module 9: haemophilus influenzae type b -...

Immunization, Vaccines and Biologicals

The Immunological Basisfor Immunization Series

Module 9: Haemophilus influenzae type b

WHO Library Cataloguing-in-Publication Data

Haemophilus influenzae type b vaccines.

(Immunological basis for immunization series ; module 9)

1.Influenza, human - prevention and control. 2.Influenza vaccines - therapeutic use. 3.Influenza B virus - drug effect. I.World Health Organization. II.Series.

ISBN 978 92 4 159613 8 (NLM classification: WC 515)

© World Health Organization 2007

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• Professor David Goldblatt and Dr Tracy Assari, UCL Institute of Child Health,London, UK

Printed in October 2007

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© World Health Organization 2007

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press,World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 3264;fax: +41 22 791 4857; email: [email protected]). Requests for permission to reproduce or translateWHO publications – whether for sale or for noncommercial distribution – should be addressed to WHOPress, at the above address (fax: +41 22 791 4806; email: [email protected]).

The designations employed and the presentation of the material in this publication do not imply theexpression of any opinion whatsoever on the part of the World Health Organization concerning the legalstatus of any country, territory, city or area or of its authorities, or concerning the delimitation of itsfrontiers or boundaries. Dotted lines on maps represent approximate border lines for which there maynot yet be full agreement.

The mention of specific companies or of certain manufacturers’ products does not imply that they areendorsed or recommended by the World Health Organization in preference to others of a similar naturethat are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguishedby initial capital letters.

All reasonable precautions have been taken by the World Health Organization to verify the informationcontained in this publication. However, the published material is being distributed without warranty ofany kind, either expressed or implied. The responsibility for the interpretation and use of the material lieswith the reader. In no event shall the World Health Organization be liable for damages arising from itsuse.

The named authors alone are responsible for the views expressed in this publication.

Printed by the WHO Document Production Services, Geneva, Switzerland

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Contents

Abbreviations and acronyms .......................................................................................... v

Preface ............................................................................................................................. vii

1. The organism and the disease ............................................................................ 11.1 Introduction..................................................................................................... 11.2 Epidemiology .................................................................................................. 11.3 The surface of Hib .......................................................................................... 4

2. The Immunology of Hib ...................................................................................... 52.1 Response to infection ..................................................................................... 6

3. Hib vaccines ........................................................................................................... 73.1 Polysaccharide vaccine responses ................................................................ 73.2 Conjugate vaccine responses ........................................................................ 8

4. Response to vaccination ..................................................................................... 94.1 Polysaccharide vaccine responses ................................................................ 94.2 Conjugate vaccine responses ........................................................................ 94.3 Impact on Hib carriage ................................................................................ 124.4 Impact of host factors .................................................................................. 134.5 Hib conjugate vaccine efficacy ................................................................... 13

5. Vaccine formulation issues: Hib interchangeability andadministration in combination ........................................................................ 155.1 Interchanging different Hib conjugate vaccines ...................................... 155.2 Simultaneous administration of Hib conjugate vaccines with

other childhood vaccines ............................................................................. 165.3 Hib combination vaccines ........................................................................... 16

6. Vaccine schedule issues ..................................................................................... 176.1 Hib conjugate immunogenicity at 2/4/6 months (USA schedule)

and effect of booster at 12-14 months ....................................................... 186.2 Hib conjugate immunogenicity at 2/3/4 months and effect of

booster at 12-14 months .............................................................................. 186.3 Hib conjugate immunogenicity at 3/5/12 months

(Scandinavian schedule) ............................................................................... 196.4 Hib conjugate immunogenicity at 6/10/14 weeks (EPI schedule) ........ 19

i v

7. Vaccine effectiveness ......................................................................................... 217.1 Developed country experience ................................................................... 227.2 Developing country experience .................................................................. 25

8. Future prospects ................................................................................................. 278.1 Hib conjugates in the EPI schedule ........................................................... 278.2 Hib conjugates in combination vaccines ................................................... 278.3 The role of a booster dose ........................................................................... 28

References ...................................................................................................................... 29

v

Abbreviations andacronyms

aP acellular pertussis

BCG bacille Calmette-Guérin (vaccine)

BPIG bacterial polysaccharide immune globulin

CDC Centers for Disease Control & Prevention (USA)

CDSC Communicable Disease Surveillance Centre

CVI Children's Vaccine Initiative

DTaP diphtheria-tetanus acellular pertussis

DTP diphtheria-tetanus-pertussis (vaccine);

DTwP diphtheria-tetanus whole-cell pertussis

ELISA enzyme-linked immunosorbent assay

EPI Expanded Programme on Immunization

GAVI Global Alliance for Vaccines and Immunization

HepB Hepatitis B

Hi Haemophilus influenzae

Hib Haemophilus influenzae type b

HIV human immunodeficiency virus

HRU Health Research Unit

Ig immunoglobulin

IPV inactivated polio vaccine

MMR measles, mumps, and rubella (vaccine)

OMP outer membrane protein of polyribosyl-ribitol- phosphate

OPV oral polio vaccine

PHLS Public Health Laboratory Service

PRP polyribosyl-ribitoal -phosphate (carbohydrate of the Hib capsule)

PRP-CRM197 polyribosyl-ribitol- phosphate-CRM197 conjugate vaccine

PRP-OMP polyribosyl-ribitol- phosphate-outer membrane protein conjugatevaccine

PRP-T polyribosyl-ribitol- phosphate-tetanus toxoid conjugate vaccine

PS polysaccharide

v i

RIA radioimmunoassay

UCLA University of California at Los Angeles

UNICEF The United Nations Children's Fund

USA The United States of America

WHO The World Health Organization

wP whole-cell pertussis

vii

Preface

This module is part of the Series “The Immunological Basis for Immunization”,which was initially developed in 1993 as a set of eight modules focusing on thevaccines included in the Expanded Programme on Immunization (EPI)1. In additionto a general immunology module, each of the seven other modules covered one ofthe vaccines recommended as part of the EPI programme, i.e. diphtheria, measles,pertussis, polio, tetanus, tuberculosis and yellow fever. These modules have becomesome of the most widely used documents in the field of immunization.

With the development of the Global Immunization Vision and Strategy (2005-2015)(http://www.who.int/vaccines-documents/DocsPDF05/GIVS_Final_EN.pdf) andthe expansion of immunization programmes in general, as well as the largeaccumulation of new knowledge since 1993, the decision has been taken to updateand extend this series.

The main purpose of the modules - which are published as separate disease/vaccine-specific modules - is to give immunization managers and vaccination professionals abrief and easily-understood overview of the scientific basis of vaccination, and alsoof the immunological basis for the WHO recommendations on vaccine use that since1998 are published in the Vaccine Position Papers. (http://www.who.int/immunization/documents/positionpapers_intro/en/index.html).

WHO would like to thank all the people who were involved in the development ofthe initial “Immunological Basis for Immunization” Series, as well as those involvedin its updating, and the development of new modules.

1 This programme was established in 1974 with the main aim of providing immunization for childrenin developing countries.

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1.1 Introduction

Haemophilus influenzae (Hi) are a genus of gram-negative coccobacilli, members ofthe Pasteurellaceae family that exist in both capsulated and nonencapsulated forms.Encapsulated strains are further classified according to the chemical composition ofthe polysaccharide forming the capsule, and six serotypes, designated a-f, have beenidentified (Pittman, 1931). Hi are carried in the moist mucosa of thehuman nasopharynx from where they can spread to cause both local andsystemic disease including meningitis, pneumonia, epiglottitis, orbital cellulitis,septic arthritis, bacteraemia, osteomyelitis, pericarditis, sinusitis and otitis media(reviewed in Barbour, 1996). Hi serotype b (Hib) is responsible for approximately95% of all invasive disease due to Hi (invasive disease is defined as the isolation ofHi from an otherwise sterile site such as the blood stream or cerebrospinal fluid),although the other serotypes can also cause invasive disease in the normal host(Kniskern, Marburg & Ellis, 1995). About 5% of children with Hib meningitis die,in spite of appropriate clinical management, and 20% to 40% of survivors sufferpermanent disability. The sequelae of Hib meningitis include blindness, deafness andlearning disabilities. Antibiotic resistance to all Hi has steadily increased in recentyears (Gessner et al., 2002). Nonencapsulated strains are an important cause ofmucosal diseases such as otitis media, sinusitis and lower respiratory tract infection,and in some clinical settings, such as an immunocompromised host, may cause invasivedisease.

1.2 Epidemiology

Although invasive Hib disease may occur in any age group, it is predominantly adisease of early childhood. Rarely occurring in infants under three months of age(WHO, 1998) or after the age of six years, the disease burden is generally highest inchildren aged between 4 and 18 months (See Figure 1), although the precise age atwhich risk is highest varies from developing countries where there is an earlier peak(Asturias et al., 2003) to developed countries, such as the Republic of Finland,where the peak is later (Peltola, 1998).

