The maturing immune system: implications for development and testing HIV-1 vaccines for children and adolescents
Jaspan, Heather Ba; Lawn, Stephen Da,b; Safrit, Jeffrey Tc; Bekker, Linda-Gaila
From the aDesmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South
bLondon School of Hygiene and Tropical Medicine, London, UK
cElizabeth Glaser Pediatric AIDS Foundation, David Geffen School of Medicine, University of California, Los Angeles, USA.
Correspondence to L.-G. Bekker, Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa. Tel: +27 21 650 6959; fax: +27 21 650 6963; e-mail: email@example.com
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 . 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 . 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 , most living in sub-Saharan Africa. Paediatric HIV infections are acquired both vertically and horizontally , 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 . 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 . 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 . 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 . 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).
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 . 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].
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 . Immunogens have been described as thymus-dependant (TD) versus thymus-independent (TI) . TI antigens include high molecular weight polymers, including polysaccharides and polynucleotides. Immune responses to TI antigens develop late in infancy by about 18 months . 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  and quantitative differences in most T-cell subsets are detectable throughout childhood and adolescence . 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 . 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 . High frequencies of cytomegalovirus (CMV)-specific CD8 T cells have been detected as early as 28 weeks of gestation . 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 . The neonatal gut is an important portal of entry for HIV, the mechanisms of which have not been elucidated.
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 .
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 . T cells and macrophages express intra- and extracellular receptors for oestrogens and androgens, implying a direct effect of these hormones on the immune system . B cells, however, express only intracellular oestrogen and androgen receptors . As a result, sex steroid hormones have many effects on the innate and adaptive immune system (reviewed in  and summarized in Table 1).
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 . Oestrogen stimulates IgG and IgM secretion by human peripheral blood mononuclear cells (PBMC) in vitro . 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 . 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 .
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 . These stress responses are maximal prior to puberty in both male and female mice . 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 . 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 . In humans, responses to tetanus toxoid were lower among female adolescents receiving booster immunizations compared to males . 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 .
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 . An important change that occurs in adolescence is the gradual involution of the thymus , which is the source of naive CD45RA T cells. Thymic involution has traditionally been thought to occur prior to adolescence, but in more recent studies, thymic output has been demonstrated into adulthood . Nevertheless, age-related changes in thymic function may affect immune responses to vaccinations at different ages.
Age-specific responses to vaccination
At birth, immune responses to protein antigens are much greater than responses to glycoprotein and polysaccharide antigens . Responses gradually improve by 6–9 months of age for glycoproteins and by 12–24 months for polysaccharides . Decreased responses to some vaccinations are thought to be partly due to the effects of maternal antibody. However, the degree of passive antibody influence varies according to vaccine . In general, antibody responses to active immunization in the first few months of life are suppressed by passively acquired maternal antibody, but priming is nevertheless adequate for induction of memory B cells and development of memory responses to vaccine boosts [35,62] (Fig. 1). Maternal antibody affects humoral responses to immunization to a greater extent than T-cell responses, and seems to depend on the ratio of maternal antibody to vaccine antigen. This is an important issue if HIV vaccines are going to be given to infants of HIV-infected or immunized mothers.
T-cell responses to vaccination also differ in early life. Vaccines that induce TH1 responses in adults do not readily elicit neonatal TH1 responses. Indeed, the overall capacity to generate both acute and persistent TH1 responses to antigen challenge in humans during the early post-natal period is compromised, unless specific TH1 stimulants are co-administered with the antigen . Furthermore, helminthic infections bias the immune profile of many children in developing countries and maternal helminth infections may have similar immuno-modulatory effects on the neonate . Pre-existing TH2 profiles may make it difficult to elicit CTL responses to HIV. Indeed, mice with schistosomiasis were not able to mount CTL responses against HIV envelope peptides whereas non-infected animals could .
Route of vaccination is an important consideration in HIV vaccine development. The vaginal and gastrointestinal mucosae are the predominant portals of HIV entry during childhood and adolescence, and are the site of initial viral replication. Therefore induction of a mucosal immune response is key. Following mucosal immunization or infection, antigen-specific T cells not only migrate within the mucosa to effector sites but also to systemic lymphoid tissue. In contrast, lymphocytes from the systemic circulation are generally more limited in their ability to migrate to mucosal lymphoid tissue. Since the various mucosal compartments utilize different T-cell homing receptors, careful choice of route of immunization is also necessary. The nasal cavity may provide an important site for the induction of a more global mucosal and systemic immune response since intranasal immunization produces superior immune responses not only in the nasal lymphoid tissue, but also in saliva and the female genital tract .
More recently, certain vaccine delivery systems and adjuvants have been found to be more efficient at inducing mucosal immunity than others (Reviewed in [67,68]). Newborn lambs immunized enterally with adenoviral vector expressing bovine herpesvirus glycoproteins mounted both humoral and cellular immune responses in lung lymph nodes, spleen, gut Peyer's patches and blood . This finding raises the question as to whether the neonatal gut may also have the potential to produce systemic and mucosal immune responses to vaccines. Additional factors that affect age-dependent mucosal responses also need to be considered. For example, the human papillomavirus virus-like particle (HPV VLP) vaccine demonstrated decreased efficacy during ovulation  and it is possible that the ovulatory cycle itself may affect vaginal mucosal responses.
Thus far, we have reviewed the complex interplay between physical maturation and immune function. This highlights the difficulties in predicting immune responses to vaccine candidates and in identifying immunological correlates of vaccine efficacy. This is borne out by data showing that responses to many established vaccines vary with age (Table 2). Data from both animal and human studies also indicate that responses to HIV vaccine candidates are similarly age-related and are discussed below and in Table 3.
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].
Subunit and peptide vaccines
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 .
Viral vectors or other delivery systems
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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