Immunization of children at risk of infection with human immunodeficiency virus

William J. Moss,¹ C. John Clements,² & Neal A. Halsey³

ABSTRACT: This paper reviews the English language literature on the safety, immunogenicity and effectiveness in children infected with the human immunodeficiency virus (HIV) of vaccines currently recommended by WHO for use in national immunization programmes. Immunization is generally safe and beneficial for children infected with HIV, although HIV–induced immune suppression reduces the benefit compared with that obtained in HIV–uninfected children. However, serious complications can occur following immunization of severely immunocompromised children with bacillus Calmette–Guérin (BCG) vaccine. The risk of serious complications attributable to yellow fever vaccine in HIV–infected persons has not been determined.
WHO guidelines for immunizing children with HIV infection and infants born to HIV–infected women differ only slightly from the general guidelines. BCG and yellow fever vaccines should be withheld from symptomatic HIV–infected children. Only one serious complication (fatal pneumonia) has been attributed to measles vaccine administered to a severely immunocompromised adult. Although two HIV–infected infants have developed vaccine–associated paralytic poliomyelitis, several million infected children have been vaccinated and the evidence does not suggest that there is an increased risk. The benefits of measles and poliovirus vaccines far outweigh the potential risks in HIV–infected children. The policy of administering routine vaccines to all children, regardless of possible HIV exposure, has been very effective in obtaining high immunization coverage and control of preventable diseases. Any changes in this policy would have to be carefully examined for a potential negative impact on disease control programmes in many countries.

Keywords HIV infections/immunology; BCG vaccine/immunology/adverse effects; Measles vaccine/immunology; Poliovirus vaccine, Oral/immunology; Yellow fever vaccine/immunology/adverse effects; Diphtheria–tetanus–pertussis vaccine/immunology; Hepatitis B vaccines/immunology; Haemophilus vaccines/immunology; Infant; Immunization programs; Guidelines; World Health Organization; Review literature (source: MeSH, NLM).

Mots clés HIV, Infection/immunologie; Vaccin BCG/immunologie/effets indésirables; Vaccin antimorbilleux/immunologie; Vaccin antipoliomyélitique Sabin/immunologie; Vaccin anti–fièvre jaune/immunologie/effets indésirables; Vaccin diphtérie–tétanos–coqueluche/ immunologie; Vaccin antihépatite B/immunologie; Vaccin antihémophilus/immunologie; Enfant; Nourrisson; Programmes de vaccination; Lignes directrices; Organisation mondiale de la Santé; Revue de la littérature (source: MeSH, INSERM).

Palabras clave Infecciones por VIH/inmunología; Vacuna BCG/inmunología/efectos adversos; Vacuna antisarampión/inmunología; Vacuna antipolio oral/inmunología; Vacuna contra la fiebre amarilla/inmunología/efectos adversos; Vacuna difteria–tétano–pertussis/inmunología; Vacunas contra hepatitis B//inmunología; Vacunas contra haemophilus/ inmunología; Vacunas bacterianas/inmunología; Vacunas virales/inmunología; Vacunas atenuadas/inmunología; Niño; Lactante; Programas de inmunización; Pautas; Organización Mundial de la Salud; Literatura de revisión (fuente: DeCS, BIREME).

Introduction

The majority of children born to women who are infected with human immunodeficiency virus (HIV) do not acquire HIV infection. Of those children who do become infected, most acquire the virus from their mothers at the time of delivery or shortly thereafter. Early in life they are immunologically normal but, in the absence of specific therapy for HIV infection, develop progressive immunodeficiency that affects all aspects of the immune system. The rate of progression to clinically apparent immunosuppression depends on maternal, infant, and viral factors. Accordingly, the safety and effectiveness of vaccines in HIV–infected children varies with age at vaccination and their immune status.

Guidelines for administering immunizations usually make special provisions for children known to have underlying immunodeficiency disorders. The following areas of concern are critical to the development of such guidelines.

• Will the effectiveness of a vaccine be impaired because of underlying immune deficiency?
• Are persons receiving a live viral vaccine or a bacterial vaccine subject to a significantly increased risk compared with non–infected persons?
• Does administering a vaccine significantly affect the rate of HIV–associated disease?

In this paper we review the literature published in English on the safety, immunogenicity and effectiveness of vaccines, including new vaccines that are being introduced in some areas, and critically evaluate WHO's recommendations on the vaccination of HIV–infected persons.

Current WHO recommendations for immunization of children with known or suspected HIV infection

Few adverse events have been observed following the immunization of HIV–infected infants. Consequently, the current WHO guidelines for immunizing children known to have HIV infection and infants born to HIV–infected women differ only slightly from the general guidelines for other infants (1). WHO's policy is based on the potential severity of vaccine– preventable diseases in HIV–infected children, on vaccine safety and immunogenicity, and on the degree of HIV–induced immunosuppression. Children with known or suspected asymptomatic HIV infection should receive all recommended vaccines in accordance with nationally recommended schedules subject to the modifications listed below.

• An extra dose of measles vaccine is recommended at 6 months of age in order to provide protection at a younger age than for non–HIV–infected infants and to improve protection against measles.
• Individuals with symptomatic HIV infection should not receive live attenuated BCG vaccine. Administration of BCG vaccine to HIV–exposed infants should be based on the risk of tuberculosis. If this risk is high, BCG vaccine should be administered at birth to children with possible HIV infection according to the standard schedule of the Expanded Programme on Immunization. If BCG vaccine remains on the schedule of a national immunization programme and the risk of tuberculosis is low, this vaccine should not be administered to children with suspected HIV infection.
• Individuals with symptomatic HIV infection should not receive live attenuated yellow fever vaccine.

