Pediatric Annals

One For All: Newer Combination Vaccines in Practice

Gary S Marshall, MD

Abstract

Editor's note: Manufacturer names, and product names as listed in the manufacturer's own product information, have been used in this article to avoid confusion caused by the complexity in the various combinations of vaccines being discussed.

Vaccine practice has become complicated. The routine childhood schedule outlined in the 1982 Red Book1 provided protection against seven diseases through the administration of three different vaccines: diphtheria, tetanus, whole-cell pertussis (DTwP) vaccine; oral (liveattenuated) polio vaccine; and measles, mumps, and rubella (MMR) vaccine. By fall 2004, the schedule will offer protection against 12 diseases through the administration of eight different vaccines: hepatitis B; diphtheria, tetanus, and acellular pertussis (DTaP); Haemophilus influenzae type b (Hib); inactivated polio (IPV); pneumococcal polysaccharide conjugate, 7-valent (PCV-7); MMR; varicella; and influenza.2·3 With universal use of hepatitis A vaccine in some areas, the totals are 13 diseases prevented through the use of nine different vaccines (Figure 1 , see page 503).

Replacing monovalent vaccines with TriHIBit reduces the number of shots by one.

COMVAX - Licensed in 1996

COMVAX essentially is a combination of PedvaxHIB and RECOMBIVAX HB (Merck & Co., hepatitis B). Each dose contains 7.5 pg of PRP-OMP and 5 pg of hepatitis B surface antigen (HBsAg), as well as alum. The vaccine provides no protection against meningococcal disease even though it contains meningococcal outer membrane protein as a carrier. The product is preservativefree and is supplied as a liquid in onedose vials.

COMVAX is labeled for prevention of invasive Hib disease and hepatitis B infection in infants age 6 weeks to 15 months born to HBsAg-negative mothers. Despite this labeling, it should be pointed out that die Advisory Committee on Immunization Practices accepts use of Comvax for infants of HBsAg-positive and -unknown mothers.

Each dose is 0.5 mL administered intramuscularly, and may be given at the same time as any other vaccines given at separate sites. Usually, doses are administered at ages 2, 4, and 12 to 15 months. If this schedule cannot be followed, the interval between the first two doses should be at least 6 weeks. Although the minimum interval between the second and last doses is 8 weeks, the last dose should be given at age 12 months or older.

As all infants should receive a birth dose of monovalent hepatitis B vaccine, use of COMVAX results in the child's receiving four total doses, which is one more than usual. Although cumbersome, extraimmunization could be avoided by substituting PedvaxHIB at age 41 months.

It is extremely important that COMVAX not be used for the birth dose of hepatitis B vaccine, nor used before age 6 weeks, because of the possibility of inducing tolerance to future doses of Hib conjugate. The immunogenicity of COMVAX when used in a series with otiher hepatitis B or Hib conjugate vaccines has not been studied, but immunogenicity data from studies of monovalent vaccines indicate that any combination of Hib conjugate vaccines may be used to complete the primary series.30·31 When COMVAX and a Hib conjugate other than PedvaxHIB are used to complete the primary series, three doses should be administered at ages 2, 4, and 6 months. Hepatitis B vaccines are considered completely interchangeable.

Replacing monovalent vaccines with COMVAX reduces the number of shots by three or two, depending on whether PedvaxHIB is already being used (Table, see page 507).

TWINRIX - Licensed in 2001

TWINRIX (GlaxoSmithKline) is essentially a combination of HAVRIX (GlaxoSmithKline), a hepatitis A vaccine, and ENGERIX-B (GlaxoSmithKline), a hepatitis B vaccine. Each dose contains at least 720 enzyme-linked immunosorbent assay units of inactivated hepatitis A virus, which is equivalent to the pediatric formulation of…

Editor's note: Manufacturer names, and product names as listed in the manufacturer's own product information, have been used in this article to avoid confusion caused by the complexity in the various combinations of vaccines being discussed.

Vaccine practice has become complicated. The routine childhood schedule outlined in the 1982 Red Book1 provided protection against seven diseases through the administration of three different vaccines: diphtheria, tetanus, whole-cell pertussis (DTwP) vaccine; oral (liveattenuated) polio vaccine; and measles, mumps, and rubella (MMR) vaccine. By fall 2004, the schedule will offer protection against 12 diseases through the administration of eight different vaccines: hepatitis B; diphtheria, tetanus, and acellular pertussis (DTaP); Haemophilus influenzae type b (Hib); inactivated polio (IPV); pneumococcal polysaccharide conjugate, 7-valent (PCV-7); MMR; varicella; and influenza.2·3 With universal use of hepatitis A vaccine in some areas, the totals are 13 diseases prevented through the use of nine different vaccines (Figure 1 , see page 503).

During the past 2 decades, me maximum number of individual vaccine doses represented by the routine childhood schedule increased from 12 to 26 (28 if hepatitis A is included). Things may get worse - or better, one should say, because new vaccines are in the pipeline, every one of which carries the promise of improved health for children. However, this progress leaves pediatricians asking how they will continue to execute an already complicated schedule, much less convince parents that the added injections are worth the pain.

The simple solution would be to combine many antigens into a single injection. In fact, this approach is not new.

Pneumococcal ride, PCV-7, meningococcal polysaccharide, DTaP, and MMR are all combination vaccines. Technically, polio and influenza vaccines also are combinations, because each contains three different strains of the respective virus. Were it not for combination products, the routine childhood schedule would represent up to 97 separate injections.

