Bekker, Linda-Gail

Coovadia, Hoosen M

Gray, Glenda E

Jaspan, Heather B

Robinson, Andrew K L

South African Medical Journal (SAMJ)

ORIGINAL ARTICLES685September 2005, Vol. 95, No. 9  SAMJUNAIDS estimates that there were 4.9 million new HIVinfections in the year 2004, and that 640 000 of these infectionsoccurred in children less than 15 years old.1 The first nationalpopulation-based survey conducted in South Africa in 20022showed that 9.3% of persons between the ages of 15 and 24years of age were HIV-positive and that female youth weremore likely to be HIV-infected than male youth (Table I).  InSouth Africa sexual debut is at an early age,3 with 50% ofadolescents sexually active by the age of 15. Transgenerationalsex, transactional sex and non-consensual sex put adolescentgirls at high risk for acquiring HIV infection.4National antenatal data show that the prevalence of HIV inwomen < 20 years old rose from 15.8% in 2003 to 19.5% in2004, indicating that the epidemic is being fuelled by incidentinfection during adolescent years.5 Approximately 1 millionwomen give birth each year in South Africa, with more than250 000 of these infants being born to HIV-infected mothers.Although there are programmes in place to prevent mother-to-child transmission (MTCT), most of the interventions currentlyavailable only impact on intrapartum and early postpartumtransmission, and have minimal impact on prevention ofpostnatal transmission through breast-feeding.6 Whatever theroute of infection, it is clear that both infant children andadolescents are at the highest risk of HIV infection.  Thisepidemiological fact makes it imperative that an HIV vaccinetarget this group to have any hope of successful epidemiccontrol. We should not withhold the availability of a vaccine tothis population because of lack of data through delays inclinical trial work.There are many promising HIV vaccine candidates in orabout to enter human clinical trials.  The road to the licensingof a successful candidate is long, since phase I - III trialsusually take at least 10 years.  No preventive HIV vaccine trialshave included adolescents, and only 2 completed trials havetargeted neonates.7-9 In South Africa, in order to license avaccine for use in children and adolescents, data must exist onthe safety, immunogenicity and efficacy of the vaccine inchildren and adolescents, although exact criteria for approvalhave not yet been defined.  In the past, vaccine trials in youngchildren and infants have been accelerated because of theexistence of correlates of immunity to the disease; however,since the immune marker necessary for protection against HIVis not yet defined, the task of approving a vaccine for infants,children and adolescents is arduous and may take longer thanusual.  As there are physiological differences between children andadults, one cannot necessarily extrapolate adult data tochildren. Surface area, body mass and metabolic differencesaffect the dosage and safety profile of drugs and vaccines.  Thebioavailability and safety of vaccines is affected byphysiological differences such as increased liver size, immatureliver enzymes, decreased renal clearance, and increased blood-brain-barrier permeability, among others.  In addition, theimmune response to vaccines is different in infants, andprobably in adolescents.  Here we review the differencesbetween the immune systems and response to vaccination inchildren (both infants and adolescents) versus adults.   The immune system, an overviewGenerally, the immune response has two arms; humoral andcellular.10 The adaptive cellular immune response is mediatedby B- and T-lymphocytes.  B-lymphocytes mature into plasmacells and produce antibody.  T-cells either express CD4 or CD8on their surface, and are known as CD4+ helper T-cells (Th)and cytotoxic T-lymphocytes (CTLs) respectively.  Th cellsprimarily exert their helper functions through secretion ofsoluble proteins called cytokines.  CTLs are thought to be veryimportant in the initial control of HIV infection and killinfected cells by lysis and/or apoptosis.Scientific justification for the participation of children andadolescents in HIV-1 vaccine trials in South AfricaHeather B Jaspan, Glenda E Gray, Andrew K L Robinson, Hoosen M Coovadia, Linda-Gail BekkerDesmond Tutu HIV Centre, University of Cape TownHeather B Jaspan, MD, PhD, FAAPLinda-Gail Bekker, MB ChB, FCP, PhDPerinatal HIV Research Unit, University of the Witwatersrand, Chris HaniBaragwanath Hospital, JohannesburgGlenda E Gray, MB BCh, FCPaed (SA)HIV Vaccine Research Unit, Medical Research Council, Africa Centre, KwaZulu-NatalAndrew K L Robinson, MB ChB, DHSM, FCCHVictor Daitz Chair in HIV/AIDS Research and Scientific Director Doris DukeMedical Research Institute, Nelson