Merck Announces Voluntary Recall of Certain Lots of Pedvaxhib and Comvax

WHITEHOUSE STATION, N.J.--(BUSINESS WIRE)--Dec 12, 2007 - Merck & Co., Inc. announced today that the Company has initiated a voluntary recall of 11 lots of its Haemophilus influenzae type B vaccine, PEDVAXHIB (Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)), and two lots of its combination Haemophilus influenzae type B/ hepatitis B vaccine, COMVAX (Haemophilus b Conjugate (Meningococcal Protein Conjugate)). The recall is specific to these 13 lots and does not affect any other vaccines manufactured by Merck. The affected doses of PEDVAXHIB and COMVAX were distributed starting in April 2007.

Merck is conducting this recall because it can not assure sterility of these specific vaccine lots. The potential contamination of these specific lots was identified as part of the Company's standard evaluation of its manufacturing processes. Sterility tests of the vaccine lots that are the subject of this recall have not found any contamination in the vaccine.

The potential for contamination of any individual vaccine is low, and, if present, the level of contamination would be low. However, because the Company cannot assure the sterility of these specific lots of vaccine, it is conducting this recall.

Merck is working closely with the U.S. Food and Drug Administration (FDA) and the U.S. Centers for Disease Control and Prevention (CDC) to inform affected healthcare providers of this recall. We are also in the process of communicating with public health authorities and healthcare providers in the U.S. and in other countries where these lots were distributed, as appropriate.

"We are taking this action because we are committed to ensuring the quality of our vaccines," said Mark Feinberg, M.D., Ph.D., vice president, Medical and Policy Affairs, Merck Vaccines and Infectious Diseases. "We know that our vaccines can play an important role in the nation's public health system, and we are committed to resolving this issue as quickly as possible to ensure that our vaccines are readily available."

Physicians are advised not to administer any vaccine from the vaccine lots being recalled. Individuals who received vaccine from these lots should complete their immunization series with a Haemophilus b conjugate-containing vaccine not affected by this recall, but do not need to be revaccinated to replace a dose they received from a recalled lot. The efficacy of the vaccine was not affected.

Select safety and additional information about PEDVAXHIB

PEDVAXHIB is indicated for routine vaccination against invasive disease caused by Haemophilius influenzae type b in infants and children two to 71 months of age. PEDVAXHIB should not be used in infants younger than six weeks of age.

PEDVAXHIB is contraindicated in patients with hypersensitivity to any component of the vaccine or the diluent; persons who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of the vaccine.

As with any vaccine, the use of PEDVAXHIB may not result in a protective antibody response in all vaccinees; PEDVAXHIB may not induce protective antibody levels immediately following vaccination.

The most frequently reported (>1 percent) adverse reactions, without regard to causality, were fever (>101F), irritability, sleepiness, injection-site pain/soreness, injection-site erythema (<2.5 cm diameter), injection-site swelling/induration (<2.5 cm diameter), unusual high-pitched crying, prolonged crying (>4 hours), diarrhea, vomiting, crying, pain, otitis media, rash, and upper respiratory infection.

Select safety and additional information about COMVAX

COMVAX (Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine) is indicated for vaccination against invasive disease caused by Haemophilus influenzae type b and against infection caused by all known subtypes of hepatitis B virus in infants six weeks to 15 months of age born to HBsAg-negative mothers.

COMVAX (Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine) is contraindicated in patients with hypersensitivity to yeast or any component of the vaccine. Patients who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of the vaccine. In clinical trials, the most common nonserious adverse experiences observed in =>1 percent of children receiving COMVAX (Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine) included injection-site reactions, somnolence, irritability, crying, and fever (=>101F); for a listing of adverse reactions, please see the Prescribing Information.

As with other vaccines, COMVAX (Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine) may not induce protective antibody levels immediately following vaccination and may not result in a protective antibody response in all individuals given the vaccine

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

PEDVAXHIB (R) is a registered trademark of Merck & co. Inc., Whitehouse Station, NJ, USA

COMVAX(R) is a registered trademark of Merck & co. Inc., Whitehouse Station, NJ, USA

Full prescribing information for PEDVAXHIB is attached and is also available at www.merckvaccines.com

Full prescribing information for COMVAX is attached and is also available at www.merckvaccines.com

9018902

Liquid PedvaxHIB(R)

(Haemophilus b Conjugate Vaccine

(Meningococcal Protein Conjugate))

DESCRIPTION

PedvaxHIB* (Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)) is a highly purified capsular polysaccharide (polyribosylribitol phosphate or PRP) of Haemophilus influenzae type b (Haemophilus b, Ross strain) that is covalently bound to an outer membrane protein complex (OMPC) of the B11 strain of Neisseria meningitidis serogroup B. The covalent bonding of the PRP to the OMPC which is necessary for enhanced immunogenicity of the PRP is confirmed by quantitative analysis of the conjugate's components following chemical treatment which yields a unique amino acid. The potency of PedvaxHIB is determined by assay of PRP.

Haemophilus influenzae type b and Neisseria meningitidis serogroup B are grown in complex fermentation media. The PRP is purified from the culture broth by purification procedures which include ethanol fractionation, enzyme digestion, phenol extraction and diafiltration. The OMPC from Neisseria meningitidis is purified by detergent extraction, ultracentrifugation, diafiltration and sterile filtration.

Liquid PedvaxHIB is ready to use and does not require a diluent. Each 0.5 mL dose of Liquid PedvaxHIB is a sterile product formulated to contain: 7.5 mcg of Haemophilus b PRP, 125 mcg of Neisseria meningitidis OMPC and 225 mcg of aluminum as amorphous aluminum hydroxyphosphate sulfate (previously referred to as aluminum hydroxide), in 0.9% sodium chloride, but does not contain lactose or thimerosal. Liquid PedvaxHIB is a slightly opaque white suspension.

This vaccine is for intramuscular administration and not for intravenous injection. (See DOSAGE AND ADMINISTRATION.)

CLINICAL PHARMACOLOGY

Prior to the introduction of Haemophilus b Conjugate Vaccines, Haemophilus influenzae type b (Hib) was the most frequent cause of bacterial meningitis and a leading cause of serious, systemic bacterial disease in young children worldwide.(1,2,3,4)

Hib disease occurred primarily in children under 5 years of age in the United States prior to the initiation of a vaccine program and was estimated to account for nearly 20,000 cases of invasive infections annually, approximately 12,000 of which were meningitis. The mortality rate from Hib meningitis is about 5%. In addition, up to 35% of survivors develop neurologic sequelae including seizures, deafness, and mental retardation.(5,6) Other invasive diseases caused by this bacterium include cellulitis, epiglottitis, sepsis, pneumonia, septic arthritis, osteomyelitis and pericarditis.