Immunogenicity and effectiveness

Non–replicating vaccines

Diphtheria–tetanus–pertussis vaccine

Following primary immunization in infancy, 40–100% of symptomatic and asymptomatic HIV–infected children respond to diphtheria and tetanus toxoids by developing protective levels of diphtheria and tetanus antitoxins (Table 1). However, HIV–infected children and adults develop lower geometric mean antitoxin titres and are more likely than uninfected persons to lose antibody within a few years after vaccination. Some studies have correlated antibody titres with CD4+ T–lymphocyte counts (Table 1). Comparable data for pertussis vaccines are more limited and their interpretation is more difficult since serological correlates of protection have not been identified. The available data suggest that the proportion of children who seroconvert and the geometric mean antibody titres to pertussis toxin are lower for HIV– infected children than for healthy controls (2). There is no evidence that HIV–infected children have higher vaccine failure rates than HIV–uninfected children following diphtheria, tetanus or pertussis immunization, but there have been no rigorous studies of the effectiveness of diphtheria–tetanus– pertussis vaccine in HIV–infected children.

Hepatitis B vaccines

The serological response to hepatitis B vaccines is lower for HIV–infected children and adults than for uninfected persons of similar age (Table 2). Serological response rates have varied, but most studies have reported that only 25–50% of HIV–infected children have developed protective antibodies. As with tetanus and diphtheria toxoids, response rates appear to be higher for younger children and in some studies correlate with CD4+ T–lymphocyte counts. Attempts to overcome the decreased response by administering higher doses or extra doses of hepatitis B vaccine have not been promising in children (3, 4). However, one study of 20 HIV–infected adults reported that seven of the nine individuals who failed to respond to the initial three–dose series developed a protective antibody response after three additional doses of hepatitis B vaccine (5). HIV–infected children and adults who respond to hepatitis B vaccine have a more rapid decline in antibody titre than uninfected persons. For example, only 42% of HIV–infected children who seroconverted after the primary three–dose series or after receipt of the adult dose of hepatitis B vaccine had protective antibody titres 13–18 months after immunization (6). Long–term follow–up studies suggest that most HIV–uninfected children and adults have continued protection against becoming clinically ill and chronic HBsAg carriers after exposure, despite loss of detectable antibody (7). It is not known whether such protection occurs in HIV–infected persons with undetectable antibody levels. In immunologically normal persons, however, loss of detectable antibody after developing a protective antibody response (> 10 mIU) does not mean that protection against hepatitis B has been lost.

Polysaccharide and polysaccharide–protein conjugate vaccines

In the absence of acquired immunodeficiency syndrome (AIDS) or profoundly diminished CD4+ T–lymphocyte counts, 37–86% of HIV–infected children developed protective antibody responses to Haemophilus influenzae type b conjugate vaccine, but the geometric mean titres were lower than those reported for HIV–uninfected persons of similar ages (8–12). Antibody levels decline more rapidly in HIV–infected children but booster doses of vaccine induce rapid increases in the levels, suggesting the retention of immunological memory in many HIV–infected children (11). One study reported that antibody titres decreased to below 1 mg/ml in 43% of 48 HIV–infected children one year after vaccination, whereas the corresponding proportion was only 11% for HIV–uninfected children (10). The absence of high rates of vaccine failure among HIV–infected children in settings where routine immunization has been introduced suggests that many such children are protected against invasive disease following immunization with conjugate H. influenzae type b vaccines.

No data are available on the response of HIV–infected children or adults to meningococcal polysaccharide or conjugate vaccines, but the response to 23–valent pneumococcal polysaccharide vaccine is poorer than that of HIV–uninfected persons. The antibody response to a glycoprotein conjugate pneumococcal vaccine was better than that of the polysaccharide vaccine in HIV–infected persons, except for those with very low CD4+ T–lymphocyte counts (13, 14). Since polysaccharides are processed as T–independent antigens, the immune response is not affected by HIV–induced impairment of the immune response to the same extent as with T–dependent antigens. However, the antibody response to specific pneumococcal polysaccharide serotypes varies, some serotypes eliciting poor antibody responses in HIV–infected persons with CD4+ T–lymphocyte counts below 200 cells/ mm³ (15). In HIV–infected Ugandan, adults the 23–valent pneumococcal polysaccharide vaccine did not prevent first episodes of invasive pneumococcal disease (16).

Live bacterial vaccines

Bacillus Calmette–Guérin (BCG) vaccine

The tuberculin skin test is the only practical tool for determining the response to BCG vaccination, but the diameter of the skin test following immunization is not a good predictor of protection against Mycobacterium tuberculosis disease. In Rwanda, only 37% of HIV–infected infants developed a skin test response exceeding 6 mm in diameter after BCG vaccination, whereas the corresponding proportions for HIV–uninfected infants born to HIV–infected women and for infants born to HIV–uninfected women were 57% and 70%, respectively (17).

The protection conferred by BCG vaccination against tuberculous meningitis and miliary tuberculosis in HIV– uninfected populations varies widely, most probably because of differences in BCG strains and in study methodologies, but a recent meta–analysis indicated that the overall protection was approximately 80% (18). In Zambia the proportion of children with BCG scars (83%) was the same for 30 HIV–infected children with tuberculosis and for 18 such children who did not have tuberculosis, i.e. there was no evidence of protection from BCG vaccination (19). This study did not have sufficient power to evaluate protection against tuberculous meningitis or miliary disease. Studies of tuberculosis in adults who had received BCG vaccine in infancy have not shown a clear protective benefit (20, 21). These data are not adequate to permit definitive conclusions about the effectiveness of BCG vaccine to protect HIV–infected children or adults against tuberculosis.

