The Immunological Basis for Immunization Series
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The Immunological Basis for Immunization Series The Immunological Basis for Immunization Series Document Transcript

  • The Immunological Basis for Immunization Series Module 9: Haemophilus influenzae type b Immunization, Vaccines and Biologicals
  • The Immunological Basis for Immunization Series Module 9: Haemophilus influenzae type b Immunization, Vaccines and Biologicals
  • 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 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; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Printed in Switzerland
  • The Department of Immunization, Vaccines and Biologicals thanks the donors whose unspecified financial support has made the production of this document possible. This module was produced for Immunization, Vaccines and Biologicals, WHO, by: • Professor David Goldblatt and Dr Tracy Assari, UCL Institute of Child Health, London, UK Printed in October 2007 Copies of this publications as well as additional materials on immunization, vaccines and biological may be requested from: World Health Organization Department of Immunization, Vaccines and Biologicals CH-1211 Geneva 27, Switzerland • Fax: + 41 22 791 4227 • Email: vaccines@who.int • © 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: bookorders@who.int). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; email: permissions@who.int). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication. Printed by the WHO Document Production Services, Geneva, Switzerland ii
  • Contents Abbreviations and acronyms .......................................................................................... v Preface ............................................................................................................................. vii 1. The organism and the disease ............................................................................ 1 1.1 Introduction..................................................................................................... 1 1.2 Epidemiology .................................................................................................. 1 1.3 The surface of Hib .......................................................................................... 4 2. The Immunology of Hib ...................................................................................... 5 2.1 Response to infection ..................................................................................... 6 3. Hib vaccines ........................................................................................................... 7 3.1 Polysaccharide vaccine responses ................................................................ 7 3.2 Conjugate vaccine responses ........................................................................ 8 4. Response to vaccination ..................................................................................... 9 4.1 Polysaccharide vaccine responses ................................................................ 9 4.2 Conjugate vaccine responses ........................................................................ 9 4.3 Impact on Hib carriage ................................................................................ 12 4.4 Impact of host factors .................................................................................. 13 4.5 Hib conjugate vaccine efficacy ................................................................... 13 5. Vaccine formulation issues: Hib interchangeability and administration in combination ........................................................................ 15 5.1 Interchanging different Hib conjugate vaccines ...................................... 15 5.2 Simultaneous administration of Hib conjugate vaccines with other childhood vaccines ............................................................................. 16 5.3 Hib combination vaccines ........................................................................... 16 6. Vaccine schedule issues ..................................................................................... 17 6.1 Hib conjugate immunogenicity at 2/4/6 months (USA schedule) and effect of booster at 12-14 months ....................................................... 18 6.2 Hib conjugate immunogenicity at 2/3/4 months and effect of booster at 12-14 months .............................................................................. 18 6.3 Hib conjugate immunogenicity at 3/5/12 months (Scandinavian schedule) ............................................................................... 19 6.4 Hib conjugate immunogenicity at 6/10/14 weeks (EPI schedule) ........ 19 iii
  • 7. Vaccine effectiveness ......................................................................................... 21 7.1 Developed country experience ................................................................... 22 7.2 Developing country experience .................................................................. 25 8. Future prospects ................................................................................................. 27 8.1 Hib conjugates in the EPI schedule ........................................................... 27 8.2 Hib conjugates in combination vaccines ................................................... 27 8.3 The role of a booster dose ........................................................................... 28 References ...................................................................................................................... 29 iv
  • Abbreviations and acronyms 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 conjugate vaccine PRP-T polyribosyl-ribitol- phosphate-tetanus toxoid conjugate vaccine PS polysaccharide v
  • 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 vi
  • 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 the vaccines included in the Expanded Programme on Immunization (EPI)1. In addition to a general immunology module, each of the seven other modules covered one of the vaccines recommended as part of the EPI programme, i.e. diphtheria, measles, pertussis, polio, tetanus, tuberculosis and yellow fever. These modules have become some 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) and the expansion of immunization programmes in general, as well as the large accumulation of new knowledge since 1993, the decision has been taken to update and 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 a brief and easily-understood overview of the scientific basis of vaccination, and also of the immunological basis for the WHO recommendations on vaccine use that since 1998 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 of the initial “Immunological Basis for Immunization” Series, as well as those involved in its updating, and the development of new modules. 1 This programme was established in 1974 with the main aim of providing immunization for children in developing countries. vii
  • viii
  • 1.The organism and the disease 1.1 Introduction Haemophilus influenzae (Hi) are a genus of gram-negative coccobacilli, members of the Pasteurellaceae family that exist in both capsulated and nonencapsulated forms. Encapsulated strains are further classified according to the chemical composition of the polysaccharide forming the capsule, and six serotypes, designated a-f, have been identified (Pittman, 1931). Hi are carried in the moist mucosa of the human nasopharynx from where they can spread to cause both local and systemic 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 approximately 95% of all invasive disease due to Hi (invasive disease is defined as the isolation of Hi 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 suffer permanent disability. The sequelae of Hib meningitis include blindness, deafness and learning disabilities. Antibiotic resistance to all Hi has steadily increased in recent years (Gessner et al., 2002). Nonencapsulated strains are an important cause of mucosal diseases such as otitis media, sinusitis and lower respiratory tract infection, and in some clinical settings, such as an immunocompromised host, may cause invasive disease. 1.2 Epidemiology Although invasive Hib disease may occur in any age group, it is predominantly a disease 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 in children aged between 4 and 18 months (See Figure 1), although the precise age at which 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
