Development, evaluation and implementation of Haemophilus influenzae type b vaccines for young children in developing countries: current status and priority actions

Haemophilus influenzae is an important cause of morbidity and mortality from pneumonia, meningitis and other invasive infections among infants and young children in developing countries. Virtually all episodes of H. influenzae meningitis and most episodes of severe H. influenzae pneumonia are caused by serotype b (Hib), and these 2 entities together are estimated to cause >375 000 deaths annually in children <5 years old.1, 2 Invasive diseases caused by Hib now can be prevented by immunization with polysaccharide-protein conjugate vaccines that were developed in the 1980s and have proved to be safe, immunogenic and highly effective when given to infants.3 In the industrialized countries Hib meningitis and other invasive Hib diseases have been virtually eliminated through widespread use of the vaccines.4, 5 Until now, however, the vaccines have not been added to the routine immunization schedules of developing countries. The aims of this article are to review the epidemiology and burden of Hib disease among infants and young children, especially in developing countries, describe the status of Hib conjugate vaccines, identify factors that will affect the introduction and routine use of Hib conjugate vaccines in developing countries and recommend priority actions to facilitate such use. BURDEN OF HIB DISEASE Strains of H. influenzae are either encapsulated or nonencapsulated. The encapsulated strains are differentiated into six serotypes (a through f) based on the antigenic structure of the capsular polysaccharide; nonencapsulated strains are classified as nontypable. Although all serotypes of H. influenzae and the nonencapsulated strains may cause invasive disease, Hib is responsible for most episodes of severe disease among children <5 years of age. Hib pneumonia.Diagnostic methods. Efforts to define the burden of morbidity and mortality resulting from Hib pneumonia have been hindered by a lack of sensitive and specific tests to determine the etiology of pneumonia. Problems in the use of culture depend on the type of specimen being evaluated. Culture of fluid aspirated from the lung is sensitive and specific, but lung aspirates are performed rarely, may be dangerous and can be done only in hospitalized children with lobar disease. Blood cultures are more widely available and are highly specific but are insensitive. Secretions from the lower respiratory tract are difficult to obtain from children and often are contaminated with upper respiratory tract flora, making interpretation of culture results difficult. Nasopharyngeal (NP) swab specimens are easy to obtain, but there is no evidence that culture results reliably predict the etiology of pneumonia. The sensitivity of tests to detect Hib capsular antigen from urine or cerebrospinal fluid has varied between studies but frequently has been <50% for culture-documented invasive infection. Specificity also may be reduced by upper respiratory carriage of Hib, which may cause positive antigen assays in urine samples. Attempts to detect Hib infection by detecting antibody to the type b capsular antigen have been from developing but the sensitivity and of this are The of this also is by in and from young also the use of antigen and for other of pneumonia. studies that use a of culture and have a or in to of children with pneumonia, with of in children with severe are in of which may of the tests or the of evidence of infection with Hib and a is is that the respiratory infection and of the lower respiratory tract by results from however, is that the is is based in on the more of from children with severe disease and on evidence that to children with pneumonia of of Hib in pneumonia. the etiology of most episodes of pneumonia be have been developed to the of specific to the burden of pneumonia morbidity and has been to that results from lung studies to all is however, aspirates are performed only on children with lobar pneumonia, a caused by a more important in pneumonia, especially episodes that are not in this is to the of specific by the burden of pneumonia and infection and mortality as or and and deaths in based on the of as by review of the available of H. influenzae is not in all studies and of the that disease may for type b and other H. influenzae pneumonia deaths caused by all H. influenzae which the of type b is this all H. influenzae all serotypes and are estimated to cause 000 pneumonia deaths among children <5 years in the developing which is of all pneumonia deaths not with or Although of these deaths in only of when most from H. influenzae pneumonia also is more among but the is for of the in the from pneumonia are estimated to in of and disease being most The of H. influenzae pneumonia and deaths caused by Hib are not The of caused by Hib can be estimated from studies with cultures of fluid by lung in children with lobar pneumonia. In such studies Hib for a of of all H. influenzae to In the of Hib to in studies based on from children with H. influenzae pneumonia. that most of H. influenzae pneumonia are caused by strains other Hib, most of H. influenzae