Safety and efficacy of combination vaccines

For 130 years or more after Jenner introduced a vaccine for smallpox this was the only vaccine in general use. Ten vaccines are now included in the routine childhood vaccination programme in the United Kingdom , with multiple doses of most. The use of combination vaccines reduces distress to the recipients and is likely to increase uptake rates. Many combinations are as efficacious as the separate vaccines, but the increasing number of antigens could theoretically pose problems in terms of reduced immunogenicity or increased reactogenicity.

Good post-marketing surveillance will become important in monitoring both the clinical efficacy of combination vaccines and adverse effects. With respect to clinical efficacy this may be a particular problem with combination conjugate vaccines. Using combination vaccines in the routine childhood programme in the United Kingdom amounts to giving 11 injections (24 in the United States), whereas, if given separately, 27 (almost 70 in the United States) would be needed. The alternative approaches are combining as many antigens into as few injections as possible, giving multiple simultaneous injections, or giving the required vaccines over several visits. Generally parents tend to have fewer concerns than health professionals about multiple injections.¹,² However, it would seem cruel to give more injections than required. In addition, if many injections are due at the same time, some may be delayed or not given at all.³ Pentavalent vaccines such as diphtheria, tetanus, wholecell pertussis vaccine (DTwP), Haemophilus influenzae type B (Hib) vaccine, and inactivated polio vaccine (IPV) are widely available. Hexavalent vaccines such as diphtheria, tetanus, acellular pertussis vaccine (DTaP), hepatitis B virus (HBV) vaccine, IPV, and Hib are being developed.

The safety, efficacy, and immunogenicity of a combined vaccine may be affected by interactions, not only between the antigens but also between these and other components such as adjuvants, stabilisers, and preservatives. Research on combination vaccines is more difficult than on single antigen vaccines because they are often replacing widely used single vaccines, making trials with placebos unethical. The disease may no longer be common, so the production of antibodies or immunogenicity, rather than protection from disease (clinical efficacy), has to be assessed. This may be satisfactory when antibody concentrations correlate closely with protection, but for some diseases (for example, pertussis) this is not the case. Thus post-marketing surveillance is essential.

Combining vaccines into one product does not increase the overall rate of adverse events, and with some combinations, such as DTaP, the rates are lower than when the component vaccines are given separately.⁴ Schmitt et al compared antibody responses in children receiving DTaP-HBV-IPV-Hib as one injection with children receiving the same antigens but with the Hib given at a different site. No difference was found in adverse events associated with the different regimens.⁵

In 1998 a paper in the Lancet was interpreted as showing a link between measles, mumps, and rubella vaccine and pervasive developmental disorder and bowel disease,⁶ even though the authors said they had not proved such a link. Subsequent research has failed to find evidence for this link ⁷ The suggested mechanism behind the hypothesis was that combining antigens produced an unpredictable response. Some parents are concerned that multiple antigens may overload the infant's immune system. A recent review set in context the antigenic load from vaccines in comparison with that from the environment and emphasised the capacity of the immune system to respond effectively to numerous simultaneous antigens.⁸ Using data linkage, Miller et al found no evidence for an increase in admissions to hospital for serious bacterial infections following MMR vaccination. ⁹

One disadvantage of giving vaccines in combination is that it may not always be clear which component is responsible for a particular adverse event. As important as safety is ensuring that combining antigens does not compromise the protection afforded by each antigen. In the study by Schmitt et al, no difference was found in subjects achieving protective concentrations of antibodies against diphtheria, tetanus, hepatitis B, and polio.⁵ Concentrations of pertussis antibody were the same for both groups and comparable with those achieved in trials of DTaP alone. However, the concentrations of Hib polyribosylribitol phosphate (PRP) antibody were statistically significantly lower in those children receiving all the antigens mixed together. The clinical significance of this is uncertain.

One of the longest established combination vaccines is DTwP. Two Swedish vaccine trials found a significant difference in post-immunisation levels of diphtheria antitoxin depending on the presence and nature of any pertussis antigens in the vaccine.¹⁰ The addition of an efficacious wholecell pertussis (wP) component to diphtheria and tetanus vaccine increased the geometrical mean titre of diphtheria antitoxin in the recipients, whereas the addition of acellular pertussis (aP) or a poorly efficacious wholecell pertussis vaccine produced lower concentrations than only diphtheria and tetanus vaccine. In a few children, the concentrations reached were considered non-protective, confirming the well known adjuvant effect of efficacious wholecell pertussis vaccines. DTwP vaccines can be combined with Hib vaccines with no clinically significant loss in immunogenicity, but when DTaP is used instead lower concentrations of Hib PRP antibodies have been observed,¹¹ and in some cases these are below protective levels. The clinical significance of this was unclear.

However, there has been a rise in Hib cases in fully immunised children in the United Kingdom. This is probably in part due to the use of a combined DTaP/Hib preparation.¹² Dagan et al reported that infants who were given a diphtheria-tetanus-pertussis-polio-Hib vaccine, in which the Hib component was conjugated to tetanus, simultaneously with a pneumococcal vaccine also conjugated to tetanus toxoid had lower Hib PRP antibody concentrations than infants who had received pneumococcal vaccine conjugated to diphtheria toxoid.¹³ Furthermore, children who had received higher doses of pneumococcal tetanus conjugate had poorer responses. This implies that difficulties may arise in using simultaneous or combined vaccines that have conjugates in common.