Prior to the introduction of the vaccine, it was estimated that 17% of all cases of Hib disease occurred in infants less than 6 months of age.(7) The peak incidence of Hib meningitis occurs between 6 to 11 months of age. Forty-seven percent of all cases occur by one year of age with the remaining 53% of cases occurring over the next four years.(2,20)

Among children under 5 years of age, the risk of invasive Hib disease is increased in certain populations including the following:

-- Daycare attendees(8,9)

-- Lower socio-economic groups(10)

-- Blacks(11) (especially those who lack the Km(1) immunoglobulin allotype)(12)

-- Caucasians who lack the G2m(n or 23) immunoglobulin allotype(13)

-- Native Americans(14,15,16)

-- Household contacts of cases(17)

-- Individuals with asplenia, sickle cell disease, or antibody deficiency syndromes(18,19)

An important virulence factor of the Hib bacterium is its polysaccharide capsule (PRP). Antibody to PRP (anti-PRP) has been shown to correlate with protection against Hib disease.(3,21) While the anti-PRP level associated with protection using conjugated vaccines has not yet been determined, the level of anti-PRP associated with protection in studies using bacterial polysaccharide immune globulin or nonconjugated PRP vaccines ranged from >0.15 to >1.0 mcg/mL.(22-28)

Nonconjugated PRP vaccines are capable of stimulating B-lymphocytes to produce antibody without the help of T-lymphocytes (T-independent). The responses to many other antigens are augmented by helper T-lymphocytes (T-dependent). PedvaxHIB is a PRP-conjugate vaccine in which the PRP is covalently bound to the OMPC carrier(29) producing an antigen which is postulated to convert the T-independent antigen (PRP alone) into a T-dependent antigen resulting in both an enhanced antibody response and immunologic memory.

Clinical Evaluation of PedvaxHIB

PedvaxHIB, in a lyophilized formulation (lyophilized PedvaxHIB), was initially evaluated in 3,486 Native American (Navajo) infants, who completed the primary two-dose regimen in a randomized, double-blind, placebo-controlled study (The Protective Efficacy Study). At the time of the study, this population had a much higher incidence of Hib disease than the United States population as a whole and also had a lower antibody response to Haemophilus b Conjugate Vaccines, including PedvaxHIB.(14,15,16,30,33)

Each infant in this study received two doses of either placebo or lyophilized PedvaxHIB with the first dose administered at a mean of 8 weeks of age and the second administered approximately two months later; DTP and OPV were administered concomitantly. Antibody levels were measured in a subset of each group (TABLE 1). -0-

                               TABLE 1

                 Antibody Responses in Navajo Infants

----------------------------------------------------------------------

                                                              Anti-PRP

             No. of                      % Subjects with         GMT

                                     ------------------------

Vaccine     Subjects      Time       >0.15 mcg/mL >1.0 mcg/mL (mcg/mL)

----------------------------------------------------------------------

Lyophilized  416**   Pre-Vaccination           44          10     0.16

 PedvaxHIB*   416    Post-Dose 1               88          52     0.95

              416    Post-Dose 2               91          60     1.43

----------------------------------------------------------------------

Placebo*     461**   Pre-Vaccination           44           9     0.16

              461    Post-Dose 1               21           2     0.09

              461    Post-Dose 2               14           1     0.08

----------------------------------------------------------------------

Lyophilized   27+    Prebooster                70          33     0.51

 PedvaxHIB     27    Postbooster++            100          89     8.39

----------------------------------------------------------------------

* Post-Vaccination values obtained approximately 1-3 months after each

 dose.

** The Protective Efficacy Study

+ Immunogenicity Trial(34)

++ Booster given at 12 months of age; Post-Vaccination values obtained

 1 month after administration of booster dose.

----------------------------------------------------------------------

Most subjects were initially followed until 15 to 18 months of age. During this time, 22 cases of invasive Hib disease occurred in the placebo group (8 cases after the first dose and 14 cases after the second dose) and only 1 case in the vaccine group (none after the first dose and 1 after the second dose). Following the primary two-dose regimen, the protective efficacy of lyophilized PedvaxHIB was calculated to be 93% with a 95% confidence interval of 57%-98% (p=0.001, two-tailed). In the two months between the first and second doses, the difference in number of cases of disease between placebo and vaccine recipients (8 vs. 0 cases, respectively) was statistically significant (p=0.008, two-tailed); however, a primary two-dose regimen is required for infants 2-14 months of age.

At termination of the study, placebo recipients were offered vaccine. All original participants were then followed two years and nine months from termination of the study. During this extended follow-up, invasive Hib disease occurred in an additional seven of the original placebo recipients prior to receiving vaccine and in one of the original vaccine recipients (who had received only one dose of vaccine). No cases of invasive Hib disease were observed in placebo recipients after they received at least one dose of vaccine. Efficacy for this follow-up period, estimated from person-days at risk, was 96.6% (95 C.I., 72.2-99.9%) in children under 18 months of age and 100% (95 C.I., 23.5-100%) in children over 18 months of age.(33)

Since protective efficacy with lyophilized PedvaxHIB was demonstrated in such a high risk population, it would be expected to be predictive of efficacy in other populations.

The safety and immunogenicity of lyophilized PedvaxHIB were evaluated in infants and children in other clinical studies that were conducted in various locations throughout the United States. PedvaxHIB was highly immunogenic in all age groups studied.(31,32)

Lyophilized PedvaxHIB induced antibody levels greater than 1.0 mcg/mL in children who were poor responders to nonconjugated PRP vaccines. In a study involving such a subpopulation,(33,34) 34 children ranging in age from 27 to 61 months who developed invasive Hib disease despite previous vaccination with nonconjugated PRP vaccines were randomly assigned to 2 groups. One group (n=14) was vaccinated with lyophilized PedvaxHIB and the other group (n=20) with a nonconjugated PRP vaccine at a mean interval of approximately 12 months after recovery from disease. All 14 children vaccinated with lyophilized PedvaxHIB but only 6 of 20 children re-vaccinated with a nonconjugated PRP vaccine achieved an antibody level of >1.0 mcg/mL. The 14 children who had not responded to revaccination with the nonconjugated PRP vaccine were then vaccinated with a single dose of lyophilized PedvaxHIB; following this vaccination, all achieved antibody levels of >1.0 mcg/mL.

In addition, lyophilized PedvaxHIB has been studied in children at high risk of Hib disease because of genetically-related deficiencies (Blacks who were Km(1) allotype negative and Caucasians who were G2m(23) allotype negative) and are considered hyporesponsive to nonconjugated PRP vaccines on this basis.(35) The hyporesponsive children had anti-PRP responses comparable to those of allotype positive children of similar age range when vaccinated with lyophilized PedvaxHIB. All children achieved anti-PRP levels of >1.0 mcg/mL.

