Oral Drug Delivery Choicest Route Drug Administration Biology Essay


Oral drug delivery is the choicest route for drug administration because of its non-invasive nature. The advantage of oral route is avoiding pain and discomfort which is caused by injections as well as contaminations is neglected. However, bioactive drugs like peptides and proteins when administered orally must be able to resist the hostile gastric and intestinal environments. They must then be able to stay long enough to adhere to apical surface of the cell and then, transcytosed by intestinal cells. Therefore, peptides and proteins remain poorly available in the intestine, because of their low mucosal permeability and lack of stability in the gastrointestinal environment, resulting in degradation of the compound prior to absorption.

For the improvement of oral delivery of therapeutic peptides and proteins; various studies and strategies have been thus developed to enhance drug and vaccine oral delivery 1-12. The association of oral delivery with colloidal carriers, such as polymeric nanoparticles, is one of the several approaches proposed to improve their oral bioavailability. Polymeric nanoparticles are of special interest from the pharmaceutical point of view. First they are more stable in the gastrointestinal tract than other colloidal carriers, e.g. liposomes, they can protect encapsulated drugs from gastrointestinal secretions. The use of various polymeric materials enable the modulation of physicochemical characteristics (e.g. hydrophobicity, zeta potential), drug release properties (e.g. delayed, prolonged, triggered), and biological behavior (e.g. targeting, bio adhesion, improved cellular uptake) of nanoparticles 12. Finally, the particle surface can be modified by adsorption or chemical grafting of certain molecules such as poly (ethylene glycol) (PEG), poloxamers, and bioactive molecules (lectins, invasins) Moreover, their submicron size and their large specific surface area favor their absorption compared to larger carriers. Consequently, it has already been extensively shown that nano encapsulation of peptides and a protein colloidal particle protects them against the acidic environment of the gastrointestinal tract 13, and enhances their transmucosal transportation 14, 15. Intestinal epithelium is composed of many cells and has different structures. Villi epithelium is mainly of enterocytes and goblet cells. The main functions of enterocytes are to control the passage of macromolecules and pathogenic organisms, and, at the same time, it allows the digestive absorption of many dietary substances. Goblet cells secrete a viscous fluid consisting primarily of highly glycosylated proteins i.e. mucins suspended in a solution of electrolytes. Dispersed through the intestinal mucosa, lymphoid nodules called O-MALT (Organized Associated Lymphoid Mucosa), individually or aggregated into Peyer's patches, mainly due to the presence in these structures of particular cells, named Mcells16. Which is also composed of enterocytes and few goblet cells.Mcells deliver samples of foreign material from the lumen to underlying organized mucosa lymphoid tissues in order to induce immune responses. M cells are specialized for antigen sampling, but they are also exploited as a route of host invasion by many pathogens 17, 18. Furthermore, M cells represent a potential portal for oral delivery of peptides and proteins and for mucosal vaccination, since they possess a high transcytotic capacity and are able to transport a broad range of materials, including nanoparticles19, 20. Uptake of particles, microorganisms and macromolecules by Mcells, have been described to occur through adsorptive endocytosis by way of clathrin coated pits and vesicles, fluid phase endocytosis and phagocytosis 21. In addition, M cells, compared with normal epithelial cells have reduced levels of membrane hydrolase activity, which can influence the uptake of protein-containing or protein decorated nanoparticles. The relatively sparse nature of the glycocalyx facilitates the adherence of both microorganisms and inert particles to their surfaces22. Villous-M cells located outside the FAE have been recently observed 23, but the transport of antigens and microorganisms across the intestinal mucosa is carried out mainly by the FAE-M cells 24. Although less numerous than enterocytes, Mcells present enhanced transcytosis abilities which made them very interesting for oral drug delivery applications.