1.The organism andthe disease

The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines2

Figure 1: Age distribution of Hib infection fromOctober 1990 to September 1991 in six regions in England and Wales

0

30

60

90

120

150

<1 1 2 3 4 5-14 15-44 45-64 65+ NK

Age group (years)

Num

ber o

f cas

es

Age distribution of Hib infection from October 1990 to September 1991 in six regions in England andWales. Out of 433 reported cases, 362 (84%) were due to Hib, 54 (13%) were due to non-serotypableHi, and 13 cases were not serotyped. Adapted from (Nazareth et al. 1992).

In the pre-vaccine era in developed countries, meningitis accounted for approximatelyhalf of all invasive Hib disease. In the United Kingdom for example, an analysis ofinvasive Hib disease revealed that 56% of isolates were from patients withmeningitis, 13% from patients with epiglottitis, and 6% from patients withpneumonia (Nazareth et al., 1992). Data from some countries with goodsurveillance systems illustrates how incidence figures in childhood may vary.For example, in the pre-vaccine era, reported incidence rates per 100 000 for invasiveHib disease below five years of age ranged from 21 to 44 in the United Kingdom(Booy et al., 1994; Anderson et al., 1995a; Hargreaves et al., 1996), 20 to 50 in theUnited States of America (USA) excluding Alaska (Broome, 1987), and 42 in theFederative Republic of Brazil (Bryan et al., 1990). In the Republic of the Gambia,the pre-1990 incidence rates for Hib meningitis <five years of age was 60/100 000and as high as 200 /100 000 for those <1 year of age (Bijlmer et al., 1990). In south-east asia, the exact contribution of Hib to the overall burden of meningitis andpneumonia remains unclear. The incidence of Hib meningitis among children aged 0to 4 years in Hong Kong Special Administrative Region of China has been reportedto be as low as 1.75 per 100 000 per year (Lau et al., 1998) and also 3.22 per 100 000under five years of age in China (Province of Taiwan) (Shao et al., 2004), althoughthe incidence of Hib disease among Vietnamese refugee children in Hong Kong,SAR exceeds 42 per 100 000 (Lau, 1999). The overall burden of Hib pneumonia ingeneral is difficult to quantify because only a small percentage of Hib pneumonia isaccompanied by bacteraemia. Studies incorporating a wide range of diagnostic

3

techniques, including lung aspirates, which are often considered the gold standardfor identifying a pathogen in pneumonia, have suggested that the burden ofHib pneumonia in children under five years of age in the Republic of theGambia may be as high as 42% (Vuori-Holopainen & Peltola, 2001), while a vaccineprobe study there found that at least 21% of pneumonia was caused by Hib(Mulholland et al., 1997).

Not all individuals within a population are at equal risk and a number of factors havebeen identified that are associated with an increased risk of Hib disease. Hib diseasein the United States has been noted to be 1.2-1.5 times higher in boys than in girls(Cochi & Broome, 1986; Wenger, 1998) and to be 2-4 times higher for black thanfor white children younger than five years of age (Tarr & Peter, 1978;Wenger, 1998). Indigenous populations, such as those of Australia (Aboriginals),and North America (Alaskan Eskimos, and Apache and Navajo Indians) have beenshown to have the greatest known endemic risk of invasive Hib disease(Bulkow et al., 1993; Wenger, 1998; Singleton et al., 2000) with rates as highas 408/100 000 described (Ward et al., 1981). The reason for these very high rates islikely to be due to a combination of genetic and environmental interactions.Environmental factors that affect exposure to Hib, such as nursery settings,and increased population density, have been associated with an increased risk ofinvasive disease (Tarr & Peter, 1978; Wenger, 1998), while pre-existingconditions such as sickle cell disease, human immunodeficiency virus (HIV),bone-marrow transplant and complement deficiencies, are also known to be importantindividual risk factors.

Estimates of rates of nasopharyngeal carriage also reveal that carriage is related tothe age of the individual, presumably reflecting the relative immaturity ofthe immune system in young children. In the pre-vaccine era about four inevery 100 children in the United Kingdom carried the Hib organism(McVernon et al., 2004a). This compares to a similar rate of 3.5% in the Republic ofFinland (Takala et al., 1989) and 2%—5% in the United States (Millar et al., 2000).Carriage studies in the Republic of the Gambia have suggested higher rates of carriage,although rates have varied between villages studied and between studies, with ratesas high as 12% (Adegbola et al., 2005) or 33% reported (Bijlmer et al., 1989).

Recent reports of invasive Hi non-b capsular serotypes in the era since developmentof conjugate vaccines have prompted concern about serotype replacement.Unusual clusters of invasive infection due to Hi serotype a with clinical featuresthat resemble those of infection due to Hi serotype b have been described.A unique feature often associated with more virulent Hi serotype a isolates is theIS1016-bexA partial deletion, which was previously identified in the capsule locusof Hi serotype b strains (Kapogiannis et al., 2005). The presence of the necessarybexA gene deletion has also been demonstrated in the capsulation locus of a sizeableproportion of Hi types f and a isolates from invasive infections in the Republic of theGambia (Kroll et al., 1994; Ogilvie et al., 2001). To date however no widespreadlevel of replacement disease is evident.


1.3 The surface of Hib

The surface of Hib is composed of a cell wall and polysaccharide capsule.Polysaccharide capsules are common cell-surface components of bacterialpathogens that cause systemic disease. Based on in vitro studies, it is known thatpolysaccharide capsules mediate resistance to important host defencemechanisms, including phagocytosis and complement-mediated killing(Sukupolvi-Petty, Grass & St Geme, 2006). The Hib capsule is made up of repeatingpolymers of ribosyl and ribitol-phosphate and is thus designated polyribosyl-ribitol-phosphate (PRP). The repeating sugar has homology to a number of otherbacterial-derived capsules including that of E. coli K100 (Bradshaw et al., 1971).The other Hi capsular serotypes are composed of hexose rather than pentose sugars,and only occasionally cause invasive disease, although the reason for the differencesin pathogenicity are not well understood. Encapsulated organisms can penetrate theepithelium of the nasopharynx and invade capillaries directly which accounts for theinvasive potential of Hib. The antiphagocytic capsule prevents the induction of thealternative complement pathway by inhibiting or delaying complement proteins onthe cell surface (particularly C3b), so that the bacterium can invade the blood orcerebrospinal fluid without attracting phagocytes or provoking an inflammatoryresponse and complement-mediated bacteriolysis (Hetherington, Patrick & Hansen,1993). For this reason, anticapsular antibody which is able to bind to capsule andwhich promotes both phagocytosis (via Fc interactions with other cells) andbacteriolysis (by allowing complement to bind), is critical for protection againstencapsulated organisms (Tosi, 2005). Anti PRP antibodies have been shown to beproduced on exposure to Hib and are known to provide protection against disease(CDC, 1998; Heath, 1998; Granoff, 2001).

The Hi cell wall contains several different outer membrane proteins (OMPs) thatmay also be targets of human IgG. These OMPs include P1, P2, P4, P5, P6, a 98kDsurface protein, and a 42kD protein called protein D. Antibodies to P1, P4, and P6have been shown to bind to proteins on the surface of diverse Hi strains.Animal models have suggested that antibody to several different proteins may beprotective, and development of a Hi OMP vaccine to prevent otitis media has beenactively pursued. A recent study by Prymula and others (Prymula et al., 2006) usinga Hi protein D as a carrier for pneumococcal polysaccharide vaccines appeared todemonstrate protection against both pneumococcal and Hi otitis media.

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Studies of the epidemiology of invasive Hib disease coupled with animal experimentshave provided clues to the key components mediating immunity to Hib. The strikingage-dependent susceptibility to invasive disease was initially shown in the 1930's tocorrelate with the absence of bactericidal activity in the blood (Fothergill & Wright,1933). Antibodies to Hib capsule were identified as key mediators of this effect andshown to confer type-specific protection of lethal Hib disease in a rabbitmodel. Subsequent studies in humans on the bactericidal activity of bloodidentified a discrepancy between bactericidal activity and anticapsular antibody titre(Anderson & Smith, 1977). At the same time, anti-PRP IgG was shown to be inverselycorrelated to the incidence of Hib meningitis (Peltola et al., 1977). The absence ofinvasive Hib infections in children with X-linked agammaglobulinaemia onreplacement immunoglobulin therapy, provided further evidence for the protectiveeffect of serum IgG in humans (Siber et al., 1992) while a formal trial in theUnited States of the efficacy of bacterial polysaccharide immune globulin (BPIG)was conducted in White Mountain Apache Indian infants (a group with very highincidence of invasive Hib disease) and shown to be protective (Santosham et al.,1987).

