Haemophilus Influenzae B Disease

Nitin Shah
HIB Prevention
As discussed above, the burden of Hib disease is tremendous. 3 million children suffer from invasive Hib disease annually world-over, of which 0.37 million succumb to it. Of the survivors of Hib meningitis, 20-30% have long term sequelae. Increasing microbial resistance has forced us to use 3rd generation cephalosporins as 1st line dung adding to the cost of therapy. Poor health infrastructure in developing countries leads to increased mortality. Chemoprophylaxis will only succeed in blocking 29% of transmission which occurs from index case & is not a long lasting solution.

Excellent conjugate Hib vaccines are available & used for mass vaccination since 1980. They have proved to be extremely potent, safe and efficacious. Mass vaccination has lead to elimination of Hib disease from countries like Finland, UK, USA etc. It is possible to eradicate Hib by universal immunisation world over.

Natural immunity:
Transplacental maternal antibodies protect a newborn till 6-8 weeks. Acquired immunity develops in baby only after 18-24 months following subclinical infection as before 18-24 months the immune system of baby is less developed. This leads to a susceptible period mainly during 3-18 months of life; the Hib disease peaks during this period. Hence Hib vaccine has to be effective during this period of 3-18 months for it to be meaningful (2).

PRP :The first Hib vaccines contained capsular PRP alone. Hib capsule is made up of repetitive limits of polyribitol ribitol polysaccharide. Anti PRP antibodies have been shown to be produced on exposure to Hib & are protective in nature.

Being carbohydrate antigen, PRP is a poor immunogen as it can not stimulate T cells. Instead it can only stimulate B cells. This leads to two problems. One, it is not effective in <18-24 months old children as B cell immunity is not well developed at that age and hence it can be given only for >18-24 months old children. Secondly in absence of T cell assistance it can only induce IgM antibodies which are short lasting & in low titres. Hence PRP failed to induce protection in the most vulnerable period i.e. <18 months of age & it induced short lasting immunity. It also failed to reduce carrier state.

Field studies done in Finland showed good efficacy of PRP vaccine given at 24 months, as the peak of disease occurs during that age in Finland. In other countries like UK, USA where peak occurs early, PRP failed to demonstrate good efficacy given at 18-24 months of age (2)

Conjugated Hib vaccines:
2nd generation Hib vaccines are conjugated Hib vaccines. Here the PRP is conjugated with a carrier protein. The carrier protein sort of "fools" T cell & induces them to respond to attached PRP. This makes PRP now T cell dependent. The advantages of conjugate vaccine are 3 folds. Firstly, it is effective from 6 weeks of age onwards. Secondly, it induces IgG antibodies & leads to boosting on repeated doses leading to better short term & long term immunity. Being T cell dependent it stimulates memory T cells which will lead is anamnestic response even years later. Lastly it also induces IgA antibodies which are secreted in nasal secretions. This will postpone & reduce the chances of carrier rate leading to herd immunity.

Types of conjugated Hib Vaccines:
The conjugate Hib vaccines differs from one another depending on the size of the PRP molecule, the type of carrier protein, the type of linkage between PRP & carrier protein and presence or absence of an adjuvant in the vaccine as shown in table III.

This vaccine has Tetanus Toxoid as the carrier protein which is attached to PRP via 6 carbon linkage or carbodimide condensation. It contains 10mcg-15mcg of large PRP per dose & has 30mcg of tetanus toxoid. It is an excellent & potent vaccine with proven field efficacy in many trials. It has no adjuvant. It is effective from 6 weeks of age onwards.

Table III : Types of Hib conjugate vaccine

HIB Vaccine

Anti PRP antibody:
All the vaccines induce anti PRP antibodies which are protective. In past, when PRP was the only vaccine available 2 levels of antibodies were taken as significant. Titres >0.15 mcg/ml were taken as protective for immediate but short term period where as titres>1.0mcg/ml were taken as high titres which will protect for long term up to 5 yrs of life. This is because PRP was effective only>18-24 months leading to poor titres & no boosting effec

Now with availability of conjugate vaccine there is T cell response which leads to very high titres, IgG type of antibodies and boosting effect due to T memory cells. Hence all such vaccines will naturally lead to long term protection. Even if titres fall there will anamnestic response on exposure to Hib. Hence titres of >1.0mcg/ml is probably irrelevant today. Yet more studies talk of cut off levels of >0.15 mcg/r ml & >1.0 mcg/ml while describing immune response to vaccine (2).