The modern era of combination vaccines began in the 1990s with the licensure of two products that combined existing traditional vaccines. TETRAMUNE (Wyeth Pharmaceuticals), licensed in 1993, was a combination of DTwP with polyribosylribitol phosphate (the capsular antigen of Hib) conjugated to a mutant diphtheria toxoid, known as HbOC. ActHIB/DTwP (Aventis Pasteur), also licensed in 1993, used DTwP vaccine to reconstitute polyribosylribitol phosphate conjugated to tetanus toxoid (PRP-T). While neither of these vaccines is used today, they paved the way for many useful combinations, some of which are discussed in this article.

POTENTIAL ADVANTAGES AND DISADVANTAGES

Combination vaccines offer many potential advantages, most of which are self-evident (Sidebar, see page 504).

The potential disadvantages are less obvious, however. For example, whereas decreased visits may be an advantage from me payer's point of view, pediatricians depend on vaccine visits to achieve other healmcare goals such as anticipatory guidance. In addition, inserting certain combination vaccines into the schedule may result in extra doses of one or more antigens. While unaesthetic, extra doses of an antigen do not appear to increase reactogenicity, except possibly in the cases of tetanus4 and pneumococcal polysaccharide5 vaccines. Immunogenicity also does not appear to be affected adversely. In fact, it may actually be improved, such as when four doses of hepatitis B vaccine are given as a monovalent birth dose, followed by subsequent doses of a combination containing hepatitis B at ages 2, 4, and 6 months.6 The "super-immunity" mat may result from extra-immunization probably is not necessary, but at the same time it probably won't hurt infants.

Parent and Provider Perspectives

Several studies have confirmed that multiple injections at a single visit are distressing to parents, nurses, and physicians; in fact, physicians may actually be more distressed man parents.7 One study showed parents would be willing to pay $20 for their child to receive one shot instead of two; by comparison, they would pay $100 to avoid severe pain, $500 to avoid an outpatient case of pertussis, and $15,000 to avoid blindness.8 It stands to reason that more injections mean more time and effort on the part of office personnel. More important, however, a long, drawn-out series of monovalent vaccines carries the risk of noncompletion and, therefore, nonprotection.

It was demonstrated in the early 1990s mat coverage rates would increase significantly if physicians would take advantage of opportunities for simultaneous administration of traditional vaccines.9 Although combination vaccines have the potential to do mis automatically, few studies have looked at whether such returns are realized in actual practice. One study examined the effects of ^ switching from monovalent hepatitis B and Hib vaccines to COMVAX (Merck & Co.), a combination of hepatitis B vaccine witìi polyribosylribitol phosphate (tire capsular antigen of Hib), conjugated to the outer membrane protein of Neisse- * ria meningitidis, or PRP-OMP.'0 The switch took place in a large Seattle-based health-maintenance organization in July 1997 and was 90% complete within 1 year. Children born during the year after the switch were compared witfi those born in the 6 months preceding the switch. No significant differences were seen in up-to-date status at ages 1 or 2, although children who received COMVAX spent 19 more days up-to-date for i Hib by age 2. The absence of a significant result here may have been due to a ceiling effect, as vaccine coverage levels were already high before the switch.

The Combination Vaccines Impact on Satisfaction and Epidemiology (COVISE) Study," funded by GlaxoSmithKline, intends to determine the potential effect of PEDIARIX (GlaxoSmithKline), which is a combination of DTaP3 (the number indictating pertussis components), hepatitis B, and IPV, on coverage rates, provider and parent satisfaction, costs, and office logistics. Not surprisingly, preliminary data show each additional injection during a vaccine visit adds an incremental minute of preparation, administration, and recordkeeping. Interestingly, me time spent disseminating vaccine information and obtaining consent appears to be independent of the number of injections. Therefore, PEDIARDv may save money by saving time.

Will enough time be saved, however, to allow for reductions in staffing and consequent reductions in payroll, and will diese savings be negated by the loss of administration fees and the cost of me vaccine? Will the newfound time be used to deliver care that was previously neglected, resulting in a cost-neutral improvement in quality? Will administration fees for combination vaccines someday be higher than for monovalent vaccines to make up the difference? New pediatric-specific codes for 2005 will recognize physician work in counseling parents about vaccines but will not single out combination vaccines. There are currently no answers to these questions, and given the variety of practice settings, staffing models, purchasing plans, and payer mixes, each provider will need to find individual answers.

Modeling data from the COVISE study12 do suggest PEDIARIX has the potential to increase coverage levels at age 12 months. The improvements in coverage are predicted to occur through earlier completion of the hepatitis B vaccine and IPV schedules. The routine childhood schedule2 calls for the third dose of hepatitis B vaccine to be given between age 24 weeks and 18 months and the third dose of IPV to be given between age 6 and 1 8 months. If PEDIARJX is used at age 2, 4, and 6 months, the hepatitis B series is completed, as is the primary series of IPV However, an IPV booster is still needed at age 4 to 6.

Figure l.The number of diseases preventable by routine vaccination (circles), doses represented by the routine childhood schedule (squares), and new vaccine types available in the United States (triangles) is shown by Red Book publication year. Note that influenza vaccine is included in year 2003 even though the official recommendation for routine administration was not made until 2004. Dotted lines represent inclusion of hepatitis A vaccine.

Figure l.The number of diseases preventable by routine vaccination (circles), doses represented by the routine childhood schedule (squares), and new vaccine types available in the United States (triangles) is shown by Red Book publication year. Note that influenza vaccine is included in year 2003 even though the official recommendation for routine administration was not made until 2004. Dotted lines represent inclusion of hepatitis A vaccine.