The safety and immunogenicity of Liquid PedvaxHIB were compared with those of lyophilized PedvaxHIB in a randomized clinical study involving 903 infants 2 to 6 months of age from the general U.S. population. DTP and OPV were administered concomitantly to most subjects. The antibody responses induced by each formulation of PedvaxHIB were similar. TABLE 2 shows antibody responses from this clinical study in subjects who received their first dose at 2 to 3 months of age. -0-

                               TABLE 2

Antibody Responses to Liquid and Lyophilized PedvaxHIB in Infants From

                      the General U.S. Population

======================================================================

                                              % Subjects with Anti-PRP

              Age                     No. of      anti-PRP       GMT

                                              ---------------

                                              >0.15    >1.0

Formulation (Months)      Time       Subjects  mcg/mL  mcg/mL (mcg/mL)

----------------------------------------------------------------------

                     Pre-Vaccination   487      32       7      0.12

  Liquid      2-3    Post-Dose 1*      480      94      64      1.55

 PedvaxHIB           Post-Dose 2**     393      97      80      3.22

 (7.5 mcg    12-15   Prebooster        284      80      30      0.49

   PRP)              Postbooster**     284      99      95     10.23

              24+    Persistence        94      97      55      1.29

                     Pre-Vaccination   171      37       6      0.13

Lyophilized   2-3    Post-Dose 1*      169      97      72      1.88

 PedvaxHIB           Post-Dose 2**     133      99      81      2.69

  (15 mcg    12-15   Prebooster         87      71      28      0.39

   PRP)              Postbooster**      87      99      91      7.64

              24+    Persistence        37      97      54      1.10

----------------------------------------------------------------------

* Approximately two months Post-Vaccination

** Approximately one month Post-Vaccination

+ Approximately

----------------------------------------------------------------------

A booster dose of PedvaxHIB is required in infants who complete the primary two-dose regimen before 12 months of age. This booster dose will help maintain antibody levels during the first two years of life when children are at highest risk for invasive Hib disease. (See TABLE 2 and DOSAGE AND ADMINISTRATION.)

In four United States studies, antibody responses to lyophilized PedvaxHIB were evaluated in several subpopulations of infants initially vaccinated between 2 to 3 months of age. (See TABLE 3.) -0-

                               TABLE 3

                         Antibody Responses*

  After Two Doses of Lyophilized PedvaxHIB Among Infants Initially

                             Vaccinated at

               2-3 Months of Age By Racial/Ethnic Group

----------------------------------------------------------------------

                             LYOPHILIZED

     Racial/Ethnic       No. of  % Subjects With Anti-PRP Anti-PRP GMT

                                 ------------------------

        Groups          Subjects >0.15 mcg/mL >1.0 mcg/mL (mcg/mL)

----------------------------------------------------------------------

Native American+           54         96          70          2.47

Caucasian                 201         99          82          3.52

Hispanic                   76         99          88          3.54

Black                      23        100          96          5.40

----------------------------------------------------------------------

* One month after the second dose

+ Apache and Navajo

----------------------------------------------------------------------

In two United States studies, antibody responses to Liquid PedvaxHIB were evaluated in several subpopulations of infants initially vaccinated between 2 to 3 months of age. (See TABLE 4.) -0-

                               TABLE 4

                         Antibody Responses*

          After Two Doses of Liquid PedvaxHIB Among Infants

   Initially Vaccinated at 2-3 Months of Age By Racial/Ethnic Group

======================================================================

                                LIQUID

     Racial/Ethnic       No. of  % Subjects With Anti-PRP Anti-PRP GMT

                                 ------------------------

Groups                  Subjects >0.15 mcg/mL >1.0 mcg/mL   (mcg/mL)

----------------------------------------------------------------------

Native American**             90           97          78         2.76

Caucasian                    143           94          72         2.16

Hispanic                     184           98          85         4.34

Black                         18          100          94         7.58

----------------------------------------------------------------------

* One month after the second dose

** Apache and Navajo

----------------------------------------------------------------------

Antibodies to the OMPC of N. meningitidis have been demonstrated in vaccinee sera, but the clinical relevance of these antibodies has not been established.(33)

Interchangeability of Licensed Haemophilus b Conjugate Vaccines and PedvaxHIB

Published studies have examined the interchangeability of other licensed Haemophilus b Conjugate Vaccines and PedvaxHIB.(42,43,44,45,52 )According to the American Academy of Pediatrics, excellent immune responses have been achieved when different vaccines have been interchanged in the primary series. If PedvaxHIB is given in a series with one of the other products licensed for infants, the recommended number of doses to complete the series is determined by the other product and not by PedvaxHIB. PedvaxHIB may be interchanged with other licensed Haemophilus b Conjugate Vaccines for the booster dose.(52)

Use with Other Vaccines

Results from clinical studies indicate that Liquid PedvaxHIB can be administered concomitantly with DTP, OPV, eIPV (enhanced inactivated poliovirus vaccine), VARIVAX* (Varicella Virus Vaccine Live (Oka/Merck)), M-M-R* II (Measles, Mumps, and Rubella Virus Vaccine Live) or RECOMBIVAX HB* (Hepatitis B Vaccine (Recombinant)).(33) No impairment of immune response to individual tested vaccine antigens was demonstrated.

The type, frequency and severity of adverse experiences observed in these studies with PedvaxHIB were similar to those seen when the other vaccines were given alone.

In addition, a PRP-OMPC-containing product, COMVAX* (Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine), was given concomitantly with a booster dose of DTaP (diphtheria, tetanus, acellular pertussis) at approximately 15 months of age, using separate sites and syringes for injectable vaccines. No impairment of immune response to these individually tested vaccine antigens was demonstrated. COMVAX has also been administered concomitantly with the primary series of DTaP to a limited number of infants. PRP antibody responses are satisfactory for COMVAX, but immune responses are currently unavailable for DTaP (see Manufacturer's Product Circular for COMVAX). No serious vaccine-related adverse events were reported.(33)

INDICATIONS AND USAGE

Liquid PedvaxHIB is indicated for routine vaccination against invasive disease caused by Haemophilus influenzae type b in infants and children 2 to 71 months of age.

Liquid PedvaxHIB will not protect against disease caused by Haemophilus influenzae other than type b or against other microorganisms that cause invasive disease such as meningitis or sepsis. As with any vaccine, vaccination with Liquid PedvaxHIB may not result in a protective antibody response in all individuals given the vaccine.

BECAUSE OF THE POTENTIAL FOR IMMUNE TOLERANCE, Liquid PedvaxHIB IS NOT RECOMMENDED FOR USE IN INFANTS YOUNGER THAN 6 WEEKS OF AGE. (See PRECAUTIONS.)

Revaccination

Infants completing the primary two-dose regimen before 12 months of age should receive a booster dose (see DOSAGE AND ADMINISTRATION).

CONTRAINDICATIONS

Hypersensitivity to any component of the vaccine or the diluent.