The incidence of Hib disease is relatively low in the first few months of lifedue to the transfer of maternal IgG specific for PRP across the placenta, although insome indigenous populations incidence of early invasive disease is high despite thisantibody. Generally, once maternal antibodies wane, the incidence of diseaseincreases (peaking at different times in different populations, see Section 1.2), but bythe age of five years the incidence of disease is universally low and remains lowthroughout adulthood with only a small increase in the incidence in the very elderly(Farley et al., 1992). Like other bacterial-derived polysaccharides, PRP is classifiedas a T-independent antigen stimulating B cells directly without the help of T cells,and antigens of this type are known to be poorly immunogenic in childhood.Thus one of the reasons that young children are so susceptible to invasive Hib diseaseis that they are unable to mount robust responses to pure polysaccharide antigensbefore approximately 18 months of age.

2. The Immunology of Hib


2.1 Response to infection

Hib is the most virulent of the Haemophilus genus and 95% of bloodstream andmeningeal Haemophilus infections in children are due to type b. Hib colonizes thehuman upper respiratory tract, although only a fraction of those acquiring carriageof the bacteria will subsequently develop clinical disease. The time between infectionand the appearance of symptoms is thought to be between two and ten days.Symptoms of Hib meningitis can include headache, fever, vomiting, stiffness of theneck, sensitivity to bright lights, joint pains, drowsiness, confusion, hypothermiaand coma (Herson & Todd, 1977). If Hib infection occurs in a previously healthyunimmunized child over the age of 24 months, the child generally develops a robustimmune response (Pichichero, Hall & Insel, 1981). Both humoral and cellular immuneresponses play an important role in individual protection against Hib disease.IgG, IgM and IgA antibodies to PRP may all be induced by infection as well asvaccination. Variable immunoglobulin isotype and IgG subclass responses toPRP polysaccharide after natural Hib exposure, disease, and immunization,have been described (Jennings, 1983; Barrett, 1985). Most individuals respond withIgG antibodies after PRP immunization, although some children have predominantlyIgA or IgM responses (Ramadas et al., 1986). IgG2 is the IgG subclass that iscommonly found, along with IgG1, in the natural response to polysaccharideantigens. There is an increased susceptibility to Hib disease in patients who areimmunosuppressed and in those who are deficient in IgG2 and IgG4(Ambrosino et al., 1992b). Rising Hib anticapsular antibodies have been detectedwithin as little as 2-3 days of the diagnosis of Hib meningitis (Anderson et al., 2000),and a role for mucosal antibodies in the initial defence against colonisation and infectionhas been suggested. However, the majority of studies have focused on serum-derivedIgG with relatively few studies focussing on the role of mucosal antibodies.Most of the studies of Hib have also focussed on PRP responses alone, and relativelylittle is known about the immune response or relative importance of responses toHib proteins. Antibodies directed against the capsular PRP or the outer membraneproteins of Hib promote bactericidal activity, complement 3 binding, and ingestionby phagocytic cells (Heath, 1998; Granoff, 2001).

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3.1 Polysaccharide vaccine responses

The first vaccine developed against Hib was produced in the early 1970s and wascomposed of purified Hib capsular polysaccharide capsule (PRP). A double-blindefficacy trial of PRP vaccine was conducted in the Republic of Finland in the early1970s involving 60 000 vaccinees between the ages of three months and five years.The vaccine showed short-term efficacy in children who received vaccineaged 18 months or older, but no protection in younger children (Peltola et al., 1977).The absence of efficacy in those less than 18 months of age was due to the poorimmunogenicity of the PRP in the infants. Furthermore, no boost in antibody titrewas observed with repeated doses of PRP, the antibody that was producedwas relatively low-affinity IgM with minimal IgG production, and the vaccine hadno effect on nasopharyngeal carriage of Hib (Stein, 1992; Barbour, 1996).Follow-up of the vaccinated cohort indicated that protection overall for the childrenvaccinated over the age of 18 months was approximately 90% (Kayhty et al., 1984;Peltola et al., 1984).

On the basis of this and other efficacy studies (Lepow, Samuelson & Gordon, 1985;Eskola et al., 1987), pure polysaccharide vaccines (see Table 1) were licensed in theUnited States in 1985, and recommended for use in those between two and fiveyears of age, or those over 18 months of age attending day care.Experience with this vaccine varied geographically with some states reportingnegative efficacy and an increased risk of disease in the weeks following receipt ofPRP (Black et al., 1991b). This increased susceptibility in the weeks after vaccinationwas associated with a transient reduction of PRP antibody in the serum of vaccinatedinfants (Institute of Medicine, 1994). Overall the vaccine was thought tobe 50%-60% effective (Harrison et al., 1988) and was used until 1988 when it wassuperseded by conjugate vaccines.

3. Hib vaccines


3.2 Conjugate vaccine responses

In the 1920s the pioneering work of Avery and Goebel (Avery & Goebel, 1929)established that the immunogenicity of carbohydrate antigens in rabbits could beimproved by the conjugation of the sugars to a protein carrier. This work laid thefoundation for the development of conjugate vaccines for use in humans, but it wasonly in the 1970s that work began seriously on the prototype vaccine for use inhumans - a Hib conjugate (Lepow, 1987; Tai et al., 1987; Campion & Casto, 1988).The chemical attachment (conjugation) of PRP to protein antigens, such as diphtheriaand tetanus toxoids, was the initial basis for the development of Hib conjugate vaccines(Peltola, 1998) as these antigens were known to be capable of eliciting T cell help,and in turn the T cells were able to provide appropriate signals to the carbohydrate-specific B cell, thus improving both the immunogenicity and the quality of the immuneresponse to the PRP component of the vaccine.

The vaccines currently licensed for use against Hib disease are based onPRP conjugated to a protein carrier, PRP conjugated to tetanus toxoid (PRP-T),an oligosaccharide of PRP conjugated to a mutated non-toxic diphtheria toxin,CRM-197 (HbOC), and PRP conjugated to a Neisseria meningitidis type b outermembrane protein complex (PRP-OMP) (as reviewed in Santosham, 1993).PRP conjugated to diphtheria toxoid (PRP-D) was one of the first vaccines to beproduced, but is no longer manufactured (Table 1). The conjugate vaccines differ intheir carrier protein, method of chemical conjugation, and by polysaccharide size,giving them somewhat different immunological properties. These vaccines were firstlicensed in 1987 (USA), and initially restricted to children aged 15 to 18 months,but subsequently in 1990, the license was extended to include infants in the first yearof life (Shapiro & Ward, 1991).

Table 1: Hib polysaccharide and polysaccharide-protein conjugate vaccinescurrently or previously licensed

(http://darwin.nap.edu/openbook/0309048958/gifmid/238.gif)

Saccharide(s) Protein(s)

Type b native polysaccharide None

Type b polysaccharide Diphtheria toxoid ('PRP-D')

Type b saccharide Mutant non-toxic diphtheria toxinCRM197 ('HbOC')

Type b saccharide Neisseria meningitidis outer membraneprotein in outer membrane vesicles('PRP-OMP')

Type b polysaccharide Tetanus toxoid ('PRP-T')

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4.1 Polysaccharide vaccine responses

Much of our understanding of the immunology of responses to PRP comes from thepivotal studies of Porter Anderson and David Smith (Anderson, Johnston & Smith,1972), as well as the subsequent PRP vaccine trial performed in theRepublic of Finland in the 1970s (Kayhty et al., 1984). These studies demonstratedthe poor immunogenicity of PRP in young children whose B cell immunity is notwell developed at that age, and consequently the absence of protection, along withthe fact that repeated doses of PRP vaccine failed to elicit a memory response.In older children, >18 months, the maturation of the immune system is associatedwith the acquisition of responsiveness to PRP, and thus as titres in children risenaturally with age, presumably stimulated through natural encounter with Hib inthe nasopharynx, or encounter with cross-reactive antigens (Bradshaw et al., 1971),the incidence of disease declines. It is likely that ongoing exposure to Hib resultingin the maintenance of detectable circulating antibody to PRP is important inmaintaining long-term protection against Hib. Serum antibodies to PRP were initiallymeasured by radioimmunoassay (RIA) but have been superseded by the introductionof a robust enzyme-linked immunosorbent assay (ELISA) which is now widely usedfor the measurement of PRP-specific IgG (Madore et al., 1996).

4.2 Conjugate vaccine responses

The simultaneous development of four different conjugate vaccines started in the1970s. PRP-D was the prototype vaccine and the first to go into clinical trials.PRP-D was shown to be moderately immunogenic with typically only 40% of infantsreceiving the primary immunisation series, achieving antibody concentrations of1.0 µg/ml, and 70% achieving 0.15 µg/ml (Eskola et al., 1990), but it was shown tobe efficacious in clinical trials in the Republic of Finland (Takala et al., 1989;Peter, 1998). However it had low efficacy and elicited a poor immuneresponse when tested in Alaskan Eskimos who are at high risk for Hib disease.Although initially licensed in many countries, PRP-D is no longer licensed ormanufactured for use in infants below 18 months of age (Ward et al., 1988).