Chemical and Biologic Interactions

One cannot make the assumption that a combination of individual vaccines will work as well as the individual vaccines given separately. The chemical constituents themselves may interact in unexpected ways. For example, the preservative thimerosal decreases the immunogenicity of polio type 1 antigens in trivalent IPV without affecting types 2 and 3, whereas the preservative 2-phenoxyethanol has no such differential effect.13 This chemical interaction would remain unknown until the components were combined and me experiment was done.

In addition, antigens may interfere with each other for recognition by the immune system (Figure 2, see page 505). The mechanisms are not well understood, but the, effects are real. For example, examine what happens when Hib conjugate vaccines are combined with DTaP (Figure 3, see page 506). No matter which products are used, the responses to the Hib polysaccharide capsular antigen, PRP, are diminished. This phenomenon has delayed the introduction of pre-mixed combinations containing Hib conjugate in the United States.

There is, however, some controversy surrounding this. Although the percentage of children who achieve protective levels of antibody is decreased, the question remains of what constitutes a "protective" level of antibody. Original estimates of this level (0.15 pg/mL at the time of exposure, 1 pg/mL post-immunization) were derived principally from studies of the pure polysaccharide vaccine, a vaccine mat does not induce immunological memory.14 Would a child who received a protein-polysaccharide conjugate vaccine, which does induce memory, still be protected from disease even though the child's antibody level has fallen below the accepted level? In the United Kingdom, where booster doses of Hib conjugate are not routinely given, effectiveness of vaccination seems to persist even though PRP antibody levels wane.15

At the individual level, this may be due to anam-nestic immunity; at the population level, reduced colonization probably plays a role. It has been demonstrated that after die primary series of Hib conjugate, responses to pure PRP polysaccharide, a surrogate for re-exposure to Haemophilus influenzae itself, are rapid.16 It is unknown, however, if responses will be rapid enough to protect an individual child from fulminant infection after a heavy inoculum exposure. The first combination vaccine to overcome these concerns in the United States may be PENTACEL (Aventis Pasteur), a combination of DTaPS, IPV, and PRP-T (Table, see page 507).

Another example of interference is when MMR is mixed with varicella vaccine (MMRV); responses to die varicella component are diminished, presumably because measles virus replication interfere with replication of the varicella component.17 ProQuad (Merck & Co.), an MMRV vaccine, may be the first vaccine to overcome this problem in the United States. The solution, it appears, is fairly simple - increase the amount of varicella in the mixture. This overcomes the problem of the vaccine not taking without substantially increasing reactogenicity.

Clearly, responses to multiple antigens in a single shot may be achieved, as evidenced in immunogenicity studies of COMVAX,18 PEDIARIX,19 and PENTACEL.20 It is important to differentiate immunological interference as discussed previously from the idea mat multiple vaccines somehow "use up" or overwhelm the immune system, an idea popularized by some of tiiose opposed to vaccinations. Infants have the theoretical capacity to respond to hundreds of vaccine antigens at the same time, and there is no evidence that administration of multiple vaccines causes immune incompetence or increases the risk of heterologous infection.21 For tfiose parents who may still be concerned, it is important to point out that the vaccinepreventable diseases themselves, not the vaccines, increase a child's risk of succumbing to other infections. Classic examples include bacterial pneumonia in the setting of influenza and invasive group A streptococcal infection complicating chickenpox.

Reactogenicity

Theoretically, combining vaccines could increase the frequency or severity of known reactions.22 Although there are some examples of increased local reactions, these generally are mild and are offset by the benefits of fewer needle sticks and fewer limbs involved.23 Some combinations may increase fever rates, but these are usually low-grade fevers and without clinical consequence. Combination vaccines have not caused reactions that have not previously been seen.

AUTHORITATIVE GUIDELINES

Based on me potential for improved coverage rates, reduced costs, and facilitation of introduction of new vaccines, the Advisory Committee on Immunization Practices of the Centers for Disease Control and Prevention, the American Academy of Pediatrics, and the American Academy of Family Physicians issued a joint statement in 1999 indicating a clear preference for combination vaccines as opposed to separate injection of monovalent components.24 The same statement advised against combining separate vaccines into die same syringe unless the products were specifically labeled for dus use; currently, only TriHIBit (Aventis Pasteur, PRP-T reconstituted wim DTaP2) is indicated for this.

Figure 2. Panel A: Vaccine antigens compete with each other for presentation on the class II major histocompatibility molecules of local antigen presenting cells.Those that compete favorably siphon away T-cell help that would have been available for other antigens in this case, a polysaccharide antigen that is conjugated to CRM197. Panel B: B-cells that produce polysaccharide antibody and B-cells that produce protein (tetanus) antibody compete with each other for limiting numbers of T-helper cells (in this case, both types of B-cells receive help from T-helper cells that recognize tetanus toxoid peptides presented on the B-cell surface in the context of MHC class Il molecules). Clonal dominance of the carrier (tetanus)-specific B-cells shunts free conjugate vaccine into stimulating tetanus antibody production rather than polysaccharide antibody production. In addition, T-cell help is shunted away from polysaccharide-specific B-cells.

Figure 2. Panel A: Vaccine antigens compete with each other for presentation on the class II major histocompatibility molecules of local antigen presenting cells.Those that compete favorably siphon away T-cell help that would have been available for other antigens in this case, a polysaccharide antigen that is conjugated to CRM197. Panel B: B-cells that produce polysaccharide antibody and B-cells that produce protein (tetanus) antibody compete with each other for limiting numbers of T-helper cells (in this case, both types of B-cells receive help from T-helper cells that recognize tetanus toxoid peptides presented on the B-cell surface in the context of MHC class Il molecules). Clonal dominance of the carrier (tetanus)-specific B-cells shunts free conjugate vaccine into stimulating tetanus antibody production rather than polysaccharide antibody production. In addition, T-cell help is shunted away from polysaccharide-specific B-cells.

