Combination Vaccines


The combining of multiple antigens into a single vaccine is not a new concept; combination vaccines have long been a bedrock of immunization programs. Since the early 1990s, we have transitioned from a world in which DTP (diphtheria, tetanus, and pertussis vaccines combined) and MMR (measles, mumps, and rubella vaccines combined) represented essentially the only combination vaccines in use to one in which vaccines combining antigens targeting six or more diseases are in routine use. National immunization programs of developing countries rely on pentavalent combination vaccines incorporating DTP, hepatitis B (HepB), and conjugate Hemophilus influenzae type b (Hib) components. Indeed, the field of combination vaccines has matured to the point where many combination vaccines are available, with relatively few in development. These efforts, undertaken by many manufacturers and research groups worldwide, have been driven by the recognition that the continual increase in the number of effective childhood vaccines posed substantial economic and logistic difficulties. Providing these vaccines as separate injections requires multiple needlesticks, leading to distressed parents, providers, and vaccinees. Scheduling additional vaccination visits to reduce the number of injections per visit increases costs, burdens staff, and jeopardizes the entire immunization program by increasing the likelihood of missed vaccinations. The shipping, handling, storage, and accountability of a plethora of vaccines are burdensome and expensive and increase the possibility of error. However, the development and evaluation of combination vaccines can pose numerous issues, as discussed further in this chapter and reviewed elsewhere. ,

The combination vaccines in common use before the 1990s included diphtheria and tetanus toxoids, available alone (DT or Td) or combined with whole-cell pertussis vaccine (DTwP); inactivated (IPV) or live oral (OPV) trivalent poliovirus vaccine; and measles and rubella vaccine, available alone (MR) or with mumps vaccine (MMR). The first combination vaccine licensed in the United States was a trivalent influenza vaccine, approved in November 1945, and the second was a hexavalent polysaccharide pneumococcal vaccine licensed in 1947. Although developed in 1943, DTwP was not licensed until March 1948. IPV was licensed in 1955, trivalent OPV in June 1963, MMR and MR in April 1971, and quadrivalent polysaccharide meningococcal vaccine in 1978. These traditional combination vaccines are discussed in their respective chapters.

Most modern pediatric combination vaccines begin with a DTwP or DT/acellular pertussis (DTaP) vaccine and add such antigens as IPV, Hib, and HepB. As development efforts for the DTaP-based combinations have matured, some manufacturers have turned their efforts toward developing so-called second-shot or companion combinations designed to be given in coordination with a DTaP-based combination, incorporating, for example, conjugate meningococcal antigens. A third developmental stream has been directed toward combination vaccines targeted principally at travelers, typically based on HepB or hepatitis A (HepA) components.

Our focus in this chapter is on the most relevant current combination vaccines, which merge products such as IPV, HepB, Hib, or meningococcal vaccines with each other or with one or more of the previously mentioned traditional combination vaccines. Readers interested in combination vaccines of historical interest (e.g., yellow fever/smallpox) or combinations based on components no longer available are referred to the fourth through seventh editions of this text.

TERMINOLOGY

The vaccine industry has undergone dramatic consolidation during the past 20 years; long-established companies and new biotechnology start-ups have been acquired or merged. These changes render nomenclature problematic. For vaccines currently marketed, we will use the name of the current manufacturer, even when describing studies conducted by a predecessor company. For products not presently marketed, we will use the name of the company that produced them, even if that company now is owned or operated under a successor name. To further assist readers, Table 45.4 (Chapter 45) lists most current major vaccine manufacturers, along with the names of predecessor, component, or acquired companies.

Box 16.1 explains the symbols used in this chapter (plus sign [+], single virgule [/], and double virgule [//]) to differentiate various types of combination vaccines. Because so many different combination vaccines are available within some classes (e.g., DTaP/Hib), and simple, unambiguous generic names do not exist for the various products, trade names are used whenever possible to refer to specific combination vaccines.

BOX 16.1
Key to Typography
DTaP, diphtheria, tetanus toxoids, and acellular pertussis; Hib, Hemophilus influenzae type b.

Symbol Meaning
Plus sign (+) The vaccines linked by the plus sign are administered at separate sites during a single vaccination session. Example: DTaP + Hib , two separate vaccines given separately but at the same visit.
Single virgule (/) The vaccines linked by a single virgule are premixed from the manufacturer and are administered in a single injection. Example: DTaP/Hib ; the two vaccines are shipped by the manufacturer mixed together in a single container.
Double virgule (//) The liquid vaccine(s) preceding the double virgule are used to reconstitute the dry vaccine following the double virgule. Example: DTaP//Hib ; the manufacturer ships together a container of liquid DTaP and a container of lyophilized Hib, with the DTaP used to reconstitute the Hib and the resulting mixture administered as a single injection.
A number following “aP” A number following “aP” (e.g., DTaP3 ) indicates the number of pertussis proteins contained in the acellular pertussis vaccine component of the combination vaccine.

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Table 16.1 provides an overview of currently marketed combination vaccines.

