HIB Vaccine
Nitin Shah
Disease Spectrum of Hib Infection?
Hib infection usually leads to invasive disease like meningitis, epiglottitis, pneumonitis, cellulitis, arthritis, septicemia etc. Of the invasive H. influenzae infections in children, 99% are due to type b and rarely due to type a or other non- typeable H. influenzae organisms.

Various studies show that 15- 20% of cases of ALRI and 30- 40 % cases of pyogenic meningitis are due to Hib infection

Non-type b & non - capsulated H. influenza infection commonly lead to upper respiratory tract infections, otitis media, sinusitis, chronic respiratory tract infection and other non- invasive infections especially in children> 7 years of age.

Hib infection is most commonly seen in children < 5 years of age. The mean age of onset is 6-24 months after which it declines gradually till 5 years. 95% of Hib infections occur before 5 years of age.

Higher the incidence of Hib in community, earlier is the age of onset, more is the chance of meningitis and less is the chance of epiglottitis. In developed countries 10% of Hib disease occurs before 6 months of age, 40% by 1 year and 75% by 2 years. In developing countries 45% of total Hib infections occur by 6 months of age and 65 - 75 % by 1 year. This has a bearing on the immunization strategy, as earlier the age of onset (like in India), earlier should be the completion of 3 primary doses of Hib vaccine.

Annual incidence of Hib meningitis varies from country to country. It varies from 35 - 300 cases / 1,00,000 children <5 years of age. In developed countries it is low, like in USA before universal Hib immunization, it was 60 - 70/1,00,000 children <5 years of age and in Europe 35/100,000 children <5 years of age. In developing countries, it is higher e. g. in Alaska it is 300/100,000 children <5 years of age.

In the west, of the total cases of invasive Hib disease, 40-75% present with meningitis, 25 % with epiglottitis and 25% with rest of the illnesses. Higher the incidence, higher is the rate of meningitis and lower is epiglottitis. In India, IDIS study has shown that of the total cases of Hib diseases, 66% present as meningitis, 7% as pneumonitis, 7% as skin and soft tissue infections, 7% as sepsis and rest as other manifestations.

Exact incidence of Hib in Indian community is not known. Looking at the world experience it is likely to be as high as the other developing countries. There are two problems in our country. First is lack of community based data and second is lack of laboratory facilities to culture Hib as Hib is a fastidious organism to grow.

In a study from Pune, Maharashtra it was shown that protective levels of anti PRP antibodies (>0.15 mcg/ml) were present in 20% of children by 1 year of age, 35% by 3 years and 80% by 5 years. It suggests the pattern of natural, clinical or subclinical infection and immunity acquired at different ages. Yet, majority of them are not protected in the early months or years of life.

There are only hospital- based data available, which suggest that 15-40 % of cases of pyogenic meningitis and 7-15% of cases of lobar pneumonia in children are due to Hib infection. There are reports of occasional cases of invasive H. influenzae disease caused by type a or other non-typeable strains. In children, more then 95% of cases of invasive H.influenza disease are due to Hib. The data from India shows similar pattern as seen in Europe before mass vaccination there. In such case, extrapolation of their data to India, estimates the incidence of Hib meningitis to be 60-80/100,000 children <5 years of age in India.

Hib leads to very severe infections at a very young age. The case fatality rate of Hib meningitis in developed countries is 2-4% but that in developing countries is as high as 30 -40% or even nearly 100% depending on drug resistance and type of drug used primarily.

The long-term sequelae of meningitis and epiglottitis are also high. Post meningitis sequelae are seen in 15- 30% of cases in the form of deafness or blindness or severe neurological damage etc.

Newborns are protected against Hib by maternal antibodies for first few months of life. After that the child coming in contact with Hib develops nasopharyngeal carrier state from where it can spread and lead to invasive Hib disease or spread to other susceptible hosts in community.

The carrier state in developed countries is estimated to be 2-3 % and in developing countries 5- 10 %. In day care centers it can reach as high 20-30%. In family contacts of index case it is 10-12%.

After effective immunization, the carrier rate has decreased from 6 % to 1.5 % in some studies.

Before 1984, studies suggested almost 100% sensitivity of Hib to common antibiotics. Since then many reports have shown emergence of multi-drug resistant strains to the tune of 40-60% of total Hib cases. However, all of them appear to be sensitive to 3rd generation cephalosporins at present. The drug resistance appears to be mediated by R plasmid. It appears to be uniform all over the country.