In addition, the rules for product and manufacturer interchangeability were reiterated, because the issue of mixing and matching products in the series is likely to come up as combinations enter the market. These rules are as follows:

* Diphtheria, tetanus, hepatitis A, hepatitis B, and IPV antigens are considered completely interchangeable.

* For Hib, the total number of doses in the primary series is determined by whether HbOC (HibTITER, Wyeth Pharmaceuticals) or PRP-T (ActHIB) is used. If either of these products is used even once, a total of three doses of Hib conjugate vaccine is needed for the primary series; if only PRP-OMP (PedvaxHIB, Merck & Co.) has been given, then the primary series is completed with two doses. A booster dose is given at age 12 to 15 months, regardless of product.

Whenever feasible, the same DTaP product should be used, at least for the first three doses. Vaccination should not be deferred if the same product is not immediately available or if the previous products are not known.

The joint statement concludes that combination vaccines may be used whenever any component is indicated and other components are not contraindicated. It is recognized that this may result in unnecessary doses of a given component, but the benefits in terms of timely coverage probably outweigh the risks. The statement asks insurers and managed care systems to reimburse for these extra doses. In fact, recognizing that many children will be given a birth dose of monovalent hepatitis B vaccine and three subsequent doses of a combination containing hepatitis B vaccine, the Vaccines for Children Program has supported requests from grantees for four doses of hepatitis B vaccine in the routine vaccination of infants.28

Figure 3. Studies are shown by vaccine manufacturer and trade name. Upper bars represent immunogenicity when Hib vaccine was given separately. Lower bars represent immunogenicity when Hib vaccine was given in combination with the indicated DTaP vaccine.

Figure 3. Studies are shown by vaccine manufacturer and trade name. Upper bars represent immunogenicity when Hib vaccine was given separately. Lower bars represent immunogenicity when Hib vaccine was given in combination with the indicated DTaP vaccine.

The Food and Drug Administration has issued specific guidelines to manufacturers that address issues unique to combination vaccines.29 The guidelines state compatibility of all components, including buffers, preservatives, adjuvants, and inactive substances, must be demonstrated, and that clinical trials must compare the new combination to its constituent vaccines administered simultaneously at separate sites. Reactogenicity of the combination should be compared to the most reactogenic of the individual components. For antigens that have established serologic correlates of protection (eg, diphtheria, tetanus, Hib, hepatitis B, and polio), it may be enough to demonstrate protective antibody levels. For antigens such as pertussis that do not have established serologic correlates of protection, combination vaccines should demonstrate antibody responses similar to those measured in previous studies showing efficacy of the individual components.

"Noninferiority" also must be demonstrated, loosely defined as no clinically relevant reduction in protection, often interpreted as no more than a 10% reduction in protection rates; this concept is somewhat elusive (Figure 4). Although it is intended to ensure that protection is not compromised for the sake of convenience, this has been an obstacle in bringing certain combination vaccines to market. For example, DTaP and Hib conjugate combinations may fail the noninferiority test because they produce lower levels of antibody to PRP, even though, as discussed previously, they may be protective. In the following discussions of combination vaccines that have achieved licensure, non-inferiority is assumed and safety, immunogenicity, and efficacy are not discussed.

NEWER LICENSED COMBINATION VACCINES

TriHIBit - Licensed in 1996

TriHIBit is a DTaP/Hib conjugate combination. It is not a true preformed combination, but rather a mixture made by reconstituting ActHIB (PRP-T) with Tripedia (Aventis Pasteur, DTaP2). It is labeled for the prevention of invasive Hib disease in children ages 15 to 18 months who have been immunized previously with three doses of either DTwP or Tripedia and three or fewer doses of ActHIB in the first year of life. Simply, it should only be used for the fourth dose.

The product is packaged with a single lot number as one-dose vials of lyophilized ActHIB and one-dose vials of liquid Tripedia; bodi vials are preservative-free. No other DTaP and Hib vaccine may be combined in this fashion or substituted for any of the components of TriHIBit, although it is acceptable to combine ActHIB and Tripedia that have not been specifically supplied as TriHIBit. However, if this is done, the lot numbers of both vaccines should be recorded.

The vaccine should be administered within 30 minutes of reconstitution as a 0.5 mL intramuscular dose and may be given at the same time as other vaccines at separate sites. TriHIBit can be used regardless of which Hib conjugate vaccine was given for the primary series. It also can be used if the child is 12 months or older and has received at least one prior dose of Hib vaccine at least 2 months earlier, and if this will be the last dose of Hib. TriHIBit should not be used if the child has not received prior Hib doses.

Figure 4. Antibody responses to a hypothetical monovalent vaccine and a combination vaccine containing it as a component are shown. The noninferiority criterion for the combination vaccine component is met as long as the upper limit of the 95% confidence interval for the difference in protection rates between the two vaccines (monovalent minus combination) is less than 10%, a pre-specified difference considered to be clinically important.

Figure 4. Antibody responses to a hypothetical monovalent vaccine and a combination vaccine containing it as a component are shown. The noninferiority criterion for the combination vaccine component is met as long as the upper limit of the 95% confidence interval for the difference in protection rates between the two vaccines (monovalent minus combination) is less than 10%, a pre-specified difference considered to be clinically important.

Table

TABLE.

TABLE.

Replacing monovalent vaccines with TriHIBit reduces the number of shots by one.

COMVAX - Licensed in 1996

COMVAX essentially is a combination of PedvaxHIB and RECOMBIVAX HB (Merck & Co., hepatitis B). Each dose contains 7.5 pg of PRP-OMP and 5 pg of hepatitis B surface antigen (HBsAg), as well as alum. The vaccine provides no protection against meningococcal disease even though it contains meningococcal outer membrane protein as a carrier. The product is preservativefree and is supplied as a liquid in onedose vials.