R Mandela School of Medicine, University ofKwaZulu-Natal, DurbanHoosen M Coovadia, MB BS, FCP (Paed), MSc (Immunol), MDCorresponding author: H B Jaspan (heather.jaspan@hiv-research.org.za)Table I. HIV prevalence by age group from the HSRCNational Survey, South Africa, 20022Percentage Age N HIV-positive 95% CIChildren (2 - 14 years) 2 348 5.6 3.7 - 7.4Youth 9.3 (12% females,(15 - 24 years) 2 099 6% males) 7.3 - 11.2Adults (> 25 years) 3 981 15.5 13.5 - 17.5Total 8 428 11.4 10.0 - 12.7Pg 685-687 spot  9/7/05  9:28 AM  Page 685ORIGINAL ARTICLES686Paediatric immunityThe immaturity of the infant immune system is demonstratedby the increased susceptibility of children to infections by bothviral and bacterial pathogens.  The humoral arm of theimmune system is underdeveloped and differs greatly fromthat of adults. Infants only develop the ability to make asignificant amount of immunoglobulins at around 6 - 12months of life.  Maternal immunoglobulin G (IgG) is activelytransported across the placenta predominantly during the thirdtrimester, and is present at high levels.  Maternal immuno-globin A (IgA) is secreted in breast-milk.10 These passivelyacquired antibodies can alter the antibody-dependent responseto immunogens in as long as 18 months in infants of infected orimmunised mothers, but other cellular immunity seems lessaffected by maternal antibody.  There are less obvious impairments in the T-cell repertoire ofthe infant immune system.  Antigen-specific T-cell precursorsare lower in neonates than in adults.11 Differences in cytokineprofiles exist and may be responsible for much of the poorcapabilities of the developing immune system and an impairedinduction of cytotoxic CD8 T-cells.12,13Puberty is characterised by an increase in gonadotropichormones which promote the secretion of androgens andoestrogens in both boys and girls.  There is direct evidence thatimmunology and sex steroids are linked both at thephysiological and cellular level. Post-pubertal females are atincreased risk for autoimmunity, which strongly suggests thatsex steroids affect immune function.  Most cells of the immunesystem express both intra and extracellular receptors for sexsteroids.14 In addition to the effects of pubertal hormones onimmunity, there are quantitative differences in the cells of theimmune system between infants, children, adolescents andadults.Since there are vast differences in all arms of the immunesystem between different age groups, it is difficult to predictresponses to vaccinations without actual clinical trials.Paediatric responses to vaccinationHIV vaccinology has required innovative approaches tovaccine design.15,16 Briefly, the live-attenuated vaccine approachis considered too risky for use in a human HIV vaccine, killedvirus is poorly immunogenic, subunit vaccines are unlikely toelicit neutralising antibodies and are poor T-cell stimulants,and some promising DNA vaccines and vector-based vaccinesare in phase I and II trials at the moment.At birth, the ability to respond to antigens is greatest forprotein antigens and less for glycoproteins and polysaccha-rides.17 The decreased response to some vaccinations isthought to be due partly to the effects of maternal antibody.However, the degree of passive antibody influence variesaccording to vaccine.  In general, passively acquired antibodiesmay suppress humoral response to active immunisation in thefirst few months of life dependent on the maternal antibody/vaccine antigen ratio, but do not affect the response toboosting.18 Maternal antibody seems to have less of an effecton T-cell responses.18 T-cell response to vaccination can alsodiffer in early life.  Neonatal Th1 responses are not easilyelicited with conventional vaccines capable of eliciting Th1responses in adults.19There are multiple viral and bacterial vector-based HIVvaccines in human trials and in the pipeline (www.iavi.org;www.hvtn.org).  Pre-existing titres to the vector deliverysystem can affect the response to the immunogen and thereforecan be affected by age.  For example, schoolchildren may havehigher adenoviral titres, although age-related adenoviral titresare yet to be determined in South Africa.  In addition to theoretical differences in the immune responsethat children may have to vaccines, there are many examples invivo of how children and adolescents behave differently tospecific vaccines (Table II).  There are limited human data onage-related responses to HIV vaccine candidates; however, thefirst preventive trial in neonates born to HIV-1 infectedmothers used recombinant gp120.  