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Diverse strategies have been developed to improve the bioavailability of peptide and protein drugs and vaccines, encapsulated in polymeric nanoparticles. Some focused on M cells, while others target not only M cells but all intestinal cells, enterocytes mainly. Two main approaches prevailed to significantly improve transport: (i) by modifying surface physicochemical properties of nanoparticles, or (ii) by coupling a targeting molecule at the nanoparticle surface.

Chitosan is a modified natural carbohydrate polymer prepared by the partial N-deacetylation of chitin, a natural biopolymer derived from crustacean shells such as crabs, shrimps and lobsters. Chitosan is also found in some microorganisms, yeast and fungi25. The primary unit in the chitin polymer is 2-deoxy-2-(acetylamino) glucose. These units combined by β-(1,4) glycosidic linkages, forming a long chain linear polymer. Although chitin is insoluble in most solvents, chitosan is soluble in most organic acidic solutions at pH less than 6.5 including formic, acetic, tartaric, and citric acid26. It is insoluble in phosphoric and sulfuric acid. Chitosan is available in a wide range of molecular weight and degree of deacetylation. Molecular weight and degree of deacetylation are the main factors affecting the particle size, particles formation and aggregation.

Preparation method

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Chitosan NP preparation technique has been developed based on chitosan microparticles technology. There are at least four methods available: ionotropic gelation, microemulsion, emulsification solvent diffusion and polyelectrolyte complex. The most widely developed methods are ionotropic gelation and self assemble polyelectrolytes.

• Easy to synthesize and characterize

• Inexpensive

• Biocompatible

• Biodegradable

• Non-immunogenic

• Non-toxic

• Water soluble

Nanoparticle delivery systems

• Simple and inexpensive to manufacture and scale-up

• No heat, high shear forces or organic solvents involved in their preparation process

• Reproducible and stable

• Applicable to a broad category of drugs; small molecules, proteins and polynucleotides

• Ability to lyophilize

• Stable after administration

• Non-toxic

many advantages such as simple and mild preparation method without the use of organic solvent or high shear force. Thus, they would be applicable to a broad categories of drugs including macromolecules which notorious as labile drugs.

In general, the factors found to affect nanoparticles formation including

particle size and surface charge are molecular weight and degree of deacetylation of chitosan. The entrapment efficiency is found to be dependent on the pKa and solubility of entrapped drugs. The drug is mostly found to be associated with chitosan via electrostatic interaction, hydrogen bonding, and hydrophobic interaction.

Ionotropic gelation

Chitosan NP prepared by ionotropic gelation technique was first reported by Calvo et al.,(1997b) and has been widely examined and developed (Janes et al., 2001; Pan et al., 2002). The mechanism of chitosan NP formation is based on electrostatic interaction between amine group of chitosan and negatively charge group of polyanion such as tripolyphosphate . This technique offers a simple and mild preparation method in the aqueous environment. First, chitosan can be dissolved in acetic acid in the absence or presence of stabilizing agent, such as poloxamer, which can be added in the chitosan solution before or after the addition of polyanion. Polyanion or anionic polymers was then added and nanoparticles were spontaneously formed under mechanical stirring at room temperature. The size and surface charge of particles can be modified by varying the ratio of chitosan and stabilizer.27

Microemulsion method

Chitosan NP prepared by microemulsion technique. This technique is based on formation of chitosan NP in the aqueous core of reverse micellar droplets and subsequently cross-linked through glutaraldehyde. In this method, a surfactant was dissolved in N-hexane. Then, chitoan in acetic solution and glutaraldehyde were added to surfactant/hexane mixture under continuous stirring at room temperature. Nanoparticles were formed in the presence of surfactant. The system was stirred overnight to complete the cross-linking process, which the free amine group of chitosan conjugate with glutaraldehyde. The organic solvent is then removed by evaporation under low pressure. The yields obtained were the cross-linked chitosan NP and excess surfactant. The excess surfactant was then removed by precipitate with CaCl2 and then the precipitant was removed by centrifugation. The final nanoparticles suspension was dialyzed before lyophilyzation.28 This technique offers a narrow size distribution of less than 100 nm and the particle size can be controlled by varying the amount of glutaraldehyde that alter the degree of cross-linking.