First generation of Hib vaccine contained the PRP (Poly Ribosiyl Polysaccharide) antigen. PRP per se leads to non-T dependent type of immune response characterized by IgM type of antibody, which are lower in magnitude, shorter lasting, without any T cell memory and like other polysaccharide vaccines not immunogenic below 18 months of age.

Since 1987, 2nd generation of Hib vaccines are available where the PRP hapten is conjugated (linked) with a carrier protein. This, so as to say, fools the T cell and leads to T cell dependent response characterized by IgG type of antibodies which is of higher magnitude, long lasting and has T cell memory. It is also immunogenic from 6 weeks to 8 weeks of age & hence can be used at an early age when it is actually required the most.

The principal antigen in all the 2nd generation Hib vaccine is PRP antigen. Depending on the carrier protein to which it is conjugated there are four different vaccines as shown below. Of these HbOC and PRP- T vaccines are available in India.



Carrier ProteinType of linkage
1) PRP-T (Hibest, Act Hib, Hiberix)Polysaccharide large
15 mcg Polysaccharide 10 mcg
Tetanus toxoid 20 mcg Tetanus toxoid 30 mcg6 carbon carbodiimide condensation
2) HbOC (Hibtitre)Oligosaccharide 10 mcgCRM 197 + Variant of Diphtheria toxin 25 mcg-
3) PRP-OMP (Pedvax)Polysaccharide medium 15 mcgGroup B meningo Coccus outer membrane protein vesicle 250 mcgThioether
4) PRP-D (Prohibit)Polysaccharide medium 25 mcgDiphtheria toxoid6 carbon

Hib vaccines are available as mono dose or as 10-dose containing multidose vial. HbOC is available as ready to use liquid while PRP-T is available as lyophilized powder with diluent available separately. Diluent used is distilled water or normal saline. The dose given is 0.5ml per dose. The cost of one dose varies from Rs 400-500 at present.

Hib vaccine is given intramuscularly over the anterolateral aspect of the thigh or the deltoid region.

Hib vaccine is stored between 2-80C. It should never be frozen and should be discarded if frozen by mistake. The shelf life is for 2 years if stored properly. It should not be stored in the door compartment. Even the diluent should be kept at 2-80C.

As discussed before, unconjugated PRP vaccine leads to IgM type anti-PRP antibody and conjugate vaccine leads to IgG type anti- PRP antibody. These can be detected by Farr type RIA or ELISA.

Anti-PRP antibody levels> 0.15 mcg/ml are protective against Hib for short period and level> 1.0 mcg/ml suggest long term protection.

Antibody level following each vaccine: The comparative studies show the following results in table 2.

Anti PRP antibody levels in mcg/ml
AfterPRP-T >0.15 >1.0HbOC >0.15 >1.0PRP-OMP >0.15 >1.0PRP-D >0.15 >1.0
1stdose82% 19%82% 10%98% 40%-
2nddose91% 90%85% 17%100% 45%-
3rddose98% 90%92% 63%92% 48%58% 29%

Primary vaccination: Only conjugate vaccines should be used for primary vaccination. PRP -T or HbOC are both equally effective and safe and any one of them can be used. The efficacy at the end of 3 doses is>95%. Protective antibody levels are achieved with 2 doses of PRP- T and 3 doses of HbOC. However, chances of breakthrough infection before completion of 3 doses have been found to be higher with HbOC than PRP-T in some studies.

PRP- D is the least immunogenic vaccine and is not licensed in USA for use in primary vaccination. PRP-OMP vaccine was found to have batch to batch variability. In addition, the antibody titres at the end of 3 doses were not as good as with PRP- T or HbOC as only 40% children develop titre> 1.0 mcg/ml. The advantage of PRP-OMP is that the antibody titers> 0.15 mcg/ml are achieved after first dose itself in 90% of vaccinees giving immediate protection and reducing the chances of breakthrough infection. Hence many studies have suggested using PRP-OMP as first dose so that immediate protection starts. This has to be followed by 2nd and 3rd dose of PRP-T or HbOC so as to achieve good titres at the end of the schedule.

Booster dose: Any of the 4 Vaccines can be used for booster dose.

For a child less than 6 months, 3 primary doses are necessary. The first dose can be given at 6 weeks along with OPV/DPT and subsequent 2 doses at 4 weeks interval along with subsequent OPV/DPT. One can also keep 2 months gap between the doses. But giving the 3 doses at 6, 10and 14 weeks will complete the vaccination faster and protect earlier. One booster will be necessary between 15-18 months of age.