  • Figure 1: Age distribution of Hib infection from October 1990 to September 1991 in six regions in England and Wales 150 120 Number of cases 90 60 30 0 <1 1 2 3 4 5-14 15-44 45-64 65+ NK Age group (years) Age distribution of Hib infection from October 1990 to September 1991 in six regions in England and Wales. Out of 433 reported cases, 362 (84%) were due to Hib, 54 (13%) were due to non-serotypable Hi, and 13 cases were not serotyped. Adapted from (Nazareth et al. 1992). In the pre-vaccine era in developed countries, meningitis accounted for approximately half of all invasive Hib disease. In the United Kingdom for example, an analysis of invasive Hib disease revealed that 56% of isolates were from patients with meningitis, 13% from patients with epiglottitis, and 6% from patients with pneumonia (Nazareth et al., 1992). Data from some countries with good surveillance systems illustrates how incidence figures in childhood may vary. For example, in the pre-vaccine era, reported incidence rates per 100 000 for invasive Hib 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 the United States of America (USA) excluding Alaska (Broome, 1987), and 42 in the Federative 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 60/100 000 and 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 and pneumonia remains unclear. The incidence of Hib meningitis among children aged 0 to 4 years in Hong Kong Special Administrative Region of China has been reported to be as low as 1.75 per 100 000 per year (Lau et al., 1998) and also 3.22 per 100 000 under five years of age in China (Province of Taiwan) (Shao et al., 2004), although the 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 in general is difficult to quantify because only a small percentage of Hib pneumonia is accompanied by bacteraemia. Studies incorporating a wide range of diagnostic 2 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • techniques, including lung aspirates, which are often considered the gold standard for identifying a pathogen in pneumonia, have suggested that the burden of Hib pneumonia in children under five years of age in the Republic of the Gambia may be as high as 42% (Vuori-Holopainen & Peltola, 2001), while a vaccine probe 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 have been identified that are associated with an increased risk of Hib disease. Hib disease in 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 than for 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 been shown to have the greatest known endemic risk of invasive Hib disease (Bulkow et al., 1993; Wenger, 1998; Singleton et al., 2000) with rates as high as 408/100 000 described (Ward et al., 1981). The reason for these very high rates is likely 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 of invasive disease (Tarr & Peter, 1978; Wenger, 1998), while pre-existing conditions such as sickle cell disease, human immunodeficiency virus (HIV), bone-marrow transplant and complement deficiencies, are also known to be important individual risk factors. Estimates of rates of nasopharyngeal carriage also reveal that carriage is related to the age of the individual, presumably reflecting the relative immaturity of the immune system in young children. In the pre-vaccine era about four in every 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 of Finland (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 rates as 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 development of conjugate vaccines have prompted concern about serotype replacement. Unusual clusters of invasive infection due to Hi serotype a with clinical features that 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 the IS1016-bexA partial deletion, which was previously identified in the capsule locus of Hi serotype b strains (Kapogiannis et al., 2005). The presence of the necessary bexA gene deletion has also been demonstrated in the capsulation locus of a sizeable proportion of Hi types f and a isolates from invasive infections in the Republic of the Gambia (Kroll et al., 1994; Ogilvie et al., 2001). To date however no widespread level of replacement disease is evident. 3
  • 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 bacterial pathogens that cause systemic disease. Based on in vitro studies, it is known that polysaccharide capsules mediate resistance to important host defence mechanisms, including phagocytosis and complement-mediated killing (Sukupolvi-Petty, Grass & St Geme, 2006). The Hib capsule is made up of repeating polymers of ribosyl and ribitol-phosphate and is thus designated polyribosyl-ribitol- phosphate (PRP). The repeating sugar has homology to a number of other bacterial-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 differences in pathogenicity are not well understood. Encapsulated organisms can penetrate the epithelium of the nasopharynx and invade capillaries directly which accounts for the invasive potential of Hib. The antiphagocytic capsule prevents the induction of the alternative complement pathway by inhibiting or delaying complement proteins on the cell surface (particularly C3b), so that the bacterium can invade the blood or cerebrospinal fluid without attracting phagocytes or provoking an inflammatory response and complement-mediated bacteriolysis (Hetherington, Patrick & Hansen, 1993). For this reason, anticapsular antibody which is able to bind to capsule and which promotes both phagocytosis (via Fc interactions with other cells) and bacteriolysis (by allowing complement to bind), is critical for protection against encapsulated organisms (Tosi, 2005). Anti PRP antibodies have been shown to be produced 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) that may also be targets of human IgG. These OMPs include P1, P2, P4, P5, P6, a 98kD surface protein, and a 42kD protein called protein D. Antibodies to P1, P4, and P6 have been shown to bind to proteins on the surface of diverse Hi strains. Animal models have suggested that antibody to several different proteins may be protective, and development of a Hi OMP vaccine to prevent otitis media has been actively pursued. A recent study by Prymula and others (Prymula et al., 2006) using a Hi protein D as a carrier for pneumococcal polysaccharide vaccines appeared to demonstrate protection against both pneumococcal and Hi otitis media. 