About one-third of theinfants were able to mount lymphoproliferative and antibodyresponses.20,21 An important finding was that the antibodyresponse in the accelerated schedule subjects was not affectedby the higher levels of maternal antibody found at earlier age.Current HIV envelope vaccine candidates elicit high gp120antibody titres, but neutralising antibody is difficult to elicit.16There are not a lot of data on vector vaccine approaches,other than data for gene therapy.  There have been HIV vaccinetrials involving poxvirus vectors in HIV-exposed neonates.PACTG 326 part I evaluated the safety and immunogenicity ofALVAC vCP205 (high dose versus low dose) in neonates bornto HIV-infected mothers.  This canarypox vector contains HIV-1subtype B envelope genes, plus gag and pol genes.  Lympho-proliferative and CTL responses were present in about one-third of vaccine recipients.  CTL responses were detected asearly as 6 weeks of age.9 Another arm of PACTG 326, a phaseI/II study of ALVAC-HIV vCP1452, a modified recombinantcanarypox expressing multiple HIV-1 genes alone or withEnvelope (AIDSVAX B/B), also showed lymphoproliferativeand CTL responses in a few subjects at preliminary analysis.22DiscussionThe development of a vaccine for paediatric and adolescent useis an urgent global priority.  There is a complex interplaybetween age and immune function, which will make responsesto vaccination difficult to predict.  Additionally, adolescence, atime of rapid physiological change, also poses potentialimmunological challenges.  Almost every vaccine category hasan example of an age-dependent response.  We cannot justexpect that a vaccine that shows promise in adults is going tobe safe, immunogenic and efficacious in children.  To enrolSeptember 2005, Vol. 95, No. 9  SAMJPg 685-687 spot  9/7/05  9:28 AM  Page 686ORIGINAL ARTICLES687September 2005, Vol. 95, No. 9  SAMJonly adults in HIV vaccine research will result in even greaterdelay for the benefits of a vaccine to reach children andadolescents, owing to the requirement for safety,immunogenicity and efficacy data in the age groups for whichthe vaccine will be licensed.  The window of opportunity existsto ensure that this information is gathered now, and delay forwhatever reason can be seen as a failure to safeguard our mostvulnerable population.References1. UNAIDS. 2004 Report on the Global AIDS Epidemic. Geneva: UNAIDS, 2004.2. Reproductive Health Research Unit, Medical Research Council. National Survey of HIV andSexual Behaviour among Young South Africans. Johannesburg: Reproductive Health ResearchUnit, 2004.3. Wood K, Jewkes R. Violence, rape, and sexual coercion: everyday love in a South Africantownship. Gender and Development 1997; 5: 41-46.4. Buga GA, Amoko DH, Ncayiyana DJ. Sexual behaviour, contraceptive practice andreproductive health among school adolescents in rural Transkei. S Afr Med J 1996; 86: 523-527.5. Department of Health. National HIV and Syphilis Antenatal Sero-Prevalence Survey In SouthAfrica. Pretoria: DOH, 2004.6. Jaspan HB, Garry RF. Preventing neonatal HIV: A review. Curr HIV Res 2003; 1: 321-327.7. Safrit JT. HIV vaccines in infants and children: past trials, present plans and futureperspectives. Curr Mol Med 2003; 3: 303-312. 8.  Cunningham CK, Wara DW, Kang MH, et al. Safety of 2 recombinant humanimmunodeficiency virus type 1 (HIV-1) envelope vaccines in neonates born to HIV-1-infectedwomen. Clin Infect Dis 2001; 32: 801-807.9. McFarland E, Johnson D, Fenton T, et al. A phase I/II study of the safety and immunogenicityof an HIV-1 ALVAC vaccine in infants born to HIV-infected mothers. 10th Conference onRetroviruses and Opportunistic Infections. Boston, Mass.: 10 - 14 February 2003,  abstract no. 99. Available at http://www.retroconference.org/2003/CD/Abstract/404.htm (last accessed8 August 2005).10. Janeway CA, Travers P, Walport M, Shlomchik M. Immunobiology: The Immune System inHealth and Disease. 6th ed.  New York: Garland Publishing, 2004.11. Hassan J, Reen DJ. Reduced primary antigen-specific T-cell precursor frequencies in neonatesis associated with deficient interleukin-2 production. Immunology 1996; 87: 604-608.12. Martinez X, Brandt C, Saddallah F, et al. DNA immunization circumvents deficient inductionof T helper type 1 and cytotoxic T lymphocyte responses in neonates and during early life.Proc Natl Acad Sci USA 1997; 94: 8726-8731. 13. Barrios C, Brandt C, Berney M, Lambert CH, Siegrest CA. Partial correction of the TH2/TH1imbalance in neonatal murine responses to vaccine antigens through selective adjuvanteffects. Eur J Immunol 1996; 26: 2666-2670.14. Stimson WH.  Oestrogen and human T lymphocytes: presence of specific receptors in the T-suppressor/cytotoxic subset. Scand J Immunol 1988; 28: 345-350.15. Graham B, Wright P. Candidate AIDS Vaccines. N Engl J Med 2004; 333: 1331-1339.16. Mwau M, Cebere I, Sutton J, et al. A human immunodeficiency virus 1 (HIV-1) clade Avaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA andrecombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 2004; 85:911-919.17. Glezen WP. Maternal vaccines.  