Combination vaccines: are we there yet?

April 2003

---Philip A. Brunell, MD

An international conference on how to combine existing vaccines was held at the NIH recently. Everyone agreed on the urgent need for combining vaccines. Unfortunately, the goal still seems pretty elusive. However, everyone is trying.

The problems are more than simply the frequently maligned FDA. They are real. They involve both the safety and efficacy of giving single vaccines as compared with combining them in a single preparation. The safety question probably is the simpler of the two to sort out. One can measure whether reactions are less than, equal to, the sum of, or more than the sum of giving the vaccines separately. This is simple with regard to the immediate reactions to vaccines, e.g. fever or local soreness. The same caveats pertain to remote reactions or rare reactions to combinations as to reactions to single vaccines. The intussusception-rotavirus experience was a sobering one. It illustrates, however, how clues obtained during the premarketing clinical trials can help in alerting us to what to watch for after the vaccines are licensed.

All combinations probably will require field-testing before they can be released. This involves convincing parents to allow their children to receive combinations of vaccines that may or may not be as effective and safe as the existing vaccines with which we have had considerable experience. The trade-off, of course, is fewer injections. All of these vaccines will have been tested prior to being given to large numbers of children just as the current single vaccines to be certain they are OK.

Efficacy issue

The efficacy issue is probably more complicated than the safety issue. In the ideal world we could simply mix existing vaccines in a syringe and expect them to be as effective as if they were given as separate injections. Unfortunately it does not work this way. We already have a considerable amount of experience with combined vaccines. It was learned that to get the individual components of measles-mumps-rubella or trivalent polio vaccines to work as effectively, we needed to adjust the quantity of the individual components so that there were greater amounts of type 1 poliovirus than type 3 and less measles virus than the other components. This was done to get the same response one would have gotten had they been given separately, because of interference between the components. In the case of these virus vaccines we had what we believed were fairly good serologic correlates of protection. In any case these combinations have been as safe and effective as the individual vaccines.

With the newer vaccines, we do not have good serologic correlates with the possible exception of Haemophilus influenzae type b vaccine (Hib). The acellular pertussis (aP) vaccines of different manufacturers may not even contain the same components. The antigen or antigens that are required in a pertussis vaccine to confer protection are still uncertain. There is much discussion about which antibody is protective. If, therefore, one combines aP with another vaccine and there is a reduction in the amount of a pertussis antibody produced with the combination, one could not really be certain whether it would affect protection. Unfortunately, pertussis antibody titers have been affected when given with other vaccines and the conjugate vaccines Interference also has been observed with Hib and pneumococcal vaccines.

One would like to be able to use antibody to predict protection, ie, have serologic correlates, to avoid expensive and time-consuming clinical trials. How a vaccine performs in practice is the ultimate standard. However, the interpretation of these is not always easy. In Alaska, where there is a high risk of invasive Haemophilus influenzae disease among the Eskimos, and it occurs at an earlier age than in infants in the “lower 48,” Hib vaccine had virtually eliminated the disease. It had, at least until instead of giving Hib and DTP vaccines separately a combined vaccine was substituted. Invasive Hib disease started to reappear. However the type of Hib vaccine was changed, the one given singly was more likely to produce an early antibody response and protect younger infants who are particularly high-risk in this population. The Hib conjugate vaccine in the combination took a few doses until “protective” levels of antibody were achieved. So, was it the particular Hib vaccine that resulted in the reappearance of invasive Hib disease, or was the fact that Hib was given as a combined vaccine the problem?

Combined vaccines, are we there yet? As you tell your kids, soon!