Live viral vaccines

Oral poliovirus vaccine (OPV)

The proportion of HIV–infected children who responded to three doses of OPV exceeded 90% in most studies (Table 3). In the Democratic Republic of Congo (formerly Zaire), 97% of HIV–infected children developed protective antibody titres to poliovirus types 1, 2, and 3 after three doses of OPV (22). However, this study was conducted when there was widespread circulation of wild–type polioviruses, which could have contributed to the high proportion of children with antibody. Although no direct estimates of the efficacy of poliovirus vaccine have been conducted in HIV–infected children, wild– type polioviruses have been eliminated from several countries with high prevalence rates of HIV infection.

Measles virus vaccine

Antibody response to measles vaccine is impaired in HIV– infected persons (Table 4). Approximately one–fourth to one– third of HIV–infected children have responded to a single dose of standard–titre measles vaccine in most prospective studies (23–26). In a study of HIV–seropositive children in Zaire, 65% had protective titres of measles antibody three months after measles vaccination at 9 months of age; only 36% of 11 symptomatic children seroconverted, whereas 77% of 26 asymptomatic children did so (23). The response to a second dose of vaccine varied but was generally poor (25, 27–30). In cross–sectional studies there were wide variations in the age at immunization, the number of vaccine doses received, the interval between immunization and assay, the type of measles antibody assay, and the degree of immunosuppression at the time of assessment. In children, the prevalence of measles antibody varied from 17% to 100%, with a median value of 60% (24, 25, 27, 29–33). Most HIV–infected adults, however, were seropositive for measles antibodies (34, 35). An association between lack of measles–specific antibodies after vaccination and low CD4+ T–lymphocyte counts (3) was documented in one prospective study (25) and two cross–sectional studies (30, 33). In a study of Ugandan children, a poor antibody response to measles vaccine was associated with stunting but not with HIV infection (36). HIV–infected children appear to experience a more rapid decline in measles antibodies than HIV–uninfected children (30), the median time to loss of antibody detectable by enzyme immunosorbent assay was 30 months in a study of 17 HIV–infected children (33).

Experience in southern Africa suggests that the number of measles cases can be reduced in regions of high HIV prevalence by maintaining high immunization rates coupled with periodic supplemental campaigns (39). However, primary and secondary vaccine failures in HIV–infected children and the potential for prolonged measles virus shedding (40) could hinder the long–term control or elimination of measles in regions of high HIV prevalence.

Yellow fever virus vaccine

Limited data suggest that HIV–infected children respond poorly to yellow fever vaccine (41). However, seroconversion rates were high in HIV–infected adults who were not severely immunocompromised (42). Only 3 of 18 HIV–infected children (17%) developed an antibody response to yellow fever vaccine, whereas 74% of 57 HIV–uninfected children did so (41). No data are available on protection against disease following yellow fever vaccination of HIV–infected persons. Despite the possibility of reduced protection, it seems justifiable to encourage the use of the vaccine even in areas of high HIV prevalence.

Safety of vaccines in HIV–infected persons

Non–replicating vaccines

Non–replicating vaccines are not associated with increased risks of complications in immunocompromised persons. However, a study of HIV–infected Ugandan adults found a higher incidence of pneumonia among recipients of 23–valent pneumococcal polysaccharide vaccine than among unvaccinated HIV–infected adults (16). The authors hypothesized that immunization might result in the destruction of polysaccharide–responsive B–cell clones but presented no specific data to support this suggestion. Additional studies are needed on this issue.

BCG vaccine

Complications arising from BCG vaccination include regional, extraregional localized, and disseminated disease. The rates of these complications in HIV–uninfected children vary. BCG causes local ulcers and regional lymphadenitis in normal hosts at rates varying from 4 to 30 per 1000 vaccinated infants, depending on the vaccine strain, the technique of administration, and the dose (43). There are several reports of regional lymphadenitis, poorly healing ulcers, and fistulae in HIV–infected infants (Table 5). Administration of BCG to HIV–infected children in the first month of life is associated with relatively low rates of complications because immune suppression takes several months to develop. In direct comparisons, the rates of these complications have been similar in HIV–infected and HIV–uninfected infants, but lymphadenitis has been more severe in HIV–infected children.

More than 28 cases of disseminated BCG infection have been reported in HIV–infected children and adults (Table 5) (44, 45). Because the diagnosis cannot be made on clinical criteria alone and requires laboratory facilities to culture the organism and differentiate it from other mycobacteria, this complication has undoubtedly occurred in more HIV–infected individuals than has been reported in the published literature. Although disseminated disease usually occurs between several months and a few years following vaccination, it was reported in one 30–year–old with HIV infection who received BCG vaccine at birth (46). Disseminated BCG infection is more likely to occur when the vaccine is administered to individuals with clinical AIDS or advanced immunosuppression. Progressive immune suppression can lead to the reactivation of latent BCG organisms, causing regional or disseminated disease (46, 47). In one study, however, no cases of disseminated BCG infection were found among 155 adult patients with AIDS who had received BCG vaccine in infancy and whose blood was cultured for mycobacteria (21).

Live viral vaccines

Oral poliovirus vaccine

The risk of vaccine–associated paralytic poliomyelitis is increased in persons with primary B cell immunodeficiency disorders. Nevertheless, in the USA more than 1000 HIV–infected children received at least one dose of OPV without complications before it was known that they or their mothers were HIV–infected, and several thousand HIV–infected children in other countries have been vaccinated. We estimate that, in the 20 years since the HIV epidemic has been recognized, more than 500 000 HIV–infected children have received one or more doses of OPV. Only two HIV–infected children have been reported with vaccine–associated paralytic poliomyelitis following the receipt of OPV (Table 3): a 2–year– old Romanian girl (48) and a child in Zimbabwe (49). In Romania the rate of vaccine–associated paralytic poliomyelitis in all children was approximately ten times higher than the estimated 1 case per 2.5 million doses administered in the USA and Europe, most probably because of the use of multiple injections (50). The HIV infections in these two children with vaccine–associated paralytic poliomyelitis could be chance associations and not evidence of an increased risk associated with HIV infection. If the risk of vaccine–associated paralytic poliomyelitis is greater for HIV–infected persons, the attributable risk is very low. Studies in progress are evaluating the possibility of prolonged excretion of poliovirus vaccine strain by HIV–infected children.