Nevertheless, some disadvantages exist such as the use of organic solvent, time-consuming preparation process, and complexity in the washing step.

Emulsification solvent diffusion method

chitosan NP prepared by emulsion solvent diffusion method, This method is based on the partial miscibility of an organic solvent with water. An o/w emulsion is obtained upon injection an organic phase into chitosan solution containing a stabilizing agent (i.e. poloxamer) under mechanical stirring, follow by high pressure homogenization. The emulsion is then diluted with a large amount of water to overcome organic solvent miscibility in water. Polymer precipitation occurs as a result of the diffusion of organic solvent into water, leading to the formation of nanoparticles. This method is suitable for hydrophobic drug and showed high percentage of drug entrapment. The major drawbacks of this method include harsh processing conditions (e.g., the use of organic solvents) and the high shear forces used during nanoparticle preparation.29-30 Polyelectrolyte complex (PEC) Polyelectrolyte complex or self assemble polyelectrolyte is a term to describe complexes formed by self-assembly of the cationic charged polymer and plasmid DNA. Mechanism of PEC formation involves charge neutralization between cationic polymer and DNA leading to a fall in hydrophilicity as the polyelectrolyte component self assembly. Several cationic polymers (i.e. gelatin, polyethylenimine) also possess this property. Generally, this technique offers simple and mild preparation method without harsh conditions involved. The nanoparticles spontaneously formed after addition of DNA solution into chitosan dissolved in acetic acid solution, under mechanical stirring at or under room temperature 31. The complexes size can be varied from 50 nm to 700 nm.

Applications of chitosan nanoparticles

Parenteral administration

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Nano-sized particles can be administered intravenously because the diameter of the smallest blood capillary is approximately 4 μm. The biodistribution of nanoparticles can vary depending on the size, surface charge and hydrophobicity of the administered particles32. Particles greater than 100 nm in diameter are rapidly taken up by the reticuloendothelial system (RES) in the liver, spleen, lung and bone marrow, while smaller-sized particles tend to have a prolonged circulation time. Negatively-charged particles are eliminated faster than positively-charged or neutral particles 33. In general, opsonins (serum proteins that bind to substrates leading to their being taken up by the RES) prefer to adsorb on hydrophobic rather than hydrophilic surfaces. The creation of a hydrophilic coating (such as polyethylene glycol (PEG) or a nonionic surfactant) on hydrophobic carriers significantly improves their circulation time 34. Together, these data suggest that generating nanoparticles with a hydrophlilic but neutral surface charge is a viable approach to reduce macrophage phagocytosis and thereby improve the therapeutic efficacy of loaded drug particles.

Peroral administration

The idea that nanoparticles might protect labile drugs from enzymatic degradation in the gastrointestinal tract (GIT) leads to the development of nanoparticles as oral delivery systems for macromolecules, proteins and polynucleotides and vaccines. This approach was extensively studied after a report that blood glucose levels were reduced in diabetic rats following the oral administration of insulin nanoparticles 35. Limiting nano-sized particles to less than 500 nm in diameter seems to be a key factor in permitting their transport through the intestinal mucosa most probably through an endocytotic mechanism36. However, besides the enzymes, mucus layer, which hamper diffusion of drug molecules and nanoparticles 37, and the epithelial absorption barriers are main hurdles against gastrointestinal protein drug absorption. Therefore, drug bioavailability can be improved by controlling the particle size along with prolonging the residence time of drug carrier systems in GIT 38. Among polymeric nanoparticles, chitosan NP showed to be attractive carriers for oral delivery vehicle as they promote absorption of drug.

The absorption promoting effect of chitosan has been extensively studied by several research groups and found to be due to a combination of mucoadhesion and transient opening of tight junctions in the mucosal cell membrane which have been verified both in vitro and in vivo 39.