4 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 2. The Immunology of Hib Studies of the epidemiology of invasive Hib disease coupled with animal experiments have provided clues to the key components mediating immunity to Hib. The striking age-dependent susceptibility to invasive disease was initially shown in the 1930's to correlate with the absence of bactericidal activity in the blood (Fothergill & Wright, 1933). Antibodies to Hib capsule were identified as key mediators of this effect and shown to confer type-specific protection of lethal Hib disease in a rabbit model. Subsequent studies in humans on the bactericidal activity of blood identified a discrepancy between bactericidal activity and anticapsular antibody titre (Anderson & Smith, 1977). At the same time, anti-PRP IgG was shown to be inversely correlated to the incidence of Hib meningitis (Peltola et al., 1977). The absence of invasive Hib infections in children with X-linked agammaglobulinaemia on replacement immunoglobulin therapy, provided further evidence for the protective effect of serum IgG in humans (Siber et al., 1992) while a formal trial in the United States of the efficacy of bacterial polysaccharide immune globulin (BPIG) was conducted in White Mountain Apache Indian infants (a group with very high incidence 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 life due to the transfer of maternal IgG specific for PRP across the placenta, although in some indigenous populations incidence of early invasive disease is high despite this antibody. Generally, once maternal antibodies wane, the incidence of disease increases (peaking at different times in different populations, see Section 1.2), but by the age of five years the incidence of disease is universally low and remains low throughout adulthood with only a small increase in the incidence in the very elderly (Farley et al., 1992). Like other bacterial-derived polysaccharides, PRP is classified as 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 disease is that they are unable to mount robust responses to pure polysaccharide antigens before approximately 18 months of age. 5
  • 2.1 Response to infection Hib is the most virulent of the Haemophilus genus and 95% of bloodstream and meningeal Haemophilus infections in children are due to type b. Hib colonizes the human upper respiratory tract, although only a fraction of those acquiring carriage of the bacteria will subsequently develop clinical disease. The time between infection and the appearance of symptoms is thought to be between two and ten days. Symptoms of Hib meningitis can include headache, fever, vomiting, stiffness of the neck, sensitivity to bright lights, joint pains, drowsiness, confusion, hypothermia and coma (Herson & Todd, 1977). If Hib infection occurs in a previously healthy unimmunized child over the age of 24 months, the child generally develops a robust immune response (Pichichero, Hall & Insel, 1981). Both humoral and cellular immune responses 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 as vaccination. Variable immunoglobulin isotype and IgG subclass responses to PRP polysaccharide after natural Hib exposure, disease, and immunization, have been described (Jennings, 1983; Barrett, 1985). Most individuals respond with IgG antibodies after PRP immunization, although some children have predominantly IgA or IgM responses (Ramadas et al., 1986). IgG2 is the IgG subclass that is commonly found, along with IgG1, in the natural response to polysaccharide antigens. There is an increased susceptibility to Hib disease in patients who are immunosuppressed and in those who are deficient in IgG2 and IgG4 (Ambrosino et al., 1992b). Rising Hib anticapsular antibodies have been detected within 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 infection has been suggested. However, the majority of studies have focused on serum-derived IgG 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 relatively little is known about the immune response or relative importance of responses to Hib proteins. Antibodies directed against the capsular PRP or the outer membrane proteins of Hib promote bactericidal activity, complement 3 binding, and ingestion by phagocytic cells (Heath, 1998; Granoff, 2001). 6 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 3. Hib vaccines 3.1 Polysaccharide vaccine responses The first vaccine developed against Hib was produced in the early 1970s and was composed of purified Hib capsular polysaccharide capsule (PRP). A double-blind efficacy trial of PRP vaccine was conducted in the Republic of Finland in the early 1970s involving 60 000 vaccinees between the ages of three months and five years. The vaccine showed short-term efficacy in children who received vaccine aged 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 poor immunogenicity of the PRP in the infants. Furthermore, no boost in antibody titre was observed with repeated doses of PRP, the antibody that was produced was relatively low-affinity IgM with minimal IgG production, and the vaccine had no effect on nasopharyngeal carriage of Hib (Stein, 1992; Barbour, 1996). Follow-up of the vaccinated cohort indicated that protection overall for the children vaccinated 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 the United States in 1985, and recommended for use in those between two and five years of age, or those over 18 months of age attending day care. Experience with this vaccine varied geographically with some states reporting negative efficacy and an increased risk of disease in the weeks following receipt of PRP (Black et al., 1991b). This increased susceptibility in the weeks after vaccination was associated with a transient reduction of PRP antibody in the serum of vaccinated infants (Institute of Medicine, 1994). Overall the vaccine was thought to be 50%-60% effective (Harrison et al., 1988) and was used until 1988 when it was superseded by conjugate vaccines. 7
  • 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 be improved by the conjugation of the sugars to a protein carrier. This work laid the foundation for the development of conjugate vaccines for use in humans, but it was only in the 1970s that work began seriously on the prototype vaccine for use in humans - a Hib conjugate (Lepow, 1987; Tai et al., 1987; Campion & Casto, 1988). The chemical attachment (conjugation) of PRP to protein antigens, such as diphtheria and 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 immune response to the PRP component of the vaccine. The vaccines currently licensed for use against Hib disease are based on PRP 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 outer membrane protein complex (PRP-OMP) (as reviewed in Santosham, 1993). PRP conjugated to diphtheria toxoid (PRP-D) was one of the first vaccines to be produced, but is no longer manufactured (Table 1). The conjugate vaccines differ in their carrier protein, method of chemical conjugation, and by polysaccharide size, giving them somewhat different immunological properties. These vaccines were first licensed 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 year of life (Shapiro & Ward, 1991). Table 1: Hib polysaccharide and polysaccharide-protein conjugate vaccines currently 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 toxin CRM197 ('HbOC') Type b saccharide Neisseria meningitidis outer membrane protein in outer membrane vesicles ('PRP-OMP') Type b polysaccharide Tetanus toxoid ('PRP-T') 8 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 4. Response to vaccination 4.1 Polysaccharide vaccine responses Much of our understanding of the immunology of responses to PRP comes from the pivotal studies of Porter Anderson and David Smith (Anderson, Johnston & Smith, 1972), as well as the subsequent PRP vaccine trial performed in the Republic of Finland in the 1970s (Kayhty et al., 1984). These studies demonstrated the poor immunogenicity of PRP in young children whose B cell immunity is not well developed at that age, and consequently the absence of protection, along with the 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 associated with the acquisition of responsiveness to PRP, and thus as titres in children rise naturally with age, presumably stimulated through natural encounter with Hib in the nasopharynx, or encounter with cross-reactive antigens (Bradshaw et al., 1971), the incidence of disease declines. It is likely that ongoing exposure to Hib resulting in the maintenance of detectable circulating antibody to PRP is important in maintaining long-term protection against Hib. Serum antibodies to PRP were initially measured by radioimmunoassay (RIA) but have been superseded by the introduction of a robust enzyme-linked immunosorbent assay (ELISA) which is now widely used for 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 the 1970s. 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 infants receiving the primary immunisation series, achieving antibody concentrations of 1.0 µg/ml, and 70% achieving 0.15 µg/ml (Eskola et al., 1990), but it was shown to be efficacious in clinical trials in the Republic of Finland (Takala et al., 1989; Peter, 1998). However it had low efficacy and elicited a poor immune response 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 or manufactured for use in infants below 18 months of age (Ward et al., 1988). 9