4. Response to vaccination

The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines1 0

The development of PRP-OMP, HbOC and PRP-T continued simultaneously,and early immunogenicity studies illustrated good antibody responses in infants fromtwo months onwards (Eskola et al., 1987; Lepow, 1987). The PRP-OMP vaccinewas the only vaccine not to use a diphtheria or tetanus-based carrier protein.Immunogenicity studies revealed the unique properties of this formulation whichelicits an anti-PRP concentration of 0.15 µg/ml and 1.0 µg/ml, a level correlatedwith short-term and long-term protection respectively in a larger proportion ofchildren after a single dose (Decker & Edwards, 1998; Watt, Levine & Santosham,2003). For this reason, PRP-OMP was designated the vaccine of choice for use inpopulations that had a high proportion of disease in the first six months of life.However, the geometric mean titres elicited after the PRP-OMP primary series(3 doses) were shown to be lower than those elicited after the PRP-T or HbOCprimary series, and booster responses appeared attenuated compared to those seenwith PRP-T and HbOC. HbOC contains a unique short Hi oligosaccharideconjugated to a mutant toxin (CRM197) isolated from Corynebacterium diphtheriaand elicits high levels of anti-PRP antibody after a 3-dose primary series(Decker & Edwards, 1998; Watt, Levine & Santosham, 2003). PRP-OMP andHbOC both show a positive correlation between age and the IgG response(Madore et al., 1990). PRP-T was the last Hib conjugate vaccine to be evaluated andwas licensed for use in 1992. It contains tetanus toxoid as the carrier protein, attachedto PRP via 6- carbon linkage or carbodimide condensation, and has no adjuvant.Comparative immunogenicity of the four different Hib conjugate vaccines developed,when administered at 2, 4 and 6 months of age together with routine childhoodimmunizations, is illustrated in Figure 2. As can be seen, apart from PRP-OMP,the majority of the antibodies induced to Hib occurred after the third dose administeredat six months of age.

Figure 2: Comparison of antibody responses tofour different Hib conjugate vaccines

3.5

4

3

2.5

2

1.5

1

0.5

0Before After 1st dose After 2nd dose After 3rd dose

µg/m

L

PRP-D PRP-OMP PRP-CRM197 PRP-T

(in order from left to right)

Doses were given at 2, 4, and 6 months of age. Adapted from (Watt et al. 2003)

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In addition to the level of IgG responses induced by conjugate vaccines,conjugates induce immune memory to the PRP component of the vaccine which isnot seen when pure PRP vaccines are administered. Memory can be measured byadministering pure PRP and eliciting a response in a primed but not an unprimedindividual (such as a toddler). An increase in antibody avidity following primaryimmunization and boosting has also been demonstrated in Hib conjugateimmunogenicity trials (Goldblatt, Vaz & Miller, 1998; Anttila et al., 1999).This phenomenon of avidity maturation is not seen following PRP vaccination.Avidity measurements have thus been proposed as a surrogate marker for thesuccessful generation of immunological memory. The relative importance of memoryversus circulating antibody levels for clinical protection by conjugate vaccines isunclear (see below).

Experiments with the administration of hyperimmune anti-PRP IgG in bothanimal models (Ambrosino et al., 1983; Akkoyunlu et al., 1997) and in humans(Shenep et al., 1983; Siber et al., 1992), illustrated that a level of 0.15 µg/ml wasassociated with short-term protection from invasive Hib disease. By contrast,experience from field studies of PRP vaccine illustrated good protection in childrenmounting a response of at least 1 µg/ml one month after completion of vaccination.Thus during the development and evaluation of Hib conjugate vaccines,these two thresholds were used to define short and long-term protection respectively.However, neither threshold takes cognisance of the fundamental difference in thenature of the immune response to conjugate vaccine as compared to PRP.Extensive use of Hib vaccines and observation of their clinical efficacy in practicehas questioned the relevance of the 0·15-1·0 µg/ml concentration as surrogates ofprotection following conjugate vaccination (Eskola et al., 1999) although they arestill widely used today. The fact that conjugate vaccines induce memory,suggests that irrespective of the titre achieved after vaccination, priming for memoryresponses may provide protection of longer duration than that achieved afterPRP vaccine, particularly if ongoing exposure to Hib is able to maintain circulatingantibody titres. The demonstration of efficacy for the PRP-D vaccine in theRepublic of Finland, despite its relatively poor immunogenicity, suggested that theremay be a role for memory in protection against Hib disease. The experience inAlaska however established that in a high risk setting, higher antibody titres arerequired for protection. Protection against invasive Hib disease in the face of vaccine-induced memory but the absence of circulating antibody is not clearly established(Galil et al., 1999) and is described further when discussing the recent experience inthe United Kingdom in Section 7.


4.3 Impact on Hib carriage

Takala and colleagues (Takala et al., 1991) first showed that Hib conjugate vaccine,unlike Hib polysaccharide vaccine, was able to prevent oropharyngeal colonisationby Hib. Pure PRP vaccines are known not to impact on carriage, but reduction innasopharyngeal carriage of Hib has been demonstrated in several trials ofHib conjugate administered at different schedules in the United States(Lepow, Samuelson & Gordon, 1985; Takala et al., 1991; Black et al., 1991b),the Republic of the Gambia (Adegbola et al., 1998), the Federative Republic ofBrazil (Forleo-Neto et al., 1999) and the United Kingdom (Barbour et al., 1995).While baseline rates of carriage have differed in each country (see Section 1.2),the widespread use of conjugate vaccines has led to decreases in diseaseincidence that were greater than rates of vaccination coverage, as well as decreasesin Hib disease in unvaccinated individuals and groups (Barbour et al., 1995;Barbour, 1996; Peltola, 1998; Adegbola et al., 1999). The impact of herd effect canbe seen by the tenfold reduction in Hib disease rates in the United Kingdom inunvaccinated children <1 year of age in 1998 compared with rates in similarly agedchildren before vaccination began (Heath et al., 2000b). Another reflection of herdeffect is the impact of childhood Hib vaccination on adult Hib disease. A review ofadult cases of Hib disease in five English regions between 1990 and 1995 showed ahalving of case numbers between the first three-year period and the last two-yearperiod (Sarangi et al., 2000). Ongoing surveillance for Hib disease by Moulton andcolleagues (Moulton et al., 2000) demonstrated that immunization of 40% ofNavajo Indian infants (USA) between the years 1988 to 1992 resulted in a 75%reduction of Hib disease among infants that were living in the same community.This demonstrates that countries that implement Hib immunization programmesmay receive greater benefits at the community level than those hitherto seen due tothe direct protection conferred on the individual through vaccination. Antibody levelsrequired for the protection against colonisation are thought to be higher than thoserequired for protection against invasive disease. A study suggests that protectionagainst nasopharyngeal Hib colonization requires serum antibody concentrations ofapproximately 5 µg/ml (Fernandez et al., 2000) which is identical to the concentrationthought to protect against pneumococcal colonisation (Goldblatt et al., 2005),while studies of passive administration of antibodies into the peritoneum of infantrats has suggested that a titre of >7 micrograms/ml is able to prevent colonisation(Kauppi, Saarinen & Kayhty, 1993).

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4.4 Impact of host factors

Optimal interventions to reduce Hib disease and transmission are likely todepend upon many factors, including vaccine type, schedule of vaccination,the specific population epidemiology, and programme performance, as well as otherenvironmental factors. Hib conjugate vaccine is immunogenic in patients withincreased risk for invasive disease, e.g. those with sickle-cell disease(Goldblatt, Johnson & Evans, 1996b; O'Brien et al., 2000), leukaemia(Feldman et al., 1990), human immunodeficiency virus (HIV) infection(De Sousa dos et al., 2004), and those who have had a splenectomy(Ambrosino et al., 1992a). However in persons with HIV infection,immunogenicity varies with stage of infection and degree of impaired immunity(Rutstein, Rudy & Cnaan, 1996). Immunogenicity of the Hib conjugate vaccines isnot equal in all populations. Castillo de Febres and colleagues (Castillo de,Febres et al., 1994) compared PRP-T vaccine responses in infants in Nashville,Tenessee (USA) and those living in Valencia in the Bolivarian Republic of Venezuela,and demonstrated a 10-fold increased response to an identical primary immunisationseries in the Venezuelan children. Greenberg and colleagues (Greenberg et al., 1994)identified differences in the immunogenicity of Hib conjugates administered tochildren resident in California (USA) when stratified by race, with the lowestresponses in white children and the highest in Asian children. In the same study,responses were significantly correlated with gestational age and breastfeeding tosix months. Levine and colleagues (Levine et al., 1997) studied a subgroup ofChilean children demonstrating a significant response after two Hib doses and showedthat low maternal education (adjusted OR 1.68 p=0.05), mean number of persons inthe house, and the mean number of children under the age of six years in the house,all correlated with responses to Hib conjugate vaccine. The authors postulated thatindigenous South Americans might be overrepresented in this group and the improvedresponses might thus be attributed to host genetics. Enhanced responses to PRP-Tcompared to PRP-OMP and HbOC have been reported in Philippine infants(Capeding et al., 1998).