Persons who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of the vaccine.

PRECAUTIONS

General

As for any vaccine, adequate treatment provisions, including epinephrine, should be available for immediate use should an anaphylactoid reaction occur.

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

It is important to use a separate sterile syringe and needle for each patient to prevent transmission of hepatitis B or other infectious agents from one person to another.

As with other vaccines, Liquid PedvaxHIB may not induce protective antibody levels immediately following vaccination.

As reported with Haemophilus b Polysaccharide Vaccine(36) and another Haemophilus b Conjugate Vaccine(37), cases of Hib disease may occur in the week after vaccination, prior to the onset of the protective effects of the vaccines.

There is insufficient evidence that Liquid PedvaxHIB given immediately after exposure to natural Haemophilus influenzae type b will prevent illness.

The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and on the etiology of the disease. The Advisory Committee on Immunization Practices (ACIP) has recommended that vaccination should be delayed during the course of an acute febrile illness. All vaccines can be administered to persons with minor illnesses such as diarrhea, mild upper-respiratory infection with or without low-grade fever, or other low-grade febrile illness. Persons with moderate or severe febrile illness should be vaccinated as soon as they have recovered from the acute phase of the illness.(46)

If PedvaxHIB is used in persons with malignancies or those receiving immunosuppressive therapy or who are otherwise immunocompromised, the expected immune response may not be obtained.

Instructions to Healthcare Provider

The healthcare provider should determine the current health status and previous vaccination history of the vaccinee.

The healthcare provider should question the patient, parent, or guardian about reactions to a previous dose of PedvaxHIB or other Haemophilus b Conjugate Vaccines.

Information for Patients

The healthcare provider should provide the vaccine information required to be given with each vaccination to the patient, parent, or guardian.

The healthcare provider should inform the patient, parent, or guardian of the benefits and risks associated with vaccination. For risks associated with vaccination, see ADVERSE REACTIONS.

Patients, parents, and guardians should be instructed to report any serious adverse reactions to their healthcare provider who in turn should report such events to the U. S. Department of Health and Human Services through the Vaccine Adverse Event Reporting System (VAERS), 1-800-822-7967.(47)

Laboratory Test Interactions

Sensitive tests (e.g., Latex Agglutination Kits) may detect PRP derived from the vaccine in urine of some vaccinees for at least 30 days following vaccination with lyophilized PedvaxHIB;(38) in clinical studies with lyophilized PedvaxHIB, such children demonstrated normal immune response to the vaccine.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Liquid PedvaxHIB has not been evaluated for carcinogenic or mutagenic potential, or potential to impair fertility.

Pregnancy

Pregnancy Category C: Animal reproduction studies have not been conducted with PedvaxHIB. Liquid PedvaxHIB is not recommended for use in individuals 6 years of age and older.

Pediatric Use

Safety and effectiveness in infants below the age of 2 months and in children 6 years of age and older have not been established. In addition, Liquid PedvaxHIB should not be used in infants younger than 6 weeks of age because this will lead to a reduced anti-PRP response and may lead to immune tolerance (impaired ability to respond to subsequent exposure to the PRP antigen).(49-51) Liquid PedvaxHIB is not recommended for use in individuals 6 years of age and older because they are generally not at risk of Hib disease.

Geriatric Use

This vaccine is NOT recommended for use in adult populations.

ADVERSE REACTIONS

Liquid PedvaxHIB

In a multicenter clinical study (n=903) comparing the effects of Liquid PedvaxHIB with those of lyophilized PedvaxHIB, 1,699 doses of Liquid PedvaxHIB were administered to 678 healthy infants 2 to 6 months of age from the general U.S. population. DTP and OPV were administered concomitantly to most subjects. Both formulations of PedvaxHIB were generally well tolerated and no serious vaccine-related adverse reactions were reported.

During a three-day period following primary vaccination with Liquid PedvaxHIB in these infants, the most frequently reported (>1%) adverse reactions, without regard to causality, excluding those shown in TABLE 5, in decreasing order of frequency, were: irritability, sleepiness, injection site pain/soreness, injection site erythema ((<=)2.5 cm diameter, see also TABLE 5), injection site swelling/induration ((<=)2.5 cm diameter, see also TABLE 5), unusual high-pitched crying, prolonged crying (>4 hr), diarrhea, vomiting, crying, pain, otitis media, rash, and upper respiratory infection.

Selected objective observations reported by parents over a 48-hour period in these infants following primary vaccination with Liquid PedvaxHIB are summarized in TABLE 5. -0-

                               TABLE 5

       Fever or Local Reactions in Subjects First Vaccinated at

             2 to 6 Months of Age with Liquid PedvaxHIB*

======================================================================


                                Post-Dose 1              Post-Dose 2

                                    (hr)                     (hr)

                               --------------           --------------

                     No. of                    No. of

 Reaction            Subjects                 Subjects

                     Evaluated  6    24   48  Evaluated  6    24   48

----------------------------------------------------------------------

                                 Percentage               Percentage

                               --------------           --------------

Fever**

>38.3(degree)C

(>=101(degree)F)

Rectal                  222    18.1 4.4  0.5     206    14.1 9.4  2.8

Erythema

>2.5 cm

diameter                674    2.2  1.0  0.5     562    1.6  1.1  0.4

Swelling

>2.5 cm

diameter                674    2.5  1.9  0.9     562    0.9  0.9  1.3


----------------------------------------------------------------------

* DTP and OPV were administered concomitantly to most subjects.

** Fever was also measured by another method or reported as normal for

 an additional 345 infants after dose 1 and for an additional 249

 infants after dose 2; however, these data are not included in this

 table.

----------------------------------------------------------------------

Adverse reactions during a three-day period following administration of the booster dose were generally similar in type and frequency to those seen following primary vaccination.

Lyophilized PedvaxHIB

In The Protective Efficacy Study (see CLINICAL PHARMACOLOGY), 4,459 healthy Navajo infants 6 to 12 weeks of age received lyophilized PedvaxHIB or placebo. Most of these infants received DTP/OPV concomitantly. No differences were seen in the type and frequency of serious health problems expected in this Navajo population or in serious adverse experiences reported among those who received lyophilized PedvaxHIB and those who received placebo, and none was reported to be related to lyophilized PedvaxHIB. Only one serious reaction (tracheitis) was reported as possibly related to lyophilized PedvaxHIB and only one (diarrhea) as possibly related to placebo. Seizures occurred infrequently in both groups (9 occurred in vaccine recipients, 8 of whom also received DTP; 8 occurred in placebo recipients, 7 of whom also received DTP) and were not reported to be related to lyophilized PedvaxHIB.

In early clinical studies involving the administration of 8,086 doses of lyophilized PedvaxHIB alone to 5,027 healthy infants and children 2 months to 71 months of age, lyophilized PedvaxHIB was generally well tolerated. No serious adverse reactions were reported. In a subset of these infants, urticaria was reported in two children, and thrombocytopenia was seen in one child. A cause and effect relationship between these side effects and the vaccination has not been established.

