Circulating innate and adaptive immunity against anti- Haemophilus influenzae type b

Abstract

Haemophilus influenzae type b (Hib) are one of most dangerous microbes that occupies the paediatric nasopharyngeal as a commensal opportunistic bacterium, which may lead to meningitis in uncontrolled infection. Colonisation of pharyngeal tissues is the starting point for most H. influenzae infections, which may develop into invasive diseases, such meningitis. The vaccination against Hib in specific, as well as against most of vaccines preventable diseases; in general, play a major role in reducing children ( $<$ 5 years old) Hib meningitis from 57/100,000 to the lowest known Hib meningitis incidents in the history. First invented Hib vaccine was licensed in 1985 and contained Hib capsular polysaccharide (CPS); afterward, conjugate vaccines have been innovated and licensed on the road to improve Hib vaccine efficacy. Polyribosylribitol phosphate (PRP) is the main vaccine unite structure. Since anti-CPS antibodies in the serum reflect the extent of the acquired immunity against Hib infections, the concentration of $\geqslant$ 0.15 g/ml of anti-CPS is believed to be an indicator for short-term protection from invasive Hib diseases, whereas one-month post-completion of primary Hib immunization concentration of $\geqslant$ 1.0 g/ml is trusted to be immunological protective. As considered that serum anti-CPS antibodies are effectively linked to protection, the evaluation of antibodies concentration and reconsideration of published worldwide populations antibodies concentration are consider vital strides on the way to accurate valuation of Hib immunity that induced by vaccination; either direct or herd. As documented, some populations; worldwide, still susceptible to invasive Hib infections. Several populations worldwide remain vulnerable to Hib-related infections. We believe that up-to-date review article regarding circulated Hib immunology, represented in anti-Hib antibodies and worldwide Hib incidences will provide a precious information for microbiologists, public health officials, epidemiologists, immunologists, and strategic preventive healthcare executives.

Keywords

Haemophilus influenzae type b anti-CPS innate immunity vaccines seroepidemiology antibody isotypes herd immunity

1. Haemophilus influenzae type b

Haemophilus influenzae solely presents in the human upper respiratory tract as an opportunistic commensal bacterium [54]. Colonisation of pharyngeal tissues is the starting point for most H. influenzae infections, which may develop into invasive diseases, such meningitis. The prevalence carriage rate of H. influenzae type b (Hib) in non-immunized individuals varies between 0.7 and 5.3%; however, these percentages increase to 48–71% in children attending day-care centres. These data suggest that many non-vaccinated toddlers and children are colonised with Hib; therefore, they could represent a focal point for the spread of bacteria. Hib spreads via Flügge droplets and nasopharyngeal secretions. Transmission is prevented 24 to 48 hours after initiating antibiotic treatment [3]. In the pre-vaccination era, most H. influenzae infections were caused by Hib [8, 68, 70, 100]. Hib infections are most commonly observed at 6–8 months of age in non-vaccinated infants [93].

2. Hib vaccination

In 1985 the earliest Hib CPS vaccine (polyribosylribitol phosphate – PRP vaccine) was licensed in the United States (US). It was subsequently found to provide low levels of immunogenicity in children younger than 18 months and was only effective in children above this age. The US, Canada, and Saudi Arabia were the only countries throughout the world in which PRP vaccines were licensed for public use in children aged 24 to 59 months [51, 75].

Improving the immunogenicity of polysaccharides was accomplished; many years ago in 1931, through polysaccharide-protein conjugation [59]. Such conjugates provoke PRP-specific serum antibodies, and the antibody levels could be improved by a booster dose of the conjugate [24]. PRP-protein conjugate vaccines were investigated, developed, and confirmed to be effective for use in all children, including those aged below 18 months [51].

As a result of using conjugated Hib vaccines in 1989–2000, the annual incidence of invasive Hib disease in children aged $<$ 5 years reduced dramatically by 99% to reach a rate of $<$ 1/100,000 children. During 2000–2012, the mean annual incidence of invasive Hib disease for children aged $<$ 5 years in the US continued to remain lower than the Healthy People 2020 goal of 0.27/100,000 children [4, 23]. Attributable to herd immunity, Hib incidence has reduced in the US to around 1% of the previously reported incidence when only 60% of children were vaccinated [65].