4.5 Hib conjugate vaccine efficacy

Eight randomised placebo-controlled efficacy trials of Hib conjugate vaccines havebeen performed and all have used invasive disease as the primary endpoint(reviewed in Obonyo & Lau, 2006). All studies and all vaccines, with the exceptionof PRP-D in Alaskan Eskimo (USA) infants, have demonstrated high efficacy.The studies and efficacy endpoints are summarized in Table 2. Peltola and colleagues(Peltola et al., 1994) also demonstrated in a randomised Finnish study that bothPRP-D and HbOC vaccines were safe and effective and that a 2-dose primaryvaccination schedule was appropriate in producing high antibody concentrations.


Table 2: Vaccine efficacy estimates from effectiveness trials of the Hib vaccine(CI confidence interval)

Vaccine Vaccine 95% CI Endpoint Study site Referenceefficacy %

PRP-T 95 67-100 Invasive disease The Gambia (Mulholland et al., 1997)100 55-100 Pneumoniae after 2 or 3 doses21.1 4.6-34.9 Radiologically defined pneumonia

PRP-D 95 83-98 Invasive disease Finland (Eskola et al., 1990)

PRP-D 35 57-73 Invasive disease in Alaskan Natives USA (Ward et al., 1990)

PRP-T 90 50-99 Invasive disease U K (Booy et al., 1994)

PRP-T 90.2 74.5-100 Invasive disease Chile (Lagos et al., 1996)

PRP-OMP 95 72-99 Invasive disease, Navajo infants USA (Santosham et al., 1991)93 53-98 Meningitis

HbOC 100 64-100 Invasive disease, California USA (Black et al., 1991a)

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There are currently various formulations of Hib conjugate vaccine: liquid Hibconjugate vaccine (monovalent); liquid Hib conjugate combined with diphtheria-tetanus-pertussis vaccine (DTP) and hepatitis B (HepB); liquid Hib conjugate andHepB combined vaccines; lyophilised (freeze-dried) Hib conjugate with saline diluent(monovalent), and lyophilised Hib conjugate vaccine to be used with liquid DTP,DTP-HepB, DTP-IPV, DTaP, or DTaP/IPV in combination. With so many productson the market, there are clearly issues regarding the compatibility of vaccines duringsimultaneous administration, and questions about the interchanging of products.Hib conjugate vaccine can be given safely and effectively at the same time as bacilleCalmette-Guérin (BCG), DTP, measles, polio (OPV or IPV), HepB, yellow fevervaccines, and vitamin A supplementation. If Hib conjugate vaccine is given as aseparate injection at the same time as other vaccines, it should be administered at adifferent site. It should not be mixed in the vial or syringe with any other vaccineunless it is manufactured as a combined product (e.g. DTP-Hib) as studies haveshown that the mixture induces an immune response that is inferior to separateinjections of the respective antigens.

5.1 Interchanging different Hib conjugate vaccines

In the past it has been considered ideal to finish a schedule of primary dosing andboosting with the same licensed product. However for logistical reasons it hasbeen important to ascertain whether Hib conjugate vaccines from differentmanufacturers using the same or different carriers could be interchanged.Several studies have reported on the safety and immunogenicity of vaccines whenHib conjugates are interchanged during the primary schedule. Goldblatt and colleagues(Goldblatt et al., 1996a) found no significant changes in immunogenicity in a studywhere infants in the United Kingdom were given PRP-T or HbOC in variouscombinations at 2, 3 and 4 months. Here a greater number of infants receiving mixedcombinations of conjugates achieved long-term protective antibody titresof >1µg/ml compared to those receiving three doses of the same conjugate(91% versus 93%). Similar studies by Greenberg and colleagues (Greenberg et al.,1995), and Anderson and colleagues (Anderson et al., 1995b) (PRP-OMP and HbOC)and also Scheifele and colleagues (Scheifele et al., 1996) (PRP-T and HbOC),provide reassuring evidence that interchanging Hib conjugate vaccines whenadministered at 2, 4 and 6 months is safe, and as immunogenic as schedules of singleHib conjugate vaccines. In certain circumstances interchanging vaccines may beadvantageous. In a study of the safety and immunogenicity of PRP-OMP and HbOCadministered as a booster dose in 12 to 15-month-old Navajo Indian (USA) infantsprimed with PRP-OMP, a booster dose of HbOC produced a significantly higherantibody response compared to PRP-OMP (Reid et al., 1993). Currently, any licensedconjugate vaccine may be used for the booster dose, regardless of what wasadministered in the primary series.

5. Vaccine formulation issues:Hib interchangeability and

administration in combination


5.2 Simultaneous administration of Hib conjugate vaccines with otherchildhood vaccines

Hib conjugate vaccines have been administered simultaneously with avariety of antigens including DTwP (Bell et al., 1998; Joshi & Joshi, 2005;Berrington et al., 2006), measles, mumps, and rubella (MMR) (Black et al., 2006),pneumococcal vaccines (Obonyo & Lau, 2006), and meningococcal C conjugatevaccines (Bramley et al., 2001; Buttery et al., 2005) without any significant impacton the immune responses to the Hib conjugate vaccine or to the simultaneouslyadministered antigen. However some combination vaccines containing DTaP andHib have been shown to induce lower Hib responses when used in particular schedules(see below).

5.3 Hib combination vaccines

Hib conjugate vaccine is generally administered at the same time as diphtheria-tetanus-pertussis (DTP) and other childhood vaccines, and this has led to thedevelopment of combination vaccines. Combination vaccines have several advantages,including programmatic simplification, and decreased number of injections, storagespace, and medical waste. However, interference between different components ofcombination vaccines has been observed, particularly with vaccines that containHib conjugates and acellular pertussis antigens (Watt, Levine & Santosham, 2003).Hib conjugate vaccine has been combined with DTaP (quadrivalent), DTaP/IPV orDTaP/HepB (pentavalent) and DTaP/IPV/HepB (hexavalent).

Attenuation of the Hib response when PRP-T is administered in combination withDTPa-IPV compared to separate administration, was first noticed by Eskola andcolleagues (Eskola et al., 1996) and subsequently reported by several other studies(Eskola et al., 1999; Vidor, Hoffenbach & Fletcher, 2001). Attenuation of theHib response was particularly prominent when the vaccine was given in anaccelerated schedule (e.g. at 2, 3 and 4 months of age) such as that used in theUnited Kingdom (Goldblatt et al., 1999) compared to more extended schedules(Vidor, Hoffenbach & Fletcher, 2001). The attenuation was thought to be due in partto the effect of aluminium hydroxide affecting the integrity of the PRP-T as hadbeen previously demonstrated for Hib conjugates stored with aluminium hydroxide(Claesson et al., 1988). As a result of these studies, the United States Food and DrugAdministration recommended that DTaP and Hib conjugate vaccines should not begiven as a combined injection to infants. Attempts to overcome the reduced Hibresponse led to the development of DTaP-Hib combinations using aluminiumphosphate and these have been associated with less attenuation (Lee et al., 1999).More recently it has become clear that the attenuation of the Hib response is also inpart due to an inhibition of the immune response as a result of excess tetanustoxoid, a form of carrier-induced epitope suppression. Dagan and colleagues(Dagan et al., 1998) showed that with the administration of increasing amounts oftetanus there is a dose dependent effect on PRP-T responses. This effect is not asmarked with DTwP-containing combinations as it is likely that the adjuvanteffect of the wP masks this phenomenon. Recently a case-control study in theUnited Kingdom has demonstrated an increased risk for invasive Hib disease inchildren who received >2 doses of DTaP-Hib, which suggests that the reduced PRPresponses seen may be clinically relevant (McVernon et al., 2003) (see Section 7.1).

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Differences in the epidemiology of Hib disease and in public-health practices haveled to the adoption of several different schedules of immunization. Immunogenicityis influenced by the schedule used, with intervals of two months between dosesgiving better responses than intervals of one month (CDC, 1991). The mean titresof antibody are directly correlated with increasing age at administration of thefirst dose of Hib conjugate vaccine (Fritzell & Plotkin, 1992). Current vaccineschedules in use in selected countries around the world are shown below in Table 3.

Table 3: Recommended schedules and Hib vaccinesused in childhood immunization

Country Schedule

United kingdom 2, 3, 4 , 12-15 monthsSlovenia risk groups onlyPoland 2, 4, 12-15 monthsHungary 2, 4, 5 monthsItaly 3, 5, 11-12 monthsIsrael 2, 4, 12 monthsIceland 3, 5, 12 monthsGreece 2, 4, 6, 15-18 monthsGermany 2, 3, 4 months, plus 11-14 monthsFrance 2, 4, 18 months (vaccine with 5 antigens at 3 months)Finland 4, 6 & 14-18 monthsThe czech republic 2, 3, 4 & 18-20 monthsAustralia 2, 4, 12 monthsCanada 2, 4, 6, 15-18 monthsThe united states of America 2, 4, 6, 12-15 monthsChile 2, 4, 6 monthsThe gambia 2, 3, 4 monthsUganda 6, 10, 14 weeksSouth africa 6, 10, 14 weeksTunisia 3, 4, 5 monthsBahrain 2, 4, 6, 18 monthsJamaica 6 weeks, 3, 5 months

6. Vaccine schedule issues

(adapted from http://www.euibis.org/links.htm and http://www.who.intimmunization_monitoring) (2004) and WHO, http://www.who.int/immunization_monitoring/en/globalsummary/ScheduleResult.cfm (2006).