  • The development of PRP-OMP, HbOC and PRP-T continued simultaneously, and early immunogenicity studies illustrated good antibody responses in infants from two months onwards (Eskola et al., 1987; Lepow, 1987). The PRP-OMP vaccine was the only vaccine not to use a diphtheria or tetanus-based carrier protein. Immunogenicity studies revealed the unique properties of this formulation which elicits an anti-PRP concentration of 0.15 µg/ml and 1.0 µg/ml, a level correlated with short-term and long-term protection respectively in a larger proportion of children after a single dose (Decker & Edwards, 1998; Watt, Levine & Santosham, 2003). For this reason, PRP-OMP was designated the vaccine of choice for use in populations 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 HbOC primary series, and booster responses appeared attenuated compared to those seen with PRP-T and HbOC. HbOC contains a unique short Hi oligosaccharide conjugated to a mutant toxin (CRM197) isolated from Corynebacterium diphtheria and elicits high levels of anti-PRP antibody after a 3-dose primary series (Decker & Edwards, 1998; Watt, Levine & Santosham, 2003). PRP-OMP and HbOC 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 and was licensed for use in 1992. It contains tetanus toxoid as the carrier protein, attached to 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 childhood immunizations, 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 administered at six months of age. Figure 2: Comparison of antibody responses to four different Hib conjugate vaccines 4 3.5 3 2.5 µg/mL 2 1.5 1 0.5 0 Before After 1st dose After 2nd dose After 3rd dose (in order from left to right) PRP-D PRP-OMP PRP-CRM197 PRP-T Doses were given at 2, 4, and 6 months of age. Adapted from (Watt et al. 2003) 10 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • In addition to the level of IgG responses induced by conjugate vaccines, conjugates induce immune memory to the PRP component of the vaccine which is not seen when pure PRP vaccines are administered. Memory can be measured by administering pure PRP and eliciting a response in a primed but not an unprimed individual (such as a toddler). An increase in antibody avidity following primary immunization and boosting has also been demonstrated in Hib conjugate immunogenicity 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 the successful generation of immunological memory. The relative importance of memory versus circulating antibody levels for clinical protection by conjugate vaccines is unclear (see below). Experiments with the administration of hyperimmune anti-PRP IgG in both animal 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 was associated with short-term protection from invasive Hib disease. By contrast, experience from field studies of PRP vaccine illustrated good protection in children mounting 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 the nature of the immune response to conjugate vaccine as compared to PRP. Extensive use of Hib vaccines and observation of their clinical efficacy in practice has questioned the relevance of the 0·15-1·0 µg/ml concentration as surrogates of protection following conjugate vaccination (Eskola et al., 1999) although they are still widely used today. The fact that conjugate vaccines induce memory, suggests that irrespective of the titre achieved after vaccination, priming for memory responses may provide protection of longer duration than that achieved after PRP vaccine, particularly if ongoing exposure to Hib is able to maintain circulating antibody titres. The demonstration of efficacy for the PRP-D vaccine in the Republic of Finland, despite its relatively poor immunogenicity, suggested that there may be a role for memory in protection against Hib disease. The experience in Alaska however established that in a high risk setting, higher antibody titres are required 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 in the United Kingdom in Section 7. 11
  • 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 colonisation by Hib. Pure PRP vaccines are known not to impact on carriage, but reduction in nasopharyngeal carriage of Hib has been demonstrated in several trials of Hib 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 of Brazil (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 disease incidence that were greater than rates of vaccination coverage, as well as decreases in Hib disease in unvaccinated individuals and groups (Barbour et al., 1995; Barbour, 1996; Peltola, 1998; Adegbola et al., 1999). The impact of herd effect can be seen by the tenfold reduction in Hib disease rates in the United Kingdom in unvaccinated children <1 year of age in 1998 compared with rates in similarly aged children before vaccination began (Heath et al., 2000b). Another reflection of herd effect is the impact of childhood Hib vaccination on adult Hib disease. A review of adult cases of Hib disease in five English regions between 1990 and 1995 showed a halving of case numbers between the first three-year period and the last two-year period (Sarangi et al., 2000). Ongoing surveillance for Hib disease by Moulton and colleagues (Moulton et al., 2000) demonstrated that immunization of 40% of Navajo 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 programmes may receive greater benefits at the community level than those hitherto seen due to the direct protection conferred on the individual through vaccination. Antibody levels required for the protection against colonisation are thought to be higher than those required for protection against invasive disease. A study suggests that protection against nasopharyngeal Hib colonization requires serum antibody concentrations of approximately 5 µg/ml (Fernandez et al., 2000) which is identical to the concentration thought to protect against pneumococcal colonisation (Goldblatt et al., 2005), while studies of passive administration of antibodies into the peritoneum of infant rats has suggested that a titre of >7 micrograms/ml is able to prevent colonisation (Kauppi, Saarinen & Kayhty, 1993). 12 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 4.4 Impact of host factors Optimal interventions to reduce Hib disease and transmission are likely to depend upon many factors, including vaccine type, schedule of vaccination, the specific population epidemiology, and programme performance, as well as other environmental factors. Hib conjugate vaccine is immunogenic in patients with increased 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 is not 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 immunisation series in the Venezuelan children. Greenberg and colleagues (Greenberg et al., 1994) identified differences in the immunogenicity of Hib conjugates administered to children resident in California (USA) when stratified by race, with the lowest responses in white children and the highest in Asian children. In the same study, responses were significantly correlated with gestational age and breastfeeding to six months. Levine and colleagues (Levine et al., 1997) studied a subgroup of Chilean children demonstrating a significant response after two Hib doses and showed that low maternal education (adjusted OR 1.68 p=0.05), mean number of persons in the 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 that indigenous South Americans might be overrepresented in this group and the improved responses might thus be attributed to host genetics. Enhanced responses to PRP-T compared 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 have been performed and all have used invasive disease as the primary endpoint (reviewed in Obonyo & Lau, 2006). All studies and all vaccines, with the exception of 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 both PRP-D and HbOC vaccines were safe and effective and that a 2-dose primary vaccination schedule was appropriate in producing high antibody concentrations. 13
