Geometric Mean Titre (GMT) (µg/mL)

Table II
Anti-PRP Antibody Responses in 2-Month-Old Infants NIH Trial in Minnesota and Texas

Geometric Mean Titre (GMT) (µg/mL)

No. = Number of children

** P=0.0001 for PRP-T vs HbOC

*** P=0.0001 for PRP-OMP vs PRP-T, and for PRP-OMP vs HbOC

(1) Haemophilus b Conjugate vaccine (Tetanus Protein-Conjugate)

(2) Haemophilus b Conjugate vaccine (Diphtheria Toxoid-Conjugate)

(3) Haemophilus b Conjugate vaccine (Meningococcal Protein Conjugate)

(4) Haemophilus b Conjugate vaccine (Diphtheria CRM 197 Protein Conjugate)

Multi-centre trials in the United States have evaluated a single dose of Act-HIB in 12 to 15, 18 and 17 to 24 month-old children. In this age group, a single dose of Act-HIB produced an anti-PRP antibody response which was comparable to that seen after 3 doses were administered in infants.

Following 3 doses of Act-HIB at 6 weeks, 4 and 6 months of age, 81% of native Alaskan infants showed an anti-PRP antibody titre of ≥ 1 µg /mL with a GMT of 4.17 µg/mL.

In clinical trials conducted in England and France, infants received 3 doses of Act-Hib at 1 month intervals. Anti-PRP responses were comparable to those trials where 2 month intervals were used.

Clinical Data—Act-HIB Reconstituted with DPT Adsorbed: In a clinical trial conducted in Canada, 424 infants received 3 doses of either Act-HIB reconstituted with Connaught's DPT Adsorbed or the same vaccines administered simultaneously at separate sites. Anti-PRP responses were comparable after either vaccination regimen (see Table III).

Protective antitoxin levels (≥ 0.01 lU/mL) against diphtheria and tetanus toxoids were achieved in 100% of recipients.

Pertussis agglutinins were detected in 99.6% of participants. Over 96% had titres ≥ 1:64. The combination of Act-HIB with DPT Adsorbed resulted in lower litres to pertussis when compared to administration at separate sites; GMT's differed by 11.5 to 32%. However, 95% of recipients receiving the vaccine at the same site still had titres ≥ 1:64.

Three hundred and fifty-eight of these infants were available for follow-up and received one dose of either Act-HIB reconstituted with Connaught's DPT Adsorbed (n=180) or the same vaccines administered at separate sites (n=178) at age 18 months. Anti-PRP levels were ≥ 1µg/mL in 100%. This demonstrates T-cell dependent (memory) responses for anti-PRP.

Clinical Data Act-HIB Reconstituted with DPT Polio Adsorbed: In a clinical trial conducted in Canada, 427 infants received 3 doses of either Act-HIB reconstituted with Connaught's DPT Polio Adsorbed or the same vaccines administered simultaneously at separate sites. Anti-PRP responses following the third dose did not differ significantly between groups (see Table III).

Table III
Summary of Anti-PRP Responses with Various Diluents

Pertussis agglutinins were detected in all but 2 subjects and 92.4% had titres > 64. The responses in terms of distribution of titres and GMT's were similar in the combined and separate groups.

There was no difference in diphtheria antitoxin response after combined and separate vaccine, with 99.1% of infants developing a minimum protective antitoxin level (≥ 0.01 IU/mL) after the third dose of combined vaccines.

Protective levels of tetanus antitoxin (≥ 0.01 IU/mL) developed in 99.5% of infants after the third dose of combined vaccines, and 100% of infants after separate vaccines. However, the geometric mean antitoxin concentrations were significantly lower after combined (0.50 µg/mL) than after separate vaccine (0.76 µg/mL).

There were no significant differences in the polio neutralizing antibody in response to separate or combined vaccine. The proportions of infants with titres of ≥ 8 after 3 doses of combined vaccines were 98.6% to type 1, 98.1% to type 2, and 100% to type 3.

Indications: Routine: For the routine immunization of all children between 2 and 59 months of age. In infants, 3 injections are to be given i.m. at 2, 4 and 6 months of age, followed by a booster at 18* months of age. Infants starting their primary immunization series between the age of 3 and 6 months should receive 3 doses at 2 month intervals with a booster dose at 18* months of age.