Potential Adverse Reactions

The use of Haemophilus b Polysaccharide Vaccines and another Haemophilus b Conjugate Vaccine has been associated with the following additional adverse effects: early onset Hib disease and Guillain-Barre syndrome. A cause and effect relationship between these side effects and the vaccination was not established.(36,37,39,40,41,49)

Post-Marketing Adverse Reactions

The following additional adverse reactions have been reported with the use of the lyophilized and liquid formulations of PedvaxHIB:

Hemic and Lymphatic System

Lymphadenopathy

Hypersensitivity

Rarely, angioedema

Nervous System

Febrile seizures

Skin

Sterile injection site abscess

DOSAGE AND ADMINISTRATION

Liquid PedvaxHIB

FOR INTRAMUSCULAR ADMINISTRATION

DO NOT INJECT INTRAVENOUSLY

If there is an interruption or delay between doses in the primary series, there is no need to repeat the series, but dosing should be continued at the next clinic visit. (See CONTRAINDICATIONS and PRECAUTIONS.)

2 to 14 Months of Age

Infants 2 to 14 months of age should receive a 0.5 mL dose of vaccine ideally beginning at 2 months of age followed by a 0.5 mL dose 2 months later (or as soon as possible thereafter). When the primary two-dose regimen is completed before 12 months of age, a booster dose is required (see below and TABLE 6). Infants born prematurely, regardless of birth weight, should be vaccinated at the same chronological age and according to the same schedule and precautions as full-term infants and children.(46)

15 Months of Age and Older

Children 15 months of age and older previously unvaccinated against Hib disease should receive a single 0.5 mL dose of vaccine.

Booster Dose

In infants completing the primary two-dose regimen before 12 months of age, a booster dose (0.5 mL) should be administered at 12 to 15 months of age, but not earlier than 2 months after the second dose.

Vaccination regimens for Liquid PedvaxHIB by age group are outlined in TABLE 6. -0-

                          TABLE 6

         Vaccination Regimens for Liquid PedvaxHIB

                       By Age Groups

============================================================

   Age (Months)           Primary           Age (Months)

  at First Dose                            at Booster Dose

------------------------------------------------------------

       2-10        2 doses, 2 mo. apart         12-15

      11-14        2 doses, 2 mo. apart          --

      15-71               1 dose                 --

------------------------------------------------------------

Interchangeability

PedvaxHIB may be interchanged with other licensed Haemophilus b Conjugate Vaccines for the primary and booster doses.(52) (See CLINICAL PHARMACOLOGY.)

Use with Other Vaccines

Results from clinical studies indicate that Liquid PedvaxHIB can be administered concomitantly with DTP, OPV, eIPV (enhanced inactivated poliovirus vaccine), VARIVAX (Varicella Virus Vaccine Live (Oka/Merck)), M-M-R II (Measles, Mumps, and Rubella Virus Vaccine Live) or RECOMBIVAX HB (Hepatitis B Vaccine (Recombinant)). No impairment of immune response to these individually tested vaccine antigens was demonstrated.

The type, frequency and severity of adverse experiences observed in these studies with PedvaxHIB were similar to those seen with the other vaccines when given alone. (See CLINICAL PHARMACOLOGY.)

In addition, a PRP-OMPC-containing product, COMVAX (Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine), was given concomitantly with a booster dose of DTaP (diphtheria, tetanus, acellular pertussis) at approximately 15 months of age, using separate sites and syringes for injectable vaccines. No impairment of immune response to these individually tested vaccine antigens was demonstrated. COMVAX has also been administered concomitantly with the primary series of DTaP to a limited number of infants. PRP antibody responses are satisfactory for COMVAX, but immune responses are currently unavailable for DTaP (see Manufacturer's Product Circular for COMVAX). No serious vaccine-related adverse events were reported.(33)

Parenteral drug products should be inspected visually for extraneous particulate matter and discoloration prior to administration whenever solution and container permit.

Liquid PedvaxHIB is a slightly opaque white suspension. (See DESCRIPTION.)

The vaccine should be used as supplied; no reconstitution is necessary.

Shake well before withdrawal and use. Thorough agitation is necessary to maintain suspension of the vaccine.

Inject 0.5 mL intramuscularly, preferably into the anterolateral thigh or the outer aspect of the upper arm. The buttocks should not be used for active vaccination of infants and children, because of the potential risk of injury to the sciatic nerve.

HOW SUPPLIED

Liquid PedvaxHIB is supplied as follows:

No. 4897 -- A box of 10 single-dose vials of liquid vaccine, NDC 0006-4897-00.

Storage

Store vaccine at 2-8(degree)C (36-46(degree)F).

DO NOT FREEZE.

REFERENCES

1. Cochi, S. L., et al: Immunization of U.S. children with Haemophilus influenzae type b polysaccharide vaccine: A cost-effectiveness model of strategy assessment. JAMA 253: 521-529, 1985.

2. Schlech, W. F., III, et al: Bacterial meningitis in the United States, 1978 through 1981. The National Bacterial Meningitis Surveillance Study. JAMA 253: 1749-1754, 1985.

3. Peltola, H., et al: Prevention of Haemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 310: 1561-1566, 1984.

4. Cadoz, M., et al: Etude epidemiologique des cas de meningitis purulentes hospitalises a Dakar pendant la decemie 1970-1979. Bull WHO 59: 575-584, 1981.

5. Sell, S. H., et al: Long-term Sequelae of Haemophilus influenzae meningitis. Pediatr 49: 206-217, 1972.

6. Taylor, H. G., et al: Intellectual, neuropsychological, and achievement outcomes in children six to eight years after recovery from Haemophilus influenzae meningitis. Pediatr 74: 198-205, 1984.

7. Hay, J. W., et al: Cost-benefit analysis of two strategies for prevention of Haemophilus influenzae type b infection. Pediatr 80(3): 319-329, 1987.

8. Redmond, S. R., et al: Haemophilus influenzae type b disease: an epidemiologic study with special reference to daycare centers. JAMA 252: 2581-2584, 1984.

9. Istre, G. R., et al: Risk factors for primary invasive Haemophilus influenzae disease: increased risk from daycare attendance and school age household members. J Pediatr 106: 190-195, 1985.

10. Fraser, D.W., et al: Risk factors in bacterial meningitis: Charleston County, South Carolina. J Infect Dis 127: 271-277, 1973.

11. Tarr, P. I., et al: Demographic factors in the epidemiology of Haemophilus influenzae meningitis in young children. J Pediatr 92: 884-888, 1978.