Prim Care 2001; 28: 791-806.18. Gans H, DeHovitz R, Forghani B, Beeler J, Maldonado Y, Arvin AM.  Measles and mumpsvaccination as a model to investigate the developing immune system: passive and activeimmunity during the first year of life.  Vaccine 2003; 21: 3398-3405.19. Holt PG, Macaubas C. Development of long-term tolerance versus sensitisation toenvironmental allergens during the perinatal period. Curr Opin Immunol 1997; 9: 782-787.20. McFarland EJ, Borkowsky W, Fenton T, et al. for the AIDS Clinical Trials Group 230Collaborators. Human immunodeficiency virus type 1 (HIV-1) gp120-specific antibodies inneonates receiving an HIV-1 recombinant gp120 vaccine. J Infect Dis 2001; 184:1331-1335.21. Borkowsky W, Wara D, Fenton T, et al. Lymphoproliferative responses to recombinant HIV-1envelope antigens in neonates and infants receiving gp120 vaccines. AIDS Clinical TrialGroup 230 Collaborators. J Infect Dis 2000; 181: 890-896.22. Johnson D, McFarland E, Muresan P, et al. PACTG 326: A phase I/II study to evaluate thesafety and immunogenicity of Alvac HIV vaccines alone and with AIDSVax B/B in childrenborn to HIV-infected mothers: Preliminary results. Conference on Retroviruses andOpportunistic Infections. Boston, Mass.: 10 - 14 February 2003, abstract no. 404. Available at:http://www.retroconference.org/2003/CD/Abstract/404.htm (last accessed 8 August 2005).23. Christenson B, Bottinger M. Vaccination against measles, mumps and rubella, (MMR): Acomparison between the antibody responses at the ages of 18 months and 12 years andbetween different methods of antibody titration.  J Biol Standards 1985; 13: 167-172.24. Kutlu NO, Akinci A, Sonmezgoz E, Temel I, Evliyaogle E. The effects of androstenediol anddihydorepiandrostendione on the immune response to BCG at puberty.  J Trop Pediatr 2003;49: 181.  25. US Department of Health and Human Services. Immunization of adolescents: Recommen-dations and reports. MMWR Morb Mortal Wkly Rep 1996; 45: RR-13.26. Department of Health and Human Services. Notice to Readers: Alternate two-dose hepatitisB vaccination schedule for adolescents aged 11 to 15 years. Recommendations and Reports.MMWR Morb Mortal Wkly Rep 2000; 49(12): 261.27. Bojang KA, Milligan PJ, Pinder M, et al. Efficacy of RTS,S/AS02 malaria vaccine againstPlasmodium falciparum infection in semi-immune adult men in The Gambia: a randomisedtrial. Lancet 2001; 358: 1927-1934.28. Stoute JA, Kester KE, Krzych U, et al. Long-term efficacy and immune responses followingimmunization with the RTS,S malaria vaccine. J Infect Dis 1998; 178: 1139-1144.29. Alonso PL, Sacarlal J, Aponte JJ, et al. Efficacy of the RTS,S/AS02A vaccine againstPlasmodium falciparum infection and disease in young African children: randomisedcontrolled trial. Lancet, 2004; 364: 1411-1420.Accepted 17 May 2005.Table II. Age-related responses to vaccines for pathogensother than HIV according to vaccine typeVaccine type Pathogen Age-related responseLive Mumps Seroconversion rates forattenuated mumps-susceptible Swedish toddlers were 95%, versus only 80% in adolescents.23Seroconversion rates to mumps vaccination are generally slightly lower in adults than in childrenBCG In the pubertal period androgen levels have an effect on BCG immune response. Responses to BCG vaccination via tuberculin test were affectedby pubertal stage, and testicularvolume24Varicella Administered to children < 13 years of age, induces protective antibodies in > 95% of recipients after a single dose. For susceptible persons > 13 years of age, 2 doses separated by 4 - 8 weeks are recommended25Killed Hepatitis A The dosage of both forms of inactivated hepatitis A vaccines licensed in the USA are half of the adult dose in those 2 - 18 years of ageProtein Hepatitis B Adolescents may require only 2subunit doses26RTS,S/AS02A A 3-dose phase IIb in 1 - 4-year-olds showed efficacy for thefirst clinical episodes of 29.9%.  Efficacy for severe malaria was 57.7%.  Immunogenicity wasgreater in the < 24-month agegroup.  There was no evidenceof waning efficacy againstclinical disease and limitedwaning efficacy againstinfection. This sustainedprotection was not found intrials in malaria-naïvevolunteers or Gambian adults27-29Pg 685-687 spot  9/7/05  9:28 AM  Page 687

Scientific justification for the participation of children and adolescents in HIV-1 vaccine trials in South Africa

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Scientific justification for the participation of children and adolescents in HIV-1 vaccine trials in South Africa

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