The mucoadhesive properties of chitosan are due to an interaction between positively charged chitosan and negatively charge of mucin which provide a prolonged contact time between the drug and the absorptive surface, and thereby promoting the absorption 40. Chitosan mucoadhesion is also supported by the evidence that chitosan increases significantly the half time of its clearance . Furthermore, in vitro studies in Caco-2 cells have shown that chitosan is able to induce a transient opening of tight junctions thus increasing membrane permeability particularly to polar drugs, including peptides and proteins 41. Recent studies have shown that only protonated soluble chitosan, in its uncoiled configuration, can trigger the opening of the tight junctions, thereby, facilitating the paracellular transport of hydrophilic compounds 42. This property implies that chitosan would be effective as an absorption enhancer only in a limited area of the intestinal lumen where the pH values are below or close to its pKa. Although chitosan was able to open up the tight junctions, the uptake of particle > 50 nm could not be explained by a widening of the intercellular spaces 43. Mechanism of chitosan NP transport across GIT is most probably through adsorptive endocytosis. Electrostatic interaction between positively charged chitosan and negatively charged sialic acid of mucin causes association of chitosan NP to the mucus layer and subsequently internalization via endocytosis.Chitosan NP internalization was found to be higher in the jejunum and ileum than in duodenum 44. The ability of chitosan to enhance hydrophilic compounds transport across mucosal epithelial membrane depends on the chemical compositions and molecular weights of chitosan. A high degree of deacetylation (>65%) and/or high molecular weights appears to be necessary to increase epithelial permeability 45. As the degree of deacetylation increases, the charge density increases, and thereby improving drug transportation. Similarly, it was shown that the molecular weight has some importance in that a molecular weight of at least 100 kDa was needed to obtain the optimal effect. Although, the difference in chemical composition and molecular weight of chitosan enhance the drug transport in a different way, they have very similar mechanism at the cellular level 46. Pan et al. reported that hypoglycemic effect was observed in induced diabetic rats after orally administration of chitosan nanoparticles 47. Furthermore, chitosan can be employed as a coating material for liposomes, micro/nanocapsules to enhance their residence time, thereby improving drug bioavailability 48.

In addition to being used as an oral delivery carrier, chitosan NP could also be applied to other mucous membrane systems. Pulmonary and nasal routes are considered as promising routes to deliver peptides and proteins since they possess very large surface areas and manifest less intracellular and extracellular enzymatic degradation 49. Thus, nasal drug delivery may not need protection against enzymatic degradation by formulating as nanoparticles as oral drug delivery. It may be administered as solution or powder with absorption enhancing agent to slow down mucociliary clearance process and thereby prolong the contact time between the formulation and nasal tissue.

Non-viral gene delivery vectors

Although viruses can efficiently transfer genes into cells, concerns such as host immune response, residual pathogenicity, and potential induction of neoplastic growth following insertional mutagenesis have led to the exploration of non-viral gene transfer system 50. These latter delivery systems are generally considered to be safer since they are typically less immunogenic and lack mutational potential.There are usually considered to be five primary barriers that must be overcome for successful gene delivery:

in vivo stability,

cell entry,

endosome escape,

intracellular trafficking and

nuclear entry.