TABLE 16.1
Combination Vaccines a Currently Marketed or in Development
Combined Components Availability
Trade Names and Supplier Canada Europe United States Other In Development
DTaP/IP V
Infanrix IPV or Infanrix Tetra (GSK)
Kinrix (GSK)
Quadracel (SP)
Tetravac; Tetraxim (SP)
DTaP/IPV/Hib or DTaP/IPV//Hib
Infanrix IPV Hib or Infanrix Quinta (GSK)
Pediacel (SP)
Pentacel (SP)
Pentavac; Pentaxim (SP)
DTaP/IPV/Hep B
Pediarix (GSK)
DTaP/IPV/HepB/Hib
Hexaxim, Hexacima, or Hexyon (SP)
Infanrix hexa (GSK)
Vaxelis (Merck [Europe] or SP [in United Kingdom, United States])
DTwP/Hib
No brand name (SII)
DTwP/Hep B
No brand name (SII)
DTwP/HepB/Hib
Easyfive-TT (Panacea)
Eupenta (LG Chem)
No brand name (Biological E)
No brand name (SII)
Pentabio (PT Bio Pharma)
Shan-5 (SP)
DTwP/HepB/Hib/IP V
EasySix (Panacea)
No brand name (Biological E)
No brand name (LG Life Sciences)
No brand name (PT Bio Farma)
No brand name (SII)
Shan6 (SP)
HepB/Hep A
Ambirix (GSK)
Twinrix or Twinrix Adult (GSK)
Twinrix Junior or Twinrix Paediatric (GSK)
HepA/Typhoid
Viatim or Vivaxim or Tyavax (SP)
MnC/Hib
Menitorix (GSK)
Td/IP V
Revaxis or Dultavax (SP)
Tdap/IP V
Boostrix IPV or Boostrix Polio (GSK)
Repevax, Adacel Polio, or Triaxis Polio (SP)
aP, acellular pertussis vaccine (infant formulation); ap, acellular pertussis vaccine (adolescent/adult formulation); D, diphtheria toxoid vaccine (infant formulation); d, diphtheria toxoid vaccine (adolescent/adult formulation); GSK, GlaxoSmithKline; HepA, hepatitis A vaccine; HepB, hepatitis B vaccine; Hib, conjugate Hemophilus influenzae type b vaccine; IPV, enhanced inactivated trivalent poliovirus vaccine; MMRV, measles, mumps, rubella, and varicella vaccine; MnC, meningococcal conjugate type C vaccine; SII, Serum Institute of India; SP, Sanofi Pasteur (including Sanofi Healthcare India); T, tetanus toxoid vaccine; wP, whole-cell pertussis vaccine. See Table 45.4 for information on prior names of pharmaceutical companies.

a Products combining only multiple serotypes of a single pathogen are excluded, as are DT (diphtheria and tetanus toxoids–pediatric), Td (reduced diphtheria and tetanus toxoids–adult), DTP (diphtheria, tetanus, pertussis), DTaP (diphtheria, tetanus toxoids, and acellular pertussis), Tdap (tetanus, reduced diphtheria, and acellular pertussis), OPV (oral polio vaccine), IPV (inactivated polio vaccine), MMR (measles, mumps, rubella), and MMRV (measles, mumps, rubella, varicella). Only those manufacturers who distribute their products internationally are listed; other manufacturers may produce some products (e.g., DTP/IPV) for local or regional use. Some products represent components derived from, or joint efforts of, more than one manufacturer; in such cases, their principal distributor is shown.

PRINCIPLES OF COMBINED VACCINES

Simultaneous Vaccines

A combination vaccine consists of two or more separate immunogens that have been physically combined in a single preparation. This concept differs from that of simultaneous vaccines, which, although administered concurrently, are physically separate (i.e., injected at separate sites or given by separate routes). Although some studies have shown altered immune responses to various vaccines when they are given concurrently with other vaccines but at separate sites, there is no evidence that the efficacy of any vaccine recommended for routine use in childhood is materially altered by concomitant administration with any other vaccines recommended for administration at the same age. Thus, we will not review the many studies that have evaluated simultaneous administration, except to the extent that they provide reference data to which results from combined vaccines can be compared. Similarly, adverse events after concomitant administration of multiple vaccines generally are increased only modestly, if at all, compared with events after the administration of the most reactogenic vaccine alone. Accordingly, adverse event data are included only if noteworthy.

Combination Vaccines and the Immune System

Carrier-Induced Epitope-Specific Effects

Theories regarding the human immune response and vaccine studies in animals and humans suggest that simultaneous exposure to multiple conjugate antigens might result in enhanced or diminished immune responses.

The phenomenon of carrier-induced epitope-specific modification (suppression or enhancement) of the immune response is one in which antibody responses to haptens presented on a carrier are inhibited or augmented by prior immunization with the specific carrier. Studies in animals show that the dose, route, choice of carrier protein, and presence of adjuvant all contribute to determining whether epitope-specific suppression or enhancement of the immune response occurs. Suppression more frequently occurs when large amounts of carrier protein are used for priming and high anticarrier antibody titers are achieved. Concurrent administration of two conjugate vaccines using the same carrier also may lead to interference. For example, a study among infants given a combination vaccine containing Hib capsular polysaccharide (polyribosylribitol phosphate [PRP]) conjugated to tetanus toxoid (PRP-T) plus a quadrivalent pneumococcal conjugate vaccine (PCV) conjugated to tetanus or diphtheria toxoid found reduced Hib antibodies among the infants whose vaccine was conjugated to tetanus toxoid rather than diphtheria toxoid. Another study showed markedly reduced antibody responses to tetanus-conjugated serotypes in a PCV11 when administered concomitantly with a DTaP2/IPV//PRP-T combination vaccine. Tashani and colleagues randomized adult travelers to receive Tdap, PCV13 (conjugated to CRM 197 ), and MCV4 (conjugated to tetanus toxoid) simultaneously or with the Tdap either 3–4 weeks before or 3–4 weeks after the PCV13 and MCV4. Receipt of Tdap 3–4 weeks before PCV13 and MCV4 significantly reduced GMTs to seven of the 13 pneumococcal serotypes.