For children between 6 months to 12 months: 2 primary doses at 4-8 weeks interval are given followed by a booster at 15-18 months of age. For children between 12-15 months only single primary dose is given followed by a booster at 15-18 months of age. If a child present beyond 15 months till 15 years of age, only one dose is given straight as the booster dose. It is usually not given after 5 years of age.

Delayed dose: There is no need to restart the schedule if a dose is delayed or missed. One should just complete the age appropriate schedule of remaining vaccines. However, one is not protected well till one has completed the recommended schedule. Hence, delay in vaccination is not desirable.

Booster dose: As we have seen before,> 90% of vaccinees achieve a titre of>1.0 mcg/ml after 3 primary doses giving long term protection till 15-18 months of age. In 10-50% of them, the titre falls to <0.15 mcg/ml or less than the minimum protective level by 18 months. If a booster is given at 15 -18 months of age the titre rises by 30-90 fold in all of them and reaches levels as high as 40 mcg/ml. Hence a booster is recommended at 15-18 months of age.

Studies have shown that sero-response is same when the same vaccine is used all throughout or when they are interchanged to complete the course. In fact, some studies have shown better sero-response when different vaccines were used one after another. As we saw before, PRP- OMP leads to protective antibody titre after first dose itself so that protection starts early. This, when followed by 2nd and 3rd dose of PRP-T/HbOC, leads to a better and long term protection at the end of 3 doses. Hence, these studies recommend using PRP-OMP as first dose and PRP-T/ HbOC for the 2nd and 3rd doses.

Again studies have shown equal if not better response when another vaccine is used as booster as compared to original vaccine used for primary doses.

In short, the vaccines can be used interchangeably both for primary as well as booster doses.

Local reactions can occur like redness (16%), swelling (16%), pain (27%), etc. They are more common with first dose than with subsequent doses. Systemic side effects seen include fever (5-10%), which is mild and lasts for 24 hours, excessive crying, fussiness, irritability (30%), vomiting (5%), drowsiness, anorexia (20%), diarrhea etc. Rarely anaphylaxis can occur like with any other vaccine

With need to use so many vaccines during early infancy, one has to use more than two vaccines together. Hib can be given along with other vaccines such as OPV/DPT/HBV at 6, 10 and 14 weeks of age. However they should be given at different sites using separate syringes.

Some studies have been carried out including in India, where Hib and DPT have been mixed in the same syringe and given, with the same or better response to Hib than when given at individual sites. The response to DPT especially anti-tetanus toxoid antibodies and the pertussis agglutinins have been shown to be less when the vaccines are mixed but still the levels are above protective levels.

Of late combination vaccines containing DPT plus Hib are available. DPT+HbOC is available as ready to use solution (Tetramune). DPT + PRP-T is available separately as DPT liquid in ampoule and PRP-T as lyophilized powder in a bulb. One has to dissolve the PRP-T powder in the DPT liquid to make PRP-T + DPT vaccine, just before the injection (TetraHibest). The studies have shown that such combination vaccines produce same if not better anti PRP antibody titres than when given simultaneously but at different sites. Even anti Tetanus, anti Pertussis and anti Diphtheria antibody titres are same with combination vaccine as when given separately. The side effects are also not more with combination vaccines. The advantage of combination vaccines are many like timely completion of schedule, less number of visits to the doctor, less number of pricks to the child, less space & cost of transportation & storage and better compliance from parents. Hence, whenever available such combinations should be used.

In western world, combinations like IPV+DPT+Hep B or IPV+DPT+Hib or even IPV+DPT+Hib+Hep B are available as penta or hexavalent vaccines. They have shown similar efficacy and side effects as when given separately.

Studies are done on such combination containing acellular pertussis instead of whole cell pertussis in DPT combined with Hib, Hepatitis B or both with/without IPV. Initial studies showed poor anti PRP and anti Tetanus response when such combinations of acellular DPT were used as primary doses. Later studies have shown equally good response with DPaT as with DPwT containing combination vaccines used for primary vaccination. As booster, DPaT containing combination vaccines are as good if not better as DPwT containing combination vaccines.

One word of caution while using the combination vaccines- One should use the same brand of DPT and Hib recommended by the manufacturer in combination and not any DPT with any Hib

Poor cold chain maintenance can be one of the reasons for poor response. True failure is seen in <3-5% of cases. The cases include poor choice of vaccine (e.g. PRP-D), immune compromised host or breakthrough infection occurring before the schedule can be completed.

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