Measles virus vaccine

Prospective studies revealed that the risk of adverse events in the few weeks following immunization with standard–titre and high–titre measles vaccines was no different for HIV–infected and HIV–uninfected children (51), although one HIV–infected adult developed fever, rash, coryza and conjunctivitis 12 days after measles immunization (52). A retrospective survey conducted by the New York City Department of Health found no complications following measles immunization of HIV–infected children (53). Measles vaccine virus was detected by means of the polymerase chain reaction in a 14–month–old HIV–infected boy who developed diarrhoea and a febrile illness associated with a 4–day generalized rash after receiving measles–mumps–rubella vaccine (54). No evidence of persistent excretion of measles vaccine virus was found in 10 HIV– infected children immunized with this vaccine (28).

Only one serious adverse event has been reported following the administration of measles vaccine to an HIV– infected person (55). A 20–year–old HIV–infected man, who had a very low CD4+ T–lymphocyte count at the time he received a second dose of measles–mumps–rubella vaccine, developed cough and progressive pulmonary infiltrates 10 months after immunization. An open lung biopsy showed giant cell pneumonitis, and measles vaccine virus was identified in the lung tissue. The patient died several months later from the progressive pneumonitis

Yellow fever vaccine

WHO became concerned about the theoretical risk of yellow fever vaccine causing illness in immunocompromised individuals and about early unconfirmed reports of serious adverse events in HIV–infected persons and issued guidelines on avoiding the use of yellow fever vaccine in symptomatic HIV– infected individuals (1). Few severe complications attributable to the inadvertent immunization of immunocompromised individuals with yellow fever vaccine have been reported, but experience is limited. Fatal myeloencephalitis caused by yellow fever vaccine was reported in a 53–year–old HIV–infected man in Thailand (56), although no adverse events were observed following yellow fever vaccination of two HIV–infected adults (57). Seven cases of severe illness resembling yellow fever, six of them fatal, were reported with evidence of vaccine virus in affected tissues, but there was no evidence of HIV infection (58). These findings are encouraging but more studies are needed in order to confirm the safety of yellow fever vaccine in HIV–infected persons. On the basis of the available information, the authors consider that, in the event of an outbreak, yellow fever vaccine should be administered to the whole population at risk, irrespective of their HIV infection status. Travel clinics for healthy adults are generally more conservative, and administer yellow fever vaccine only to those with adequate CD4+ T–lymphocyte counts.

Effect of vaccination on HIV disease progression

The activation of CD4+ T–lymphocytes following immunization could potentially augment HIV replication and result in accelerated progression to disease. Several, but not all investigators (59) have described increased HIV RNA plasma levels lasting several days following immunization with tetanus toxoid (60) and with influenza (61–64), pneumococcal (65, 66) and hepatitis B vaccines (5, 67). Importantly, no investigators have observed prolonged elevation of HIV RNA viral load, decreased CD4+ lymphocyte counts or accelerated HIV disease progression following immunization (68). Although the transient rise in HIV viral load following the administration of tetanus toxoid to pregnant women could theoretically affect the risk of maternal–infant HIV transmission, an increased risk of transmission is unlikely if vaccination occurs at least four weeks before delivery.

Conclusions

The current WHO recommendations for the vaccination of HIV–infected children and adults are appropriate. However, the factors discussed below should be taken into consideration.

Timing of immunizations

Because of the decreased immune response to vaccines with increasing age in HIV–infected children, immunization should take place as early in life as possible in children born to HIV– infected women. For hepatitis B vaccine, early immunization is especially important because the risk of becoming a chronic carrier is higher for HIV–infected children and adults than for uninfected persons (69). A preference for immunization at birth should be indicated in countries with a high maternal HIV infection rate as well as in those where there are high rates of perinatal hepatitis B transmission. The limited available data do not suggest that there is a need for administering extra doses of hepatitis B vaccine to HIV–infected children.

BCG vaccine

Most infants born to HIV–infected women do not acquire HIV infection. BCG vaccine provides some protection against severe disease for children in areas of high risk for tuberculosis. If it were possible to administer BCG vaccine only to HIV–uninfected children in the first month of life, the incidence of severe complications from this vaccine could be reduced. However, in most areas it is not practical at this time to identify HIV–infected children early in their lives. The current policy of administering BCG vaccine to all asymptomatic infants at risk of acquiring tuberculosis is appropriate. In regions where the risk of contracting tuberculosis is low, BCG vaccine should not be administered to children with known or suspected HIV infection.

Poliovirus vaccine

It is not necessary or practical to consider the use of inactivated poliovirus vaccine for children born to HIV–infected women in most countries. Some countries that have been free of wild–type polioviruses for many years routinely use inactivated poliovirus vaccine to vaccinate HIV–infected children. In order to avoid the possible increased risk of vaccine–associated paralytic poliomyelitis, countries where wild–type polioviruses have been eliminated may consider the use of inactivated poliovirus vaccine for immunocompromised HIV–infected children if the necessary resources are available.