6.1 Hib conjugate immunogenicity at 2/4/6 months (USA schedule) andeffect of booster at 12-14 months

Three Hib conjugate vaccines (PRP-T, PRP-OMP, HbOC) are currently licensedfor use in various countries. Original studies among Alaskan Eskimo infants,and infants in California, USA, demonstrated that the three conjugate vaccines inducemarkedly different immunologic responses. Only 60% of Alaskan Eskimo childrenachieved an anti-PRP level of at least 1 µg/ml after a 3-dose series of PRP-OMP(Bulkow et al., 1993), and low titres have been associated with higher susceptibilityto colonization (Fernandez et al., 2000). In 1997, a schedule for high-risk childrenwas introduced with PRP-OMP given as the first dose at two months followed byHbOC at 4, 6, and 12 months. PRP-T and HbOC are administered in a 3-doseprimary series at 2, 4, and 6 months of age, with a booster dose recommended for allinfants at 12 to 15 months. Canada and the Kingdom of Belgium are also among thecountries using the same 2, 4 and 6-month schedule, with a booster dose in thesecond year of life.

6.2 Hib conjugate immunogenicity at 2/3/4 months and effect of boosterat 12-14 months

An accelerated schedule of 2, 3 and 4 months with a booster in the second year oflife is in use in a number of European countries, including the French Republic,the United Kingdom and the Kingdom of Belgium. In the United Kingdom,Phase II studies of Hib conjugates showed good immunogenicity at the acceleratedschedule (Finn, 2004), and Hib conjugates were introduced in 1992, initially withouta booster dose. A study was performed to document the persistence ofvaccine-induced antibody in children in the United Kingdom, and this showed adecline over the first five years of life. By 72 months of age, 32% of children(95% CI 21% to 46%) had concentrations <0.15 µg/ml and so were apparentlyunprotected (Heath et al., 2000a). The authors concluded that despite low measuredantibody concentrations, immunological memory was present in the populationstudied, and this accounted for the ongoing reduced risk of contracting Hib in theUnited Kingdom.

Pre-1996, Hib was given simultaneously (HbOC or PRP-T) with DTP in theUnited Kingdom, but since then combination vaccines have been used exclusively sothat only PRP-T is administered in the primary series (combinations includingHbOC are not available). Evaluation of DTaP in the United Kingdom schedule hasrevealed that Hib titres are reduced with such combination vaccines whenadministered at the accelerated schedule (Bell et al., 1998), although even in the faceof poor primary responses, infants are primed for an excellent memory response(Goldblatt et al., 1999). Due to an increase in Hib disease in the United Kingdom(see Section 7.1) a routine Hib booster dose was introduced into the infantimmunization schedule with effect from September 2006. This is administeredsimultaneously with meningococcal C conjugate vaccine at 12 months of age.

In the Kingdom of the Netherlands, Hib conjugate vaccine became part of theprimary course of childhood immunizations in 1993 at 3, 4, and 5 months of age,with a booster given at the age of 11 months. In 1999, the primary infant vaccinationschedule was changed to 2, 3, and 4 months, with booster vaccination at 11 monthsof age.

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6.3 Hib conjugate immunogenicity at 3/5/12 months(Scandinavian schedule)

In Scandinavian countries Hib disease occurs slightly later and a 2-dose scheduleat 3 and 5 months is used, followed by a booster third dose early in the second yearof life. In the Republic of Finland in 1990 and 1991, approximately 110 000 infantsreceived two doses of PRP-T at 4 and 6 months, with a booster dose at 14 to18 months. This schedule was shown to be highly efficacious (Peltola, Kilpi & Anttila,1992). In the Kingdom of Sweden it has been reported that the Hib vaccine has been96% (95% CI) successful in reducing incidence after the first six years after itsintroduction. One study (Garpenholt et al., 2000), during a six-year period foundsix true vaccine failures, six apparent vaccine failures and one possible vaccinefailure in the 0-14 year age group in nearly two million vaccinated child-years(Garpenholt et al., 2000; Farhoudi, Lofdahl & Giesecke, 2005). Another study inthe Kingdom of Sweden (Knutsson et al., 2001) found that mixing DTaP-IPV(in which the pertussis vaccine consisted only of pertussis toxoid) with a Hib conjugatevaccine led to an impaired antibody response to the Hib polysaccharide, but,since protective levels of anti-Hib polysaccharide antibodies were achieved by allsubjects, the clinical relevance of this was probably of little clinical importance.

6.4 Hib conjugate immunogenicity at 6/10/14 weeks (EPI schedule)

The Expanded Programme on Immunization (EPI) schedule designed by theWorld Health Organization (WHO) has been adopted by many different countries.Hib conjugate vaccine is given in combination with DPwT at 6, 10 and 14 weeks ofage, at the same time as OPV, and this schedule has been found to be safe,immunogenic and well tolerated. In the Republic of India, a study evaluated theimmune response to mixed or separate DTwP and Hib administered according to theEPI schedule (Cherian et al., 2002), and found the mixed vaccines to be safe andimmunogenic and with the advantage of reducing the number of injectionsadministered per visit. DTPw-HBV/Hib vaccine was also reported in theRepublic of the Philippines (Gatchalian et al., 2005) to be immunogenic and welltolerated when administered according to the EPI schedule. Capeding andcolleagues (Capeding et al., 1996) showed that all three Hib conjugate vaccines(PRP-T, HbOC, and PRP-OMP) were immunogenic after three primary doses amongPhilippine infants on the EPI schedule. Most infants immunised with Hib conjugatesaccording to the EPI schedules in the Republic of the Niger, and Cape Town in theRepublic of South Africa, achieved a level of anti-PRP antibodies >0.15 microgram/ml, indicative of short-term protection, while over 70% achieved a level >1 g/ml,indicative of long-term protection (Campagne et al., 1998; Hussey et al., 2002).In the Republic of Kenya, introduction of Hib vaccine into the routine childhoodimmunization EPI programme reduced Hib disease-incidence among childrenyounger than five years to 12% of its baseline level. This impact was observed bythe third year after vaccine introduction. (Cowgill et al., 2006).


Cost constraints have led to studies of fewer than the recommended numbers ofHib conjugate doses or the administration of fractional doses of Hib. A study in theFederative Republic of Brazil used a 2-dose regime and found that mean PRP antibodytitres were >1.0 µg/ml after two doses of PRP-T (Guimaraes et al., 2002). Nicol andcolleagues (Nicol et al., 2002) conducted a randomized trial comparing the use ofHib conjugate vaccine diluted in a multidose vial of DTP with that of the fullHib dose, to observe whether fractional dosing had an impact upon immunogenicity.In this trial 168 South African infants received either the full dose Hib PRP-T vaccineor a 1/10 dilution prepared by reconstituting the full dose in a 10-dose DTP vial.Infants were vaccinated according to the EPI schedule at 6, 10 and 14 weeks of ageand received a full dose as a test of immunologic memory at nine months of age.They showed that after the primary vaccination series, 95% of infants in the fulldose arm, and 94% of infants in the 1/10 dose arm achieved anti-PRP IgG antibodyconcentrations of >1.0 µg/ml, and infants receiving the diluted vaccine also hadsignificantly higher titres of anti-PRP antibody in response to the booster dose.In the Republic of Chile, a study of fractional dosing found that a mean of 91%(83-96) to 100% (95-100) of infants immunized with one-half or one-third of a fulldose of Hib conjugate, developed protective antibody concentrations against Hib(Levine et al., 1998). A recent study in the Republic of India showed similar findings(Punjabi et al., 2006). However, it is unlikely that vaccine manufacturers willreformulate their vaccines to produce substantially cheaper products, because a66.7% reduction in antigen content is estimated to reduce costs by only 10% andreformulation would also require companies to seek a new product licence(Booy, 1998).

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Following introduction of Hib conjugate vaccines into routine childhoodimmunization programmes in the 1990s, Hib disease has largely disappeared inwestern Europe, Canada, the United States, Australia and New Zealand.Re-emergence of invasive Hib disease in a well-vaccinated population in Alaska,USA in 1997 (Galil et al., 1999) was attributed to ongoing carriage of Hib in thecontext of a low prevalence of Hib antibody because of a change of Hib conjugatevaccine. Vaccine efficacy has been shown in some cases to exceed 95% in infantswith a complete Hib vaccination schedule who are immunized starting fromtwo months of age (CDC, 2002). However, in some countries such as theRepublic of Finland (Eskola et al., 1999), high efficacy has been reported when thevaccination schedule starts later, thereby showing that efficacy and effectivenessdepends on epidemiology.