12. Granoff, D. M., et al: Response to immunization with Haemophilus influenzae type b polysaccharide-pertussis vaccine and risk of Haemophilus meningitis in children with Km(1) immunoglobulin allotype. J Clin Invest 74: 1708-1714, 1984.

13. Ambrosino, D. M., et al: Correlation between G2m(n) immunoglobulin allotype and human antibody response and susceptibility to polysaccharide encapsulated bacteria. J Clin Invest 75: 1935-1942, 1985.

14. Coulehan, J. L., et al: Epidemiology of Haemophilus influenzae type b disease among Navajo Indians. Pub Health Rep 99: 404-409, 1984.

15. Losonsky, G. A., et al: Haemophilus influenzae disease in the White Mountain Apaches: molecular epidemiology of a high risk population. Pediatr Infect Dis J 3: 539-547, 1985.

16. Ward, J. I., et al: Haemophilus influenzae disease in Alaskan Eskimos: characteristics of a population with an unusual incidence of disease. Lancet 1: 1281-1285, 1981.

17. Ward, J. I., et al: Haemophilus influenzae meningitis: a national study of secondary spread in household contacts. N Engl J Med 301: 122-126, 1979.

18. Ward, J., et al: Haemophilus influenzae bacteremia in children with sickle cell disease. J Pediatr 88: 261-263, 1976.

19. Bartlett, A. V., et al: Unusual presentations of Haemophilus influenzae infections in immuno-compromised patients. J Pediatr 102: 55-58, 1983.

20. Recommendations of the Immunization Practices Advisory Committee. Polysaccharide vaccine for prevention of Haemophilus influenzae type b disease. MMWR 34(15): 201-205, 1985.

21. Santosham, M., et al: Prevention of Haemophilus influenzae type b infections in high-risk infants treated with bacterial polysaccharide immune globulin. N Engl J Med 317: 923-929, 1987.

22. Siber, G. R., et al: Preparation of human hyperimmune globulin to Haemophilus influenzae b, Streptococcus pneumoniae, and Neisseria meningitidis. Infect Immun 45: 248-254, 1984.

23. Smith, D. H., et al: Responses of children immunized with the capsular polysaccharide of Haemophilus influenzae type b. Pediatr 52: 637-645, 1973.

24. Robbins, J. B., et al: Quantitative measurement of 'natural' and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res 7: 103-110, 1973.

25. Kaythy, H., et al: The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis 147: 1100, 1983.

26. Peltola, H., et al: Haemophilus influenzae type b capsular polysaccharide vaccine in children: a double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland. Pediatr 60: 730-737, 1977.

27. Ward, J. I., et al: Haemophilus influenzae type b vaccines: Lessons For the Future. Pediatr 81: 886-893, 1988.

28. Daum, R. S., et al: Haemophilus influenzae type b vaccines: Lessons From the Past. Pediatr 81: 893-897, 1988.

29. Marburg, S., et al: Bimolecular chemistry of macromolecules: Synthesis of bacterial polysaccharide conjugates with Neisseria meningitidis membrane protein. J Am Chem Soc 108: 5282-5287, 1986.

30. Letson, G. W., et al: Comparison of active and combined passive/active immunization of Navajo children against Haemophilus influenzae type b. Pediatr Infect Dis J 7(111): 747-752, 1988.

31. Einhorn, M. S., et al: Immunogenicity in infants of Haemophilus influenzae type b polysaccharide in a conjugate vaccine with Neisseria meningitidis outer-membrane protein. Lancet 2: 299-302, 1986.

32. Ahonkhai, V.I., et al: Haemophilus influenzae type b Conjugate Vaccine (Meningococcal Protein Conjugate) (PedvaxHIB TM): Clinical Evaluation. Pediatr 85(4): 676-681, 1990.

33. Data on file at Merck Research Laboratories.

34. Granoff, D. M., et al: Immunogenicity of Haemophilus influenzae type b polysaccharide--outer membrane protein conjugate vaccine in patients who acquired Haemophilus disease despite previous vaccination with type b polysaccharide vaccine. J. Pediatr. 114(6): 925-933, June 1989.

35. Lenoir, A. A., et al: Response to Haemophilus influenzae type b (H. influenzae type b) polysaccharide N. meningitidis outer membrane protein (PS-OMP) conjugate vaccine in relation to Km(1) and G2m(23) allotypes. Twenty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy (Abstract #216) 133, 1986.

36. Mortimer, E. A.: Efficacy of Haemophilus b polysaccharide vaccine: An enigma. JAMA 260: 1454, 1988.

37. Meekison, W., et al: Post-marketing surveillance of adverse effects following ProHIBiT vaccine. British Columbia Canada Diseases Weekly Report 15-28: 143-145, 1989.

38. Goepp, J. G., et al: Persistent urinary antigen excretion in infants vaccinated with Haemophilus influenzae type b capsular polysaccharide conjugated with outer membrane protein from Neisseria meningitidis. Pediatr Infect Dis J 11(1): 2-5, 1992.

39. Milstein, J. B., et al: Adverse reactions reported following receipt of Haemophilus influenzae type b vaccine: An analysis after one year of marketing. Pediatr 80: 270, 1987.

40. Black, S., et al: b-CAPSA 1 Haemophilus influenzae type b capsular polysaccharide vaccine safety. Pediatr 79: 321-325, 1987.

41. D'Cruz, O. F., et al: Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome) after immunization with Haemophilus influenzae type b Conjugate Vaccine. J Pediatr 115: 743-746, 1989.

42. Recommendations of the Immunization Practices Advisory Committee. Recommendations for use of Haemophilus b Conjugate Vaccines and a combined diphtheria, tetanus, pertussis, and Haemophilus b vaccine. MMWR 42(RR-13): 1-15, 1993.

43. Daum, R. S., et al: Interchangeability of Haemophilus influenzae type b vaccines for the primary series (mix and match): a preliminary analysis (Abstract 976). Pediatr Res 33: 166A, 1993.

44. Greenberg, D. P., et al: Enhanced antibody responses in infants given different sequences of heterogenous Haemophilus influenzae type b Conjugate Vaccines. J Pediatr 126: 206-211, 1995.

45. Anderson, E. L., et al: Interchangeability of Conjugated Haemophilus influenzae type b Vaccines in Infants. JAMA 273: 849-853, 1995.

46. Recommendations of the Immunization Practices Advisory Committee. General Recommendations on Immunization. MMWR 43(RR-1), 1994.

47. Vaccine Adverse Event Reporting System - United States. MMWR 39(41): 730-733, October 19, 1990.

48. Institute of Medicine Adverse Events Associated With Childhood Vaccines Evidence Bearing on Causality. National Academy Press, Washington, D.C., 260-261, 1994.