Cationic polymers and lipids have both shown promise as gene delivery agents since their polycationic nature produces particles that reduce one or more of these barriers. For example, by collapsing DNA into particles of reduced negative or increased positive charge, binding to the cell surface and enhanced endocytosis may be promoted 51. In many cases, cationic polymers seem to produce more stable complexes thus offering more protection during cellular trafficking than cationic lipids 52. Among cationic polymers, PEI is particularly promising as a vector given its relatively high level of transfection in a number of target organs by various delivery routes 53. The high charge density of PEI is thought to be a key factor that contributes to its high transfection efficiency. Unfortunately, the polycationic nature of PEI also appears to be the main origin of its marked toxicity, a property it shares with many other polycations (e.g. polylysine). This toxicity has severely limited its use as a gene delivery vector in vivo. On the contrary, chitosan is a cationic polymer with extremely low toxicity. It showed significantly lower toxicity than poly-L-lysine and PEI 54.Chitosan as a promising gene delivery vector was first proposed by Mumper 55. Chitosan mediates efficient in vitro gene transfer at nitrogen to phosphate (N/P) ratio of 3 and 5. At these ratios, small chitosan-DNA complexes can be prepared in the range of 50-100 nm with a positively surface charge of approximately +30 mV. Sato et al. found that in vitro chitosan-mediated transfection depends on the cell type, serum concentration, pH and molecular weight of chitosan 56.

Delivery of vaccines

Nanoparticles often exhibit significant adjuvant effects in parenteral vaccine delivery since they may be readily taken up by antigent presenting cells 57. Moreover, oral and nasal delivery of nanoparticles are thought to have the potential to provide mucosal protective immune responses, one of the most desired goals of modern vaccinology. The submicron size of nanoparticles allows them to be taken up by M-cells, in mucosa associated lymphoid tissue (MALT) i.e. gut-associated, nasal-associated and bronchus-associated lymphoid tissue, 58 initiating sites of vigorous immunological responses. Immunoglobulin A (IgA), a major immunoglobulin at mucosal surface, and the generation of B-cell expressing IgA occur primarily in MALT. The B-cell then leave the MALT and reach systemic circulation where they clonally expand and mature into IgA plasma cells. Therefore, providing not only protective IgA at the pathogen entered sites, but also systemic immunity.

There are two main administration routes for mucosal vaccine delivery, oral and nasal. The main targeted for oral delivery vaccine are Peyer's patches. By incorporating vaccine into nanoparticles systems, the vaccine is protected against enzymatic degradation on its way to the mucosal tissue and efficiently taken up by M-cells. In contrast to oral administration, nasal administered vaccines have to be transported over a very small distance, remain only about 15 minutes in the nasal cavity, and are not exposed to low pH values and degradative enzymes. Thus, nasally delivery vaccines may not necessary formulated as nanoparticles as discussed earlier. It may be administered as solution or powder with absorption enhancing agent to slow down mucociliary clearance process and thereby prolong the contact time between the formulation and nasal tissue.

Among the polymers used to form vaccine nanoparticles, chitosan is one of the most recently explored and extensively studied as prospective vaccine carrier 59. Its absorption promoting effect is believed to improve mucosal immune response. The mechanism of action of chitosan in improving transport of drug across mucosal membrane can be explained by the same theory as discuss earlier in peroral administration section. Illum et al. successfully developed chitosan vaccines containing influenza, pertussis and diphtheria antigens for nasal delivery. They demonstrated that these vaccines produced a significant antibody level in mice, both serum and secretory IgA.Despite the potential carrier for mucosal delivery vaccine, chitosan has also been reported to act as an adjuvant for systemic vaccine delivery such as increasing the accumulation and activation of macropharges and polymorphonuclear cells. Activation of macropharges is initiated after uptake of chitosan 60.

Furthermore, chitosan has also been widely explored as the application for DNA mucosal vaccines. For instance, a chitosan-based DNA flu vaccine has been developed by Illum et al.

Ocular administration

Nanoparticles have been found to be potential carriers for ocular delivery following the observation that various types of nanoparticles tend to adhere to the ocular epithelial surface 61. The resulting prolonged residence time of nanoparticles leads to a much slower elimination rate compared to conventional ophthalmologic formulations, thereby improving drug bioavailability.