Vaccine failures can however occur in a vaccinated population. Factors associatedwith possible vaccine failure include prematurity (premature infants develop lowerantibody concentrations compared to full-term infants (Washburn et al., 1993;Heath et al., 2003)), immunoglobulin deficiency, and clinical risk factors such asmalignancy and neutropaenia (Heath & McVernon, 2002).

While host factors might influence the risk of vaccine failure, there has also been aninterest in identifying bacterial factors that may play a role. Recently Cerquitti andcolleagues (Cerquetti et al., 2005) studied the frequency of a genetic duplication ofthe capsulation locus frequently seen in invasive strains. The authors found thatstrains containing amplified capb sequences were quite common among Hib strains,and were significantly more frequent among strains from children with true vaccinefailure than among those from unvaccinated children, which suggests that theamplification of the capb locus may contribute to vaccine failure because of theincreased virulence of the bacteria.

7. Vaccine effectiveness


7.1 Developed country experience

The United States

Before the introduction of Hib conjugate vaccines, there were an estimated20 000 cases of invasive Hib disease each year in the United States in children youngerthan five years of age (Cochi, Broome & Hightower, 1985). Figure 3 shows thatafter the introduction of Hib conjugate vaccines for toddlers in 1987 and forinfants in 1990, the incidence of invasive Hib disease declined by more than 99%(Watt, Levine & Santosham, 2003). Hib conjugate vaccine has also been effective inthose populations within the United States who have a high incidence of Hib disease,such as the American Indian and Alaskan Eskimo populations. The vaccinationpolicies in Alaska have changed several times over the past 10 years in response toepidemiologic data and programmatic considerations. Routine Hib conjugatevaccination was first implemented in 1991, with PRP-OMP being used statewide.In 1996, Hib conjugate vaccine was changed to HbOC in combination with DTwP.PRP-OMP continues to be the only Hib conjugate vaccine used in the Navajoand Apache Indian populations in a schedule of 2, 4, and 12 to 15 months.Coverage with Hib conjugate vaccine on the Navajo and White Mountain ApacheIndian reservations is higher than 90%.

Figure 3: Incidence of invasive Hib disease in the United States, 1990-2004

1990

Year

1992 1994 1996 1998 2000 2002 20040

5

10

15

20

25

Inci

denc

e

Doses were given at 2, 4, and 6 months with a booster at 12-15 months of age. x-axis: year; y-axis: casesper 100 000 children <5 years of age. Reference: CDC, Pink Book: Haemophilus Influenzae Type b,(http://www.cdc.gov/nip/publications/pink/hib.pdf).

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The United Kingdom

In the pre-vaccine era there were approximately 1500 annual cases of invasiveHib disease in the United Kingdom, of which 900 were cases of meningitis and60 resulted in death (Booy et al., 1995). Figure 4 shows the rapid decline of diseaseafter the introduction of Hib conjugate vaccines. When initially introduced in 1992,the United Kingdom Hib conjugate vaccine programme had a number of uniquefeatures, including an accelerated schedule with completion by four months of age,the absence of a routine booster dose, and the inclusion of a catch-up component atthe beginning of the programme in which all children under the age of five yearswere immunized within 12 months of the campaign starting. The rationale for theUnited Kingdom approach was the belief that immunological memory afterthree doses in infancy would be sufficient for protection through the early childhoodyears when susceptibility was greatest (Heath & McVernon, 2002). The catch-upcampaign provided rapid protection for a large proportion of the susceptiblepopulation and rapidly reduced rates of disease, protecting all of the at-risk group asquickly as possible (Gay et al., 1997; Salisbury, 2001). As a result, the annual incidenceof Hib disease declined by 90%, falling to from 21/100 00 in the pre-vaccine era to0.65 per 100 000 (Ramsay et al., 2003), and remained low throughout the 1990s.Estimates of the efficacy of the vaccine suggested that seven to eight years after theintroduction of vaccine into the United Kingdom infant schedule, efficacy was stillin the order of 97% (McVernon et al., 2004b). Surveillance data also confirmed thatthere was no compensatory increase in invasive disease due to non-typeable Hi.

Figure 4: Invasive Hib infections by age, 1990 to 2004,England and Wales, combined PHLS HRU/CDSC data

0

50

100

150

200

250

300

350

400

450

500

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Under 1yr1-4 yrs5-14 yrs15+ years

Data from the Health Protection Agency. http://www.hpa.org.uk/infections/topics_az/Haemophilus_influenzae/menu.htm.


However in the late 1990s the number of invasive Hib infections rose, with an increaseyear-on- year in the number of cases in children born between 1996 and 2001.By 2002 the disease incidence had reached 4.58 per 100 000 in those underfive years of age (Ramsay et al., 2003). Vaccine failures were occurring primarily inchildren aged one to four years who completed the primary vaccination series,but an increase in disease in those over 15 years of age was also seen.An acellular pertussis combination vaccine (DTaP-Hib) was used briefly in2001/2002 because of a shortage of the whole cell pertussis combination(DTwP-Hib) vaccine, and this exacerbated the rise in the number of cases(Heath & McVernon, 2002). A case-control study performed at the time demonstratedan increased risk of vaccine failure in those who received the DTaP-Hib combination(Ramsay et al., 2003). Despite intensive study and the supposition that Hib carriagemust have increased in the period, associated with increased disease,adequately powered studies of Hib carriage in various age groups failed to revealsignificant Hib carriage in the United Kingdom population during this period(Heath & McVernon, 2002). Trotter and colleagues (Trotter et al., 2003) studiedserum samples obtained from different birth cohorts and showed that Hib antibodytitres beyond the first year of life in cohorts immunized after the catch-up campaigndid not differ significantly from titres in similarly aged children in the pre-vaccineera. McVernon and colleagues (McVernon et al., 2004b) analysed anti-PRPIgG titres in the serum stored from adults in the United Kingdom, spanning theperiod 1991 to 2003, and showed that titres in adults declined and remained lowfollowing the introduction of Hib conjugate. This was presumably as a result ofreduced exposure to Hib due to the reduction in carriage associated with theintroduction of conjugate. Low circulating titres in toddlers and adults may thusexplain the increase in invasive disease in the United Kingdom between 1999 and2002, which suggests that immune memory alone in a vaccinated child is unable toprovide robust protection against invasive Hib disease. A catch-up campaign wasundertaken in the United Kingdom in 2003 for all children under the age offive years, and the incidence of invasive Hib disease reduced (Figure 4). A routineHib booster dose was introduced into the United Kingdom schedule in 2006.

Other European countries

In the Republic of Finland, Hib conjugate was introduced in 1986 at a 4, 6 and15 month schedule and has proven to be highly efficacious (Eskola & Kayhty, 1996).In the Kingdom of Norway, a routine infant vaccination programme (introduced at3, 5 and 11-12 months), was accompanied by a catch-up programme for children upto and including four years of age (Peltola et al., 1990). In the Kingdom of Swedenfollowing the introduction of routine Hib conjugate vaccination at 3, 5 and 12 months,Hib epiglottis decreased from an incidence of 20.9 per 100 000 children <5 years oldin 1987 to 0.9 per 100 000 in 1996 (Garpenholt et al., 1999). The Kingdom of theNetherlands, the French Republic and the Kingdom of Belgium have virtuallyeliminated Hib disease, and the Republic of Iceland completely eliminated Hib diseasethree years after the introduction of the vaccine.

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7.2 Developing country experience

In July 1996, the Republic of Chile became the second non-industrialized nation,after the Eastern Republic of Uruguay, to introduce Hib conjugate for routine use at2, 4, and 6 months of age along with DTP and oral polio vaccine (Lagos et al., 1998).Subsequently the Ministry of Health in the Republic of Chile decided to exploreways to lower the cost of vaccination without compromising the vaccine'seffectiveness. Recent studies there have shown that two months after thesecond dose of a primary vaccination series most patients have seroprotectiveantibody titres and geometric mean titres are well above seroprotective thresholds(Riedemann et al., 2002) suggesting that two doses may suffice, although this is notyet Chilean government policy. Figure 5 shows the decline of Hib disease followingthe introduction of Hib conjugate vaccine in the Republic of Chile and the EasternRepublic of Uruguay.

A randomized, placebo-controlled trial of Hib conjugate was conducted in theWestern Region of the Republic of the Gambia between 1993 and 1995 and showedthat the vaccine provided 95% protective efficacy against all culture-confirmed,invasive Hib disease, as well as 21% efficacy against radiographically-definedpneumonia, and 60% protection against oropharyngeal carriage of Hib (Bijlmer &Van, 1992; Mulholland et al., 1997). The Republic of the Gambia incorporated PRP-T into its EPI in 1997, and since the introduction the incidence of Hib meningitis ininfants has declined from 200 per 100 000 to 21 per 100 000 (Adegbola et al., 1999).Between 2001 and 2002, the Republic of Malawi, along with several other Africancountries, introduced Hib conjugate vaccine with the assistance of the Vaccine Fundof the Global Alliance for Vaccines and Immunization (GAVI), and the incidence ofHib disease reduced by 88% in children <5 and 87% in children <2 (Hib Focus Vol11, No. 4). Furthermore, vaccine effectiveness in preventing Hib meningitis amongHIV positive children with two or more doses while adjusting for age and residencewas close to 100%. Recently it has been reported that three years after introduction,routine vaccination of infants against Hib in the Republic of Kenya showed invasiveHib disease rates significantly reduced by 88% (Cowgill et al., 2006).