49. Keyserling, H.L., et al: Program and Abstracts of the 30th ICAAC, (Abstract #63), 1990.

50. Ward, J.I., et al: Program and Abstracts of the 32nd ICAAC, (Abstract #984), 1992.

51. Lieberman, J.M., et al: Infect Dis, (Abstract #1028), 1993.

52. American Academy of Pediatrics. Recommended Childhood Immunization Schedule - United States, January-December 1998. Pediatr 101(1): 154-157, 1998.

Issued January 2001

Printed in USA

* Registered trademark of MERCK & CO., Inc. COPYRIGHT (C) MERCK & CO., Inc., 1998 All rights reserved

COMVAX(R) 9376602

(Haemophilus b Conjugate (Meningococcal Protein Conjugate)

and Hepatitis B (Recombinant) Vaccine)

9376602

COMVAX(R)

(HAEMOPHILUS b CONJUGATE (MENINGOCOCCAL PROTEIN CONJUGATE) and HEPATITIS B (RECOMBINANT) VACCINE)

DESCRIPTION

COMVAX* (Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine) is a sterile bivalent vaccine made of the antigenic components used in producing PedvaxHIB* (Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)) and RECOMBIVAX HB* (Hepatitis B Vaccine (Recombinant)). These components are the Haemophilus influenzae type b capsular polysaccharide (polyribosylribitol phosphate (PRP)) that is covalently bound to an outer membrane protein complex (OMPC) of Neisseria meningitidis and hepatitis B surface antigen (HBsAg) from recombinant yeast cultures.

Haemophilus influenzae type b and Neisseria meningitidis serogroup B are grown in complex fermentation media. The primary ingredients of the phenol-inactivated fermentation medium for Haemophilus influenzae include an extract of yeast, nicotinamide adenine dinucleotide, hemin chloride, soy peptone, dextrose, and mineral salts and for Neisseria meningitidis include an extract of yeast, amino acids and mineral salts. The PRP is purified from the culture broth by purification procedures which include ethanol fractionation, enzyme digestion, phenol extraction and diafiltration. The OMPC from Neisseria meningitidis is purified by detergent extraction, ultracentrifugation, diafiltration and sterile filtration.

The PRP-OMPC conjugate is prepared by the chemical coupling of the highly purified PRP (polyribosylribitol phosphate) of Haemophilus influenzae type b (Haemophilus b, Ross strain) to an OMPC of the B11 strain of Neisseria meningitidis serogroup B. The coupling of the PRP to the OMPC is necessary for enhanced immunogenicity of the PRP. This coupling is confirmed by analysis of the components of the conjugate following chemical treatment which yields a unique amino acid. After conjugation, the aqueous bulk is then adsorbed onto an amorphous aluminum hydroxyphosphate sulfate adjuvant (previously referred to as aluminum hydroxide).

HBsAg is produced in recombinant yeast cells. A portion of the hepatitis B virus gene, coding for HBsAg, is cloned into yeast, and the vaccine for hepatitis B is produced from cultures of this recombinant yeast strain according to methods developed in the Merck Research Laboratories. The antigen is harvested and purified from fermentation cultures of a recombinant strain of the yeast Saccharomyces cerevisiae containing the gene for the adw subtype of HBsAg. The fermentation process involves growth of Saccharomyces cerevisiae on a complex fermentation medium which consists of an extract of yeast, soy peptone, dextrose, amino acids and mineral salts.

The HBsAg protein is released from the yeast cells by mechanical cell disruption and detergent extraction, and purified by a series of physical and chemical methods, which includes ion and hydrophobic chromatography, and diafiltration. The purified protein is treated in phosphate buffer with formaldehyde and then coprecipitated with alum (potassium aluminum sulfate) to form bulk vaccine adjuvanted with amorphous aluminum hydroxyphosphate sulfate. The vaccine contains no detectable yeast DNA, and 1% or less of the protein is of yeast origin.

The individual PRP-OMPC and HBsAg adjuvanted bulks are combined to produce COMVAX. Each 0.5 mL dose of COMVAX is formulated to contain 7.5 mcg PRP conjugated to approximately 125 mcg OMPC, 5 mcg HBsAg, approximately 225 mcg aluminum as amorphous aluminum hydroxyphosphate sulfate, and 35 mcg sodium borate (decahydrate) as a pH stabilizer, in 0.9% sodium chloride. The vaccine contains not more than 0.0004% (w/v) residual formaldehyde.

The potency of the PRP-OMPC component is measured by quantitating the polysaccharide concentration by an HPLC method. The potency of the HBsAg component is measured relative to a standard by an in vitro immunoassay.

The product contains no preservative.

COMVAX is a sterile suspension for intramuscular injection.

CLINICAL PHARMACOLOGY

Haemophilus influenzae type b Disease

Prior to the introduction of Haemophilus b conjugate vaccines, Haemophilus influenzae type b (Hib) was the most frequent cause of bacterial meningitis and a leading cause of serious, systemic bacterial disease in young children worldwide.1-4

Hib disease occurred primarily in children under 5 years of age, and in the United States prior to the initiation of a vaccine program was estimated to account for nearly 20,000 cases of invasive infections annually, approximately 12,000 of which were meningitis. The mortality rate from Hib meningitis is about 5%. In addition, up to 35% of survivors develop neurologic sequelae including seizures, deafness, and mental retardation.5,6 Other invasive diseases caused by this bacterium include cellulitis, epiglottitis, sepsis, pneumonia, septic arthritis, osteomyelitis, and pericarditis.

Prior to the introduction of the vaccine, it was estimated that 17% of all cases of Hib disease occurred in infants less than 6 months of age. The peak incidence of Hib meningitis occurred between 6 to 11 months of age. Forty-seven percent of all cases occurred by one year of age with the remaining 53% of cases occurring over the next four years.2,20

Among children under 5 years of age, the risk of invasive Hib disease is increased in certain populations including the following:

-- Daycare attendees7,8,9

-- Lower socio-economic groups10

-- Blacks11 (especially those who lack the Km(1) immunoglobulin allotype)12

-- Caucasians who lack the G2m(23) immunoglobulin allotype13

-- Native Americans14-16

-- Household contacts of cases17

-- Individuals with asplenia, sickle cell disease, or antibody deficiency syndromes.18,19

Prevention of Hib Disease with Vaccine

An important virulence factor of the Hib bacterium is its polysaccharide capsule (PRP). Antibody to PRP (anti-PRP) has been shown to correlate with protection against Hib disease.3,21 While the anti-PRP level associated with protection using conjugated vaccines has not yet been determined, the level of anti-PRP associated with protection in studies using bacterial polysaccharide immune globulin or nonconjugated PRP vaccines ranged from (>=)0.15 to (>=)1.0 mcg/mL.22-28

Nonconjugated PRP vaccines are capable of stimulating B-lymphocytes to produce antibody without the help of T-lymphocytes (T-independent). The responses to many other antigens are augmented by helper T-lymphocytes (T-dependent). PedvaxHIB is a PRP-conjugate vaccine in which the PRP is covalently bound to the OMPC carrier29 producing an antigen which is postulated to convert the T-independent antigen (PRP alone) into a T-dependent antigen resulting in both an enhanced antibody response and immunologic memory.