As a consequence, nanoparticles have been developed for targeted ophthalmic delivery of anti-inflammatory, antiallergic and beta-blocker drugs62. Among mucoadhesive polymers explored now, chitosan has attracted a great deal of attention as an ophthalmic drug delivery carrier because of its absorption promoting effect. Chitosan not only enhance cornea contact time through its mucoadhesion mediated by electrostatic interaction between its positively charged and mucin negatively charged, its ability to transient opening tight junction is believed to improve drug bioavailability. Felt et al. found that chitosan solutions prolonged the cornea resident time of antibiotic in rabbits 63. The same effects were also observed employing chitosan NP as demonstrated by De Campos et al. that chitosan NP remained attached to the rabbits' cornea and conjunctiva for at least 24 hr 64. Chitosan also shown to be a low toxic material, ophthalmic formulation based on chitosan.


H. influenzae type b (Hib) is estimated to cause at least 3 million cases of serious disease and 4 0 0 0 0 0 . 7 0 0 0 0 0 deaths each year in young children. R arely occurring in infants under three months, and after the age of six years, the disease burden is highest at 4 . 1 8 months of age. In both developed and developing countries Hib is the dominant cause of non-epidemic bacterial meningitis in this age group, and is frequently associated with severe neurological sequelae despite prompt and adequate antibiotic treatment. In economically developed countries meningitis accounts for the majority of invasive Hib disease, whereas in developing countries acute respiratory infection, particularly the estimated 2 . 3 million cases of Hib pneumonia occurring each year, represents an even heavier disease burden. Other important, but less frequent, manifestations of Hib disease include epiglottitis, osteomyelitis septic arthritis, and septicaemia.65

Haemophilus influenzae type b vaccine

Following introduction of Hib conjugate vaccines into routine childhood immunization services in the 1990s, Hib disease has largely disappeared in Australia, Canada, New Zealand, the United States and Western Europe.

The pathogen

H. influenzae is a Gram-negative bacterium. Serious infection is usually caused by strains carrying a polysaccharide capsule. Of the six capsular types, type b (Hib) causes almost all systemic infections. This polysaccharide is a polymer of D-ribose-ribitol-phosphate (PRP) and is an essential virulence factor. Up to 15% of children in non-immunized populations may harbour Hib in their nasopharynx. However, only a fraction of those acquiring the microorganism will subsequently develop clinical disease. Transmission of Hib is by droplets originating from colonized persons and hence, asymptomatic carriers are important disseminators of the organism.

The non-encapsulated strains that are more frequently isolated from naso-pharyngeal secretions are mainly associated with mucosal infections such as bronchitis and otitis. Facilities for reliable cultivation of Hib and identification of the capsular polysaccharide by immunological techniques are found in laboratories well-equipped for clinical microbiology, but are not easily available throughout the world.

Immune response in older children and adults the Hib polysaccharide induces production of bactericidal antibodies. However, this polysaccharide does not reliably elicit protective levels of antibodies in children less than 18 months of age. Furthermore, it does not induce immunological memory and consequently no booster response with subsequent exposure to the polysaccharide. For these reasons, a new generation of vaccines was developed by conjugating a T-cell dependent protein antigen to the Hib polysaccharide. These Hib conjugate vaccines not only induce protective circulating antibodies and immunological memory in infants, but also result in decreased nasopharyngeal colonization of Hib. Thus, a herd effect is achieved through reduced transmission of the microorganism.66

Justification for vaccine control of Hib disease

Hib disease, mainly meningitis and pneumonia in young children, is a significant public health concern in both developed and developing countries. In developed countries meningitis is the most important manifestation, whereas in developing countries pneumonia is more common. However, due to inherent problems regarding etiological diagnosis, especially of pneumonia, the true burden of Hib may be seen only by a reduction in the incidence of pneumonia and meningitis following vaccination. Antibiotics are essential for treatment, but have only a minor role in control, and development of bacterial resistance to some of the most efficient antibiotics underlines the need for prevention. V accines are the only public health tool available to prevent the vast majority of Hib disease.