Diphtheria toxoid conjugate (PRP-D; ProHIBiT) was the first licensed Hib conjugate vaccine, and it was shortly followed by a mutant diphtheria toxin conjugate (PRP-CRM or HbOC; HibTITER), a meningococcal outer membrane protein conjugate (PRP-OMP; PedvaxHIB), and a tetanus toxoid conjugate (PRP-T; ActHIB, OmniHIB, or Hiberix) [75]. It was clear that the initial dose of PRP-T and PRP-CRM197 were usually unsuccessful in inducing an antibody response, and that 2–3 doses were required to reach protective levels [9, 82].

Reports from the UK have shown lower anti-Hib antibodies titres post primary vaccination with a combination Hib vaccine including acellular pertussis (DTaP-Hib), rather than whole cell pertussis, and this may make vaccinated individuals more susceptible to invasive Hib infection, regardless of the existence of immune memory. Even though three doses of DTaP-Hib vaccines provoke lower anti-Hib titres than monovalent vaccines, such combinations are effectual in lowering the incidence of invasive Hib disease if a fourth dose is given as a booster [95, 96, 103]. Accordingly, the UK childhood immunization programme now includes a booster dose of the Hib vaccine [3]. The schedule for routine vaccinations in children and adults have been amended and improved many times over recent years worldwide, following the licensure of new vaccines, the outcomes of clinical trials, and evidence-supporting declining immunity [7].

The risk factors that may affect the proficiency of Hib vaccination in children include under vaccination, sickle cell anaemia, and/or immunocompromising [34]. Environmental factors and socioeconomic status have also a negative effect on non-immunized populations [76]. Moreover, a history of respiratory viral infections and acute otitis media are linked to an increased susceptibility to invasive Hib disease [36]. Vaccine failure is identified as invasive Hib disease following completion of a primary vaccination series. In 2013, the first case of a possible Hib vaccine failure in Kuwait was reported [80].

3. Anti-hib antibodies

Anti-Hib antibodies initiate their protective effect by initiating complement-mediated activity, including opsonisation and bacterial lysis. Such antibodies can be acquired through intrauterine placental passage, with age, or by vaccination. Physico-chemical properties of antibodies, e.g. specific determinants, molecular size, conformation, etc., can play a major role in their response to CPS antigens [109].

Hib disease rarely strikes in children less than 2 months of age, since neonates are protected by maternal antibodies. IgG antibodies, unlike immunoglobulin M (IgM) and immunoglobulin A (IgA), proficiently cross the placenta, and among IgG subclasses, with subclass IgGl crossing better than IgG2 [32]. The recognition of factors affecting the passage of antibodies across the placenta may be crucial in selecting vaccines for use in planning maternal immunization prevention strategies.

Antibodies against pathogenic bacteria, e.g. Hib, have been found in adults without a known history of previous exposure to or infection with this bacteria [91]. It is estimated that 95% of the population aged over six years are protected by naturally acquired anti-Hib antibodies [15, 56]. These protective antibodies have been found to be produced in response to cross-reactive antigens among pharyngeal and intestinal bacteria [57]. Consequently, planned intestinal colonisation with cross-reacting bacteria in adult humans and animals can stimulate the production of anti-CPS antibodies to pathogenic bacteria [39].

IgG antibodies in the presence of complement is opsonic and bactericidal, but IgM antibodies are bactericidal only, and IgA antibodies have neither activity [13]. Furthermore, antibodies of a similar isotype may have different functional activities. Anti-PRP IgG1 antibodies, for example, appear to be functionally more effective than IgG2 antibodies, although both subclasses are protective [14]. Antibody function can be estimated by a serum bactericidal antibody assay (SBA), which measures the antibody titre that binds and fixes complement onto the surface of a target strain, thereby initiating complement-mediated lysis [94].