  • Table 2: Vaccine efficacy estimates from effectiveness trials of the Hib vaccine (CI confidence interval) Vaccine Vaccine 95% CI Endpoint Study site Reference efficacy % PRP-T 95 67-100 Invasive disease The Gambia (Mulholland et al., 1997) 100 55-100 Pneumoniae after 2 or 3 doses 21.1 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 UK (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) 14 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 5. Vaccine formulation issues: Hib interchangeability and administration in combination There are currently various formulations of Hib conjugate vaccine: liquid Hib conjugate vaccine (monovalent); liquid Hib conjugate combined with diphtheria- tetanus-pertussis vaccine (DTP) and hepatitis B (HepB); liquid Hib conjugate and HepB 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 products on the market, there are clearly issues regarding the compatibility of vaccines during simultaneous administration, and questions about the interchanging of products. Hib conjugate vaccine can be given safely and effectively at the same time as bacille Calmette-Guérin (BCG), DTP, measles, polio (OPV or IPV), HepB, yellow fever vaccines, and vitamin A supplementation. If Hib conjugate vaccine is given as a separate injection at the same time as other vaccines, it should be administered at a different site. It should not be mixed in the vial or syringe with any other vaccine unless it is manufactured as a combined product (e.g. DTP-Hib) as studies have shown that the mixture induces an immune response that is inferior to separate injections 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 and boosting with the same licensed product. However for logistical reasons it has been important to ascertain whether Hib conjugate vaccines from different manufacturers using the same or different carriers could be interchanged. Several studies have reported on the safety and immunogenicity of vaccines when Hib conjugates are interchanged during the primary schedule. Goldblatt and colleagues (Goldblatt et al., 1996a) found no significant changes in immunogenicity in a study where infants in the United Kingdom were given PRP-T or HbOC in various combinations at 2, 3 and 4 months. Here a greater number of infants receiving mixed combinations of conjugates achieved long-term protective antibody titres of >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 when administered at 2, 4 and 6 months is safe, and as immunogenic as schedules of single Hib conjugate vaccines. In certain circumstances interchanging vaccines may be advantageous. In a study of the safety and immunogenicity of PRP-OMP and HbOC administered as a booster dose in 12 to 15-month-old Navajo Indian (USA) infants primed with PRP-OMP, a booster dose of HbOC produced a significantly higher antibody response compared to PRP-OMP (Reid et al., 1993). Currently, any licensed conjugate vaccine may be used for the booster dose, regardless of what was administered in the primary series. 15
  • 5.2 Simultaneous administration of Hib conjugate vaccines with other childhood vaccines Hib conjugate vaccines have been administered simultaneously with a variety 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 conjugate vaccines (Bramley et al., 2001; Buttery et al., 2005) without any significant impact on the immune responses to the Hib conjugate vaccine or to the simultaneously administered antigen. However some combination vaccines containing DTaP and Hib 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 the development of combination vaccines. Combination vaccines have several advantages, including programmatic simplification, and decreased number of injections, storage space, and medical waste. However, interference between different components of combination vaccines has been observed, particularly with vaccines that contain Hib conjugates and acellular pertussis antigens (Watt, Levine & Santosham, 2003). Hib conjugate vaccine has been combined with DTaP (quadrivalent), DTaP/IPV or DTaP/HepB (pentavalent) and DTaP/IPV/HepB (hexavalent). Attenuation of the Hib response when PRP-T is administered in combination with DTPa-IPV compared to separate administration, was first noticed by Eskola and colleagues (Eskola et al., 1996) and subsequently reported by several other studies (Eskola et al., 1999; Vidor, Hoffenbach & Fletcher, 2001). Attenuation of the Hib response was particularly prominent when the vaccine was given in an accelerated schedule (e.g. at 2, 3 and 4 months of age) such as that used in the United Kingdom (Goldblatt et al., 1999) compared to more extended schedules (Vidor, Hoffenbach & Fletcher, 2001). The attenuation was thought to be due in part to the effect of aluminium hydroxide affecting the integrity of the PRP-T as had been previously demonstrated for Hib conjugates stored with aluminium hydroxide (Claesson et al., 1988). As a result of these studies, the United States Food and Drug Administration recommended that DTaP and Hib conjugate vaccines should not be given as a combined injection to infants. Attempts to overcome the reduced Hib response led to the development of DTaP-Hib combinations using aluminium phosphate 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 in part due to an inhibition of the immune response as a result of excess tetanus toxoid, a form of carrier-induced epitope suppression. Dagan and colleagues (Dagan et al., 1998) showed that with the administration of increasing amounts of tetanus there is a dose dependent effect on PRP-T responses. This effect is not as marked with DTwP-containing combinations as it is likely that the adjuvant effect of the wP masks this phenomenon. Recently a case-control study in the United Kingdom has demonstrated an increased risk for invasive Hib disease in children who received >2 doses of DTaP-Hib, which suggests that the reduced PRP responses seen may be clinically relevant (McVernon et al., 2003) (see Section 7.1). 16 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 6. Vaccine schedule issues Differences in the epidemiology of Hib disease and in public-health practices have led to the adoption of several different schedules of immunization. Immunogenicity is influenced by the schedule used, with intervals of two months between doses giving better responses than intervals of one month (CDC, 1991). The mean titres of antibody are directly correlated with increasing age at administration of the first dose of Hib conjugate vaccine (Fritzell & Plotkin, 1992). Current vaccine schedules in use in selected countries around the world are shown below in Table 3. Table 3: Recommended schedules and Hib vaccines used in childhood immunization Country Schedule United kingdom 2, 3, 4 , 12-15 months Slovenia risk groups only Poland 2, 4, 12-15 months Hungary 2, 4, 5 months Italy 3, 5, 11-12 months Israel 2, 4, 12 months Iceland 3, 5, 12 months Greece 2, 4, 6, 15-18 months Germany 2, 3, 4 months, plus 11-14 months France 2, 4, 18 months (vaccine with 5 antigens at 3 months) Finland 4, 6 & 14-18 months The czech republic 2, 3, 4 & 18-20 months Australia 2, 4, 12 months Canada 2, 4, 6, 15-18 months The united states of America 2, 4, 6, 12-15 months Chile 2, 4, 6 months The gambia 2, 3, 4 months Uganda 6, 10, 14 weeks South africa 6, 10, 14 weeks Tunisia 3, 4, 5 months Bahrain 2, 4, 6, 18 months Jamaica 6 weeks, 3, 5 months (adapted from http://www.euibis.org/links.htm and http://www.who.int immunization_monitoring) (2004) and WHO, http://www.who.int/immunization_monitoring/ en/globalsummary/ScheduleResult.cfm (2006). 17