'The safety, efficacy and effectiveness of the Hib conjugate vaccines are clearly demonstrated in developed countries, where rapid declines in disease incidence have been documented in every country in which the vaccine has been used routinely in childhood immunization services. Furthermore, several studies demonstrate high efficacy of the vaccines against invasive disease in high-incidence and developing country settings, including studies in Chile, in the Gambia and in a Native American population in the United States. In the Gambian trial, vaccinated infants were protected against laboratory-confirmed Hib pneumonia, and the incidence of all X -ray documented pneumonia was reduced by approximately 20%. A series of cost-benefit analyses in industrialized countries underscores the value of routine immunization against Hib disease. Substantially more disease could be prevented in the developing world, where the burden of disease and death is many times higher. An assessment of the situation in representative countries of most geographical regions was recently made by the Childrens Vaccine Initiative.

Haemophilus influenzae type b conjugate vaccines (Hib-vaccines)

The vaccines currently licensed for use against Hib disease are based on Hib-polysaccharide conjugated to a protein carrier, such as diphtheria toxoid (PRP-D), a diphtheria toxoid-like protein (PRP-HbOC), tetanus toxoid (PRP-T), or meningococcal outer membrane protein (PRP-OM P). The conjugation of PRP to the protein induces a T-cell dependent immune response to the Hib-polysaccharide.

The conjugate vaccines differ in their carrier protein, method of chemical conjugation and by polysaccharide size, giving them somewhat different immunological properties.

The vaccine is usually given in infancy as repeated doses together with diphtheria/ tetanus/ pertussis (DTP) and other vaccines of the national childhood immunization services. A booster dose is recommended in most countries at 12.18 months of age, but may not be necessary, especially in developing countries where most of the Hib disease occurs before this age. In adults and children over 18 months of age a single dose is sufficient to induce immunity.67

All conjugate Hib vaccines are given by the intramuscular route. No serious side-effects are recorded, and no contraindications known, except for hypersensitivity to the vaccine components. The Hib vaccine may safely be administered concurrently with any vaccine of the EPI or corresponding national childhood vaccination programmes, as well as with pneumococcal and meningococcal vaccines.


The commercially available Hib conjugate vaccines are all of known good quality. The indication for the use of these vaccines is protection of children below five years of age, particularly infants. WHO encourages the introduction of Hib vaccines worldwide. However, because of differences in epidemiology, health priorities and economic capacity, Hib vaccines will in practice be introduced at different speeds into national immunization services. The emphasis is on introduction in countries with the highest disease burden.

The efficacy and effectiveness of the Hib conjugate vaccines have been clearly demonstrated in developed countries, where rapid declines in disease incidence have been documented in every country in which the vaccine has been used routinely. Several studies also demonstrate the efficacy in high-incidence and developingcountry settings.68

Three out of the four currently-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. Furthermore, these vaccines are easily adapted to the routine schedule of the national immunization services. One of the vaccines (PRP-D) performs less well in children below 18 months of age, and is therefore not licensed for use in infants in many countries.69

Unfortunately, in large areas of Asia as well as in the Newly Independent States, population-based data on the burden of Hib disease are largely missing, and so far, few Asian countries have adopted Hib vaccine as part of their routine immunization service. Data from additional surveillance studies are needed to assist public health planners in these areas. A WHO-sponsored protocol to evaluate Hib disease burden is available on request. However, the lack of simple, rapid and reliable techniques for etiological diagnosis of pneumonia is a challenge to future research.70

Other issues which must be faced as the vaccine is introduced into developing countries include combination with other antigens such as locally produced DTP, and conceivably with pneumococcal and/or meningococcal vaccines.71


In 1930, two major categories of H. influenzae were defined: the unencapsulated strains and the encapsulated strains. Encapsulated strains were classified on the basis of their distinct capsular antigens. There are six generally recognized types of encapsulated H. influenzae: a, b, c, d, e, and f.72 Genetic diversity among unencapsulated strains is greater than within the encapsulated group. Unencapsulated strains are termed nontypable (NTHi) because they lack capsular serotypes; however, they can be classified by multilocus sequence typing. The pathogenesis of H. influenzae infections is not completely understood, although the presence of the capsule in encapsulated type b (Hib), a serotype causing conditions such as epiglottitis, is known to be a major factor in virulence. Their capsule allows them to resist phagocytosis and complement-mediated lysis in the nonimmune host. The unencapsulated strains are almost always less invasive; they can, however, produce an inflammatory response in humans, which can lead to many symptoms. Vaccination with Hib conjugate vaccine is effective in preventing Hib infection. Several vaccines are now available for routine use against Hib, but vaccines are not yet available against NTHi.