These data make it clear that the effect of prior or concomitant administration of proteins used in conjugate vaccines is unpredictable and must be evaluated for each vaccine combination, and the data have prompted evaluation of alternative protein carriers (e.g., protein D from nontypeable H. influenzae , as used in a PCV; see below and Chapter 45).

Another interesting example of interference was observed in studies of infants randomized to receive aP3 vaccine or HepB vaccine at birth; all subsequently received DTaP3/IPV/HepB//PRP-T vaccine at 2, 4, 6, and 12–23 months. Robust pertussis antibody responses were seen in all, but those given aP3 at birth had substantially lower responses to both HepB and Hib after the primary series and after the toddler booster, as well as lower diphtheria antibody levels preceding and following the booster. ,

Other Issues Affecting Immune Responses

Chemical or physical interactions among the vaccine components being combined can result in an alteration of the immune response to vaccine. Adjuvants such as aluminum hydroxide and aluminum phosphate bind to inactivated vaccines by noncovalent ionic binding. The combination of one vaccine that is generally administered with adjuvant with another vaccine that is not administered with adjuvant may lead to displacement of the adjuvant and reduced immunogenicity of the first vaccine. Furthermore, the adjuvant might combine with the second antigen and thereby alter the immune response to the second vaccine as well.

Buffers, stabilizers, excipients, and similar components included in one vaccine may interfere with the components of another vaccine (e.g., thimerosal can destroy the potency of IPV). Although such vaccines cannot be shipped mixed together in a single vial, distribution of the two vaccines in a dual-chambered syringe can circumvent this problem. ,

When combining different live attenuated viral vaccine strains, competition between the viruses is the most frequently observed problem. It can be circumvented by increasing the number of vaccine doses (e.g., OPV) or modifying the concentrations of the individual viral strains in the vaccine (e.g., OPV; MMR and measles–mumps–rubella–varicella [MMRV] vaccine).

The interpretation of antibody responses requires correlation of antibody responses with protection from disease. For discussions of correlates of protection, please refer to Chapter 3 and to the sixth edition of this textbook.

Other Impediments to the Development of Combination Vaccines

Combination vaccines can present difficult issues with respect to investment of the funds necessary for clinical development. Typically, at the time of commercial introduction of a new combination vaccine, its component vaccines already are available and would continue to be used instead of the combination, should the combination’s price exceed the additional amount buyers are willing to pay for the convenience of the combination. Thus, the price of the combination is effectively capped, and its costs of development must be expected to be recoverable within that cap or the combination will not be developed. Moreover, systems that base compensation on the number of separate vaccines administered discourage administration of combination vaccines.

Patent and other proprietary issues also complicate the generation of combination vaccines. Vaccine manufacturers cannot market vaccines that contain antigens they do not own or license. The best possible combination vaccine might be one that incorporates components from two or more manufacturers, but, absent agreement between the companies, this combination will not become available. Although the dramatic consolidation in recent years among vaccine manufacturers has eased this problem, as have cross-licensing agreements, it has not fully disappeared.

Combining multiple antigens into one injection requires demonstration in clinical trials that the combination will not materially reduce the safety or immunogenicity of the component vaccines (and, in some instances, that efficacy is retained). Two strategies are commonly followed. One strategy involves comparing the new vaccine with a previously approved combination vaccine that differs by lacking only a single component that has been added to the new combination. This approach has generally been followed in the European Union, which has approved a full range of combinations, each adding one further antigen. When this approach is followed, the sponsor might have several predecessor combinations to choose from; for example, either DTaP/IPV + Hib or DTaP/Hib + IPV might serve as the control group for a study of a DTaP/IPV/Hib vaccine. In such cases, one almost always finds that the choice made was the one with the lowest risk of failure (e.g., comparing with DTaP/Hib + IPV rather than DTaP/IPV + Hib avoids the risk of revealing once again a reduced Hib response in the new DTaP/IPV/Hib combination as compared with separately administered Hib). In the other approach, the new combination is evaluated against each of its major building blocks given alone. For example, a DTaP/IPV/Hib combination vaccine might be compared with concurrent but separate injections of DTaP, trivalent IPV, and Hib vaccines. This had been the approach in the United States while separate injections represented the standard of care. However, in 2015, after pentavalent DTaP-based combination vaccines had become the standard of care in the United States, the U.S. Food and Drug Administration (FDA) approved a DTaP/IPV/Hib/HepB vaccine that was evaluated following the European approach.

Another advantage of a study that incorporates a previously evaluated combination vaccine is that it may allow comparison of the current results with those obtained in other arms of an earlier study. This bridging technique was used in the Swedish aP efficacy trials to compare the results from each trial. The methodological risks of this approach can be reduced through coordinated efforts to enhance the comparability of serologic and reaction data gathered for similar vaccines in independent studies.

Licensure of Combination Vaccines

To be licensed, vaccines must be demonstrated to be safe and effective. For example, U.S. law states that a combination pharmaceutical product may be licensed when “combining of the active ingredients does not decrease the purity, potency, safety, or effectiveness of any of the individual active components” (21 CFR 601.25[d][4]). Most licensing authorities have similar criteria for the evaluation of these parameters.