IgA antibodies have a key role in immunity, mainly at the mucosa. Many pathogenic bacteria have developed strategies to precisely avoid or destroy the immune activity of IgA antibodies. These avoidance strategies consist of proteins that specifically attach to IgA antibodies and the secretory component, and then obstruct their activities via specialised proteases that deactivate IgA antibodies through cleavage. Bacteria that emit IgA1 proteases often inhabit or invade mucosal membranes, and frequently found in the genital tract and the oral cavity, where they are responsible for infection and also deadly meningitis [108].

A concentration of $\geqslant$ 0.15 g/ml human serum of anti-PRP is believed to be a serological indication for short-term protective immunity against invasive Hib, while a concentration of $\geqslant$ 1.0 g/ml one month after the completion of the primary immunization series is believed to be an indication of long-term protection [52]. Nevertheless, as immunological memory and antibody avidity maturation are vital features of immunity stimulation through conjugate vaccines, these concentrations may not be as valid for beneficiaries of conjugate vaccine compared to those receiving pure PRP vaccine [3]. Moreover, these levels do not reflect the differences observed in IgG subclasses, specificity of idiotype, functional ability of antibodies, nature or strength of bacterial infection, and the types of techniques used to estimate levels of anti-Hib antibodies [92]. Therefore, it may be reasonable to provide Hib immunization to immunocompromised individuals with a history of recurrent bacterial infections or serum anti-Hib antibody levels of $<$ 1 g/ml [45]. However, Hib vaccination provokes a combination of IgM, IgG, and IgA [18]. Both serum IgGl and IgG2 antibodies play a significant role in the IgG antibody reaction in the majority of vaccinated adults with Hib CPS [97].

Immunogenicity in Saudi infants was examined after three doses of the HbOC vaccine. Anti-Hib antibodies were found to be 14.4 g/ml, which is higher than the levels reported in the US ( $\sim$ 4.4 g/ml), but similar to those previously reported (16.8 g/ml) [11, 12, 53, 72]. This phenomenon of low antibody levels has been observed in countries where there is wide scale use of a Hib vaccine and for all types of Hib vaccines [30]. This may be caused by a total decrease in the overall exposure of infants to Hib infection, and consequently, the absence of the natural boosting effect in addition to the vaccine [72]. The geometric mean titre (GMT) after a booster dose was comparable (39–48 g/ml) to those observed in other studies from the US (31.1 g/ml), which used HbOC, and Canada (38.1 g/ml), where PRP-T was used [53].

Interesting relationships in the IgG subclass-specific immune responses to Hib infection have been noted; first, the anti-PRP specific IgG4 response is considerably higher after invasive disease than among children without known disease; second, the IgG4 response to Hib appears to be independent of age; third, levels of anti-PRP specific IgG2, total IgG4, and total anti-PRP antibodies do not differ between infected cases and non-infected healthy children; and fourth, Eskimos have slightly lower IgG4 antibody levels than expected for their ages. Therefore, IgG4 antibodies may be vital in the immune response to Hib infections in naturally weakly-immune young children [81, 87]. The response of anti-PRP specific IgG4 antibodies observed after invasive Hib infections could represent antibodies with functional activity, which facilitates protection. It is of significance that the increased IgG4 antibody levels appear to be unaffected by age or time since illness, and this suggests that anti-PRP specific IgG4 antibodies may be a possibly valuable marker of prior invasive disease [81].

Figure 1.

Summary of Hib meningitis incidence in children younger than 5 years in pre-Hib vaccination era.

However, the positive correlation between IgG2-and IgG4-specific PRP antibodies indicates that if a subject has a high IgG2-specific PRP antibody level, then he or she typically also has a high IgG4-specific PRP antibody response, indicating some similarity in the control mechanisms regulating the production of IgG2 and IgG4 subclass antibodies within that individual. IgG4-specific PRP antibodies shows a diverse pattern of response in relation to time compared to IgG2-specific PRP or total PRP antibodies. Poor IgG2 antibody development is accompanied by repeated invasive infections caused by encapsulated bacteria [71].