Infants starting their primary immunization series between the age of 3 and 6 months should receive 3 doses at 2 month intervals with a booster dose at 18* months of age. (While an interval of 2 months between doses is recommended, an interval as short as 1 month is acceptable).

For infants between the age of 7 and 11 months, 2 doses should be given at an interval of 2 months, followed by a booster at 18* months of age.

Children between 12 and 14 months of age who have not previously received any Haemophilus b vaccine should receive 1 dose of the vaccine followed by a booster at or after 18* months of age.

Unvaccinated children between 18 and 59 months of age should receive a single dose of vaccine.

*The booster dose may be given as early as 15 months of age provided that at least 2 months have elapsed since the previous dose.

Older children or adults with chronic conditions associated with increased risk of invasive Hib disease such as persons with splenic dysfunction (e.g., sickle cell disease, asplenia), antibody deficiency, HIV infection or certain malignancies may be immunized with a single dose of the vaccine.

Connaught's DPT Adsorbed may be used for the reconstitution of lyophilized Act-HIB in place of the saline diluent normally supplied. This provides an efficient means of administering routine immunization against diphtheria, tetanus, pertussis and H. influenzae type b in a single injection at a single visit.

Connaught's DPT Polio Adsorbed may be used for the reconstitution of lyophilized Act-HIB in place of the saline diluent. This provides an efficient means of administering routine immunization against diphtheria, tetanus, pertussis, poliomyelitis and H. influenzae type b in a single injection at a single visit.

Act-HIB may be administered simultaneously with DPT, DPT-Polio and IPV at separate sites with separate syringes and OPV.

Act-HIB may also be given simultaneously with MMR at separate sites with separate syringes. This is based on data for MMR and Act-HIB alone. Data on simultaneous administration of DPT Polio, Act-HIB and MMR are not available.

Data on whether vaccination prevents acquisition and carriage of Hib are still limited. Thus, rifampin or other appropriate chemoprophylaxis should be used, in accordance with the usual recommendations, for families and people in daycare centres in which a case of invasive Hib disease has occurred and in which there are one or more contacts less than 48 months of age who have not been fully vaccinated against Hib.

At the present time, haemophilus b conjugate vaccines are not recommended for infants younger than 2 months of age.

Contraindications: Immunization should be deferred during the course of any febrile illness or acute infection. Hypersensitivity to any component of this vaccine, including tetanus protein, is a contraindication for use of this vaccine. When Act-HIB is reconstituted with Connaught's DPT Adsorbed or DPT Polio Adsorbed the contraindications for DPT Adsorbed or DPT Polio Adsorbed must also be considered.

Elective immunization of individuals should be deferred during an outbreak of poliomyelitis.

Warnings: If Act-HIB is used in persons receiving immunosuppressive therapy or who are otherwise immunocompromised, the expected immune response may not be obtained.

As with any vaccine, vaccination with Act-HIB may not protect 100% of susceptible individuals.

Capsular polysaccharide antigen can be detected in the urine of vaccinees for up to 2 weeks following immunization with conjugate vaccines. This phenomenon should not be confused with invasive Hib infections.

Precautions: General: The possibility of allergic reactions in individuals sensitive to components of the vaccine should be evaluated. Epinephrine Hydrochloride Solution (1:1 000) must be immediately available to combat unexpected anaphylactic or allergic reactions. When Act-HIB is reconstituted with Connaught's DPT Adsorbed or DPT Polio Adsorbed, the possibility of allergic reactions to the components of these vaccines must also be evaluated.

Prior to an injection of any vaccine, all known precautions should be taken to prevent adverse reactions. This includes a review of the patient's history with respect to possible hypersensitivity to the vaccine or similar vaccine.

Any febrile illness or acute infection is reason to delay the use of Act-HIB.

Special care should be taken to ensure that the injection does not enter a blood vessel.

A separate sterile syringe and needle should be used for each individual patient to prevent transmission of hepatitis or other infectious agents from one person to another.

Act-HIB may be of benefit in preventing the occurrence of secondary cases. However, epidemiological studies have not been done and rifampin prophylaxis is still recommended. Because the vaccine will not protect against non-typeable strains of H. influenzae which cause recurrent upper respiratory disease, otitis media and sinusitis, the vaccine is not recommended for these conditions.