Evaluating Effectiveness

It is uncommon to require an efficacy trial for a vaccine that combines components previously proven efficacious; instead, demonstration of adequate immunogenicity is required. Commonly, the sponsor licenses combination products by conducting noninferiority trials, which provide statistical assurance that the investigational product is not inferior by more than a predefined margin (e.g., no more than a 10% difference in seroprotection rates) as compared with the standard products. A product that meets noninferiority criteria might be superior or might be equivalent, but is not inferior to the standard (or, at least, no more inferior than the prespecified margin).

In any study of finite size, the results represent a point estimate within a definable confidence interval. For typical outcomes of interest in studies of manageable size (e.g., 300–1000 participants), the 95% confidence interval can easily span a 10% range (for such measures as seroprotection or fever rates) or a 1.5:1 ratio (for such measures as geometric mean antibody concentrations [GMCs]). Thus, although it might seem that the noninferiority margin should be set to zero so that the possibility of inferiority is completely excluded, doing so would have the undesirable effect of rejecting new products that are truly equivalent or even superior.

An FDA Guidance Document regarding combination vaccines states that “If antibody concentrations induced by the combination vaccine are lower than those induced by the component vaccines, a ‘protective’ antibody level might still be attained.” Although appropriate, this principle can prove difficult to apply in practice because of uncertainty regarding such factors as the level of circulating antibody necessary to confer protection; the minimum antibody concentration (if any) necessary for protection of a person for whom immune memory has been established; whether there is a minimum seroconversion rate required for population protection; and whether achieving antibody concentrations that substantially exceed the minimum necessary to confer personal protection provides any further benefit (e.g., by suppressing colonization and thereby reducing transmission or by assuring prolonged protection).

In the face of these difficulties, the FDA has generally been unwilling to proceed with licensure of combination products whose immune performances fail statistical noninferiority, pointing out that the option exists to conduct an efficacy or effectiveness trial of the combination and thereby escape the need for noninferiority with respect to a reference vaccination regimen. Unfortunately, for many antigens of interest (including DTP, Hib, and HepB), it is no longer possible to conduct such efficacy trials: There simply is no place left in the world where the disease in question is sufficiently prevalent, an effective vaccine is not available and recommended, and conduct of a large randomized clinical trial is logistically possible.

Evaluating Safety

As a general rule, systemic adverse events are increased only modestly, if at all, after concurrent administration of multiple vaccines compared with events after the administration of the most reactogenic vaccine alone. Local adverse events often are somewhat more common and more severe at the site of injection of the combination, but this increase usually is offset by the avoidance of adverse events that would have been caused by the eliminated separate injections. So far, no combination vaccine has elicited a new type of reaction not previously seen with its separate components.

Recent years have seen an increase in sample-size requirements for safety testing from licensing authorities in general and from the FDA in particular. In addition, many authorities expect some (or most) of the safety data to be obtained among subjects from their own countries. Both trends slow licensure without necessarily providing commensurate benefits. There is little evidence that populations differ materially in the nature or rates of vaccine-associated adverse events, and large increases in sample size require substantial increases in resources while yielding only small increases in statistical power. These issues particularly impact combination vaccines, which commonly do not provide new antigens but merely a more convenient presentation and whose uptake therefore is sensitive to price, as discussed earlier.

Question of Multiple Antigens and Immune Overload

Despite being repeatedly debunked, the assertion continues to circulate—particularly on the Internet—that the normal infant immune system can be “overloaded” and that vaccination with multiple antigens induces such overload. There is no evidence to support such an assertion and much evidence to refute it. Indeed, it may be true that the infant immune system requires a fairly intensive challenge to develop normally and that insufficient stimulation leads to an increased risk of autoimmune disorders. ,

A concern that infant immune systems may be overwhelmed by simultaneous exposure to several antigens is difficult to entertain when one considers the thousands of antigens to which a newborn is naturally exposed in the first few months of life. Moreover, although more vaccines are administered today, far fewer antigens are delivered than in the past, when DTwP and vaccinia were used routinely.

The Institute of Medicine reviewed this issue and concluded that the evidence favored rejection of a causal relationship between multiple immunizations and an increased risk of type 1 diabetes or heterologous infections and was inadequate to accept or reject a causal relationship with allergic disease, particularly asthma.

Postmarketing Surveillance

Unexpected events that occur soon after vaccination, especially if severe enough to require medical attention, should always be reported. In the United States, the National Childhood Vaccine Injury Act requires healthcare providers and manufacturers to report serious adverse events after vaccination to the Vaccine Adverse Event Reporting System (VAERS), established to provide a single system for collection and analysis of reports of all adverse events associated with vaccines. Because the VAERS reports can be submitted by any concerned person, whether parent, provider, recipient, or observer; are spontaneous and passively collected; and do not provide the ability to calculate reliable population-based rates, they are useful for generating hypotheses but not for testing them. Increasingly, postmarketing surveillance is being facilitated by the use of large databases linking information sources such as pharmacies, healthcare providers, hospitals, and commercial healthcare organizations. Integrated data information systems maintained by some governments for their publicly financed medical care or hospitalization programs also have been used for this purpose. ,

COMBINATIONS BASED ON DTWP (OR ITS COMPONENTS)