  • 6.1 Hib conjugate immunogenicity at 2/4/6 months (USA schedule) and effect of booster at 12-14 months Three Hib conjugate vaccines (PRP-T, PRP-OMP, HbOC) are currently licensed for use in various countries. Original studies among Alaskan Eskimo infants, and infants in California, USA, demonstrated that the three conjugate vaccines induce markedly different immunologic responses. Only 60% of Alaskan Eskimo children achieved 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 susceptibility to colonization (Fernandez et al., 2000). In 1997, a schedule for high-risk children was introduced with PRP-OMP given as the first dose at two months followed by HbOC at 4, 6, and 12 months. PRP-T and HbOC are administered in a 3-dose primary series at 2, 4, and 6 months of age, with a booster dose recommended for all infants at 12 to 15 months. Canada and the Kingdom of Belgium are also among the countries using the same 2, 4 and 6-month schedule, with a booster dose in the second year of life. 6.2 Hib conjugate immunogenicity at 2/3/4 months and effect of booster at 12-14 months An accelerated schedule of 2, 3 and 4 months with a booster in the second year of life 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 accelerated schedule (Finn, 2004), and Hib conjugates were introduced in 1992, initially without a booster dose. A study was performed to document the persistence of vaccine-induced antibody in children in the United Kingdom, and this showed a decline 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 apparently unprotected (Heath et al., 2000a). The authors concluded that despite low measured antibody concentrations, immunological memory was present in the population studied, and this accounted for the ongoing reduced risk of contracting Hib in the United Kingdom. Pre-1996, Hib was given simultaneously (HbOC or PRP-T) with DTP in the United Kingdom, but since then combination vaccines have been used exclusively so that only PRP-T is administered in the primary series (combinations including HbOC are not available). Evaluation of DTaP in the United Kingdom schedule has revealed that Hib titres are reduced with such combination vaccines when administered at the accelerated schedule (Bell et al., 1998), although even in the face of 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 infant immunization schedule with effect from September 2006. This is administered simultaneously with meningococcal C conjugate vaccine at 12 months of age. In the Kingdom of the Netherlands, Hib conjugate vaccine became part of the primary 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 vaccination schedule was changed to 2, 3, and 4 months, with booster vaccination at 11 months of age. 18 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 6.3 Hib conjugate immunogenicity at 3/5/12 months (Scandinavian schedule) In Scandinavian countries Hib disease occurs slightly later and a 2-dose schedule at 3 and 5 months is used, followed by a booster third dose early in the second year of life. In the Republic of Finland in 1990 and 1991, approximately 110 000 infants received two doses of PRP-T at 4 and 6 months, with a booster dose at 14 to 18 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 been 96% (95% CI) successful in reducing incidence after the first six years after its introduction. One study (Garpenholt et al., 2000), during a six-year period found six true vaccine failures, six apparent vaccine failures and one possible vaccine failure in the 0-14 year age group in nearly two million vaccinated child-years (Garpenholt et al., 2000; Farhoudi, Lofdahl & Giesecke, 2005). Another study in the 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 conjugate vaccine led to an impaired antibody response to the Hib polysaccharide, but, since protective levels of anti-Hib polysaccharide antibodies were achieved by all subjects, 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 the World 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 of age, 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 the immune response to mixed or separate DTwP and Hib administered according to the EPI schedule (Cherian et al., 2002), and found the mixed vaccines to be safe and immunogenic and with the advantage of reducing the number of injections administered per visit. DTPw-HBV/Hib vaccine was also reported in the Republic of the Philippines (Gatchalian et al., 2005) to be immunogenic and well tolerated when administered according to the EPI schedule. Capeding and colleagues (Capeding et al., 1996) showed that all three Hib conjugate vaccines (PRP-T, HbOC, and PRP-OMP) were immunogenic after three primary doses among Philippine infants on the EPI schedule. Most infants immunised with Hib conjugates according to the EPI schedules in the Republic of the Niger, and Cape Town in the Republic 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 childhood immunization EPI programme reduced Hib disease-incidence among children younger than five years to 12% of its baseline level. This impact was observed by the third year after vaccine introduction. (Cowgill et al., 2006). 19
  • Cost constraints have led to studies of fewer than the recommended numbers of Hib conjugate doses or the administration of fractional doses of Hib. A study in the Federative Republic of Brazil used a 2-dose regime and found that mean PRP antibody titres were >1.0 µg/ml after two doses of PRP-T (Guimaraes et al., 2002). Nicol and colleagues (Nicol et al., 2002) conducted a randomized trial comparing the use of Hib conjugate vaccine diluted in a multidose vial of DTP with that of the full Hib 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 vaccine or 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 age and 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 full dose arm, and 94% of infants in the 1/10 dose arm achieved anti-PRP IgG antibody concentrations of >1.0 µg/ml, and infants receiving the diluted vaccine also had significantly 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 full dose 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 will reformulate their vaccines to produce substantially cheaper products, because a 66.7% reduction in antigen content is estimated to reduce costs by only 10% and reformulation would also require companies to seek a new product licence (Booy, 1998). 20 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 7. Vaccine effectiveness Following introduction of Hib conjugate vaccines into routine childhood immunization programmes in the 1990s, Hib disease has largely disappeared in western 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 the context of a low prevalence of Hib antibody because of a change of Hib conjugate vaccine. Vaccine efficacy has been shown in some cases to exceed 95% in infants with a complete Hib vaccination schedule who are immunized starting from two months of age (CDC, 2002). However, in some countries such as the Republic of Finland (Eskola et al., 1999), high efficacy has been reported when the vaccination schedule starts later, thereby showing that efficacy and effectiveness depends on epidemiology. Vaccine failures can however occur in a vaccinated population. Factors associated with possible vaccine failure include prematurity (premature infants develop lower antibody concentrations compared to full-term infants (Washburn et al., 1993; Heath et al., 2003)), immunoglobulin deficiency, and clinical risk factors such as malignancy and neutropaenia (Heath & McVernon, 2002). While host factors might influence the risk of vaccine failure, there has also been an interest in identifying bacterial factors that may play a role. Recently Cerquitti and colleagues (Cerquetti et al., 2005) studied the frequency of a genetic duplication of the capsulation locus frequently seen in invasive strains. The authors found that strains containing amplified capb sequences were quite common among Hib strains, and were significantly more frequent among strains from children with true vaccine failure than among those from unvaccinated children, which suggests that the amplification of the capb locus may contribute to vaccine failure because of the increased virulence of the bacteria. 21