COMVAX is labeled for prevention of invasive Hib disease and hepatitis B infection in infants age 6 weeks to 15 months born to HBsAg-negative mothers. Despite this labeling, it should be pointed out that die Advisory Committee on Immunization Practices accepts use of Comvax for infants of HBsAg-positive and -unknown mothers.

Each dose is 0.5 mL administered intramuscularly, and may be given at the same time as any other vaccines given at separate sites. Usually, doses are administered at ages 2, 4, and 12 to 15 months. If this schedule cannot be followed, the interval between the first two doses should be at least 6 weeks. Although the minimum interval between the second and last doses is 8 weeks, the last dose should be given at age 12 months or older.

As all infants should receive a birth dose of monovalent hepatitis B vaccine, use of COMVAX results in the child's receiving four total doses, which is one more than usual. Although cumbersome, extraimmunization could be avoided by substituting PedvaxHIB at age 41 months.

It is extremely important that COMVAX not be used for the birth dose of hepatitis B vaccine, nor used before age 6 weeks, because of the possibility of inducing tolerance to future doses of Hib conjugate. The immunogenicity of COMVAX when used in a series with otiher hepatitis B or Hib conjugate vaccines has not been studied, but immunogenicity data from studies of monovalent vaccines indicate that any combination of Hib conjugate vaccines may be used to complete the primary series.30·31 When COMVAX and a Hib conjugate other than PedvaxHIB are used to complete the primary series, three doses should be administered at ages 2, 4, and 6 months. Hepatitis B vaccines are considered completely interchangeable.

Replacing monovalent vaccines with COMVAX reduces the number of shots by three or two, depending on whether PedvaxHIB is already being used (Table, see page 507).

TWINRIX - Licensed in 2001

TWINRIX (GlaxoSmithKline) is essentially a combination of HAVRIX (GlaxoSmithKline), a hepatitis A vaccine, and ENGERIX-B (GlaxoSmithKline), a hepatitis B vaccine. Each dose contains at least 720 enzyme-linked immunosorbent assay units of inactivated hepatitis A virus, which is equivalent to the pediatric formulation of HAVRIX, and 20 pg of recombinant HBsAg, which is equivalent to the adult formulation of ENGERIX-B, with alum as adjuvant. The product contains 2-phenoxyethanol as a preservative and is supplied as a liquid in one-dose vials or pre-filled syringes.

TWINRIX is labeled for active immunization against hepatitis A and hepatitis B in people ages 18 and older. The series consists of 1 mL doses given intramuscularly at 0, 1, and 6 months; the immunogenicity of this regimen for hepatitis A in adults is equivalent to the two-dose regimen of the adult formulation of HAVRIX, even though the hepatitis A component is equivalent to the pediatric formulation.

TWINRIX is useful for susceptible individuals ages 18 years and older who are at risk of exposure to both viruses. This may include: people traveling or relocating to areas of high endemnicity for both diseases; patients with chronic liver disease who are at risk for particularly severe outcomes from both infections; laboratory workers who handle live hepatitis A and hepatitis B viruses; police, healthcare workers, and other personnel who render first aid or emergency medical assistance; employees of daycare centers and correctional facilities; residents of drug and alcohol treatment centers; those at increased risk because of sexual practices; people who are at increased risk for hepatitis A and who are in close household contact with people who have acute or chronic hepatitis B infection; patients who frequently receive blood products; and military personnel.

It is assumed that hepatitis A and hepatitis B vaccines may be interchanged as long as the correct schedules are used. Likewise, it is assumed that TWINRIX may be given concomitantly with other vaccines.

PEDIARIX - Licensed in 2002

PEDIARIX is essentially a combination of INFANRIX (GlaxoSmithKline, DTaP3), ENGERIX-B, and an IPV that is not currently licensed in the United States as a separate vaccine but is included in combination vaccines licensed in other countries. Each dose contains 25 limit of flocculation (Lf) units of diphtheria toxoid, 10 Lf units of tetanus toxoid, 25 µg of pertussis toxin, 25 pg of filamentous hemagglutinin (FHA), 8 µg of pertactin, and 10 pg of HBsAg, all adsorbed to alum. Also included are formaldehyde-inactivated poliovirus: 40 D-antigen units (DU) of the Mahoney strain of type 1 , 8 DU of the MEF-1 strain of type 2, and 32 DU of the Saukett strain of type 3. These are the same components that are in IPOL, an IPV licensed as a stand-alone vaccine. The product contains 2-phenoxyethanol as a preservative and is supplied as a liquid in one-dose vials and prefilled syringes.

PEDIARIX is indicated for primary immunization of infants at ages 2, 4, and 6 months and should not to be used in children younger than 6 weeks or in those ages 7 or older. Newborns should still receive a birth dose of monovalent hepatitis B vaccine. Similar to COMVAX, the product is labeled only for use in infants born to HBsAg-negative mothers, but the Advisory Committee on Immunization Practices accepts use of the vaccine for infants of HBsAgpositive and -unknown women. Each dose is 0.5 mL given intramuscularly.