As noted earlier, DTwP was developed in 1943 and licensed in the United States in 1948. Its component antigens had long been available separately: the first pertussis vaccine (see Chapter 43) was licensed to the Massachusetts Public Health Biological Laboratories in 1914; mixtures of diphtheria toxin and antitoxin came into use the same year; alum-precipitated diphtheria toxoid (see Chapter 19) was licensed in 1926; and adsorbed tetanus toxoid (see Chapter 57) was licensed in 1937. Whole-cell pertussis vaccine is a potent adjuvant, and the combining of the three antigens in DTwP actually improved the immunogenicity of the toxoids compared with separate administration. , Adsorption of the vaccines with aluminum further enhanced immunogenicity while decreasing the severity of adverse reactions associated with pertussis vaccine. ,

DTwP-based combination vaccines have disappeared from North America and western Europe but are a mainstay of public vaccination programs in other parts of the world. As of October 2020, some 125 countries used a DTwP/HepB/Hib combination vaccine for the primary vaccination of infants, as compared to 23 countries outside western Europe and the Americas that used DTaP-based combinations for primary vaccination. These DTwP-based pentavalent combination vaccines are produced almost exclusively by Asian manufacturers, who are now the principal suppliers of DTwP-based vaccines to the international markets (particularly the pentavalent DTwP/HepB/Hib vaccines now widely used in Expanded Programme for Immunization [EPI] programs) and various donor or World Health Organization (WHO) agencies. The changes since the last edition in Table 16.1 reflect the continued growth of these Asian producers. At the same time, these new entrants to the global marketplace have faced growing pains; between 2010 and 2012, vaccines from Bharat Biotech, Panacea, and Shantha lost WHO prequalification status for quality issues (DTwP/HepB/Hib vaccines from Panacea and Shantha subsequently regained prequalification status). ,

With increasing interest in replacement of OPV with IPV, IPV-containing combination vaccines hold enormous attraction for EPI program countries. Although all internationally available combination vaccines containing IPV are DTaP-based as of early 2021, and thus too expensive for EPI programs, at least four Asian manufacturers have DTwP-based hexavalent combination vaccines licensed or in development. Thus, it is reasonable to hope that such vaccines will become available to EPI programs within the next few years.

In general, combinations of DTwP with IPV, HepB, and/or Hib do not demonstrate meaningful interference among their components and do not result in adverse reactions that materially exceed, in frequency or severity, those seen with the same DTwP vaccine given alone. Summary information regarding the various classes of DTwP combination vaccines is provided subsequently. Readers interested in additional details are referred to earlier editions of this text.

DTwP/IPV, DT/IPV, and Td/IPV

Clinically important interference among the diphtheria, tetanus, whole-cell pertussis (wP), and IPV components has not been commonly demonstrated for currently available combinations incorporating those antigens ( Table 16.2 ). In the studies in which combination vaccine recipients showed reduced antibody responses to diphtheria and tetanus, all or nearly all nevertheless achieved seroprotective levels. Similarly, pertussis and poliovirus seroconversion rates and absolute antibody levels remained high, even with combined vaccines; the clinical importance of any reduction in mean antibody levels, for polio or pertussis, is unknown.