Vaccine Efficacy
Hib conjugate vaccines are very immunogenic. Studies have shown excellent seroprotection and high antibody titres following vaccination with PRDT & HbOC vaccines. As discussed before PRP OMP is a good vaccine for first dose protection but not as immunogenic at the end of the schedule. PRP-O is the least immunogenic & hence not approved for use for primary dose but only as booster dose.

98-100% of vaccines develop titres >0.15 mcg/ml at the end of 3 doses and GMT achieved is also high in the range of 4-6 mcg/ml. The antibody titres fall over next 1 year. 90% still have titres >0.15 by 18-24 months. A booster given at 15-18 months leads to 100% of vaccinees reaches >0.15mcg/ml level and GMT gets boosted by 60-70 times to a level of 60-90 mcg/ml. (12)

One of the study on PRPT shown the kinetic of antibody development as seen in table IV. One can see that 50% are protected by first dose, 95% by second dose and 99% by 3rd dose of vaccines & 100% by the booster dose. The GMT at the end of 3 doses is 5.4mcg/ml which falls to 1.22 mcg/ml by 18 months & reaches a high level of 84.7 mcg/ml after the booster dose. (17)

Table 4:Kinetics of anti PRP antibody following PRPT vaccine PRPT +DPT / IPV at 3, 4, 5 months

PRP OMP and HbOC vaccine with adjuvant lead to 80% of vaccinees achieving a titre of >0.15 mcg by first dose itself. After this the titres for PRP OMP are not boosted with subsequent doses whereas HbOC with adjuvant vaccine shown similar titres & % seroprotection as PRPT or HbOC without adjuvant.

Similar results have been obtained in studies done on infants from developing countries like Gambia, Alaska, Chile, Philippines, India etc 18).

Comparison :
One study compared 4 vaccines viz. PRP D,PRP OMP, PRPT & HbOC vaccine for their immunogenicity as shown in table V. HbOC vaccine with adjuvant is recently available & data on this vaccine is shown in table VI.

Table V : Comparison of immunogenecity of various Hib vaccines (16)

Anti PRP mcg/ml










>1st GMT





>2nd GMT





>3rd GMT





% > 0.15





% > 1.0





Table VI : Kinetics of antibody after HbOC with adjuvant

Anti PRP mcg / ml

> 1st dose

> 2nd dose

> 3rd dose

% > 0.15




% > 1.0








It shows that PRPT & HbOC vaccines are excellent vaccines with protection in 50% with first dose and 95% of vaccinees with 2nd dose onwards. The % seroprotection & GMT are comparable though the titres are marginally better with PRPT than with HbOC in this study. PRP OMP was good as far as first dose protection which was achieved in majority but the titres did not get boosted with subsequent doses. PRP D was the least immunogenic with <60% seroprotected after 3 doses.

HbOC with adjuvant vaccine shows protection in 80% with first dose, 100% with second dose & the 3rd dose acts as a booster. The titres at the end of 3rd dose were 22.4 mcg/ml with this vaccine. There is one study comparing HbOC without adjuvant with HbOC with adjuvant. It showed that 93% of infants achieved titres of >0.15 mcg/ml with both the vaccines & 7-8% & 6% of infants achieved titres of >1.0 mg/ml at the end of 3 doses with adjuvant vaccines & non adjuvant vaccines respectively. This shows that both these vaccines are similar and excellent in efficacy.