  • 7.1 Developed country experience The United States Before the introduction of Hib conjugate vaccines, there were an estimated 20 000 cases of invasive Hib disease each year in the United States in children younger than five years of age (Cochi, Broome & Hightower, 1985). Figure 3 shows that after the introduction of Hib conjugate vaccines for toddlers in 1987 and for infants in 1990, the incidence of invasive Hib disease declined by more than 99% (Watt, Levine & Santosham, 2003). Hib conjugate vaccine has also been effective in those populations within the United States who have a high incidence of Hib disease, such as the American Indian and Alaskan Eskimo populations. The vaccination policies in Alaska have changed several times over the past 10 years in response to epidemiologic data and programmatic considerations. Routine Hib conjugate vaccination 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 Navajo and 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 Apache Indian reservations is higher than 90%. Figure 3: Incidence of invasive Hib disease in the United States, 1990-2004 25 20 Incidence 15 10 5 0 1990 1992 1994 1996 1998 2000 2002 2004 Year Doses were given at 2, 4, and 6 months with a booster at 12-15 months of age. x-axis: year; y-axis: cases per 100 000 children <5 years of age. Reference: CDC, Pink Book: Haemophilus Influenzae Type b, (http://www.cdc.gov/nip/publications/pink/hib.pdf). 22 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • The United Kingdom In the pre-vaccine era there were approximately 1500 annual cases of invasive Hib disease in the United Kingdom, of which 900 were cases of meningitis and 60 resulted in death (Booy et al., 1995). Figure 4 shows the rapid decline of disease after the introduction of Hib conjugate vaccines. When initially introduced in 1992, the United Kingdom Hib conjugate vaccine programme had a number of unique features, 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 at the beginning of the programme in which all children under the age of five years were immunized within 12 months of the campaign starting. The rationale for the United Kingdom approach was the belief that immunological memory after three doses in infancy would be sufficient for protection through the early childhood years when susceptibility was greatest (Heath & McVernon, 2002). The catch-up campaign provided rapid protection for a large proportion of the susceptible population and rapidly reduced rates of disease, protecting all of the at-risk group as quickly as possible (Gay et al., 1997; Salisbury, 2001). As a result, the annual incidence of Hib disease declined by 90%, falling to from 21/100 00 in the pre-vaccine era to 0.65 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 the introduction of vaccine into the United Kingdom infant schedule, efficacy was still in the order of 97% (McVernon et al., 2004b). Surveillance data also confirmed that there 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 500 450 400 Under 1yr 350 1-4 yrs 300 5-14 yrs 250 15+ years 200 150 100 50 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 Data from the Health Protection Agency. http://www.hpa.org.uk/infections/topics_az/ Haemophilus_influenzae/menu.htm. 23
  • However in the late 1990s the number of invasive Hib infections rose, with an increase year-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 under five years of age (Ramsay et al., 2003). Vaccine failures were occurring primarily in children 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 in 2001/2002 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 demonstrated an 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 carriage must have increased in the period, associated with increased disease, adequately powered studies of Hib carriage in various age groups failed to reveal significant Hib carriage in the United Kingdom population during this period (Heath & McVernon, 2002). Trotter and colleagues (Trotter et al., 2003) studied serum samples obtained from different birth cohorts and showed that Hib antibody titres beyond the first year of life in cohorts immunized after the catch-up campaign did not differ significantly from titres in similarly aged children in the pre-vaccine era. McVernon and colleagues (McVernon et al., 2004b) analysed anti-PRP IgG titres in the serum stored from adults in the United Kingdom, spanning the period 1991 to 2003, and showed that titres in adults declined and remained low following the introduction of Hib conjugate. This was presumably as a result of reduced exposure to Hib due to the reduction in carriage associated with the introduction of conjugate. Low circulating titres in toddlers and adults may thus explain the increase in invasive disease in the United Kingdom between 1999 and 2002, which suggests that immune memory alone in a vaccinated child is unable to provide robust protection against invasive Hib disease. A catch-up campaign was undertaken in the United Kingdom in 2003 for all children under the age of five years, and the incidence of invasive Hib disease reduced (Figure 4). A routine Hib 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 and 15 month schedule and has proven to be highly efficacious (Eskola & Kayhty, 1996). In the Kingdom of Norway, a routine infant vaccination programme (introduced at 3, 5 and 11-12 months), was accompanied by a catch-up programme for children up to and including four years of age (Peltola et al., 1990). In the Kingdom of Sweden following 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 old in 1987 to 0.9 per 100 000 in 1996 (Garpenholt et al., 1999). The Kingdom of the Netherlands, the French Republic and the Kingdom of Belgium have virtually eliminated Hib disease, and the Republic of Iceland completely eliminated Hib disease three years after the introduction of the vaccine. 24 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 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 at 2, 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 explore ways to lower the cost of vaccination without compromising the vaccine's effectiveness. Recent studies there have shown that two months after the second dose of a primary vaccination series most patients have seroprotective antibody titres and geometric mean titres are well above seroprotective thresholds (Riedemann et al., 2002) suggesting that two doses may suffice, although this is not yet Chilean government policy. Figure 5 shows the decline of Hib disease following the introduction of Hib conjugate vaccine in the Republic of Chile and the Eastern Republic of Uruguay. A randomized, placebo-controlled trial of Hib conjugate was conducted in the Western Region of the Republic of the Gambia between 1993 and 1995 and showed that the vaccine provided 95% protective efficacy against all culture-confirmed, invasive Hib disease, as well as 21% efficacy against radiographically-defined pneumonia, 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 in infants 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 African countries, introduced Hib conjugate vaccine with the assistance of the Vaccine Fund of the Global Alliance for Vaccines and Immunization (GAVI), and the incidence of Hib disease reduced by 88% in children <5 and 87% in children <2 (Hib Focus Vol 11, No. 4). Furthermore, vaccine effectiveness in preventing Hib meningitis among HIV positive children with two or more doses while adjusting for age and residence was 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 invasive Hib disease rates significantly reduced by 88% (Cowgill et al., 2006). In other developing country settings, the perception of low burden of Hib disease has 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 low incidence of Hib, although a recent study using Hib conjugate vaccine as a probe, identified a high incidence of Hib meningitis with case-fatality proportions between 12% and 18% (Gessner et al., 2005). The Lombok study showed that Hib conjugate vaccine prevented a substantial amount of meningitis, but not radiologically confirmed pneumonia, in young Indonesian children (Gessner et al., 2005). Despite the success of Hib conjugate vaccines it has been estimated that <8% of all Hib disease worldwide is prevented by current vaccination coverage (Peltola, 2000), with the highest disease burden in developing countries. 25