Measles vaccine

Immunocompromised HIV–infected children are at risk of death or severe complications following wild–type measles virus infection. The balance of risk clearly favours measles immunization in regions where there is transmission of wild–type measles virus. If measles virus is circulating in a community, all children, regardless of HIV infection status, should receive measles vaccine. Current WHO policy adequately addresses the need for early measles immunization of children born to HIV–infected women. Although definitive evidence is lacking, an extra dose of standard–titre measles vaccine administered to HIV–infected infants at 6 months of age is likely to result in protective antibody titres because inhibitory maternal antibody titres are low and the immune system is still unimpaired.

Where the chance of contracting wild–type measles virus infection is almost non–existent, countries with the capacity to monitor an individual's immune status may consider withholding measles vaccine from severely immunocompromised HIV–infected children. Children with moderate levels of immune suppression should continue to receive measles vaccine.

Yellow fever vaccine

Yellow fever vaccine should be withheld from HIV–symptomatic individuals until more information is available on the vaccine's safety for HIV–infected individuals.

Research

Research in several areas (see Box 1) is needed in order to further evaluate and consider future modifications of WHO policies for the vaccination of HIV–infected persons.

Acknowledgements

This work was supported in part by the World Health Organization and by a cooperative agreement from the Centers for Disease Control and Prevention (CDC) for Clinical Immunization Safety Assessment (CISA) Network.

The authors wish to thank Tina Proveaux for technical and editorial assistance.

Conflicts of interest: Dr Halsey has conducted clinical trials of vaccines supported by Glaxo SmithKline.

Résumé

Vaccination de l'enfant à risque d'infection par le virus de l'immunodéficience humaine

L'article passe en revue la littérature de langue anglaise concernant l'innocuité, l'immunogénicité et l'efficacité des vaccins actuellement recommandés par l'OMS dans le cadre des programmes nationaux de vaccination. La vaccination est en général sans danger et bénéfique chez l'enfant infecté par le virus de l'immunodéficience humaine (VIH) ; l'immunodépression induite par le VIH diminue cependant le bénéfice, comparé à celui obtenu chez des enfants indemnes d'infection. Le risque de complications graves est toutefois possible après vaccination par le bacille de Calmette et Guérin (BCG) quand l'enfant est gravement immunodéprimé. Le risque de complication post–vaccinale grave après vaccination antiamarile de personnes infectées par le VIH n'a pas été déterminé.
Les recommandations de l'OMS pour la vaccination de l'enfant atteint d'infection à VIH et du nourrisson né de mère infectée par le virus diffèrent très peu des recommandations générales. Le vaccin antiamaril et le BCG ne seront pas administrés à l'enfant symptomatique. Un seul cas de complication grave (pneumonie fatale) a été attribué au vaccin antirougeoleux administré à un adulte massivement immunodéprimé. Si deux nourrissons infectés par le VIH ont fait une poliomyélite paralytique post–vaccinale, plusieurs millions d'enfants infectés par le VIH ont été vaccinés et les données n'indiquent pas qu'il y ait augmentation du risque. Les avantages des vaccins antirougeoleux et antipoliomyélitique dépassent largement les risques potentiels chez ces enfants. La politique consistant à administrer les vaccins classiques à tous les enfants, quelle que soit leur exposition au VIH, a permis d'obtenir une bonne couverture vaccinale et la maîtrise de maladies évitables. Toute modification de cette politique devra être soigneusement pesée en raison de l'impact négatif qu'elle pourrait avoir dans de nombreux pays sur les programmes de lutte contre les maladies.

Resumen

Inmunización de los niños en riesgo de infección por el virus de la inmunodeficiencia humana

En este artículo se examina la literatura en inglés sobre la seguridad, inmunogenicidad y eficacia de las vacunas actualmente recomendadas por la OMS para los programas nacionales de vacunación. La inmunización es por lo general segura y beneficiosa para los niños infectados por el virus de la inmunodeficiencia humana (VIH), si bien la inmunodepresión causada por dicho virus atenúa los efectos beneficiosos en comparación con los conseguidos en los niños no infectados por el VIH. Sin embargo, los niños gravemente inmunodeprimidos pueden sufrir graves complicaciones tras la inmunización con la vacuna basada en el bacilo de Calmette–Guérin (BCG). No se ha determinado el riesgo de complicaciones graves atribuibles a la vacuna antiamarílica en personas infectadas por el VIH.
Las directrices de la OMS para inmunizar a los niños con infección por el VIH y los lactantes nacidos de mujeres infectadas por el VIH difieren muy poco de las directrices generales. Hay que evitar la BCG y la vacuna antiamarílica en los niños infectados por el VIH con síntomas. Sólo se ha dado un caso de complicación grave (neumonía mortal) atribuida a la vacuna antisarampionosa administrada a un adulto gravemente inmunodeprimido. Aunque dos lactantes infectados por el VIH han desarrollado poliomielitis paralítica asociada a la vacuna, son varios millones los niños infectados que han sido vacunados, y no hay ningún indicio de que corran un mayor riesgo. Los beneficios que reportan las vacunas contra el sarampión y el poliovirus superan ampliamente los riesgos potenciales en los niños infectados por el VIH. La política de administrar sistemáticamente esas vacunas a todos los niños, independientemente de su posible exposición al VIH, ha contribuido de forma muy eficaz al logro de una alta cobertura de inmunización y de control de enfermedades prevenibles. Cualquier cambio de dicha política debería verse precedido de un detenido examen de las posibles repercusiones negativas en los programas de control de esas enfermedades en muchos países.

References

1. World Health Organization. Immunization policy. Geneva: World Health Organization; 1996. WHO document WHO/EPI/GEN/95.03.p. 25–7). Available from: URL: http://whqlibdoc.who.int/hq/1995/WHO_EPI_GEN_95.03_ev.1.pdf         

2. de Martino M, Podda A, Galli L, Sinangil F, Mannelli F, Rossi ME, et al. Acellular pertussis vaccine in children with perinatal human immunodeficiency virus–type 1 infection. Vaccine 1997;5:1235–8.         