TABLE 16.2
Studies Comparing Combined or Concomitant Administration of DTwP/IPV, DTwP/Hib, and DTwP/IPV/Hib Vaccines
Ratio of Antibody Levels With Combined Vaccine to Levels With Separate Vaccines a
Poliovirus Serotypes
Place Ages (Mo) Vaccines PRP D T PT FHA AGG 1 2 3
Chile , 2, 4, 6 DTwPf//PRP-T 1 , DTwPf + PRP-T 1 0.43 b 1.00 0.85 0.97 1.07 0.62 c
Vancouver 2, 4, 6 DTwPc//PRP-T 1 (Lot 1), DTwPc + PRP-T 1 1.16 1.33 1.00 0.80 1.00 0.88
Vancouver 2, 4, 6 DTwPc//PRP-T 1 (Lot 2), DTwPc + PRP-T 1 1.03 1.33 0.78 0.80 0.75 0.68 b
Vancouver 2, 4, 6 DTwPc/IPV//PRP-T 1 , DTwPc/IPV + PRP-T 1 0.75 1.02 0.66 0.78 0.9 0.79
Chile 2, 4, 6 DTwPu//PRP-T 1 , DTwPu + PRP-T 1 0.70 1.32 b 0.78 1.10 0.86 1.41
United States 2, 4, 6 DTwPu//PRP-T 1 , DTwPu + PRP-T 1 0.88 1.09 0.94 1.01 1.00
United States 2, 4, 6 DTwPu//PRP-T 1 , DTwPu + PRP-T 1 1.60 1.14 0.96 1.44 0.69 1.55 1.38 0.79
United Kingdom 2, 3, 4 DTwPe//PRP-T 1 , DTwPe + PRP-T 1 0.75 1.01 1.83 b 1.68 1.11 1.12
Chile 2, 4, 6 DTwPf//PRP-T 1 , DTwPf 1.12 0.94 0.96
Israel 2, 4, 6 DTwPf/IPV//PRP-T 1 , DTwPf/IPV 0.86 0.65 b 0.70 b 1.01 0.78 1.29
Gambia 2, 3, 4 DTwPf//PRP-T 1 , DTwPf + PRP-T 1 0.96 1.11 1.16 0.91 0.77 d
United Kingdom 2, 3, 4 DTwPf//PRP-T 1 , DTwPf + PRP-T 1 e 0.73
Belgium 3, 4, 5 DTwPf//PRP-T 1 , DTwPf + PRP-T 1 0.25 b 0.78 0.79 0.70
Belgium 3, 4, 5 DTwPf//PRP-T 1 (DCS), DTwPf + PRP-T 1 0.61 b 1.08 0.99 1.07
Chile 3, 4.5, 6 DTwPf//PRP-T 1 , DTwPf + PRP-T 1 0.37 b 0.84 1.01 0.99
Chile 3, 4.5, 6 DTwPf//PRP-T 1 (DCS), DTwPf + PRP-T 1 0.79 b 0.89 0.97 1.01
France 2, 3, 4 DTwPf/IPV//PRP-T 1 , DTwPf/IPV + PRP-T 1 0.64 1.14 1.03 0.95 0.82
France 2, 3, 4 DTwPf/IPV//PRP-T 1 (DCS), DTwPf/IPV + PRP-T 1 1.41 b 0.74 b 0.79 0.88 0.72
Brazil 2, 4, 6 DTwPf//PRP-T 1 , DTwPf + PRP-T 1 0.62 0.48 0.15 b 0.83
Brazil 2, 4, 6 DTwPf/IPV//PRP-T 1 , DTwPf + PRP-T 1 0.79 0.33 0.11 b 0.75
United States 2, 4, 6 DTwPu/PRP (unconjugated), DTwPu 1.41
Finland 3, 4, 6 DTwPn/PRP-D, DTwPn 1.17 0.99
Gambia 2, 3, 4 DTwPu//PRP-OMP, DTwPu + PRP-OMP 1.03 0.80 0.71 0.88
United States , 2, 4, 6 DTwPv/PRP-HbOC, DTwPv + PRP-HbOC 1.51 b 1.78 b 1.82 b 2.22 b
United States 2, 4, 6 DTwPu/PRP-HbOC, DTwPu + PRP-HbOC f f f f
United Kingdom 2, 3, 4 DTwPe//PRP-HbOC, DTwPe + PRP-HbOC 1.30 0.93 1.48 b 1.06 1.39 1.10
United Kingdom 2, 3, 4 DTwPe//PRP-T 2 , DTwPe + PRP-T 2 0.51 b 1.73 b 0.75 1.20 0.97 0.78
Spain 2, 3, 4 DTwPg/PRP-CRM 197 , DTwPg + PRP-CRM 197 1.86 1.26 1.16 0.88 g
India EPI DTwPs/PRP-T 3 , DTwPf//PRP-T 1 0.98 1.07 1.08 0.90 h

AGG, pertussis agglutinins; D, diphtheria toxin; DCS, dual-chamber syringe; DTwP, diphtheria and tetanus toxoids and whole cell pertussis vaccine; DTwPc, DTwP produced by Connaught Laboratories (Canada); DTwPe, DTwP produced by Wellcome Laboratories (England); DTwPf, DTwP produced by Sanofi Pasteur (France); DTwPg, DTwP produced by Chiron Vaccines, Marburg, Germany; DTwPn, DTwP produced by National Public Health Institute of Finland; DTwPs, DTwP produced by Serum Institute of India; DTwPu, DTwP produced by Connaught Laboratories (US); DTwPv, DTwP produced by Wyeth Laboratories; EPI, Expanded Program on Immunization vaccination schedule (6, 10, 14 weeks); FHA, filamentous hemagglutinin; IPV, inactivated poliovirus vaccine; IgG, immunoglobulin G; OPV, oral poliovirus vaccine; PRP, polyribosylribitol phosphate; PRP-D, PRP-diphtheria toxoid conjugate vaccine; PRP-HbOC, PRP-diphtheria CRM 197 protein conjugate vaccine; PRP-OMP, PRP-meningococcal outer membrane protein conjugate vaccine; PRP-T 1 ( ActHIB , AvP) and PRP-T 2 ( Hiberix , GlaxoSmithKline), PRP-tetanus toxoid protein conjugate vaccine (lyophilized and reconstituted at time of use with diluent or DTwP, unless indicated as DCS); PRP-T 3 , PRP-tetanus toxoid protein conjugate vaccine produced by Serum Institute of India; PT, pertussis toxin; T, tetanus toxin.

a A ratio <1 indicates that mean antibody levels were lower with the combined vaccine than with separate injections; a ratio >1, that levels were higher with combined than separate injections. A blank cell indicates that the comparison was not possible or is not available. Differences are reported as statistically significant only when so reported by the investigator; absence of such a designation does not imply nonsignificance of differences.

b Difference significant at P ≤ 0.05.

c P value not available. However, the rate of seroconversion (AGG ≥320) was significantly lower ( P < 0.05) in the combined group (79%, vs 92%).

d Agglutinin titers were not determined. However, ratios for antibody to pertactin and fimbrial antigens were 0.55 ( P < 0.05) and 0.74, respectively.

e Combined vaccine group was compared to U.K. historical controls, who received the same PRP-T on the same schedule, but a different DTwP.

f Serologic assays were performed only for the DTwP/PRP-HbOC group (PRP, 8.20 µg/mL; D, 0.92 IU/mL; T, 7.52 units/mL; AGG, 110.1/dilution), and were said to be “comparable to values reported…in other series.”

g Pertactin, 0.56.

h Pertussis IgG.