Although some immune response to the tetanus protein component may occur, immunization with this vaccine does not substitute for routine tetanus immunization. Individuals who have received multiple doses of products containing tetanus toxoid show no differences in reaction rates when immunized with this vaccine.

Pregnancy: Animal reproduction studies have not been conducted with Act-HIB. It is also not known whether Act-HIB can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Act-HIB is not recommended for use in pregnant women.

Children with Symptomatic HIV Infection: Available data suggest that routine childhood immunizations are not hazardous to HIV-infected children. Furthermore, there is no evidence that immunization with routine vaccines leads to deterioration of the clinical condition of HIV-infected persons. Immunization with DPT (Diphtheria, Pertussis and Tetanus), IPV (Inactivated Poliomyelitis Vaccine) and Act-HIB is recommended, although immunization may be less effective than it would be for immune-competent children.

Adverse Effects: Health care providers should report any occurrences temporally related to the administration of the product in accordance with provincial and federal statutory requirements.

Local reactions including pain, redness, swelling and induration may occur at the injection site. These reactions are more common following the first dose of the vaccine. In a placebo controlled clinical trial, local reactions following the vaccine were no different from placebo except for an increase in redness at 24 hours following the third dose.

Systemic reactions including fever, irritability, drowsiness, prolonged or abnormal crying, anorexia and vomiting have occurred after immunization with Act-HIB in conjunction with DPT. The rates of reactions observed were generally comparable to those usually reported following DPT with the exception that there were slightly more febrile reactions reported among PRP-T recipients within 6 to 24 hours of vaccination.

Table IV shows systemic reactions reported in a controlled clinical trial.

Table IV
Systemic Reactions (r/o) Within 24 Hours of Vaccination

*  P›0.001

**  PRP-T Vaccine and DPT Vaccine administered at 2 different sites

(top)

In a clinical trial conducted in Canada, 442 infants received at least one dose of Act-HIB reconstituted with Connaught's DPT Adsorbed or the same vaccines administered simultaneously at separate sites.

Local adverse reactions to Act-HIB when administered alone were infrequent and mild. No increase was seen with successive doses. Mixed Act-HIB and DPT vaccines did not cause local redness or swelling more often than did DPT vaccine alone but tenderness increased from 18.1% with DPT alone to 26.2% with the combination (p < 0.001). No increase in systemic adverse effects was seen following the mixed vaccines. However, events were rated as moderate/severe slightly more often after mixed vaccines (12.4%) than after separate vaccinations (8.8%, p < 0.05).

In the Canadian study, one hypotensive-hyporesponsive episode occurred after the administration of Act-HIB reconstituted with DPT Adsorbed. This child recovered fully with no sequelae. No other serious adverse reactions were reported.

Act-HIB reconstituted with DPT Polio Adsorbed: In a clinical trial in Canada, 427 infants received 3 doses of Act-Hib reconstituted with DPT Polio Adsorbed or the same vaccine administered simultaneously at separate sites.

Local adverse reactions to Act-HIB alone were infrequent and mild. A slight increase was seen with successive doses. Although local redness, swelling and tenderness were significantly more common after vaccines containing DPT Polio Adsorbed compared with Act-HIB alone, reaction rates were lower after the combined vaccines than after DPT Polio Adsorbed alone. No significant differences in systemic adverse events was seen following Act-HIB and DPT Polio Adsorbed administered at separate sites or combined.

Three severe adverse events temporally associated with vaccination resulted in hospitalization. These included 1 infant who developed supraventricular tachycardia 48 hours after dose 1 (combined), 1 infant who woke 3 hours after dose 1 (separate) with cough, respiratory distress and cyanosis whose diagnosis was suspected aspiration or gastroesophageal reflux, and 1 infant with an episode of screaming and apnea 4 hours after dose 1 (separate). All 3 infants recovered completely. No causal relationship between the adverse events and vaccination was demonstrated.

Physicians should be aware that recipients of Haemophilus b vaccine are not protected against Hib disease in the week after vaccination, prior to the onset of the protective effects of the vaccine.

As with any vaccine, there is the possibility that broad use of the vaccine could reveal rare adverse reactions not observed in clinical trials. A temporal association of neurological disorders has been reported following the parenteral injection of other biological products and should always be carefully considered when an immunization is indicated.

