Vaccine Safety > Research
Safety of Acellular Pertussis Vaccine:
Follow-Up Studies
As published in Brown F, Greco D, Mastrantonio P, Salmaso S, Wassilak S: Pertussis Vaccine Trials. Dev Biol Stand. Basel, Karger, 1997, vol 89, p. 373-375

Although the clinical trial data presented at this meeting clearly show that the acellular pertussis vaccines as DTaP are safer than the whole-cell pertussis vaccine as DTP, several important questions about the safety of DTaPs remain to be answered. In the Swedish Stockholm trials I and II, the apparent high incidence of hypotonic, hyporesponsive episodes (HHE) observed warrants continued study to understand better the characteristics of these events and the recovery status of these infants. In addition, the change in pertussis vaccine exposure in Sweden since the 1980's and the availability of various disease registries makes Sweden an attractive site to conduct ecological or other studies examining relationship between pertussis vaccination and certain adverse events with insidious/delayed onset (e.g., asthma, diabetes mellitus).

While the efficacy of various DTaPs have been compared critically by several speakers, similar critical comparison of the "safety profiles" between the DTaPs have been limited. Almost all the discussion on safety at this meeting has focused on comparison of DTaP vs. whole-cell DTP and DT. The NIH-sponsored phase II trials of acellular pertussis vaccines did not show important differences in the frequencies of common local and systemic reactions. Nevertheless, a meta-analysis or summary paper which focuses on comparison of rates of more serious events (seizures, fever>40^oC., HHE's) would be helpful.

Clinical trials, despite their admittedly methodological purity and elegance, are limited in sample size, duration, and population heterogeneity. Rare or delayed adverse reactions, or reactions in sub-populations can only be detected after product licensing and general use. One of the major concerns with the safety of whole-cell pertussis vaccination relates to rare serious events such as acute encephalopathy, estimated to occur at 0.0-10.5 per million doses. The size of the phase I/II trials (in the hundreds to low thousands) and phase III trials (in the low tens of thousands) for acellular pertussis vaccines in infants are clearly too small to address such an issue. While the greater safety of these vaccines in prelicensing clinical trials are promising, the safety of each vaccine regarding association with the most serious adverse events can only be examined by postlicensure monitoring.

Traditionally, post-marketing surveillance systems have relied on essentially passive monitoring such as the Vaccine Adverse Event Reporting System (VAERS) in the United States (1). Such surveillance systems, however, have great difficulty in distinguishing causal from coincidental events and surveillance artefacts. Review of VAERS data from 1991-1993 provides a first perspective on the safety of DTaP vaccines in widespread use . During this period, five million net doses of DTaP have been distributed in the U.S. for the fourth and fifth doses and the overall reporting ratio for serious adverse events in children age 1-4 years appeared to have declined to one third that of whole-cell DPT vaccine (2). Similar surveillance after use of DTaP in infants, as well as any new combination vaccines, will be needed. Comparison of the "safety profile" in VAERS reports by each DTaP vaccine type may also provide some greater insights into their relative safety. The development and use of standard protocols for follow-up of serious adverse events may improve the scientific use of such reports.

Passive surveillance systems will always be severely limited, however, by their biases and limited information content. Active surveillance or definitive epidemiological studies are required to provide validation of signals of concern generated by passive surveillance (3). Ad hoc studies (e.g., National Childhood Encephalopathy Study) cannot be done on a very timely basis and are also limited in the small number of hypothesized adverse events that can be studied. Pharmacoepidemiologists studying treatments have been relying on pre-organized Large-Linked DataBases (LLDB) to provide more flexible and timely studies on the safety of drugs (3). In the U.S., CDC has worked with several health maintenance organizations since 1991 to create the Vaccine Safety Datalink (VSD) project. The VSD currently conducts comprehensive surveillance on approximately 500,000 children under seven years of age (2% of the U.S. age-specific population) annually. The computerized vaccination records (lot-specific) on these children are linked with medical outcomes (hospital, outpatient, emergency room, laboratory), and covariates (e.g., from census data tapes) for epidemiological studies (4). About 100,000 doses of DTaP have been given to this population to date. As more DTaP is used, the VSD should provide a more rigorous means of monitoring vaccine safety. Other countries (e.g., U.K., Sweden, Denmark) have also begun or are planning to embark on LLDB studies.

Finally, several lessons are available to us on the importance of monitoring vaccine safety. The first is that public confidence, once lost, is difficult to regain (3). This painful lesson was learned with public concerns regarding safety of DTP in many countries during the 1970's and 1980's. Furthermore, the principles of primum non nocere(first do no harm) are, if anything, more important in public health than in clinical medicine, since vaccines, unlike most drugs, are given to healthy persons, usually infants. The World Health Organization's Expanded Programme on Immunizations (EPI) has recently called for all national immunization programs to conduct surveillance of vaccine adverse events following vaccination (5).

The area of risk communications will become increasingly important as immunization programs successfully reduce vaccine-preventable diseases to the point where the frequency of vaccine-associated adverse events exceeds that of the disease. Risk communications will be challenging when most health care providers as well as parents have never seen a case of vaccine-preventable disease. In this new era, it may be more productive for us to speak of "vaccine safety" research, a positive concept vs. "adverse event" research. We always speak of "safety and efficacy" of a vaccine, placing safety before efficacy; we should never forget that.

References

1. Chen RT, Rastogi SC, Mullen JR, Hayes S, Cochi SL, Donlon JA, Wassilak SG. The Vaccine Adverse Event Reporting System (VAERS). Vaccine 1994;12:542-50.

2. Rosenthal S, Chen R, Hadler SC. The safety of acellular pertussis vaccine versus whole cell pertussis vaccine: a post-marketing assessment. Arch Dis Child (in press).

3. Chen RT. Special methodological issues in pharmacoepidemiology studies of vaccine safety. In: Strom BL, ed. Pharmacoepidemiology. Sussex: John Wiley & Sons, 1994.

4. Chen RT, Glasser JW, Rhodes P et al.  The Vaccine Safety Datalink Project: A new tool for improving vaccine safety monitoring in the United States.   Pediatrics 1997 (in press).

5. Expanded Programme on Immunization. Surveillance of adverse events following immunization: field guide for managers of immunization programs. Geneva:WHO/EPI/TRAM/93.2; 1993.

This page last modified on March 28, 2000