3. Zuccotti GV, Riva E, Flumine P, Locatelli V, Fiocchi A, Tordato G, et al. Hepatitis B vaccination in infants of mothers infected with human immunodeficiency virus. Journal of Pediatrics 1994;125:70–2.         

4. Choudhury SA, Peters VB. Responses to hepatitis B vaccine boosters in human immunodeficiency virus–infected children. Pediatric Infectious Disease Journal 1995;14:65–7.         

5. Rey D, Krantz V, Partisani M, Achmitt MP, Meyer P, Libbrecht E, et al. Increasing the number of hepatitis B vaccine injections augments anti–HBs response rate in HIV–infected patients. Effects on HIV–1 viral load. Vaccine 2000;18:1161–5.         

6. Scolfaro C, Fiammengo P, Balbo L, Madon E, Tovo PA. Hepatitis B vaccination in HIV–1 infected children: double efficacy doubling the paediatric dose. AIDS 1996;10:1169–70.         

7. Mahoney FJ, Kane M. Hepatitis B vaccine. In: Plotkin SA, Orenstein WA, editors. Vaccines. 3rd ed. Philadephia: W.B. Saunders Company; 1999. p. 158–82.         

8. Gibb D, Spoulou V, Giacomelli A, Griffiths H, Masters J, Misbah S, et al. Antibody responses to Haemophilus influenzae type b and Streptococcus pneumoniae vaccines in children with human immunodeficiency virus infection. Pediatric Infectious Disease Journal 1995;14:129–35.         

9. Rutstein RM, Rudy BJ, Cnaan A. Response of human immunodeficiency virus– exposed and –infected infants to Haemophilus influenzae type b conjugate vaccine. Archives of Pediatrics and Adolescent Medicine 1996;150:838–41.         

10. Gibb D, Giacomelli A, Masters J, Spoulou V, Ruga E, Griffiths H, et al. Persistence of antibody responses to Haemophilus influenzae type b polysaccharide conjugate vaccine in children with vertically acquired human immunodeficiency virus infection. Pediatric Infectious Disease Journal 1996;15:1097–101.         

11. Peters VB, Sood SK. Immunity to Haemophilus influenzae type b after reimmunization with oligosaccharide CRM₁₉₇ conjugate vaccine in children with human immunodeficiency virus infection. Pediatric Infectious Disease Journal 1997;16:711–3.         

12. Read JS, Frasch CE, Rich K, Fitzgerald GA, Clemens JD, Pitt J, et al. The immunogenicity of Haemophilus influenzae type b conjugate vaccines in children born to human immunodeficiency virus–infected women. Pediatric Infectious Disease Journal 1998;17:391–7.         

13. Ahmed F, Steinhoff MC, Rodreguez–Barradas MC, Hamilton RG, Musher DM, Nelson KE. et al. Effect of human immunodeficiency virus type 1 infection on the antibody response to a glycoprotein conjugate pneumococcal vaccine: results from a randomized trial. Journal of Infectious Diseases 1996;173:83–90.         

14. King JC, Vink PE, Farley JJ, Parks M, Smilie M, Madore D, et al. Comparison of the safety and immunogenicity of a pneumococcal conjugate with a licensed polysaccharide vaccine in human immunodeficiency virus and non–human immunodeficiency virus–infected children. Pediatric Infectious Disease Journal 1996;15:192–6.         

15. Kroon FP, van Dissel JT, Ravensbergen E, Nibbering PH, van Furth R. Antibodies against pneumococcal polysaccharides after vaccination in HIV–infected individuals: 5–year follow–up of antibody concentrations. Vaccine 2000;18:524–30.         

16. French N, Nakiyingi J, Carpenter LM, Lugada E, Warera C, Moi K, et al. 23–valent pneumococcal polysaccharide vaccine in HIV–1–infected Ugandan adults: double–blind, randomised and placebo controlled trial. Lancet 2000;355:2106–11.         

17. Msellati P, Dabis F, Lepage P, Hitimana DG, Van Goethem C, Van de Perre P BCG vaccination and pediatric HIV infection — Rwanda, 1988–1990. Morbidity and Mortality Weekly Report 1991;40:833–6.         

18. Colditz GA, Brewer TF, Berkey CS, Wilson ME, Burdick E, Fineberg HV, et al. Efficacy of BCG vaccine in the prevention of tuberculosis. Meta–analysis of the published literature. JAMA 1994;271:698– 702.         

19. Bhat GJ, Diwan VK, Chintu C, Kabika M, Masona J. HIV, BCG and TB in children: A case control study in Lusaka, Zambia. Journal of Tropical Pediatrics 1993;39:219–22.         

20. Allen S, Batungwanayo J, Kelinkowske K, Lifson AR, Wolf W, Granich R, et al. Two year incidence of tuberculosis in cohorts of HIV–infected and uninfected urban Rwandan women. American Review of Respiratory Disease 1992;146:1439–44.         

21. Marsh BJ, von Reyn CF, Edwards J, Ristola MA, Bartholomew C, Brindle RJ, et al. The risks and benefits of childhood bacille Calmette–Guérin immunization among adults with AIDS. AIDS 1997;11:669–72.         

22. Ryder RW, Oxtoby MJ, Mvula M, Batter V, Baende E, Nsa W, et al. Safety and immunogenicity of bacille Calmette–Guérin, diphtheria–tetanus–pertussis, and oral polio vaccines in newborn children in Zaire infected with human immunodeficiency virus type 1. Journal of Pediatrics 1993;122:697–702.         

