have been the DNA HIV vaccines that have been in phase I human clinical trials only weak cellular immune responses in adults HIV-1 DNA vaccine has been thus in The response to DNA vaccination can be by with a viral or other systems HIV vaccine development has greatly vaccine viral and bacterial vector-based HIV vaccines are in human trials or in the use of have the development of HIV vaccines on other viral including other which but in human cells, and provide an to DNA in a form that the I antigen presentation However, antibody titres to the system can affect the response to the and therefore can be affected by age for example, may have higher titres due to in In the recombinant vaccines expressing and proteins were to protect neonatal exposed to mucosal challenge and a antigen both protection against of the immunized and only of the immunized infants compared to all of the animals immunized at and weeks of age with virus expressing and all infected challenge but than infected Maternal antibodies not significantly reduce the efficacy of the vaccine trials have in PACTG 326 I the safety and immunogenicity of versus low HIV-1 B linked to the of and from HIV-1 responses to and were present in and of vaccine CTL responses to and were detected in and of vaccines and many of these were detectable as early as weeks In of PACTG a phase of a recombinant expressing and alone or with vaccine also showed and CTL responses in a infants at physiological of the immune system in differences in immune function and responses to vaccines. have humoral and immune function from the neonatal period through puberty and into There are many on immune responses such as maternal antibody in the neonate and the effects of sex steroid hormones in As a result, vaccine efficacy is not across these age The development of an effective HIV vaccine is a global In age vaccines are greatly to prevent HIV transmission in adolescents and acquisition of HIV infection from breast-feeding in However, to date, no HIV vaccine trials have included adolescents and only two have included neonates to The of development and of clinical efficacy trials in these age groups is by many and However, there is also a that such vaccines are and that a to develop and vaccines in these age in which the of vaccine development and testing might take into the immunological of the developing immune system are in Table Current to develop an HIV vaccine should not be but should the responses of the immune for vaccine and trial