The vaccine should not be used for the booster doses of DTaP or IPV; however, it can be used in older children as long as it is used as the primary series. Use of PEDIARIX without the birth dose of hepatitis B vaccine results in lower geometric mean titers of antibody than the traditional 0-, 1-, and 6-month schedule.32 However, there is no difference in the proportion of children who achieve protective levels of antibody, and, moreover, when a birth dose is included, antibody titers actually exceed those achieved with the traditional schedule.6

PEDIARIX may be used to complete the primary series in infants who have already received one or two doses of INFANRIX, RECOMBIVAX HB, ENGERIX-B, or IPOL and are scheduled to receive the other components of the vaccine. Because practitioners are encouraged to use the same DTaP vaccine for the whole immunization series,24 switching to PEDIARDC will raise questions about infants who have received Tripedia or DAPTACEL (Aventis Pasteur, DTaP5) in the past.

Although data are limited, there is some support for the concept that DTaP vaccines are interchangeable.33 Therefore, if the child's previous DTaP vaccine brand was not Infanrix or is not known and PEDIARIX is available and otherwise indicated, the benefits of giving PEDIARIX and avoiding a missed opportunity probably outweigh any concerns about decreased immunogenicity. PEDIARIX may be given concurrently with Hib and pneumococcal conjugate vaccines. When these are given concurrently, low-grade fevers are more common but are short-lived, do not result in increased medical visits, and are easily managed with antipyretics.

Replacing monovalent vaccines with PEDIARIXreduces the number of shots by five (Table, see page 507).

COMBINATIONS TO EXPECT IN THE NEAR FUTURE

PENTACEL

PENTACEL, which has been used universally in Canada since 1997, is analogous to TriHIBit in the sense that it is a mixture of two vaccines made by reconstituting one with the other. In this case, ActHIB (lyophilized PRP-T) is reconstituted with QUADRACEL (Aventis Pasteur), a liquid formulation of DTaP5 and IPV that is not available separately in the United States. Each 0.5mL dose contains 20 pg of pertussis toxin, 20 µg of FHA, 5 pg of Fimbriae (FIM)-2 and FIM-3 (combined), 3 µg of pertactin, 15 Lf units of diphtheria toxoid, and 5 Lf units of tetanus toxoid. Also included are 40 DU of the Mahoney strain of the poliovirus type 1, 8 DU of the MEF-1 strain of type 2, 32 DU of the Saukett strain of type 3, and 10 pg of PRP conjugated to tetanus toxoid (20 µg).

It should be noted that QUADRACEL contains IPV components identical to IPOL, and although the DTaP constituents are the same as those in Daptacel, the amounts of pertactin and FHA are higher. Aluminum phosphate is included as adjuvant and 2-phenoxyethanol as preservative. The vaccine is given intramuscularly at ages 2, 4, 6, and 15 to 18 months.

PENTACEL appears to have overcome the problem of diminished PRP responses in DTaP and Hib conjugate combinations. In a study of 135 Taiwanese infants, 68 were given a DTaPS and PRP-T combination and 67 were given separate injections of the two vaccines.34 Antibody responses to each of the vaccine antigens and adverse reactions were similar in the two groups. After the primary series, the geometric mean anti-PRP antibody concentration was 11 .8 µg/mL in the combined group and 13 µg/iriL in the separate group. All achieved levels of 0.15 µg/mL or greater, and 95% and 99%, respectively, achieved levels of 1 µg/mL or greater. After the 18-month booster, the respective antibody concentrations were 59 µg/mL and 55 µg/mL.

In a Canadian trial, 107 infants received ActHIB reconstituted with QUADRACEL, and 108 infants received the separate vaccines at ages 2, 4, and 6 months.35 The proportion of children achieving protective levels of antibody to all antigens was similar, including PRP responses. Similar results were seen in a study from 27 US centers in which infants were randomized to receive three doses of PENTACEL (n = 484) or the licensed separate vaccines (n = 1458) at ages 2, 4, and 6 months.2? In this study, PCV-7 and hepatitis B vaccines were administered concomitantly.

Replacing monovalent vaccines with PENTACEL reduces the number of shots by six or seven, depending on whether Pedvax}IIB is already being used (Table, see page 507).

ProQuad

In the United States, MMR is routinely given at age 12 to 15 months and varicella vaccine at age 12 to 18 months. Because these two live viral vaccines can be given simultaneously, it makes sense to consider combining them for convenience and other reasons. Varicella uptake nationally is approximately 80%, and MMR uptake is more than 90%,36 so by combining the two shots, one would expect vancells coverage to exceed the 90% mark. In addition, there is some interest in considering two doses of vanicella vaccine in the routine schedule because of the continued occurrence of breakthrough disease. It should be noted, however, that breakthrough disease, or "vaccine-modified vanicella' is universally mild.37 An MMRV vaccine would facilitate this, because a second dose of MMR is already routine.

Early MMRV combinations, which contained about 3,000 plaque-forming units (PFU) of an older formulation of the Oka strain of the vanicella vaccine, showed excellent seroconversion rates and antibody titers to all four viruses.38'39 However, when approximately 4,000 PFU of the modern formulation of vancelia vaccine was combined with the licensed formulation of MMR (M-M-R11 Merck & Co.) - which contains the Moraten strain of measles virus, Jeryl Lynn strain of mumps virus, and RA 27/3 strain of rubella virus - lower geometric mean titers of antibody to varicella were seen, even though the seroconversion rate was the same as when the vaccines were given separately.4? There was also a small excess of measles- and rubella-like rash in recipients of MMRV.

Subsequent dose-ranging studies showed increasing the amount of varicelIa vaccine in the mixture to around 14,000 PFU restored the immunogenicity without significantly increasing the reactogenicity.4' In a recent lot-consistency study involving almost 4,000 children, immunogenicity of ProQuad was excellent, although fever rates were somewhat higher at 39% versus 33% for the separate vaccines.42

Increased rates of fever and rash have also been seen with a candidate MMRV vaccine made by GlaxoSmithKline.43 This vaccine contains the same MMR strains as are contained in PRIORIX (GlaxoSmithKline) - Schwartz measles virus, the RIT strain of the mumps virus, and RA 27/3 rubella virus - as well as a derivative of the Oka strain of varicella virus. This formulation of MMRV is stored at refrigerator temperature, while ProQuad, like VARIVAX (Merck & Co.), must be frozen.