pneumonia are caused by all H. influenzae of pneumonia is caused by infection from the upper respiratory the however, Hib are more to cause the type b the from are no from industrialized or developing countries on the of deaths among all H. influenzae that is caused by may be to however, that this is to the of Hib among in which the of is to be that of deaths among children <5 from H. influenzae pneumonia, or 000 pneumonia deaths in the developing are caused by The are for the developing and between countries are is for that the of all deaths caused by pneumonia also by Hib is in countries with the of also is that in countries with lower mortality and of are a more cause of pneumonia are Hib 000 and 000 deaths annually from H. influenzae meningitis among children <5 years of in developing studies that of H. influenzae meningitis is caused by are from and the to of H. influenzae meningitis caused by in industrialized the of Hib meningitis from studies in industrialized countries. the use of Hib vaccines the among children <5 years of Hib meningitis and of all invasive Hib diseases were to and to 000 The to use Hib vaccines in these countries based on these of Hib meningitis and invasive Hib disease among children <5 years in industrialized countries the widespread use of Hib vaccines in developing countries. are in 2 and disease by are in from a of 000 children <5 years in the and to 000 children in were between In and the varied from to and to 000 children, in to 000 The in and were and lower In the the to being in and of Hib meningitis and invasive Hib disease among children <5 years in and countries, by in the of Hib or H. influenzae meningitis among children <5 years by of are available from or from the in this or from the of the In the and are available only from of in lower countries of these are In the only are from the countries The and and from Although studies have that Hib is a cause of meningitis in and on are in and and have the of Hib meningitis and other invasive Hib The of Hib meningitis is to 000 children <5 years and in the of Hib meningitis are the sensitivity of the of given and and The a in the in and of H. influenzae is not difficult but the use of culture of the studies not the type of and is not to the of on the of or and factors on the of Hib meningitis is difficult. the of Hib meningitis among in is that among 000 children <5 years the of the is lower that of the making to the of or and such as of Hib In developing countries the of Hib meningitis in industrialized countries. 2 this with from The the and In the of in the of and by in only of among infants and only by The an of H. influenzae meningitis by from The and from and of meningitis in developing the of infants are not to of age. is however, that this carriage of Hib immunization the of meningitis in all not In the widespread use of Hib caused a in the of meningitis in infants resulting from Hib The for Hib meningitis also among countries, with in to In the for meningitis with of status or with countries with a lower Hib meningitis is the is to of that in from to severe and In countries to of these children the of invasive Hib disease. In industrialized countries meningitis for to of all invasive Hib disease. invasive diseases caused by Hib, in to pneumonia and among children The of all invasive Hib disease in developed countries is in on the of these in developing countries. OF HIB DISEASE of infection. Hib is only for no of Hib by of respiratory from to is in the can to which may for Invasive disease in a of The of carriage of Hib from to In industrialized countries carriage from to In developing countries are carriage are in from The studies are in of Hib carriage in industrialized and developing countries of Hib is with and the of Hib disease. In industrialized countries carriage is in the of and a of to the and the of Hib disease as among carriage of Hib of as as of factors for Hib Hib infection is through with a is an of Hib or has invasive Hib disease. through with are more with invasive Hib disease. factors for Hib carriage or disease an of in a and with a with invasive Hib upper respiratory tract infections may of Hib by and of respiratory to and other respiratory may with Hib and the of developing invasive disease The of invasive disease is to an of to Hib, as by the capsular The of antibody to Hib is in as are to a by to and as a of to Hib or other with The of Hib disease a being in a in or and as antibody The of invasive Hib disease is in with a of and antibody and with infection have a of invasive H. influenzae disease and but the of infection on of Hib disease is not Although studies for Hib disease in and have a to among also are in the of Hib meningitis that not to be by in that factors also may affect to invasive Hib disease. the of Hib meningitis among children in is to that in and OF The of pneumonia in children with or difficult can be are classified to and is The for and and are effective sensitive strains of and H. has mortality caused by lower respiratory as as in of six that pneumonia can mortality among children <5 years of by to The of this has the of respiratory infection of is by the to and the of and on for children with respiratory which is in countries, may the