Infants 1 to 3 months of age were immunized with a vaccine combining diphtheria and tetanus toxoids with pertussis organisms. The combination product was adjuvanted with alum. Infants were injected at four-week intervals between 1–3 months of age and boosted at 7–9 months of age. Serum antibody determinations were done 3 months after completion of the initial three administrations; again at 7–9 months of age, 6 months after completion of the original course; and a booster injection was given and final determinations obtained on serum collected at eight to ten months of age. Utilizing a variety of antitoxin and agglutination techniques, more than 90% of infants had effective antitoxin levels against diphtheria and tetanus on all three laboratory determinations whereas only 53% at 3 months, 51% at 6 months and 80% at 10 months had titers judged protective vs pertussis. It was therefore demonstrated that infants at this young age could respond satisfactorily with humoral antibodies against both diphtheria and tetanus toxoids but less so against pertussis.
This article, written by clinical investigators from the departments of pediatrics and bacteriology at the University of Rochester School of Medicine contributed important information from studies carried out 50 years ago and raised questions, some of which still remain unanswered in 1998. If not the first, this was one of the earliest reports using an adjuvanted triple vaccine combining the previously available monovalent products, diphtheria toxoid, tetanus toxoid, and pertussis vaccine. (Of interest, especially to taxonomists,Bordetella pertussis still was called Hemophiluspertussis at that time.)
Issues of concern in 1948 were whether young infants would respond immunologically, whether they would achieve protective antibody levels against the three agents, whether a trivalent preparation would be equally effective to monovalent vaccines, which method for determination of agglutinating antibodies to pertussis would be most relevant, and whether a skin test for pertussis might be more revealing of immune status than would the conventional agglutination titers.
Motivation for the studies focused primarily on pertussis because it was well recognized that of the three, it was the most likely to cause early infancy morbidity and mortality. Previous studies had focused on passive immunization of infants by vaccinating pregnant women, but active immunization of infants had become of greater interest. One previous study published in the very first volume ofPediatrics1 had demonstrated serologic response to such a trivalent vaccine, but not in infants 1 to 3 months of age.
Rather than the current US 2-month interval between immunizations, a 1-month hiatus was used. This is almost identical to the schedules used worldwide today by the Expanded Program on Immunization of the World Health Organization, administering diphtheria–tetanus–pertussis antigens at 6 to 8 weeks, 10 to 12 weeks, and 14 to 16 weeks of age.
Of interest are the various antibody studies that Bradford et al used to assess the immunogenicity of their product. Both the tetanus and diphtheria assays were performed in vivo, the former in mice spinal cord and the latter in rabbit skin. In contrast, three different in vitro determinations were used for pertussis, reflecting the age-old quandary of how best to correlate antibody response with prophylactic efficacy of pertussis vaccines. Two of their determinations were tube dilution agglutination assays, whereas one was a slide method that relied on a clumping phenomenon. The antitoxin assays for diphtheria and tetanus were impressive, with positive results at 3, 6, and 10 months after immunization in >90% of recipients, but the pertussis antibodies, depending on the assay and titer used, were at the 50% level at 3 and 6 months and 80% at 10 months. One problem was to judge which serum dilution was most likely to correlate with prophylactic ef-ficacy.
At this juncture, it is worth noting that in 1998 there is still no consensus as to the correct surrogate of immunity for pertussis. With the dissection of the organism to produce antigens used in the current acellular pertussis vaccines (filamentous hemagglutinin, fimbria, pertussis toxin, pertactin), there is still no agreement regarding which component(s) induces antibodies that are most important in protection against illness.2-4 Also, if one can equate the 80% results that they achieved, this would fall well within the confidence limits of prophylactic efficacy demonstrated in the many European studies reported in the past several years.4 A tangential observation of this study is one that has since been observed repeatedly: the inclusion of pertussis acts as a further adjuvant to enhance the antigenicity of the other vaccine components. The vaccine used by Bradford and his colleagues was prepared and supplied by E. R. Squibb Company, a firm which since then has totally abandoned vaccine production.
One unique feature of the article is a two-sentence reference to a pertussis skin test performed with an agglutinogen 6 to 7 months after completion of the course of injections. Among 27 unimmunized control infants, results were negative; in contrast, 29 of the immunized infants (? denominator) had positive skin test results. No details are provided other than those numbers. One might speculate on the relevance of this observation, but insufficient data are reported to permit any interpretation. However, there is a role for cellular (T cell) immunity in pertussis that may have been reflected in this skin test reactivity.5
Three years were to elapse after these results were obtained before the American Academy of Pediatrics (Report of The Committee on Infectious Diseases “Red Book,” 9th ed; 1951) first recommended the use of trivalent diphtheria–tetanus–pertussis antigens in infancy. The results over the succeeding 25 years were dramatic. However, because pertussis today continues to exert its most serious manifestations, requiring hospitalization and critical care support, among infants in the first year of life,6,7 the same concerns expressed by Bradford et al pertain in 1998, although the numbers of cases are certainly reduced greatly by the success of immunization programs. In 1997, 5461 cases of pertussis were reported to the Centers for Disease Control and Prevention. It is unlikely that infant vaccination alone can reduce these numbers much more, even with the full use of the new acellular vaccines. To control and eventually eliminate pertussis will require an imaginative approach to booster immunization of adolescents/adults to reduce transmission within households from older siblings and parents to infants.8,9 This would provide a fitting tribute more than a half century later to Bill Bradford and other pioneers of the 1940s.
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- ↵Deville JG, Cherry JD, Christenson PD, et al. Frequency of unrecognized Bordetella pertussis infections in adults. Clin Infect Dis. 1995;21:639–642
- Copyright © 1998 American Academy of Pediatrics