Clinical efficacy:
There are innumerable reports of clinical efficacy of Hib vaccines in field trials. Oxford, UK study showed 100% efficacy of PRP vaccines given to infants (given 3 primary doses alone) over 2 years follow up (2). Similar studies from Finland using PRP D vaccine in >0.1 million showed 90% efficacy in infants given 3 primary doses & 1 booster dose (2). Study using HbOC in California showed 100% efficacy & in Finland 97% efficacy using 3 doses and a booster in infants (2). PRP OMP vaccine showed 97% efficacy with first dose itself in Arizona area (2). Other studies done with PRPT have shown 91.7% efficacy in Chile & 100% efficacy in Finland. It is estimated that first dose of vaccine gives 71%, 2nd dose 89% & 3rd dose 95%-100% clinical efficacy.

Effect on carrier state:
Study from Oxford, UK showed that there was significantly low level of carriage in vaccinated infants compared to controls. The carrier rate was 1.5% in vaccinated as compared to 6.3% in unvaccinated infants. Amongst children with family history of exposure to Hib the carrier rate was 8.7 % in vaccinated & 38.5& in unvaccinated group. Only 3.7% vaccinated siblings were carrier of an index carrier as compared to 12.0% in unvaccinated group. There was no difference in the period for which a child remained carrier as it was 5.2 weeks in vaccinated Vs 5.6 weeks in unvaccinated group (9). Similar study from Finland has shown that 3.5% of unvaccinated children were carrier as compared to 0% of vaccinated children (2). In Iceland it was shown that carrier rate dropped from 16% to 0.5 % in 2years after mass vaccine.

Decrease in carrier rate can explain herd immunity as seen in countries resorting to mass vaccination.

All conjugate vaccines are available as 0.5ml volume per dose. It is either ready to use liquid (HbOC) or in lyophilised form (rest of the vaccines) with diluent provided separately. It is either available as single dose or as multi dose (10 doses) vial. HbOC with adjuvant vaccine has adjuvant available separately which has to be mixed with the vaccine just before vaccinating (adjuvant mixed with vaccine is not stable & hence is provided separately). The cost of a unit dose is Rs 350 to 400 per dose.

Hib vaccines are given intramuscularly. In cases of severe bleeding disorder it can be given subcutaneously if IM injection is contraindicated. If given IM in such cases good pressure should be applied at injection site for 5 minutes & it should be preferably given after factor replacement in cases of factor deficiency (2). It should not be given IV or intradermally.

For all the vaccines the schedule depends on the age. For a child less than 6 months, 3 primary doses are given at 1-2 months interval stating from 6-8 weeks of age. It can be given along with other EPI vaccines on same day using separate sites & separate syringes. For a child between 6-12 months, 2 primary doses are given at 6-8 weeks interval. For 12-15 months old child only one primary dose is given. All these children are given booster dose at 15-18 months of age. Again the booster can be given along with MMR or booster of OPV/DPT. If the child is >15 months old he is given only one dose i.e. directly the booster.

PRP OMP is given as 2 primary doses at 2 months interval followed by a booster at 1 year of age. HbOC vaccine with adjuvant is given as 3 dose schedule below 1 year at 4-8 weeks interval (the 3rd dose acts as a booster) & as 2 dose schedule at 4-8 weeks interval for>1 year old child (the 2nd dose acts as booster) (15).

Various countries took to mass vaccination using conjugate Hib vaccine since 1985-1990. They all have shown more than 95-99% reduction in clinical cases due to Hib just in 2-5 years of such vaccination programme. In some cases the benefits were also seen in unvaccinated minority due to herd immunity effect.

In USA between 1985-87, there was no impact with use of PRP at 18-24 months of age. Between 1987-1990, PRPD was used as 3 primary & 1 booster dose which showed 80% drop in incidence. After 1990, HbOC & PRPT are extensively used. Even with 60% coverage there was 90-95% drop in incidence (2). Similarly Finland resorted to mass vaccination in 1988 using initially PRP OMP or HbOC & later HbOC or PRPT. It showed 87% drop with PRP OMP, 95% drop with HbOC & 95-98% drop with PRPT at coverage of 90-95% (2,19). In UK mass vaccination began in 1992 which showed 99% drop in <1 year old children, 97% drop in 1-2 years old & 94.7% drop in 2-3 years old children at 92% coverage (2,20).

Hence it is possible to eliminate or even eradicate Hib by mass vaccination programme.