For children age 24 to 35 months, a rise in total antibody levels and IgG4-specific antibody levels has been observed following infection, but no rise in anti-PRP specific IgG2 antibodies compared to non-infected children. This could show that in this age group, invasive disease favourably stimulates the production of IgG4 antibodies, whilst the production of IgG2 antibodies may be stimulated equally by invasive and non-invasive disease. However, there was a deep correlation of IgG2-specific PRP antibodies with total anti-PRP antibodies, suggesting that a high proportion of the total PRP antibodies may be of this subclass [81]. A Brazilian study proved the prevalence of IgG antibodies over IgM antibodies in response to CPS (ratio 17:1); IgG antibodies were mainly of the IgG1 subclass, and a rise in IgG avidity was seen throughout the post-vaccination era [64].

The term antibody affinity represents the strength of the binding of a single antibody type (e.g. monoclonal antibody) and a single antigen [87]. The antibody population within human serum is polyclonal (heterogeneous); therefore, it is impossible to measure antibody affinity. Nevertheless, variations in the concept of affinity have been developed, and measurements of the strength and stability of antigen-antibody contact in a mixed antibody population have been termed antibody avidity measurements [44]. Antibody avidity is used as a marker for the evaluation of memory induced antibodies following conjugate vaccination [40]. Although cellular and mucosal immunity could play a significant role in preventing H. influenzae disease, the existence of serum antibodies against Hib is strongly associated with protection [77].

4. Hib epidemiology and seroepidemiology

In recent times Hib invasive disease mainly occurs in developing countries and some populations within developed countries [75]. The incidence of Hib differs in different regions of the world; for example, 6/100,000 in some Asian countries compared to 109/100,000 in oceanic and Western Pacific countries [79].

The worldwide incidence of Hib meningitis in children aged $<$ 5 years was 57/100,000 during the pre-vaccination era [75]. The annual incidence ranged from 20 to 40/100,000 in Europe [46], 40 to 69/100,000 in the US [26], and from 34 to 153/100,000 in some developing countries [19], while in the Middle East, the incidence ranged from 15 to 21/100,000 [27], and from 13 to 22/100,000 in Arabian Gulf countries, and in Asia was 38 to 66/100,000 in India and Malaysia, and 8 to 10/100,000 in some East Asian countries [74]. Figure 1 summarises the worldwide incidence of Hib meningitis in children aged $<$ 5 years in the pre-Hib-vaccination era.

Several populations remain vulnerable to Hib disease despite vaccination. For example, Native American populations are up to six times more susceptible to Hib infection and Alaskan natives continue to be affected by Hib disease [98].

4.1 Western countries

The majority of American countries, Australia, and Western Europe have a high coverage of Hib vaccine and a low incidence of Hib disease [1]. The causative organism of bacterial meningitis differs with age; however, the most widespread organisms in children aged $>$ 1 month as reported by many countries are Hib, S. pneumoniae, and Neisseria meningitidis, although the age-specific incidence rates vary [10, 21, 28, 99, 107].

Although rare in the US, Hib disease does occur in children who have received the full vaccination course and booster dose. Among Hib disease-affected patients aged $<$ 5 years with an age-appropriate vaccine status reported during 2002–2012, 16% had completed the primary Hib vaccination series and 43% had completed the full Hib vaccination series [23]. Outbreaks of Hib disease still occur among inadequately vaccinated residents in the US, despite the high Hib vaccine coverage. For example, eight unvaccinated children aged $<$ 5 years were infected with Hib invasive disease in Pennsylvania between December 1999 and February 2000, with six from populations with low Hib immunization coverage and high Hib carriage [35]. In addition, some populations are more vulnerable to invasive Hib diseases than others, such as Native Alaskans [37] and Native Americans [60]. This elevated vulnerability could be explained by large numbers of individuals living in close proximity to each other [36]. In recent times, the Active Bacterial Core surveillance (ABC) and National Notifiable Diseases Surveillance System in the US have documented only a few cases of H. influenzae invasive disease in children of all ages. Considering the variability in the results for the identification of a precise serotype within laboratories, some strains noted as being unidentifiable may in fact correspond to type b [55].