DTwP/Hib (With or Without IPV)

Many studies have shown that administering DTwP and Hib in combination results in reduced mean PRP antibody levels compared with giving the same components separately (see Table 16.2 ). However, even in studies with statistically significant reductions, , , antibody levels still were high (albeit not as high as with separate administration) and at least 90% of children (typically, >95%) developed greater than 1 µg/mL of antibody to PRP after the primary series. Thus, reduced immunogenicity of Hib when given in combination with DTwP is not expected to be of clinical importance.

Surveillance data provide further reassurance that use of the combined DTwP//PRP-T does not reduce efficacy in comparison with DTwP and PRP-T administered separately. In Chile, surveillance for pertussis in matched areas that used DTwP alone or DTwP//PRP-T found no significant difference in the rates of pertussis in the two areas. In the area using DTwP//PRP-T, efficacy against invasive Hib disease was more than 90%. Surveillance in Canada found a continued low rate of invasive Hib disease after the licensure and widespread use of DTwP/PRP-T in that country, with no change in the extremely low rates of vaccine failure. , Similarly, there was no increase in invasive Hib disease in the United States after the 1993 licensure of DTwP//PRP-T and a similar product, DTwP/HbOC (PRP- Hib oligosaccharide conjugate; Tetramune, Wyeth Lederle Vaccines & Pediatrics; no longer available).

DTwP/HepB (With or Without Hib)

Several studies have evaluated vaccines that combine DTwP, HepB, and Hib components ( Table 16.3 ). In general, the addition of HepB to DTwP resulted in significantly increased mean HepB antibody levels and unchanged DTwP responses; the further addition of Hib to the combination resulted in no consistent changes in antibody responses.

TABLE 16.3
Studies Comparing Combined or Concomitant Administration of Vaccines Containing DTwP and Hepatitis B Components, With or Without Hib or IPV Components
Ratio of Antibody Levels With Combined Vaccine to Levels With Comparator Vaccine(s) a
Poliovirus Serotypes
Place Ages (Mo) Vaccines PRP D T WBP HBs 1 2 3
Spain 3, 5, 7 DTwP/HepB, b DTwP 0.79 0.70 0.79
Thailand 2, 4, 6 DTwP/HepB (5 µg), DTwP + HepB 1.18 0.73 0.92 0.54 c
DTwP/HepB (10 µg), DTwP + HepB 1.21 0.90 0.91 2.57 c
United States 2, 4, 6 DTwP/HepB//PRP-T, d DTwP/HepB b + PRP-T e 1.63 c 1.08 c 1.47 c 2.02
Chile , 2, 4, 6 DTwP/HepB//PRP-T, d DTwP/HepB b + PRP-T e 0.70 0.95 0.98 0.86 0.94
Myanmar 1.5, 3, 5 DTwP/HepB//PRP-T, d DTwP/HepB b + PRP-T e 1.07 0.74 c 2.23 c 0.95 1.00 f
Australia 2, 4, 6 DTwP/HepB/PRP-OMP, g DTwP/HepB + PRP-OMP h 0.53 c 0.36 c
DTwP/HepB/PRP-OMP, g HepB/PRP-OMP + DTwP i 0.51 c 0.28 c
DTwP/HepB/PRP-OMP, g DTwP + HepB + PRP-OMP j 1.18 0.07 c
Philippines EPI DTwP/HepB//PRP-T, d DTwP/HepB k + PRP-T l 0.78 0.37 c 1.16 1.07 0.90
DTwP/HepB//PRP-T, m DTwP/HepB k + PRP-T l 0.60 c 0.75 1.37 c 0.88 0.72
Myanmar EPI DTwP/HepB/PRP-T, d DTwP/HepB b + PRP-T n 0.92 0.76 0.96 0.63 c 0.67
Philippines 10 DTwP/HepB//PRP-T/MenAC, DTwP/HepB b + PRP-T l 0.54 c
El Salvador 15–24 DTwP/HepB/Hib, o DTwP p + PRP-T q 1.01 0.42 c 0.53 c 0.84 c
India EPI DTwP/HepB, r DTwP/HepB b 1.07 1.11 0.85 1.78
India EPI DTwP/HepB, s DTwP/HepB b 1.06 1.28 0.79 1.00
India EPI DTwP/HepB/Hib, t DTwP/HepB/Hib u 1.02 1.03 0.98 1.10 1.03
India 15–18 DTwP/Hib (given as booster to the groups in the row above) 0.97 1.01 1.01 0.99
India EPI DTwP/HepB/PRP-T, v DTwP/HepB/Hib u 0.67 1.08 0.60 1.32 0.50
India EPI DTwP/HepB/PRP-T, v DTwP/HepB b + PRP-T 0.41 2.38 0.76 0.91 0.72
India EPI DTwP/HepB/PRP-T/IPV, w DTwP/HepB/PRP-T t + IPV 1.37 0.79 1.04 1.18 1.34 0.71 0.69 0.76

AGG, pertussis agglutinins; D, diphtheria toxin; DTwP, diphtheria and tetanus toxoids and whole cell pertussis vaccine; EPI, Expanded Program on Immunization vaccination schedule (6, 10, 14 weeks); GSK, GlaxoSmithKline; HBs, hepatitis B surface antigen; HepB, hepatitis B vaccine; IU, international units; Lf, limit of flocculation; MenAC, meningococcal polysaccharide serotypes A and C conjugated to tetanus toxoid; OMP, outer membrane protein complex of Neisseria meningitidis ; PRP, polyribosylribitol phosphate; PRP-T, PRP-tetanus toxoid protein conjugate vaccine; PT, pertussis toxin; SII, Serum Institute of India; T, tetanus toxin; WBP, whole Bordetella pertussis (a mixture of serotypes 1, 2, and 3 used in a solid-phase immunoassay); wP, whole-cell pertussis.