Clinical Trials with PedvaxHIB

The protective efficacy of the PRP-OMPC component of COMVAX was demonstrated in a randomized, double-blind, placebo-controlled study involving 3486 Native American (Navajo) infants (The Protective Efficacy Study) who completed the primary two-dose regimen for lyophilized PedvaxHIB. This population has a much higher incidence of Hib disease than the United States population as a whole and also has a lower antibody response to Haemophilus b conjugate vaccines, including PedvaxHIB.14-16,30,31

Each infant in this study received two doses of either placebo or lyophilized PedvaxHIB (15 mcg Haemophilus b PRP) with the first dose administered at a mean of 8 weeks of age and the second administered approximately two months later; DTP (Diphtheria and Tetanus Toxoids and whole cell Pertussis Vaccine, Adsorbed) and OPV (Poliovirus Vaccine Live Oral Trivalent) were administered concomitantly. In a subset of 416 subjects, lyophilized PedvaxHIB (15 mcg Haemophilus b PRP) induced anti-PRP levels >0.15 mcg/mL in 88% and >1.0 mcg/mL in 52% with a geometric mean titer (GMT) of 0.95 mcg/mL one to three months after the first dose; the corresponding anti-PRP levels one to three months following the second dose were 91% and 60%, respectively, with a GMT of 1.43 mcg/mL. These antibody responses were associated with a high level of protection.

Most subjects were initially followed until 15 to 18 months of age. During this time, 22 cases of invasive Hib disease occurred in the placebo group (8 cases after the first dose and 14 cases after the second dose) and only 1 case in the vaccine group (none after the first dose and 1 after the second dose). Following the primary two-dose regimen, the protective efficacy of lyophilized PedvaxHIB was calculated to be 93% with a 95% confidence interval (C.I.) of 57-98%. In the two months between the first and second doses, the difference in number of cases of disease between placebo and vaccine recipients (8 vs 0 cases, respectively) was statistically significant (p=0.008). At termination of the study, placebo recipients were offered vaccine. All original participants were then followed two years and nine months from termination of the study. During this extended follow-up, invasive Hib disease occurred in an additional 7 of the original placebo recipients prior to receiving vaccine and in 1 of the original vaccine recipients (who had received only 1 dose of vaccine). No cases of invasive Hib disease were observed in placebo recipients after they received at least one dose of vaccine. Efficacy for this follow-up period, estimated from person-days at risk, was 96.6% (95 C.I., 72.2-99.9%) in children under 18 months of age and 100% (95 C.I., 23.5-100%) in children over 18 months of age.31 Thus, in this study, a protective efficacy of 93% was achieved with an anti-PRP level of >1.0 mcg/mL in 60% of vaccinees and a GMT of 1.43 mcg/mL one to three months after the second dose.

Hepatitis B Disease

Hepatitis B virus is an important cause of viral hepatitis. According to the Centers for Disease Control (CDC), there are an estimated 200,000-300,000 new cases of Hepatitis B infection annually in the United States.32 There is no specific treatment for this disease. The incubation period for hepatitis B is relatively long; six weeks to six months may elapse between exposure and the onset of clinical symptoms. The prognosis following infection with hepatitis B virus is variable and dependent on at least three factors: (1) Age -- infants and younger children usually experience milder initial disease than older persons but are much more likely to remain persistently infected and become at risk of developing serious chronic liver disease; (2) Dose of virus -- the higher the dose, the more likely acute icteric hepatitis B will result; and, (3) Severity of associated underlying disease -- underlying malignancy or pre-existing hepatic disease predisposes to increased mortality and morbidity.34

Hepatitis B infection fails to resolve and progresses to a chronic carrier state in 5 to 10% of older children and adults and in up to 90% of infants; chronic infection also occurs more frequently after initial anicteric hepatitis B than after initial icteric disease.34 Consequently, carriers of HBsAg frequently give no history of having had recognized acute hepatitis. It has been estimated that more than 285 million people in the world today are persistently infected with hepatitis B virus.35 The CDC estimates that there are approximately 1 million-1.25 million chronic carriers of hepatitis B virus in the USA.32 Chronic carriers represent the largest human reservoir of hepatitis B virus.

A serious complication of acute hepatitis B virus infection is massive hepatic necrosis while sequelae of chronic hepatitis B include cirrhosis of the liver, chronic active hepatitis, and hepatocellular carcinoma. Chronic carriers of HBsAg appear to be at increased risk of developing hepatocellular carcinoma. Although a number of etiologic factors are associated with development of hepatocellular carcinoma, the single most important etiologic factor appears to be chronic infection with hepatitis B virus.36 According to the CDC, hepatitis B vaccine is recognized as the first anti-cancer vaccine because it can prevent primary liver cancer.67

The vehicles for transmission of the virus are most often blood and blood products but the viral antigen has also been found in tears, saliva, breast milk, urine, semen, and vaginal secretions. Hepatitis B virus is capable of surviving for days on environmental surfaces exposed to body fluids containing hepatitis B virus. Infection may occur when hepatitis B virus, transmitted by infected body fluids, is implanted via mucous surfaces or percutaneously introduced through accidental or deliberate breaks in the skin. Transmission of hepatitis B virus infection is often associated with close interpersonal contact with an infected individual and with crowded living conditions.37

Prevention of Hepatitis B Disease with Vaccine

Hepatitis B infection and disease can be prevented through immunization with vaccines that contain viral surface antigen (HBsAg) and induce formation of protective antibody (anti-HBs).38-39

Multiple clinical studies have defined a protective level of anti-HBs as 1) 10 or more sample ratio units (SRU or S/N) as determined by radioimmunoassay or 2) a positive result as determined by enzyme immunoassay.40-46 Note: 10 SRU is comparable to 10 mIU/mL of antibody.36 The ACIP and an international group of hepatitis B experts consider an anti-HBs titer (>=)10 mIU/mL an adequate response to a complete course of hepatitis B vaccine and protective against clinically significant infection (antigenemia with or without clinical disease).36,46

Clinical Trials with RECOMBIVAX HB

In clinical studies, 100% of 92 infants under 1 year of age born of non-carrier mothers developed a protective level of antibody (anti-HBs (>=)10 mIU/mL) after receiving three 5-mcg doses of RECOMBIVAX HB at intervals of 0, 1, and 6 months.31

In one clinical study of RECOMBIVAX HB (2.5 mcg), which examined a different regimen of RECOMBIVAX HB, protective levels of antibody were achieved in 98% of 52 healthy infants vaccinated at 2, 4, and 12 months of age. Protective anti-HBs levels were achieved in 100% of 50 infants vaccinated at 2, 4, and 15 months of

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