Replacing monovalent vaccines with MMRV reduces the number of shots by one.

SUMMARY

As new combination vaccines are approved, practices must consider whether to switch. The decision is likely to be complex, involving everything from re-education of staff to recalculating the bottom line. At some point, however, change will be inevitable, driyen principally by the need to add new vaccines to the schedule.

In fall 2004, practitioners will be adding two doses of inactivated influenza vaccine to the infant schedule. More communities will be adding two doses of hepatitis A vaccine, which may become routine for all children at some point. We can hope as well for a meningococcal conjugate vaccine series, which, like Rib and PCV-7, would be administered by an infant's first birthday. In addition, there's the pentavalent bovine reassortant rotavirus vaccine (Rotateq) which, although given orally, will further crowd the schedule. The sooner we become comfortable with combination vaccines, the better.

REFERENCES

1. Klein JO, ed. Red Rook: Report oft/it Committee on Infectious Diseases. 19th ed. Evanston, IL: American Academy of Pediatrics: 1982.

2. American Academy of Pediatrics Committee on Infectious Diseases. Recommended childhood and adolescent immunization schedule - United States. January-June 2004. Pediatrics. 2004:113(1 Pt l):142-l43.

3. American Academy of Pediatrics. Policy statement: recommendations for influenza immunization of children. Available at: http://www.aap.orgipolicy/influenzafinaLpdf. Accessed june 14. 2004.

4. Jones AE, Melville-Smith M, Watkins J, et al. Adverse reactions in adolescents to reinforcing doses of plain and adsorbed tetanus vaccines. Comm unity Med. 1985:7(2):99-106.

5. Borgono JM, McLean AA. Vella PP. et al. Vaccinalion and revaccination with polyvalent pneumococcal polysaccharide vaccines in adults and infants. Proc Soc Lap Biol Med. 1978;157(l):148-154.

6. Pichichero ME, Blatter MM, Reisinger KS, et al. Impact of a birth dose of hepatitis B vaccine on the reactogenicity and immunogenicity of diphtheria-tetanus-acellular pertussishepatitis B-inactivated poliovirusHaemophutus influenzae type b combination vaccination. Pediatr Infect Dis J. 2002;21(9):854-859.

7. Woodin KA. Rodewald LB. Ilumiston SG, et al. Physician and parent opinions. Are children becoming pincushions from inimunizations? Arch Pediatr Adolesc Med. 1995: 149(8):845-849.

8. Kuppermann M, Nease RE Jr. Ackerson LM, et al. Parents' preferences for outcomes associated with childhood vaccinations. Pediatr Infect Dis J. 2000: 19(2): 129-133.

9. Dietz VJ, Stevenson J, Zell ER, et al. Potential impact on vaccination coverage levels by administering vaccines simultaneously and reducing dropout rates. Arch Pediatr Adoiesc Med. 1994;148(9):943-949.

10. Davis RL. Copian P, Meli L. et al. Impact of the introduction of a combined Haemophilus B conjugate vaccine and hepatitis B recombinant vaccine on vaccine coverage rats in a large West Coast health maintenance organization. Pediatr Infect Dis J. 2003;22(7):657658.

11. Meyerhoff AS. Greenberg DP. Baswell DLP. et al. Effect of DTaP-HepB-IPV vaccine on office vacination costs, results from the COVISE study. Pediatr Res. 2003;53(4):230A.

12. Meyerhoff AS, Greenberg DP, Jacobs RJ. Effect of DTaP-HepB-IPV combination vaccine on immunization coverage rates and costs, results from the COVISE study. Pediatr Res. 2003;53(4):230A

13. Sawyer LA, Mclnnis J, Patel A. Home AD, Albrecht P. Deleterious effect of thimerosal on the potency of inactivated poliovirus vaccine. Vaccine. 1994;12(9):851-856.

14. Anderson P. The protective level of serum antibodies to capsular polysaccharide of Haemophilus influenzae type b. J Infect Dis. 1984; 149(6): 1034-1035.

15. Heath PT, Booy R, Azzopardi HJ, et al. Antibody concentration and clinical protection after Hib conjugate vaccination in the United Kingdom. JAMA. 2000:284(18):2334-2340.

16. Zepp F, Schmitt HJ, Kaufhold A, et al. Evidence for induction of polysaccharide specific B-cell-memory in the 1st year of life: plain Haemophilus influenzae type b-PRP (Hib) boosters children primed with a tetanus-conjugate Hib-DTPa-HBV combined vaccine. Eur J Pediatr. 1997; 156(1):18-24.

17. Berger R, Just M. Interference between strains in live virus vaccines. II: Combined vaccination with varicella and measles-mumps-rubella vaccine. J Biol Stand. 1988;16(4):275-279.

18. West DJ, Hesley TM, Jonas LC, et al. Safety and immunogenicity of a bivalent Haemophilus influenzae type b/hepatitis B vaccine in healthy infants. Hib-HB Vaccine Study Group. Pediatr Infect Dis J. 1997;16(6):593-599.

19. Yen SH, Ward JI, Partridge S. et al. Safety and immunogenicity of a pentavalent diphtheria, tetanus, pertussis, hepatitis B and polio combination vaccine in infants. Pediatr Infect Dis J. 2001;20(IO):973-980.