American Indian children, followed by African American and Caucasian children, have the highest Hib incidence rates both before and after the introduction of the Hib vaccination to the US. In contrast, the lowest rates appear within Asian/Pacific Islander and Hispanic children [20]. Similarly in Australia, the incidence of Hib disease has been shown to vary between Aboriginal and non-Aboriginal individuals [43]. These racial/ethnic variations may be associated with variances in socioeconomic conditions, population vulnerability, genetic variation, vaccine coverage, and/or excessive carriage of Hib in the respiratory tract within these populations.

High post-Hib vaccination antibody levels in the serum of children at high risk of invasive Hib disease is the main factor protecting such children, and if high levels of antibodies are not reached; then there will be the re-emergence of a high Hib incidence rate, similar to that which occurred in the UK [66] and Alaska [38].

In adults, Hib infections are elevated in those aged $\geqslant$ 65 years [31], which may be explained by increased vulnerability as a result of immune senescence and high comorbidities in the elderly that confer general vulnerability to any microbial infection [61]. An observation in the UK indicated a relationship between Hib vaccination in childhood and Hib disease incidence in adults, suggesting that a high incidence of Hib in children caused by vaccine failure was associated with a subsequent rise in the incidence rate amongst adults [67]. Among children from England and Wales, invasive Hib disease is no longer a main cause of acute bacterial meningitis, instead, cases are more likely to present as pneumonia in older adults with comorbidities, similar to the less virulent non-typeable H. influenzae [25].

In a study conducted in Finland during the pre-Hib vaccination era, most Finnish children aged 4–5 years had protective antibody levels; 79% had antibody levels greater than 0.15 $\mu$ g/ml, while 32% had levels higher than 1 $\mu$ g/ml [50]. A cooperative screening programme conducted in West Africa and France during the pre-Hib vaccination era showed an average of 0.15 $\mu$ g/ml antibodies against Hib were detected in children aged $>$ 4 years [16]. In France between 2001 and 2006, more than half of all H. influenzae infections were caused by Hib, and for those with Hib disease 14% had not received Hib vaccine and 15% had not completed the vaccination schedule [78].

4.2 Non-Western countries

According to the WHO, Hib vaccine coverage is only 18% and 27% in the Western Pacific and South-East Asia Regions, respectively, while in Brazil, nearly all children (97.56%) have been vaccinated with a Hib-combined vaccine. The actual spread of Hib in North Africa and the Middle East is difficult to evaluate, since the collection of data is irregular; surveillance techniques are weak and identification of the etiologic agent in infectious diseases is infrequent [2, 6]. In certain Asian countries, it was believed that Hib was not the main etiologic agent of childhood meningitis; however, a review by Peltola et al. has revealed that Hib is the major etiologic agent of bacterial meningitis in most Asian countries [73]. However, the incidence of bacterial meningitis ranges from 5.2 to 19.2/100,000 in Asia [29] to a much higher rate of 76/100,000 in South Africa [49].

In Thailand, Rerks-Ngram et al. reported a very low incidence of Hib meningitis at 3.8/100,000 [90], while in Bohol and Manila, the annual incidence was 17.6/100,000 and 95/100,000, respectively [58]. In Kathmandu, Nepal, only 20% of children under the age of 5 years had anti-Hib antibody levels of $>$ 0.15 g/ml, rising to 83% in 15–54 year olds; and the majority of young children in Kathmandu were susceptible to disease before the introduction of a Hib vaccine [63]. A Hib vaccine was introduced into the states of Kerala and Tamil Nadu in December 2011 [41].

In China, the second most widespread organism causing pneumonia and 30–50% of bacterial meningitis in children is H. influenzae. In Beijing, Hib conjugate vaccines are obtainable from private health facilities, but the majority of children are not vaccinated [113]. Among children in Beijing aged $<$ 5 years of age with an acute respiratory tract infection, the total carriage of H. influenzae in the nasopharynx was reduced from 26.8% in 2000–2002 to 16.3% in 2010–2012, whereas the rate of isolates producing $\beta$ -lactamase increased from 8.5% to 29.2%. These data are similar to those reported in North Taiwan, where the carriage of H. influenzae in the nasopharynx of healthy children aged $<$ 5 years was minimal (5.6%) and the prevalence of $\beta$ -lactamase producing H. influenzae had reached 61.5% [106].