  • Figure 5: Impact of Hib vaccine by September 1997 in the Eastern Republic of Uruguay and Republic of Chile (adapted from: http://www.paho.org/English/HVP/HVI/hvp_hib_text.htm) No. of isolates No. of isolates 25 60 08/1994 07/1996 20 50 40 15 30 10 20 5 10 0 0 1993 1994 1995 1996 1997 1996 1997 Uruguay Chile 26 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • 8. Future prospects 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 complete primary series is given. PRP-D performs less well in children below 18 months of age, 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 given simultaneously. Furthermore, these vaccines are easily adapted to the routine schedule of the national immunization programmes. 8.1 Hib conjugates in the EPI schedule Recommendations of the Expanded Programme on Immunization of the World Health Organization encourage simultaneous administration of several childhood vaccines to attain comprehensive immunization as early as possible. In addition, depending on the epidemiologic situation, the optimal immunization schedule can vary from one country to another (WHO, 2006). A separate issue is how to provide a new highly-effective vaccine in the existing EPI system. In common with other newly developed vaccines, (including existing hepatitis B, and hepatitis A vaccines, and imminent pneumococcal conjugate vaccines), Hib conjugate vaccines are currently more expensive than those already in the EPI. WHO, the Children's Vaccine Initiative (CVI), and others, are exploring approaches to reducing the cost of these vaccines for non-industrialised countries. Reduction in disease appears to occur more completely when a catch-up campaign is instituted at the same time as routine immunization of infants is initiated. An example of this impact can be seen by comparing the Eastern Republic of Uruguay, which included a catch-up campaign, and the Republic of Chile, which did not. 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 increased cost 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 widely available for use in developing country settings. New combinations of higher valency vaccines (such as DTPa-HBV-IPV/Hib) are licensed and used routinely in developed countries but are likely to remain too costly for the foreseeable future for use in developing countries. 27
  • 8.3 The role of a booster dose Most countries introducing Hib conjugate vaccine into routine vaccination schedules 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 wanes over time (Heath et al., 2000a) leading to the concern that this may be accompanied by an increase in susceptibility to disease. Infants who underwent the primary schedule series and received a booster in the second year of life have shown elevated antibody 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 these studies were performed (the Kingdom of Sweden and the Republic of Finland respectively), the persistence of high antibody concentrations reflects the probable natural boosting due to cross reacting antigens. In the absence of vaccine boosting and with little exposure to wild type Hib for natural boosting, anti-PRP antibody levels induced by vaccination in infancy have been shown to wane over a period of 2-3 years (Heath et al., 2000a; Johnson et al., 2006), and experience in the United 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 Hib conjugates in infancy only, will mirror that seen in the United Kingdom. Further surveillance of Hib in countries that have introduced Hib conjugate in the EPI schedule is required. If boosting were required, it is important to study whether the Hib conjugate could be administered at nine months of age when measles vaccine is given. 28 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
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  • 42 The immunological basis for immunization series - Module 9: Haemophilus influenzae type b vaccines
  • The World Health Organization has provided The Quality, Safety and Standards team technical support to its Member States in the focuses on supporting the use of vaccines, field of vaccine-preventable diseases since other biological products and immunization- 1975. The office carrying out this function related equipment that meet current inter- at WHO headquarters is the Department of national norms and standards of quality Immunization, Vaccines and Biologicals (IVB). and safety. Activities cover: i ) setting norms and standards and establishing reference IVB’s mission is the achievement of a world preparation materials; ii ) ensuring the use of in which all people at risk are protected quality vaccines and immunization equipment against vaccine-preventable diseases. through prequalification activities and The Department covers a range of activities strengthening national regulatory authorities; including research and development, and iii ) monitoring, assessing and responding standard-setting, vaccine regulation and to immunization safety issues of global quality, vaccine supply and immunization concern. financing, and immunization system strengthening. The Expanded Programme on Immunization focuses on maximizing access to high These activities are carried out by three quality immunization services, accelerating technical units: the Initiative for Vaccine disease control and linking to other health Research; the Quality, Safety and Standards interventions that can be delivered during team; and the Expanded Programme on immunization contacts. Activities cover: Immunization. i ) immunization systems strengthening, including expansion of immunization services The Initiative for Vaccine Research guides, beyond the infant age group; ii ) accelerated facilitates and provides a vision for worldwide control of measles and maternal and vaccine and immunization technology neonatal tetanus; iii ) introduction of new and research and development efforts. It focuses underutilized vaccines; iv ) vaccine supply on current and emerging diseases of global and immunization financing; and v ) disease public health importance, including pandemic surveillance and immunization coverage influenza. Its main activities cover: i ) research monitoring for tracking global progress. and development of key candidate vaccines; ii ) implementation research to promote The Director’s Office directs the work of evidence-based decision-making on the these units through oversight of immunization early introduction of new vaccines; and iii ) programme policy, planning, coordination and promotion of the development, evaluation management. It also mobilizes resources and and future availability of HIV, tuberculosis carries out communication, advocacy and and malaria vaccines. media-related work. Department of Immunization, Vaccines and Biologicals Family and Community Health World Health Organization 20, Avenue Appia CH-1211 Geneva 27 Switzerland E-mail: vaccines@who.int Web site: http://www.who.int/immunization/en/ ISBN 978 92 4 159613 8