Guidance on vaccination of HIV‐infected children in Europe

Paediatric HIV disease is now, in the era of highly effective antiretroviral therapy (HAART), a chronic treatable disease, yet across Europe significant disease and death still occur despite apparent immune reconstitution, and much of this is attributable to vaccine-preventable disease. The complexities of HIV-associated immunocompromise across the paediatric age range, and the profile and time-course of immune reconstitution produced by effective HAART initiated at various ages and stages of disease, are poorly characterized. Available data point to multiple causative factors, such as suboptimal vaccine coverage in this vulnerable group; the consequences of immunocompromise at the time of primary immunization; incomplete, nonuniform immunological recovery on HAART; and vaccine responsiveness which may be blunted in magnitude and durability according to vaccine antigens. Furthermore, high-quality studies from settings relevant to European cohorts in the HAART era are very limited in number, as well as in terms of subject number and direct comparability. Safety, reactogenicity, efficacy and clinical effectiveness data on different vaccines and vaccine types in HIV-positive children are lacking, or study findings are awaited. In this context, we have developed guidance on vaccinating HIV-positive children across the European cohort to unify practice; data from relevant comparable studies are outlined to inform, but this guidance does not follow a structured evidence-based approach with a systematic literature review, and it was not possible to grade the evidence used in arriving at the recommendations. The importance of avoiding unnecessary departures from local schedules is underlined and recommendations are made regarding the utility of serological testing for certain vaccines. Despite the availability of highly active antiretroviral therapy (HAART) and its uptake by vertically infected HIV-positive children across Europe, and the ability to achieve viral suppression and immune recovery, this group of children remain at greater risk of vaccine-preventable infections than HIV-uninfected children 1-3. HIV replication in lymphoid tissue from an early age, before immunological maturation and the development of protective immune responses have occurred, results in progressive, multicomponent immunological impairment. Furthermore, reduced responsiveness to vaccination may arise from poor primary responses, impaired ability to generate memory responses and/or loss of memory cells 4, 5. Effective HAART facilitates immune function recovery over time but does not normalize every component of immune function, so treated individuals may have abnormal immune responsiveness to both pathogen and vaccine antigens 6-8. This is especially so in infancy, when there is limited responsiveness to polysaccharide antigens from either infective pathogens or vaccines, although infants respond well to protein antigens, but less so thereafter. Therefore, despite effective HAART, adequate and prolonged protection against serious infections is more difficult to achieve through vaccination; vaccination schedules may require modification in order to achieve this. In developing universal guidance for HIV-infected children across Europe, certain limitations apply, primarily as a consequence of gaps in the evidence resulting from a relative paucity of directly comparable data 9. Most studies on serious infections in HIV-positive children are from resource-poor settings, are from the pre-HAART era and/or pre-date adequate coverage of immunization programmes. Data on the effectiveness of individual or combined vaccines in HAART-treated children are especially limited, and are frequently from noncomparable settings. Immunogenicity studies are more commonly conducted in high-income countries but sample size tends to be small. Comparability of findings is limited by important differences in the vaccines used, the intervals between primary vaccine doses, definitions of immunity, immunological parameters and thresholds of immunogenicity. The impact of timing of HAART initiation on vaccine responsiveness, especially in relation to age, immunological and viral status, and the timing of previous and subsequent vaccine doses, is inconsistent between studies using different vaccines and vaccine types. For such reasons, generalizable predictors of immunity are limited. Whether depressed vaccine immunity is caused by diminished primary vaccine responses before or after HAART initiation or by a failure of HAART to fully normalize vaccine responsiveness is difficult to ascertain because few studies compare pre- and post-HAART immunity 5, 9. There is increasing clinical and laboratory evidence of a benefit from vaccinating children who have immune-reconstituted on HAART, although the immunogenicity and durability of immune protection have not been fully characterized for many vaccines 9. Fundamental limitations exist in the assays available to evaluate cellular and humoral responses to vaccination, and to reliably determine thresholds for protective immunity. Vaccine safety is an important consideration. Data from the pre-HAART era and from resource-poor settings provide some reassurance on vaccine safety for newly diagnosed HIV-infected infants and young children 10. Few live vaccines carry a greater risk