of in that more of H. influenzae from in children with pneumonia to the by the in other countries also to this but lower Hib strains also have developed to such as and most often by of but through in of in developing countries have been lower in developed countries, use of this of is more is in developing countries, however, to the and use of OF HIB DISEASE from invasive Hib disease in infants of a of on by can carriage of Hib In the and for has been to among of children with invasive Hib disease. The of is with also to of invasive Hib disease in In a among immunization with and invasive Hib disease for and for also that of a of for to In of and conjugate Haemophilus influenzae type b between the and of and not with to the and of to the routine use of are and the of with to were invasive Hib disease by the between the of Hib meningitis and the of to of Hib meningitis as the of The of by the studies of immunization with to Hib disease by to the capsular an Hib of immunization be and the be effective when given to young The of Hib vaccines of The of in children to of of for children but not children results of children of in only to of this of In the by children were of the children and among children to in the of from to but most were on the of vaccines children but were immunogenic in children of not carriage of The of in young infants is of most of which are The to reliably to is not the of results to to Hib vaccines that be immunogenic and in young by the to a a The immunogenic in a by and antibody and evidence of The with Hib conjugate vaccines is HIB and use. Hib conjugate vaccines have been of to a The vaccines in the of the and and the and of in the of these vaccines, reduced vaccines and are all or being Hib conjugate vaccines Hib conjugate vaccines now are given to infants in most industrialized countries in and the In countries this has to the of invasive Hib In the the for is for and are all are given with and and is not for infants in the of in this In the developing Hib conjugate often is available through the and a of countries have added or are Hib conjugate vaccines to on Hib conjugate vaccines can be given in the with and can of be given as a but are not more when the vaccines are given by either when is given for Hib either antibody or the of antibody to assays and assays are and difficult to these have not been to all in assays the and results as of of antibody that is the for Hib antibody were by the and for of Hib conjugate vaccines in the of the the to with and to or which also is not and can antibody to and Efforts have been to the for results from can be or of The of invasive Hib disease is to the of to The of however, has not been of the of have been based on of studies of and immunization and are as of and The of for is based on and studies antibody this in In studies with were to define the for may be to use a lower for Hib conjugate vaccines, however, of and In conjugate vaccines is that only of antibody are for and that the of antibody an has been In studies of Hib conjugate vaccines, are the of the of infants with an and the of infants with an to Hib conjugate Hib conjugate has been in Although in the studies in important the of the immunization and when specimens were the of or of the countries. The to Hib conjugate vaccines is in results of a in the the of and The to the of for the other The the of also for the however, all vaccines antibody with to of infants of Hib conjugate by of and among infants in the other have in these the of infants for to for to for and to for The of of also for these infants in for only of given of in a as with and of infants with of and is immunogenic the other only to of infants in of the studies developed of and of were only and The of Hib conjugate vaccines given in also has been of and were as immunogenic as in which a a of by of or the these vaccines can be countries. studies have the of Hib conjugate with and with given in the with a The of these studies are in The to of as as that in industrialized countries, but the to reduced of of that with in industrialized countries. these studies that Hib conjugate vaccines are immunogenic and of antibody in infants in developing from developing countries of the of Hib conjugate vaccines when in the with a studies have the of and given with but in In The infants the of of The to this with only of infants of of a from The of the of antibody given as a a in antibody by In The the to to that of infants in industrialized countries, in to of infants a of as with of infants in industrialized of the in The and were to of infants in industrialized a of Hib conjugate this given in the with can an to that in infants in industrialized countries. of Hib conjugate on of is that the of a to the not In The for the and of Hib conjugate this to The and on infants and of these added with the be Hib be given in the as this evidence that Hib is immunogenic when with and that not with to the of that Hib conjugate is immunogenic when given with on the of Hib conjugate on the to are countries. In studies of the of or given with no on to or given the vaccines in the were as to of and as the vaccines but as or and with no on the to the of however, studies have a to when the vaccines were given