Cost effectiveness of mass vaccination:
When considering cost effectiveness of mass vaccination programme by any country one has to take into consideration on one hand the cost of vaccine, cost of administering versus cost of diagnosis, treatment & management of sequelae of Hib disease. These cost will differ from country to country.

The studies from USA have shown that it is cost effective to mass vaccinate with Hib vaccine (2,21). Similar studies from developing countries need to be done depending on local factors & priorities so that decision on govt. sponsored universal immunization can be undertaken. In some countries it is estimated the vaccine will be cost effective only if each dose of vaccine cost less than one US dollar which is still not possible as the vaccines are very costly.

Primary doses:
It is ideal to finish the schedule of primary doses with the same brand. In case it is not known one can use any other vaccine. Studies have shown that the immune response is the same. PRP D is not used for primary doses. Some studies have used PRP OMP as 1st dose to get maximum 1st dose protection followed by 2nd & 3rd dose with either HbOC or PRPT to get maximum boosting titres. (22)

HbOC with adjuvant vaccine has different schedule as compared to other 4 vaccines. Hence it should not be interchanged for other vaccines. No such studies are even available.

Booster dose:
Again it is good practice to use same brand for booster as that used for primary doses. However all the 4 vaccines can be interchanged for booster. PRP D is licensed to use as booster (2.13). HbOC with adjuvant has different schedule & hence should not be interchanged with other vaccines.

Why do we need booster?
As seen before 98-99% achieved a titre of >0.15mcg/ml & 90% of them have >1.0mcg/ml level with GMT of 5-6 mcg/ml at the end of 3 doses. 90% maintain the level >0.15 mcg/ml till 15-18 months but the titre fall to 1.22 mcg/ml by that time. Hence a booster is given at 15-18 months which will lead to 100% achieve a titre >1.0 mcg/ml with GMT of 40-60 mcg/ml (17). This will protect the children for long time, certainly beyond 5 years of age.

Hib conjugate vaccines are one of the safest vaccines proved in many studies.

Local:3-5% vaccinees develop local pain, 10% develop redness, 2-4 % develop swelling. These are mild in nature & lasts for 1-2 days. One can use Paracetamol for pain (2,24).

Systemic: 10-15% develop fever which is mild, lasts for 1-2 days & responds to paracetamol. Other side effects include loss of appetite in 15-20%, restlessness in 15-20%, excessive crying in 20-22%, vomiting in 7-10% & diarrhoea in 10-15% of cases. Again these symptoms are mild and self limiting (2,24).

All the local & systemic side effects are more common with primary doses than booster dose.

OPV/IPV, DPT, Hep B & Hib vaccines need to be given at about the same age of 6-8weeks onwards. To be meaningful, the schedule of all these vaccines has to be completed in time. This means giving these vaccines on the same day.

One can give more than 1 vaccine either separately using separate syringe at separate site or use combination vaccine containing more than 1 antigen in the same vaccine. Giving vaccines separately on same day will mean multiple pricks & use of multiple syringes. It is less acceptable by parents at times whereas combination vaccines means single prick for multiple antigen, use of only one syringe which will save on cost & also easy storage in fridge as one will need to keep less number of units. Combination vaccines also save on number of visits than when given on separate days.

Hib vaccine has been combined with DPT (quadrivalent), DPaT (quadrivalent), DPT/IPV (pentavalent), DPaT/IPV (pentavalent), DPT/HepB, DPT/IPV/HepB (hexavalent). The studies show similar immune response to all the components of vaccines than when given separately. Some studies have used Hib & these other vaccines given separately at different sites but on same day whereas others have mixed Hib vaccines with these vaccines. Some studies have shown interference with anti PRP titre & anti pertussis titres by mixing vaccines. Some have shown higher anti PRP, antidiphtheria & antitetanus titres by mixing the vaccines in same syringe due to priming effect of carrier protein. Hence one should not mix Hib with other vaccine in same syringe unless recommended by manufacturers based on studies.

Haemophilus Influenzae B Disease Haemophilus Influenzae B Disease 04/09/2001
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