20. Blatter MM, Noriega F, Pentacel investigators. Immunogenicity and safety of Pentacel (diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type b vaccine) in U.S. infants 2, 4, and 6 months of age. Paper presented at: International Conference on Infectious Diseases; March 4-7, 2004; Cancun. Mexico.

21. Offit PA, Quarles J, Gerber MA, et al. Addressing parents' concerns: do multiple vaccines overwhelm or weaken the infant's immune system? Pediatrics. 2002;t09(1):124-t29.

22. Halsey NA, Safety of combination vaccines: perception versus reality. Pediatr Infect Dis J. 2001 ;20( 1 1 Suppl ):S40-S44.

23. Pichichero ME, Latiolais T, Bernstein DI, et al. Vaccine antigen interactions after a combination diphtheria-tetanus toxoid-acellular pertussis/purified capsular polysaccharide of Haemophilus influenzae type b-tetanus toxoid vaccine in two-, four- and six-month-old infants. Pediatr Infect Dis J. I997;16(9):863870.

24. Combination vaccines for childhood immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP), the American Academy of Pediatrics (AAP), and the American Academy of Family Physicians (AAFP). Pediatrics. 1999;103(5 Pt 1): 1064- 1077.

25. Insel RA. Potential alterations in immunogenicity by combining or simultaneously administering vaccine components. Ann N Y Acad Sci. 1995;754:35-47.

26. Pichichero ME. New combination vaccines. Pediatr Clin North Am. 2000;47(2):407-426.

27. Decker MD, Edwards KM. Combination vaccines: problems and promise. J Pediatr. 2000; 137(3):29 1-295.

28. Rodewald LE. VFC support for a universal hepatitis B birth dose policy. Letter to Immunization Program Managers, June 17, 2003.

29. US Department of Health and Human Services, Food and Drug Administration, Centers for Biologies Evaluation and Research. Guidance for industry for the evaluation of combination vaccines for preventable diseases: production, testing, and clinical studies. Available at: http://www.fda.gov/cber/gdlns/combvacc.pdf. Accessed June 14, 2004.

30. Anderson EL, Decker MD. Englund JA, et al. Interchangeability of conjugated Haemophilus influenzae type b vaccines in infants. JAMA. 1995:273(1 1 ):849-853.

31. Bewley KM, Schwab JG, Ballanco GA. Daum RS. Interchangeability of Haemophilus influenzae type b vaccines in the primary series: evaluation of a two-dose mixed regimen. Pediatrics. 1996;98(5):898-904. 32. Greenberg DP, Wong VK, Partridge S, Howe BJ, Ward JI. Safety and immunogenicity of a combination diphtheria-tetanus toxoids-acellular pertussis-hepatitis B vaccine administered at two, four and six months of age compared with monovalent hepatitis B vaccine administered at birth, one month and six months of age. Pediatr Infect Dis J. 2002:2 1 (8):769-777.

33. Greenberg DP, Feldman S. Vaccine interchangeability. Clin Pediatr (Phila). 2003;42(2):939-9.

34. Lee CY, Thipphawong J, Huang LM, et al. An evaluation of the safety and immunogenicity of a five-component acellular pertussis, diphtheria, and tetanus toxoid vaccine (DTaP) when combined with a Haemophilus influenzae type b-tetanus toxoid conjugate vaccine (PRP-T) in Taiwanese infants. Pediatrics. 1999; 103(0:25-30.

35. Mills E, Gold R, Thipphawong J, et al. Safety and immunogenicity of a combined five-component pertussis-diphtheria-tetanus-inactivated poliomyelitis-Haemophilus B conjugate vaccine administered to infants at two, four and six months of age. Vaccine. 1998;l6(6):576-585.

36. Centers for Disease Control and Prevention (CDC). National, state, and urban area vaccination levels among children aged 19-35 months - United States, 2002. MMWR Morb Mortal WkIy Rep. 2003:52(3 1):728-732.

37. Gershon AA. Varicella vaccine - are two doses better than one? N Engl J Med. 2002:347(24): 1962- 1963.

38. Arbeter AM, Baker L. Starr SE, et al. The combination measles, mumps, rubella and varicella vaccine in healthy children. Dev Biol Stand. 1986:65:89-93.

39. Brunell PA, Novelli VM, Lipton SV, Pollock B. Combined vaccine against measles, mumps, rubella, and varicella. Pediatrics. 1988;81(6):779-784.

40. White CJ, Stinson D, Staehle B, et al. Measles, mumps, rubella, and varicella combination vaccine: safety and immunogenicity alone and in combination with other vaccines given to children. Measles, Mumps, Rubella, Varicella Vaccine Study Group. Clin Infect Dis. 1997;24(5):925-931.

41. Shinefield H, Black S, Marchant C, et al. A dose selection study in healthy children comparing measles, mumps, rubella, and varicella (ProQuad) vaccine to M-M-R1, given constantly concomitantly with process upgrade varicella vaccine (PUVV) in separate injections. Paper presented at: 20th Annual Meeting of the European Society for Paediatric Infectious Diseases; May 29-31. 2002; Vilnius, Lithuania.

42. Lieberman J, Shinefield H, Miller J, et al. ToIerability and immunogenicity of three consistency lots of combination measles, mumps, rubella, and varicella vaccine (ProQuad). Paper presented at: 21st Annual European Society for Paediatric Infectious Diseases; April 9-11, 2003; Giardini Naxos, Sicily, Italy.

43. Nolan T, Mclntyre P, Roberton D, et al. Reactogenicity and immunogenicity of a live attenuated tetravalent measles-mumps-rubellavaricella (MMRV) vaccine. Vaccine. 2002:2 1(3-4):28 1-289.

TABLE.

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