in the given the vaccines also lower of antibody to infants given or and as however, by studies also have that Hib conjugate given in the with with lower when and Hib conjugate vaccines are given countries. of and with done in and The have no on or The on the to and are to were in studies in and The no in 2 studies in the of among 000 infants in or not 000 years of that there are no widely of the of a reduced antibody to is difficult to countries. The results of to determine the of and and of the of are in of or of Hib conjugate vaccines in studies from industrialized and developing countries of invasive Hib disease in 000 infants through a in The of of to and that of however, the not the of In a among of invasive Hib disease between and of The of a of to The of conjugate in with and of invasive Hib disease. In invasive Hib however, the estimated of not from to The of in of the in and the this not for infants in the In a of in the infants in were infants in were infants of on an and The of invasive Hib disease reduced by to in the children, with the of the of 000 were when in the In among and among for use in the on the of and countries. of in The Hib pneumonia, the most of severe Hib disease in The and other developing countries and Hib meningitis use of Hib conjugate the of use. on the of invasive Hib disease is for routine immunization be given and for the of use. In industrialized countries detect severe Hib disease by Hib from or other however, not detect pneumonia, which may be the most of severe Hib disease. the of Hib conjugate on severe morbidity and mortality may be can be by available methods. In with the for and the on has developed a for the burden of Hib disease in developing countries. The which is being is available through the on in developed and developing countries. The of Hib conjugate vaccines in industrialized countries has been In the the of invasive Hib disease among children <5 years of has by in the 5 years Hib conjugate vaccines were for routine use in In and Hib invasive disease to have no been for The of use of Hib conjugate in in of the were given with and the infants only a to that all invasive Hib disease, Hib pneumonia. of the of Hib disease among infants to were in children have been from the in an of immunization on carriage of with Hib conjugate vaccines carriage of In immunization with not affect The for this of Hib conjugate vaccines is not is to be by or or The of invasive Hib disease among children <5 years of in the by the of conjugate vaccines for use in Although of with Hib are not is estimated that not more of infants were this the in disease that the The for is through reduced to of Hib to In and the of Hib invasive disease has been by the of Hib Although the evidence for in industrialized countries is the of immunization to is not on in developing countries, and not be that on developed countries will be with the of in developing countries. in developing countries is with to of children of of on of Hib to Hib may and to the of to infection in children and is that and the may affect the of can be only by for Hib disease among children and which to has not such an and of immunization immunization with given between 2 and of a is given to The for and vaccines given between 2 and of with between in the a immunization is to for of and however, may be In the of and studies have that of are more immunogenic of In and are given in a and 5 with a to a of Hib with of be the of and be the most recommend use in developing countries. Although schedules effective and have lower a be of the and by Hib with only of the also be that are not of the Although developing countries most is to on the by also the use of a for Hib to obtain from the immunization of infants to the of a Hib conjugate can the to immunization with the conjugate given of or to of when given the of or infants were not with the In the infants to of and of or The on is a in on the of of infants with on to immunization with is in In immunization of with the the to immunization with and in with the to is with the as as the that of infants with or may be a to the of Hib Although is recommend that Hib be given with as of of the burden of Hib disease have been based on of the burden of Hib meningitis and pneumonia developed by the for the of and the of the of and 2 The estimated of Hib conjugate based on of the of Hib conjugate in infants in developing countries and on from The are in in the estimated of immunization with Hib in developing countries. In the of immunization Hib an estimated 2 000 of pneumonia and meningitis and the of years among children <5 years in developing countries. In a that not the by routine immunization with Hib conjugate deaths and of pneumonia and meningitis and in the of is routine immunization with Hib conjugate deaths and 2 of pneumonia and meningitis and a to in deaths caused by pneumonia among children <5 years in the developing of routine immunization of infants with Hib conjugate in developing countries Although invasive Hib disease is in to of episodes of of these given with be immunization through The and young infants invasive Hib disease be young infants also will be through In The immunization of with to in these not with to immunization with 