23. Oxtoby MJ, Ryder R, Mvula M, Nsa W, Baende E, Onorato I. Patterns of immunity to measles among African children infected with human immunodeficiency virus. In: Epidemic Intelligence Service Conference; 1989 April 3–5; Atlanta, GA.         

24. Krasinski K, Borkowsky W. Measles and measles immunity in children infected with human immunodeficiency virus. JAMA 1989;261:2512–6.         

25. Palumbo P, Hoyt L, Demasio K, Oleske J, Connor E. Population–based study of measles and measles immunization in human immunodeficiency virus–infected children. Pediatric Infectious Disease Journal 1992;11:1008–14.         

26. Thaithumyanon P, Punnahitananda S, Thisyakorn U, Praisuwanna P, Ruxrungtham K. Immune responses to measles immunization and the impacts on HIV–infected children. Southeast Asian Journal of Tropical Medicine and Public Health 2000;31:658–62.         

27. Brena AE, Cooper ER, Cabral HJ, Pelton SI. Antibody response to measles and rubella vaccine by children with HIV infection. Journal of Acquired Immune Deficiency Syndromes 1993;6:1125–9.         

28. Frenkel LM, Nielsen H, Garakian A, Cherry JD. A search for persistent measles, mumps and rubella vaccine virus in children with human immunodeficiency type–1 infection. Archives of Pediatrics and Adolescent Medicine 1994;148:57–60.         

29. Brunell PA, Vimal V, Sandhu M, Courville TM, Daar E, Israele V. Abnormalities of measles antibody response in human immunodeficiency virus type 1 (HIV–1) infection. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1995;10:540–8.         

30. Arpadi SM, Markowitz LE, Baughman AL, Shah K, Adam H, Wiznia A, et al. Measles antibody in vaccinated human immunodeficiency virus type 1–infected children. Pediatrics 1996;97:653–7.         

31. Molyneaux PJ, Mok JYQ, Burns SM, Yap PL. Measles, mumps, and rubella immunisation in children at risk of infection with human immunodeficiency virus. Journal of Infection 1993;27:151–3.         

32. Rudy BJ, Rutstein RM, Pinto–Martin J. Response to measles immunization in children infected with human immunodeficiency virus. Journal of Pediatrics 1994;125:72–4.         

33. Al–Attar I, Reisman J, Muehlmann M, McIntosh K. Decline of measles antibody titres after immunization in human immunodeficiency virus–infected children. Pediatric Infectious Disease Journal 1995;14:149–51.         

34. Wallace MR, Hooper DG, Graves SJ, Malone JL. Measles seroprevalence and vaccine response in HIV–infected adults. Vaccine 1994;12:1222–4.         

35. Kemper CA, Gangar M, Arias G, Kane C, Deresinski SC. The prevalence of measles antibody in human immunodeficiency virus–infected patients in Northern California. Journal of Infectious Diseases 1998;178:1177–80.         

36. Waibale P, Bowlin SJ, Mortimer EA, Whalen C. The effect of human immunodeficiency virus–1 infection and stunting on measles immunoglobulin– G levels in children vaccinated against measles in Uganda. International Journal of Epidemiology 1999;28:341–6.         

37. Lepage P, Dabis F, Msellati P, Hitimana DG, Stevens AM, Mukamabano B, et al. Safety and immunogenicity of high–dose Edmonston–Zagreb measles vaccine in children with HIV–1 infection. A cohort study in Kigali, Rwanda. American Journal of Diseases of Children 1992;146:550–5.         

38. Embree JE, Datta P, Stackiw W, Sekla L, Braddick M, Kreiss JK, et al. Increased risk of early measles in infants of human immunodeficiency virus type 1–seropositive mothers. Journal of Infectious Diseases 1992;165:262–7.         

39. Biellik R, Madema S, Taole A, Kutsulukuta A, Allies E, Eggers R, et al. First 5 years of measles elimination in southern Africa: 1996–2000. Lancet 2002;359:1564–8.         

40. Permar SR, Moss WJ, Ryon JJ, Kutsulukuta A, Allies E, Eggers R, et al. Prolonged measles virus shedding in human immunodeficiency virus–infected children, detected by reverse transcriptase–polymerase chain reaction. Journal of Infectious Diseases 2001;183:532–8.         

41. Sibailly TS, Wiktor SZ, Tsai TF, Cropp BC, Ekpini ER, Adjorlolo–Johnson G, et al. Poor antibody response to yellow fever vaccination in children infected with human immunodeficiency virus type 1. Pediatric Infectious Disease Journal 1997;16:1177–9.         

42. Goujon C, Touin M, Feuillie V, Coulaud P, Dupont B, Sansonetti P. Good tolerance and efficacy of yellow fever vaccine among carriers of human immunodeficiency virus. Journal of Travel Medicine 1995;2:145.         

43. Lotte A, Wasz–Hockert P, Poisson N, Dumitrescu N, Verron M, Couvet E. BCG complications: Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Advances in Tuberculosis Research 1984;21:107–93.         

44. O'Brien KL, Ruff AJ, Louis MA, Desormeaux J, Joseph DJ, McBrien M, et al. Bacillus Calmette–Guérin complications in children born to HIV–1–infected women with a review of the literature. Pediatrics 1995;95:414–8.         

45. Talbot EA, Perkins MD, Silva SFM, Frothingham R. Disseminated bacille Calmette–Guérin disease after vaccination: case report and review. Clinical Infectious Diseases 1997;24:1139–46.         

46. Armbruster C, Junker W, Vetter N, Jaksch G. Disseminated bacille Calmette– Guérin infection in an AIDS patient 30 years after BCG vaccination. Journal of Infectious Diseases 1990;162:1216.         