Dosage: Parenteral biological products should be inspected visually for extraneous particulate matter and/or discoloration prior to administration whenever solution and container permit. If these conditions exist, the vaccine should not be administered.

This vaccine is indicated for routine immunization against invasive disease caused by H. influenzae type b in infants and children starting at 2 months of age (see Indications). Each dose is a single injection of 0.5 mL given i.m.

Reconstitution of Freeze-Dried Vaccine: Reconstitute the vaccine using only the diluent supplied or Connaught's DPT Adsorbed or DPT Polio Adsorbed. The use of other DPT products to reconstitute Act-HIB is not recommended.

Do not remove the rubber stopper from the vial. Apply a sterile piece of cotton with a suitable antiseptic to the surface of the rubber stopper of the vial of vaccine. Holding the plunger of the syringe containing the diluent steady, pierce the centre of the rubber stopper in the vial and slowly inject the 0.5 mL of diluent into the freeze-dried vaccine. Shake the vial gently until a clear, colorless solution results. Avoid foaming since this will prevent withdrawal of the proper dose. Withdraw the entire contents of the reconstituted vaccine into the syringe and inject the total volume (about 0.5 mL).

When Connaught's DPT Adsorbed or DPT Polio Adsorbed is used for the reconstitution of Act-HIB, shake the single dose ampul well to uniformly distribute the suspension before withdrawing entire contents (about 0.5 mL). Before withdrawing the contents from an ampul, tap the container first to ensure that alt the vaccine is in the lower portion. Once the ampul has been opened, any of its contents not used immediately should be discarded. Inject all the DPT Adsorbed into the vial of Act-HIB vaccine. Swirl the vial until a cloudy, uniform suspension results. Avoid foaming since this will prevent withdrawal of the proper dose. Use a sterile needle and syringe to withdraw the entire contents for 1 dose.

Administer the vaccine l.m. The preferred site is into the anterolateral aspect of the mid-thigh (vastus lateralis muscle) or into the deltoid muscle.

Before injection, the skin over the site to be injected should be cleansed with a suitable germicide. After insertion of the needle, aspirate to ensure that the needle has not entered a blood vessel. Do not inject i.v.

Each person who is immunized should be given a permanent personal immunization record. In addition, it is essential that the health care provider also maintain a permanent record of the immunization history of each individual. This office record should contain the name of the vaccine, date given, dose, manufacturer and lot number.

Supplied: Act-HIB is a lyophilized vaccine of purified polyribose ribitol phosphate capsular polysaccharide (PRP) of H. influenzae type b, covalently bound to tetanus protein. The diluent for reconstitution is a 0.4% saline solution. The vaccine and diluent do not contain a preservative. When reconstituted with diluent, PRP-T is a clear, colorless solution. Each single dose of 0.5 mL contains: purified capsular polysaccharide 10 µg covalently bound to 20 µg of tetanus protein.

Act-Hib reconstituted with Diluent: The diluent for reconstitution is a 0.5% saline solution. After reconstitution the vaccine appears clear and colorless and does not contain a preservative.

Act-HIB reconstituted with Connaught's DPT Adsorbed: After reconstitution, the vaccine appears cloudy and uniform and the solution contains thimerosal 0.01% used in DPT Adsorbed as a preservative.

Act-HIB reconstituted with Connaught's DPT Polio Adsorbed: After reconstitution, the vaccine appears cloudy and uniform. From the DPT Polio Adsorbed, the solution contains 2-phenoxyethanol 0.5% as a preservative and trace amounts of polymyxin B and neomycin may be present from the cell growth medium.

Packages of 5 single dose vials. Diluent for reconstitution is supplied either in the same carton as the vaccine or in separate cartons of 5x1 dose.

Combipacks of a 5x1 dose carton of Act-HIB and a 5x1 dose carton of Connaught's DPT Adsorbed for reconstitution in place of the diluent normally supplied.

Combipacks of a 5x1 dose carton of Act-HIB and a 5x1 dose carton of Connaught's DPT Polio Adsorbed for reconstitution in place of the diluent.

Store between 2 and 8°C. Do not freeze. The vaccine should be used immediately after reconstitution.

Reviewed 1995