of adverse events in HIV-positive children than in other children, apart from the live Bacille Calmette-Guerin (BCG) vaccine, which is therefore contraindicated 11, 12. Live viral vaccines are safe in those who have good immune responses to killed vaccines and stable CD4 status and who are not severely immunosuppressed 13, 14. Potential harm from vaccination is also a theoretical concern; can vaccination promote increased HIV replication through T-cell activation and proliferation and cytokine release, and thereby increase the risk of disease progression? Data from studies of paediatric and adult patients, on or off effective HAART, are inconsistent. For example, in one study, plasma HIV viral loads increased after influenza vaccination of children who were not receiving HAART, although they returned to baseline within 6–8 weeks 15. Conversely, a randomized placebo-controlled trial of pneumococcal polysaccharide and conjugate vaccines showed no virological differences between adult groups on or off HAART 16, and an observational study of diphtheria/tetanus/acellular pertussis (DTaP) immunization of 2–9-year-olds receiving HAART also reported no effect on HIV viral load 17. Whether there are long-term consequences of repeated bursts of HIV viraemia post-vaccination is unknown 18 and there is currently no evidence that vaccination adversely affects the pace of HIV disease progression 19. HIV-positive children are at greater risk of vaccine-preventable infections than other children, yet vaccination coverage in this group is suboptimal in populations across Europe 20-22. Reasons for this may include physician uncertainty regarding the safety or appropriateness of vaccinating such children, deferral at times of intercurrent illness, or concerns that ‘intervention fatigue’ in patients may have adverse effects on HAART adherence. National and international societies recommend vaccination of HIV-positive children with some modification of routine schedules; for example, recommendations are available from the World Health Organization (WHO)/United Nations Children's Fund (UNICEF), the American Academy of Pediatrics and the British HIV Association (BHIVA) 5, 23-25. Variation among these guidelines, compounded by differences among national schedules, may serve to reduce vaccine coverage in this vulnerable patient group. The development of uniform schedules for all HIV-positive children living in European countries would be greatly beneficial, especially as new and more effective vaccines become available which potentially confer more benefits for HIV-infected children than for other children. However, achieving uniformity in guidelines is challenging given the inherent variation of the clinical, immunological and virological status of the cohort across Europe and within individual nations. Furthermore, increasing numbers of HIV-infected children living in Europe originate from developing countries and have incomplete or unknown vaccination status, unrelated to their immunological status or whether they are receiving HAART 26. Recommendations need to accommodate the different requirements of (a) newly diagnosed children, whether immunocompetent or already immunocompromised; (b) those on HAART, whether complete or incomplete responders; (c) partially immunized or nonimmunized children within these groups; and (d) children during time periods when they fall below thresholds for effective or safe immunization. Yet European guidelines must also aim to minimize deviation from existing routine schedules, lest they generate confusion and further reduce vaccine uptake. The Paediatric European Network for Treatment of AIDS (PENTA) is a collaboration between paediatric HIV in Europe, in This guidance on existing immunization recommendations be for HIV-positive children living in Europe in the HAART The timing of vaccination after HAART is not well few studies have this either for primary or for of vaccines. immunological thresholds for vaccination are but of CD4 number or as the of the of immune reconstitution over in CD4 and the of the of cells the of memory and in activation and 6-8. immunization of HIV-positive children was before the availability of effective HAART on the that immunity occur before There have been few data on the effect of the timing of HAART initiation in relation to the age or vaccine already In a study vaccine responsiveness in children HAART at different those in of immunity, to that of children, with those HAART more than The of children who protective immunity to vaccines was highly and after HAART, children not achieve or vaccine immunity, HAART immunity from 9. of vaccines, or complete for children HAART in by serological or HAART immune reconstitution is The early of viral load over is with recovery of of the T-cell and recovery of The HAART with virological CD4 and function, with of CD4 and reduced HAART initiation at an early age to memory function, immunity to vaccines to be as well as the ability to adequate and responses to new vaccines. In adult the CD4 to the and magnitude of CD4 recovery on HAART in children, the CD4 does not with subsequent vaccine responsiveness Conversely, CD4 at the time of vaccination may more although not more vaccine responses suppression also with vaccine responsiveness, but whether this is of CD4 recovery is 9. In clinical commonly vaccination after CD4 recovery to the for