In population-based studies conducted in Johannesburg during 1997–1998 and in Cape Town during 1991–1992 in the pre-Hib vaccination era, an annual invasive Hib incidence of 170/100,000 children younger than 1 year was reported [48, 62]. This rate was considerably higher than those noted in another investigation conducted in these two cities during July 1999–June 2000 [105]. In Gambia, 14 years after Hib vaccination using a 3-dose primary series without a booster was introduced, there was effective control of Hib invasive disease, including both pneumonia and meningitis [47, 69].

In the pre-vaccination era in Turkey, India, and in Burkina-Faso, West Africa, the majority of children aged 4 to 5 years had protective levels of anti-Hib antibodies. These results are similar to those reported for Finland by Kayhty et al. [50], indicating that 79% of children had antibody levels greater than 0.15 $\mu$ g/ml and 32% had levels greater than 1 $\mu$ g/ml [16, 79, 101].

4.3 Middle East and North African countries

A Hib-conjugated vaccine became obligatory in the national immunization programme in Saudi Arabia in 2000, and since then a considerable decline in Hib cases has been observed. During the first three years after the vaccine was made compulsory (2001–2003), there were 30 cases of H. influenzae invasive disease, compared to only six cases in the following three-year period (2004–July 2007) [11]. The coverage of the pentavalent vaccine (Diphtheria, Pertussis, Tetanus, Hib, and Hepatitis B) is 97.7% [5]. During 1988–1991, Hib was responsible for 42–58% of bacterial meningitis in children, with a fatality rate of 2.8–14.3%; children aged $<$ 1 year represented 70–77% of these fatalities, while those aged $<$ 2 years comprised 90–95% of the total cases [10]. These data are summarised in Fig. 2. However, the incidence of Hib in Saudi Arabia was almost the same as that in adjacent countries; 10/100,000 in Kuwait, 16/100,000 in Qatar, while in the UAE the overall incidence of meningitis in children aged less than 5 years was 43/100,000 and Hib-specific meningitis was 31/100,000 [104].

Figure 2.

Bacterial meningitis in children in Saudi Arabia, between 1988 and 1991 (pre-vaccination era).

In Saudi Arabia between 1995 and 1999, the yearly incidence of Hib infections in infants younger than 1 year was 15.6–20.8/100,000, while in children less than 5 years it was 4.5–6.7/100,000. There was a clear dissimilarity within regions of the Kingdom, ranging from no cases in some regions to more than 35 in others. However, some factors may affect the accuracy of these data, including laboratory inadequacies and inaccurate reporting [10].

A study conducted in Saudi Arabia between June 1999 and May 2001 reported 208 cases of meningitis across five regions, 27.8% were recognised as being caused by Hib. The patients’ ages ranged from a few days to 5 years, and the incidence was highest for patients aged 2–6 months and the median age of the patients was 8 months. No noteworthy statistical variations in terms of mean ages were noted in relation to geographical regions [10].

Again, in Saudi Arabia, it was clear that an increase in cases occurred during two periods: from March to May and from September to November. The major period of infection coincided with the Hajj season and was mainly caused by N. meningitidis, while Hib and aseptic meningitis were noted during the other period [10]. At King Fahad National Guard Hospital (KFNGH), within Riyadh districts, Saudi Arabia, bacterial meningitis was more common among children aged $<$ 2 years (85%), and Hib was identified as the most frequent causative microorganism (57%). The estimated incidence of Hib in the hospital was 40/100,000; however, this incidence dropped significantly following the introduction of a routine conjugate Hib vaccination for infants at the hospital in April 1998 [11, 12, 53]. Figure 3 shows an approximate comparable chart of the incidence of Hib meningitis in children aged less than 4 years.

Figure 3.

Approximate comparable chart showing the incidence of Hib meningitis in pre- and post- vaccination times in KFNGH within children aged less than 4 years.