47. Besnard M, Sauvion S, Offredo C, Gaudelus J, Gaillard JL, Veber F, et al. Bacillus Calmette–Guérin infection after vaccination of human immunodeficiency virus–infected children. Pediatric Infectious Disease Journal 1993;12:993–7.         

48. Ion–Nedelcu N, Dobrescu A, Strebel PM, Sutter RW. Vaccine–associated paralytic poliomyelitis and HIV infection. Lancet 1994;343:51–2.         

49. Chitsike I, van Furth R. Paralytic poliomyelitis associated with live oral poliomyelitis vaccine in child with HIV infection in Zimbabwe: case report. BMJ 1999;318:841–3.         

50. Strebel PM, Aubert–Combiescu A, Ion–Nedelcu N, Biberi–Moroeanu S, Combiescu M, Sutter RW, et al. Paralytic poliomyelitis in Romania, 1984–1992. Evidence for a high risk of vaccine–associated disease and reintroduction of wild–virus infection. American Journal of Epidemiology 1994;140:1111–24.         

51. Moss WJ, Cutts F, Griffin DE. Implications of the human immunodeficiency virus epidemic for control and eradication of measles Clinical Infectious Diseases 1999;29:106–12.         

52. Sprauer MA, Markowitz LE, Nicholson JKA, Holman RC, Deforest A, Dales LG, et al. Response of human immunodeficiency virus–infected adults to measles–rubella vaccination. Journal of Acquired Immune Deficiency Syndromes 1993;6:1013–6.         

53. McLaughlin M, Thomas P, Onorato I, Rubinstein A, Oleske J, Nicholas S, et al. Live virus vaccines in human immunodeficiency virus infected children: a retrospective survey. Pediatrics 1988;82:229–33.         

54. Goon P, Cohen B, Jin L, Watkins R, Tudor–Williams G. MMR vaccine in HIV– infected children — potential hazards? Vaccine 2001;19:3816–9.         

55. Angel JB, Walpita P, Lerch RA, Sidhu MS, Masurekar M, DeLellis RA, et al. Vaccine–associated measles pneumonitis in an adult with AIDS. Annals of Internal Medicine 1998;129:104–6.         

56. Kengsakul K, Sathirapongsasuti K, Punyagupta S. Fatal myeloencephalitis following yellow fever vaccination in a case with HIV infection. Journal of the Medical Association of Thailand 2002;85:131–4.         

57. Receveur MC, Thiebaut R, Vedy S, Malvy D, Mercie P, Bras ML. Yellow fever vaccination of human immunodeficiency virus–infected patients: report of 2 cases. Clinical Infectious Diseases 2000;31:E7–8.         

58. Marianneau P, Georges–Courbot M, Deubel V. Rarity of adverse effects after 17D yellow–fever vaccination. Lancet 2001;358:84–5.         

59. Glesby MJ, Hoover DR, Farzadegan H, Margolick JB, Saah AJ. The effect of influenza vaccination on human immunodeficiency virus type 1 load: a randomized, double–blind, placebo–controlled study. Journal of Infectious Diseases 1996;174:1332–6.         

60. Stanley SK, Ostrowski MA, Justement JS, Gantt K, Hedayati S, Mannix M, et al. Effect of immunization with a common recall antigen on viral expression in patients infected with human immunodeficiency virus type 1. New England Journal of Medicine 1996;334:1222–30.         

61. Ho DD. HIV–1 viraemia and influenza. Lancet 1992;339:1549.         

62. Staprans SI, Hamiltion BL, Follansbee SE, Elbeik T, Barbosa P, Grant RM, et al. Activation of virus replication after vaccination of HIV–1–infected individuals. Journal of Experimental Medicine 1995;182:1727–37.         

63. Ramilo O, Hicks PJ, Borvak J, Gross LM, Zhong D, Squires JE, et al. T cell activation and human immunodeficiency virus replication after influenza immunization of infected children. Pediatric Infectious Disease Journal 1996;15:197–203.         

64. Tasker SA, O'Brien WA, Treanor JJ, Weiss PJ, Olson PE, Kaplan AH, et al. Effects of influenza vaccination in HIV–infected adults: a double–blind, placebo–controlled trial. Vaccine 1998;16:1039–42.         

65. Brichacek B, Swindells S, Janoff EN, Pirruccello S, Stevenson M. Increased plasma human immunodeficiency virus type 1 burden following antigenic challenge with pneumococcal vaccine. Journal of Infectious Diseases 1996;174:1191–9.         

66. Keller M, Deveikis A, Cutillar–Garcia M, Gagajena A, Elkins K, Plaeger S, et al. Pneumococcal and influenza immunization and human immunodeficiency virus load in children. Pediatric Infectious Disease Journal 2000;19:613–8.         

67. Cheeseman SH, Davaro RE, Ellision, RT. Hepatitis B vaccination and plasma HIV–1 RNA. New England Journal of Medicine 1996;334:1272.         

68. Tovo PA, de Martino M, Gabiano C, Galli L. Pertussis immunization in HIV– 1–infected infants: a model to assess the effects of repeated T cell–dependent antigen administrations on HIV–1 progression. Italian Register for HIV Infection in Children. Vaccine 2000;18:1203–9.         

69. Hyams KC. Risk of chronicity following acute hepatitis B virus infection: a review. Clinical Infectious Diseases 1995;20:992–1000.         

¹Assistant Research Professor, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA; and W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; USA.

²Medical Officer, Department of Vaccines and Biologicals, World Health Organization, Geneva, Switzerland.

³Professor and Director, Institute for Vaccine Safety, Department of International Health, Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore, MD 21205, USA (email: nhalsey@jhsph.edu). Correspondence should be addressed to this author.

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