2 of infants to only of to such immunization with when with immunization with an of infants with of between 2 and of age. also be for immunization is the a the of immunization with or that were lower in given in given either conjugate of Although immunization of or of children Hib disease immunization is not that such a is the to with may the as of are to have immunization in a or in may immunization of be to the of a of Hib given to determine for Although the to for the of Hib in infants be in especially in this is not to a in the HIB In an the and of a or are In a the or deaths is such as or years of also may be with these are In a all and are in and the is either or however, may that such as or be a which is on the type of results can be by to determine to more to determine the of between also may be to to a and the most The and of immunization are by a often has a with other that be in the of and with to immunization and by with from to a for or to for a and of have been in Although results of a are as a of is also important to the of the will not be when the is the most effective will not be the that results in the a more that results in more may be to a more of Hib conjugate vaccines for developing countries. of the routine use of Hib conjugate in developing countries have been In a of Hib conjugate in a to the of of meningitis use of the in a in and an estimated of of a on the use of vaccines in developing countries, estimated a of by use of Hib conjugate a of but also the of developing the as an and estimated for developing countries. The which Hib be to developing countries has not been The of Hib conjugate for the in the is vaccines often are lower to developing to developed countries. that Hib conjugate be to developing countries for or for Hib conjugate through in developing countries done as of a review of for lower respiratory infections in young The results of no and the other with are of the will be as of the review by of and for of were developed by a of the of infants with antibody in studies of Hib immunization in developing were based on for vaccines by the on were based on from and the are in of and of The of a and for of conjugate is however, that Hib conjugate be given in the with of for Hib vaccines have estimated 000 and or The of severe and were estimated as to 2 of and for Hib disease. on by that of Hib infections an of and that of be hospitalized an of of of The of an and of of are based on and a that only infants be and that the of a with were with of immunization with that immunization cause a in of Hib disease among children and a among children of age. the immunization with to that immunization in a in of Hib disease among children and a in disease among children of age. for The estimated and of immunization with Hib conjugate in developing countries is in of the and with that the of Hib the prevented and are and lower with the to when Hib is in developing of for routine immunization with Hib conjugate in developing countries however, the is with the for other diseases by a from estimated the through as for the routine and for immunization the with is with the for a in be however, that may have the but the of may be the a that and 000 deaths and that and deaths have a prevented of but for a that has only to only the be the of a may determine of the or on the of invasive Hib disease are available from developed from may be In studies of the of Hib disease are not of and of the of Hib were based on from other disease and on In that the of immunization were The and of a of vaccines important diseases the of which will be into immunization vaccines are of or of the epidemiology of the disease or of have the for vaccines, the use of will be by the on which vaccines will be into immunization but introduction be by the and The of Hib by and the will the and to the to the to the countries, will to of lower and will on countries to the to be The is in Hib conjugate as a for use but not have to use. this is the the burden of disease and the priority of be and the of the to the be the of the into developing be of be and be of the of this into immunization in such as and be to and to the introduction The status of these is in of to Hib into immunization to the introduction of Hib conjugate The burden of disease, and of of introduction and for are for and countries and evidence the will be and effective in developing countries and will not be especially difficult to the and meningitis and pneumonia to be among the most diseases of and are to a these of countries Hib is are may be and may be to introduction into countries. The on has introduction of vaccines as of and all of as as the have in this of developing countries and have in introduction of Hib Problems in the introduction of Hib into developing countries. are countries and Hib disease is not to be a and to are a be to and the that the be The that the immunization is not of the introduction of vaccines, which are more the of Hib The to a with a of of of and a of is in developing countries, the of Hib be more for the is this of to this of be is available in developing countries for to and this has been a to introduction into countries. have not been to to the countries a and burden of disease and