this with data from a study in which children receiving primary vaccination developed greater immunity they been on HAART for a of with those on HAART for but data are for other vaccines. HAART vertically HIV a chronic treatable disease, also on the durability of immunity. of protective immunity the with vaccine In a study, responses against and were in and of children who were at despite apparent immune reconstitution on HAART children and may have been immunized in the of but can despite effective HAART, to infections such as and pertussis Despite good responses to primary a may be to long-term of vaccines or complete may be to protection in children. it is that HIV viraemia may be to vaccine responsiveness in children and data are very limited for infants receiving primary is in this some primary in the viraemia is in order to the for protective vaccination on on the that immune function is in infancy, that risk of vaccine-preventable and that from the vaccine studies are to this and to determine the benefits of for infants such as vaccinating The is that HIV-positive children in with routine schedules, those with immune status, on or off HAART, are to have suboptimal and immunity to certain vaccines, and this may not be or fully by HAART very early in The pace of immune recovery on HAART between pathogens so it is that the for different vaccines. are vaccines, so are safe for children. Vaccine effectiveness is not studies have the vaccine responsiveness of children and on who are immunosuppressed when HAART have reduced to protective responses to antigens, especially during the on HAART viral suppression may have limited effect on memory responses to and responses are reduced in magnitude and durability proliferation and responses to be in the but this is of the timing of vaccination or HAART initiation study that from times the baseline to times baseline within weeks in HIV-infected children, HIV-uninfected children used as responses times which were for post-vaccination times study of pre- and responses in complete incomplete HAART showed cellular and humoral responses in both with poor durability the within despite reconstitution over the on HAART, than a may be to achieve protective is a than and immunity more in children. In one study of children on HAART protective with some with the of viral suppression both and can the need for of HIV-infected children vaccination a combined and at and be to their safety pertussis vaccines than are for both the primary in and on pertussis vaccine responsiveness are by a of assays and relevant of Available data on HIV-positive children that CD4 is with poor responsiveness in those not receiving HAART treated children responses to a their previous were and the of CD4 recovery and viral suppression were Data from the AIDS cohort of children stable on HAART that they pertussis responses to despite a of previous of vaccines and immunity is also less than in children. immunological memory primary pertussis vaccination to be suboptimal and immune reconstitution by HAART on HAART after are to have immunological memory to primary pertussis so to achieve protective and responses with of vaccine is at to the age of and to and young in pertussis immunity are a of for highly and young especially their and of vaccine in is in some European schedules and be it is not routine but the pertussis vaccine is HIV-positive be it they have immune-reconstituted on HIV-positive children are to clinical or is they have been pertussis vaccines are still used in some resource-poor as with vaccines they generate suboptimal responses in HIV-infected children 10. to the for or when they become in Europe is and vaccines immune responses, primary protection to infants and the at conjugate vaccines have been in the of disease through a of direct and as have conjugate and vaccines. The of immunization with conjugate vaccines in all children to highly effective in children from disease and benefit to through immunity, although the efficacy of the the need for at of age few studies have the immunogenicity or durability of conjugate vaccines in HIV-positive children on immunization to children on HAART to age good safety but immunogenicity than in children data are awaited. for and HIV-infected children are to be at increased risk of disease the risk is than that of pneumococcal as for other it is that they a of conjugate vaccine to the age of they were in be The development of effective vaccines to be challenging because of the of with of the polysaccharide with at the time of in Europe is made against and is for HIV-positive children to to especially in with to vaccines immunity at all so vaccine is over the polysaccharide although there are no studies the in HIV-infected children. study on the safety and immunogenicity of conjugate vaccine in HIV-positive to is currently The pneumococcal conjugate vaccine which safe and in HIV-positive infants and children been by the or vaccine in many European also be and safe in and but the of studies are awaited. HIV-positive children are at greatly increased risk of pneumococcal disease, when on effective HAART; the risk is reduced by especially using conjugate vaccines immunization recommendations accommodate this. The for of for HIV-infected children by the American Academy of Pediatrics in is although we against from a primary to a individual routine schedules recommend