Combination Vaccines

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.

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.