a A ratio less than 1 indicates that mean antibody levels were lower with the combined vaccine than with separate injections; a ratio higher than 1, that levels were higher with combined than separate injections. A blank cell indicates that the comparison was not possible or is not available. Differences are reported as statistically significant only when so reported by the investigator; absence of such a designation does not imply nonsignificance of differences.

b DTwP/HepB: Tritanrix-HepB, GSK; ≥30 IU D, ≥60 IU T, 10 µg HBs.

c Difference significant at P ≤ 0.05.

d DTwP/HepB/PRP-T: Tritanrix-HepB/Hiberix, GSK; ≥30 IU D, ≥60 IU T, 10 µg HBs, 10 µg PRP-T.

e OmniHIB , GSK-distributed version of ActHIB .

f Including only those subjects seronegative at birth.

g DTwPm/HepB/PRP-OMP: Pentavax , Merck & Co; 30 Lf D, 6 Lf T, 5 µg HBs, 7.5 µg PRP conjugated to 125 µg OMPC (liquid).

h DTwPm/HepB: Quadrivax , Merck & Co; 30 Lf D, 6 Lf T, 5 µg HBs. PRP-OMP: PedvaxHIB , Merck & Co: 7.5 µg PRP conjugated to 125 µg OMPC (liquid).

i HepB/PRO-OMP: Comvax , Merck & Co; 5 µg HBs, 7.5 µg PRP conjugated to 125 µg OMPC (liquid). DTwP: CSL Ltd: 30 Lf D, 6 Lf T.

j DTwP: CSL Ltd, 30 Lf D, 6 Lf T. HepB: Merck & Co, 5 µg HBs. PRP-OMP: Merck & Co, 15 µg PRP conjugated to 250 µg OMPC (lyophilized).

k DTwP/HepB: formulated by GSK using D and T manufactured at their facility in Hungary and wP manufactured by CSL Ltd.

l PRP-T: Hiberix , GSK; 10 µg PRP-T.

m DTwP/HepB/PRP-T: formulated by GSK using D and T manufactured at their facility in Hungary, wP manufactured by CSL Ltd, combined with Hiberix.

n A GSK formulation containing 10 µg of PRP-T.

o DTwP/HepB/Hib: Quinvaxem , Crucell; ≥30 IU D, ≥60 IU T, ≥4 IU inactivated B. pertussis , 10 µg HBs, and 10 µg PRP conjugated to CRM 197 .

p DTwP: SII; ≥30 IU D, ≥60 IU T, and ≥4 IU B. pertussis .

q PRP-T: Vaxem-Hib , Novartis Vaccines and Diagnostics; 10 µg PRP conjugated to CRM 197 .

r DTwP/HepB produced by Shantha.

s DTwP/HepB produced by SII.

t DTwP/HepB/Hib (Pentavac) produced by SII.

u DTwP/HepB/Hib (Easyfive) produced by Panacea Biotech.

v DTwP/HepB/Hib (Shan-5) produced by Sanofi Healthcare India (SP).

w DTwP/HepB/Hib/IPV (EasySix) produced by Panacea Biotech.

DTwP/HepB with or without Hib has been introduced in an increasing number of countries, many of them developing countries that use the EPI 6–10–14-week schedule for their public vaccination program. DTwP/HepB/Hib combination vaccines are available from Biological E, LG Chem, Panacea, PT Bio Farma, Sanofi Healthcare India (formerly Shantha), and Serum Institute of India. These vaccines have been evaluated in a number of studies, which show them to provide acceptable and generally similar immune responses and safety profiles. , , Readers interested in data regarding discontinued DTwP-based combination vaccines are referred to the seventh and earlier editions of this text.

DTwP/HepB/Hib/IPV

In collaboration with Serum Institute of India (SII), Panacea has developed a DTwP-based hexavalent vaccine, EasySix, which is registered in India; WHO prequalification is expected in 2022. The vaccine, which incorporates the SII-Bilthoven Salk IPV, was shown to be noninferior to coadministration of SII’s Pentavac and Imovax Polio vaccine (Sanofi Pasteur).

Sanofi Healthcare India has developed a DTwP/IPV/HepB/Hib vaccine (Shan6) that has completed Phase III studies and is seeking registration in India. In a Phase I/II study, 150 infants were randomized 2:1 to receive the investigational hexavalent vaccine or the licensed pentavalent vaccine plus IPV following the EPI schedule. Postvaccination antibody responses did not materially differ between the two groups. A follow-up study evaluated antibody persistence and response to a follow-up booster; 97–100% of hexavalent recipients had antibody levels that were seroprotective for D, T, Hib, polio, and HepB prior to boosting and all had strong anamnestic responses.

Biological E, LG Chem, and SII have DTwP/IPV/HepB/Hib vaccines in Phase I–II development. In early 2019, LG Chem received a $33.4 million grant from the Bill and Melinda Gates Foundation to develop a DTwP/IPV/HepB/Hib vaccine; Phase II studies were underway in South Korea as of January 2021.

COMBINATIONS BASED ON ACELLULAR PERTUSSIS VACCINE

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