the for from to is given and the or primary does not include at one of a of is the primary was given when the CD4 was for age be recovery on HAART, especially are Recommendations regarding the pneumococcal polysaccharide vaccine are currently inconsistent. national groups currently recommend different numbers of of for data for in HIV-infected children are lacking, in with the good evidence for with increasing evidence of when the is by in young children that evidence against the of in HIV-infected children. would the number of in with the is that such benefit is by its effect on the immunogenicity to some of the to and are to different schedules at different ages and different of such we recommend the of for all of pneumococcal vaccine the primary other conjugate vaccines, the vaccine is a vaccine and safety but data to HIV-infected children are limited. The theoretical that vaccines such as and pneumococcal conjugate vaccines may promote disease progression is not in the risk of pneumococcal disease is HIV-positive children are also at increased risk of disease study in the pre- and post-HAART reported a in in HIV-infected children when infections occur despite HAART, still those of children. Few immunogenicity studies reported to HIV-positive children on In the pre-HAART responses in children to conjugate vaccine were reduced and In a of 18 children age on HAART for a of with virological protective after of vaccine, and of children who an of vaccine the benefit of this group on effective to schedules be to for HIV-positive a need for may be by especially for those who were not on HAART when infancy, children conjugate vaccine at to the age of and this be to in with recommendations for the vaccine is used across Europe in immunization and for in HIV-infected children is to on immunological status but especially from the HAART are very limited. There is guidance on from vaccine to children who have of complete the with of is between the and doses, the after the age of for of the number of vaccine protection against over would be in the need for doses, but as are not available a of is for especially before to countries the was more than guidance on for HIV-infected does not repeated of and infections is no in developed and in children have been reported in a number of European countries HIV-positive children are to serious disease, so their immunity be vaccines live of the There is good evidence of safety for vaccines in children immunocompromise 13, as by the of the in who are severely would benefit from Therefore, CD4 thresholds for be Most children at of age and a after an from to on national recommendations. However, there to be a in in children receiving effective In a study of children immunized before the initiation of HAART than of against all vaccine were and well impaired primary responses to vaccines. in a study of children on HAART, of virological one after routine vaccination, but of the 18 after receiving a the at The of children on effective HAART are to be to protective on and be is not for because the assays available are and the patient is for be immune reconstitution on of testing is difficult to because of the of testing is and is that children, especially from may have a vaccine, so a need for complete immunization against and be serological evidence is to the severely group immunization with of their immunization The of and the time of for to a be to and Live vaccines also to be safe in children who are not severely immunosuppressed and are in national routine schedules in some European study of HIV-infected children reported good vaccine safety and immunogenicity in HIV-infected developed to and a cellular to immunity. adverse events were less after of the no adverse effects on HIV viral load or CD4 were immunity to be through in HIV-uninfected children with evidence of subsequent from to a group of HIV-positive children on HAART immunized with of vaccine and protective and/or immunity, after immunization was safe and well data are as are immunogenicity data on vaccine in of HIV-positive children reported a vaccine effectiveness of against and against and when data were for the of HAART, vaccination highly protective against vaccine effectiveness data are recommendations that HIV-infected children to 18 vaccination and they be to to individuals with or they for other immunization with is HIV-positive children become to within of but to when is is may be within of There are currently no data to the of such as as in this vaccine is available in the is than in the and efficacy studies are yet to determine whether this be a for the vaccines for HIV-positive children. data are this is not for this group. In the pre-HAART HIV-infected children poorly to vaccine a study the to after immune recovery on antiretroviral therapy that those with complete virological suppression at the time of protective vaccine responses protective responses were less frequently in children of age is not currently whether of vaccine, as are used for other groups with disease, are more effective for HIV-infected some using adult of vaccine to HIV-infected children of status is also especially there is to be a risk of vaccine a good safety its in HIV-positive children, especially those with disease or or study of the given apart showed and limited in HIV-infected children on effective HAART; a was to be safe and in