In other developing country settings, the perception of low burden of Hib diseasehas meant that Hib conjugate introduction has not been perceived as a priority.Lombok Island in the Republic of Indonesia was originally thought to have a lowincidence of Hib, although a recent study using Hib conjugate vaccine as a probe,identified a high incidence of Hib meningitis with case-fatality proportionsbetween 12% and 18% (Gessner et al., 2005). The Lombok study showed thatHib conjugate vaccine prevented a substantial amount of meningitis, but notradiologically confirmed pneumonia, in young Indonesian children (Gessner et al.,2005).

Despite the success of Hib conjugate vaccines it has been estimated that <8% of allHib disease worldwide is prevented by current vaccination coverage (Peltola, 2000),with the highest disease burden in developing countries.


Figure 5: Impact of Hib vaccine by September 1997 in theEastern Republic of Uruguay and Republic of Chile

(adapted from: http://www.paho.org/English/HVP/HVI/hvp_hib_text.htm)

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Three out of the four licensed Hib conjugate vaccines (PRP-HbOC, PRP-OMP,PRP-T) have proven to be comparably efficacious in infancy, provided a completeprimary series is given. PRP-D performs less well in children below 18 months ofage, and is therefore no longer licensed or manufactured for use in infants.All conjugate vaccines have an excellent safety record, and where tested,do not interfere substantially with the immunogenicity of vaccines givensimultaneously. Furthermore, these vaccines are easily adapted to the routine scheduleof the national immunization programmes.

8.1 Hib conjugates in the EPI schedule

Recommendations of the Expanded Programme on Immunization of theWorld Health Organization encourage simultaneous administration of severalchildhood vaccines to attain comprehensive immunization as early as possible.In addition, depending on the epidemiologic situation, the optimal immunizationschedule can vary from one country to another (WHO, 2006). A separate issue ishow to provide a new highly-effective vaccine in the existing EPI system. In commonwith other newly developed vaccines, (including existing hepatitis B, and hepatitis Avaccines, and imminent pneumococcal conjugate vaccines), Hib conjugate vaccinesare currently more expensive than those already in the EPI. WHO, the Children'sVaccine Initiative (CVI), and others, are exploring approaches to reducing the costof these vaccines for non-industrialised countries.

Reduction in disease appears to occur more completely when a catch-up campaign isinstituted at the same time as routine immunization of infants is initiated.An example of this impact can be seen by comparing the Eastern Republic ofUruguay, which included a catch-up campaign, and the Republic of Chile, which didnot. In both countries cases declined by more than 90% compared to baseline,but it took somewhat longer for the Republic of Chile to reach this goal(Landaverde et al., 1999). In deciding whether to implement a catch-up campaign,consideration must be given to the gain in disease prevented relative to the increasedcost of the vaccine and delivery operations.

8.2 Hib conjugates in combination vaccines

Hib conjugate combined with DTwP vaccines in a single injection are now widelyavailable for use in developing country settings. New combinations of higher valencyvaccines (such as DTPa-HBV-IPV/Hib) are licensed and used routinely in developedcountries but are likely to remain too costly for the foreseeable future for use indeveloping countries.

8. Future prospects


8.3 The role of a booster dose

Most countries introducing Hib conjugate vaccine into routine vaccinationschedules have done so with the addition of a booster dose in the second year of life.The major reason for this is the observation that vaccine-induced antibody wanesover time (Heath et al., 2000a) leading to the concern that this may be accompaniedby an increase in susceptibility to disease. Infants who underwent the primaryschedule series and received a booster in the second year of life have shown elevatedantibody concentrations even at nine years of age (Claesson et al., 2005) or ten(Makela et al., 2003). Although carriage has been low in the countries where thesestudies were performed (the Kingdom of Sweden and the Republic of Finlandrespectively), the persistence of high antibody concentrations reflects the probablenatural boosting due to cross reacting antigens. In the absence of vaccine boostingand with little exposure to wild type Hib for natural boosting, anti-PRP antibodylevels induced by vaccination in infancy have been shown to wane over a period of2-3 years (Heath et al., 2000a; Johnson et al., 2006), and experience in theUnited Kingdom has shown that this may lead to a resurgence of Hib disease.Booster doses are not routinely provided for in the EPI schedule. However,it is unclear if the epidemiology of Hib in developing country settings using Hibconjugates in infancy only, will mirror that seen in the United Kingdom. Furthersurveillance of Hib in countries that have introduced Hib conjugate in the EPIschedule is required. If boosting were required, it is important to study whether theHib conjugate could be administered at nine months of age when measles vaccine isgiven.

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Adegbola RA et al. (2005). Elimination of Haemophilus influenzae type b(Hib) disease from The Gambia after the introduction of routine immunization witha Hib conjugate vaccine: a prospective study. Lancet, 366:144-150.

Akkoyunlu M et al. (1997). The acylated form of protein D of Haemophilus influenzaeis more immunogenic than the nonacylated form and elicits an adjuvant effect whenit is used as a carrier conjugated to polyribosyl ribitol phosphate. Infection andImmunity, 65:5010-5016.

Ambrosino D et al. (1983). Efficacy of human hyperimmune globulin in preventionof Haemophilus influenzae type b disease in infant rats. Infection and Immunity,39:709-714.

Ambrosino D et al. (1992a). Response to Haemophilus influenzae type Bconjugate vaccine in children undergoing splenectomy. Journal of Pediatric Surgery,27:1045-1047.

Ambrosino DM et al. (1992b). IgG1, IgG2 and IgM responses to twoHaemophilus influenzae type b conjugate vaccines in young infants. The PediatricInfectious Disease Journal, 11:855-859.

Anderson EC et al. (1995a). Epidemiology of invasive Haemophilus influenzaeinfections in England and Wales in the pre-vaccination era (1990-2).Epidemiology and Infection, 115:89-100.

Anderson EL et al. (1995b). Interchangeability of conjugated Haemophilus influenzaetype b vaccines in infants. JAMA: the Journal of the American Medical Association,273:849-853.

Anderson P et al. (2000). A high degree of natural immunologic priming to thecapsular polysaccharide may not prevent Haemophilus influenzae type b meningitis.The Pediatric Infectious Disease Journal, 19:589-591.

Anderson P, Johnston RB Jr., Smith DH (1972). Human serum activities againstHaemophilus influenzae, type b. The Journal of Clinical Investigation, 51:31-38.

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The World Health Organization has provided technical support to its Member States in the field of vaccine-preventable diseases since 1975. The office carrying out this function at WHO headquarters is the Department of Immunization, Vaccines and Biologicals (IVB).

IVB’s mission is the achievement of a world in which all people at risk are protected against vaccine-preventable diseases. The Department covers a range of activities including research and development, standard-setting, vaccine regulation and quality, vaccine supply and immunization financing, and immunization system strengthening.

These activities are carried out by three technical units: the Initiative for Vaccine Research; the Quality, Safety and Standards team; and the Expanded Programme on Immunization.

The Initiative for Vaccine Research guides, facilitates and provides a vision for worldwide vaccine and immunization technology research and development efforts. It focuses on current and emerging diseases of global public health importance, including pandemic influenza. Its main activities cover: i ) research and development of key candidate vaccines; ii ) implementation research to promote evidence-based decision-making on the early introduction of new vaccines; and iii ) promotion of the development, evaluation and future availability of HIV, tuberculosis and malaria vaccines.

The Quality, Safety and Standards team focuses on supporting the use of vaccines, other biological products and immunization-related equipment that meet current inter-national norms and standards of quality and safety. Activities cover: i ) setting norms and standards and establishing reference preparation materials; ii ) ensuring the use of quality vaccines and immunization equipment through prequalification activities and strengthening national regulatory authorities; and iii ) monitoring, assessing and responding to immunization safety issues of global concern.

The Expanded Programme on Immunization focuses on maximizing access to high quality immunization services, accelerating disease control and linking to other health interventions that can be delivered during immunization contacts. Activities cover: i ) immunization systems strengthening, including expansion of immunization services beyond the infant age group; ii ) accelerated control of measles and maternal and neonatal tetanus; iii ) introduction of new and underutilized vaccines; iv ) vaccine supply and immunization financing; and v ) disease surveillance and immunization coverage monitoring for tracking global progress.

The Director’s Office directs the work of these units through oversight of immunization programme policy, planning, coordination and management. It also mobilizes resources and carries out communication, advocacy and media-related work.

Family and Community Health

World Health Organization

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CH-1211 Geneva 27

Switzerland

E-mail: [email protected]

Web site: http://www.who.int/immunization/en/

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