Most strains of H. influenzae are opportunistic pathogens; that is, they usually live in their host without causing disease, but cause problems only when other factors (such as a viral infection or reduced immune function) create an opportunity.

Naturally-acquired disease caused by H. influenzae seems to occur in humans only. In infants and young children, H. influenzae type b (Hib) causes bacteremia, pneumonia, and acute bacterial meningitis. On occasion, it causes cellulitis, osteomyelitis, epiglottitis, and infectious arthritis. Due to routine use of the Hib conjugate vaccine in the U.S. since 1990, the incidence of invasive Hib disease has decreased to 1.3/100,000 in children. However, Hib remains a major cause of lower respiratory tract infections in infants and children in developing countries where the vaccine is not widely used. Unencapsulated H. influenzae causes ear infections otitis media, eye infections conjunctivitis, and sinusitis in children, and is associated with pneumonia

Clinical diagnosis of haemophilus influenza

H. influenzae, in a Gram stain of a sputum sample, appear as Gram-negative coccobacilli.73

Clinical diagnosis of H. influenzae is typically performed by bacterial culture or latex particle agglutination. Diagnosis is considered confirmed when the organism is isolated from a sterile body site. In this respect, H. influenzae cultured from the nasopharyngeal cavity or sputum would not indicate H. influenzae disease, because these sites are colonized in disease-free individuals.74 However, H. influenzae isolated from cerebrospinal fluid or blood would indicate H. influenzae infection


Haemophilus influenzae produces beta-lactamases, and it is also able to modify its penicillin-binding proteins, so it has gained resistance to the penicillin family of antibiotics. In severe cases, cefotaxime and ceftriaxone delivered directly into the bloodstream are the elected antibiotics, and, for the less severe cases, an association of ampicillin and sulbactam, cephalosporins of the second and third generation, or fluoroquinolones are preferred. Macrolide antibiotics (e.g., clarithromycin) may be used in patients with a history of allergy to beta-lactam antibiotics.


Children should get Hib vaccine at:

2 months of age

6 months of age

4 months of age

12-15 months of age

Depending on what brand of Hib vaccine is used, your child might not need the dose at 6 months of age. Your doctor or nurse will tell you if this dose is needed.

If you miss a dose or get behind schedule, get the next dose as soon as you can. There is no need to start over. Hib vaccine may be given at the same time as other vaccines.

Older Children and Adults Children over 5 years old usually do not need Hib vaccine. But some older children or adults with special health conditions should get it. These conditions include sickle cell disease, HIV/AIDS, removal of the spleen, bone marrow transplant, or cancer treatment with drugs.

Some people who should not get Hib vaccine and wait

People who have ever had a life-threatening allergic reaction to a previous dose of Hib vaccine should not get another dose.

Children less than 6 weeks of age should not get Hib vaccine.

People who are moderately or severely ill at the time the shot is scheduled should usually wait until they recover before getting Hib vaccine.


A vaccine, like any medicine, is capable of causing serious problems, such as severe allergic reactions. The risk of Hib vaccine causing serious harm or death is extremely small. Most people who get Hib vaccine do not have any problems with it.

Mild Problems

Redness, warmth, or swelling where the shot was given (up to 1/4 of children)

Fever over 101oF (up to 1 out of 20 children)

If these problems happen, they usually start within a day of vaccination. They may last 2-3 days