increased study that all HIV-infected children, those with adequate responses after of vaccine given more than apart and vaccines are for HIV-infected children as they minimize the number of for the adult may be but this is not yet influenza vaccines killed and so are safe for HIV-infected children over of are given in the of receiving the vaccine, and a is given before the influenza on efficacy in HIV-positive children on HAART is limited. study influenza vaccine responses in HIV-infected children showed poor responses in the despite effective HAART in to vaccinating all HIV-positive individuals against also vaccinating to influenza in the the time of influenza vaccines to confer or no responses to so vaccination against influenza is currently for all HIV-infected study using an influenza vaccine that it was safe and well in HIV-infected children and the of influenza those for children, be is with as for early The new live influenza vaccine been by the European for in it is and it an but HIV are among the data are it does not to have significant adverse effects in HIV-infected children and it good comparable with that of killed influenza vaccine, prolonged Data on the of in HIV-positive children are limited but to be an important of and both directly and and by with and The availability of effective vaccines with safety in recommendations for the universal vaccination of infants in a limited number of European There are currently few safety or efficacy data on the of these live vaccines in HIV-infected children and there is limited of vaccinating these children. data become be to infants who not clinical of of data an increased of infections in HIV-positive and between immune progression of to and increased risk of in HIV-infected vaccines have good efficacy against and for to The and vaccines are both highly effective in and In the vaccine There are currently no data the of vaccines in HIV-infected in the vaccine for this the for immunogenicity by the used in against the coverage of CD4 been for the safety or efficacy of vaccination, but it is that protection be in those who are more immunosuppressed study on the of in HIV-infected and to showed good safety and further efficacy For HIV-positive the and is the age of age between age with vaccination to age the patient is at the time of vaccination, may be after immune recovery on Available data also vaccinating HIV-infected patients which the to confer benefits in and in and and and schedules need to be The that HIV-infected infants not be immunized with the live because the risk of disease is significant 11, of data when a patient is immune-reconstituted on effective HAART, the increased of serious adverse events resulting from the benefits conjugate For different schedules one at is and of European countries include vaccine in the routine so the after is not on HIV this is not vaccine be available to infants of HIV-positive of are adequate as the not be children can at time with the and but individual countries to The adult the paediatric may be in immunocompetent children. that the at of age for countries using the combined vaccine is not the is also an for adequate is after the and the results are as is the vaccine that is contraindicated in HIV-infected children in vaccine live and so be for immunocompetent children and the of the is a significant vaccine polysaccharide and so is not contraindicated in HIV-positive patients but reduced immune responses For to or Europe, vaccination against is for in or early in or This vaccine is more in HIV-infected with a CD4 there are no studies in HIV-infected children vaccine also be for children over the age of before to in HIV-infected children that the vaccine is safe and after immune reconstitution The efficacy of vaccination in HIV-infected children been poorly and is not so there is utility in vaccines to the need for of In certain vaccines are available in than as so would immunity to all vaccine antigens in the In children who have been fully before there is evidence of be for vaccine when primary vaccination and have been at of who were when they of have immunity after age and before to adult age protective for vaccine-preventable are that the evidence is limited in some that the of individual protection are not available for all vaccines when of protection may not be relevant to HIV-positive protective is an for HIV-infected children with or incomplete immunization this is on the routine vaccine and currently available in the and on guidance by the Health The can be according to local schedules and be in that the of is and is not in this be for children over of age, that are given at for HIV-infected children with or incomplete immunization this is on the routine vaccine and currently available in the and on guidance by the Health The can be according to local schedules and combined diphtheria/tetanus/acellular pneumococcal conjugate combined combined diphtheria/tetanus/acellular combined diphtheria/tetanus/acellular after of the CD4 on HAART, vaccine responsiveness may be because of and immune given that responsiveness to vaccination is to the CD4 for some vaccines impaired memory responses despite effective HAART suboptimal to primary and a for of vaccine be the patient was severely when primary vaccination were complete after immune recovery on HAART be the of This may be the to achieve responses to some vaccines.