Our recent results showed higher levels of anti-Hib IgG (2.41 $\mu$ g/ml average geometric mean concentration (GMC) regardless of age and gender, followed by levels of IgM (0.91 $\mu$ g/ml) and IgA (0.34 $\mu$ g/ml), reflecting the Jeddah (Saudi Arabia) community immunity against Hib [110]. Low anti-Hib level ( $<$ 0.15 $\mu$ g/ml of anti-PRP IgG) in elderly people (males aged 57–91 years and females aged 35–64 years) may indicate a need for a booster dose of Hib vaccine to elderly people in the community. The IgG prevalence over IgM, and IgM prevalence over IgA indicate the major role of IgG over IgM and IgA in keeping immunity on the track against Hib. Low level of IgM and IgA comparing to IgG may indicate the absence of Hib acute infections in the population [110]. These protective herd immunity in the Jeddah community against Haemophilus influenzae type b (Hib) were represented by total antibody of IgM, IgG, IgA. The specific antibodies subtypes were also evaluated to be arranged in IgG1 $>$ IgG2 $>$ IgG3 $>$ IgG4. The highest concentration was for IgG1 and IgG2, and the lowest concentration was for IgG3 and IgG4. While, IgA1 concentrations were significantly higher than IgA2 in all age categories regardless of gender. These results indicate that the IgG1, IgG2 and IgA1 subclasses were the main constituent of Jeddah herd immunity against Hib [111]. The above results showed that the IgG GMC (2.41 $\mu$ g/ml), followed by levels of IgM (0.91 $\mu$ g/ml) then IgA (0.34 $\mu$ g/ml), with a fluctuated avidity profile. The IgM avidity did not reveal any significant results between male and female values, IgA avidity in male samples were significantly ( $P<$ 0.05) higher than the average of female. However, IgG anti-Hib has the strongest affinity. The result showed that a high percentage of the population has moderate to high IgG avidity [112].

In Egypt, the number of confirmed Hib meningitis cases is 23/100,000 in children aged $<$ 5 years [89]. The GMCs for both IgM and IgG in Egypt were lower than those recorded in India, Cuba and Finland [89, 102]. The prevalence of anti-PRP antibody in Egyptian children may imply that children are primed by natural infection. Since the number of confirmed Hib cases in Alexandria was 0.023% [33], it has been assumed that contact with bacteria that share the same antigenic structures with the CPS of Hib may result in the production of anti-CPS antibodies against Hib [100]. E. coli, Shigella and other enteric bacteria are abundant in countries with limited resources, and their existence in the gastrointestinal tract may trigger the production of anti-Hib antibodies [16, 22]. In a pre-vaccination era of Israel, the incidence of Hib meningitis was 18.7/100,000 for Jews and 22.6/100,000 for Bedouins [42]. In the post-Hib vaccination era, 389 cases of invasive H. influenzae infections were identified during 2003–2012; 62% were non-typeable, 26% were Hib. Children aged $<$ 1 year accounted for 51% of the overall affected population. Among children with Hib invasive infection, 40% were categorised as due to vaccine failure. However, despite the high vaccination coverage rate ( $\sim$ 95%), Hib is still circulating in Israel’s paediatric population [17].

5. Passive immunization

Pre-HIb vaccination era, the passive immunization plays a crucial role, although it was limited, but save many life’s. In addition to vaccine failures do occur too. These Protective factors (effect limited to infants younger than 6 months of age) include breastfeeding and passively acquired transplacentally maternal IgG antibodies. In both cases the passive immunization would be needed similarly to other microbial pathogens control the invasive Hib disease affected exclusively to children [82].

6. Conclusions

This brief presentation of the available information is expected to serve as a useful review for public health officials and policy makers. Moreover, monitoring the levels of circulating anti-Hib antibodies and their avidity is important in order to evaluate herd immunity, the need to vaccinate elderly and immunocompromised patients, and/or to revaluate the national immunization programme.

Footnotes

Acknowledgments

The current work is a part of the Ph.D. thesis of Mr. Adi Essam Zarei (Department of Biology, Faculty of Science, King Abdulaziz University). This work was supported in part by King Abdulaziz City for Scientific Research and Technology (KACST, PGP-37-56), Saudi Arabia.

Conflict of interest

The authors confirm that this paper content has no conflict of interests.

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