PEDIATRICS Vol. 102 No. 4 October 1998, pp. 909-912
The Effect of Investigator Compliance (Observer Bias) on Calculated Efficacy in a Pertussis Vaccine Trial
Received Jan 22, 1998; accepted Mar 19, 1998.
,, and
From the * Department of Pediatrics and the University of
California, Los Angeles Center for Vaccine Research, University of
California, Los Angeles School of Medicine, Los Angeles, California;
and the Klinik mit Poliklinik für Kinder und Jugendliche der
Friedrich-Alexander-Universität Erlangen-Nürnberg,
Erlangen, Germany.
Background. In the course of a large pertussis vaccine efficacy trial we realized that investigator compliance could have a major impact on calculated vaccine efficacy.
Design. In our pertussis vaccine efficacy trial, the study
investigators were to monitor illness in study families by telephone
every 2 weeks. If a cough illness of 
7 days duration was noted, the study child was to be evaluated. If the cough illness persisted for
14 days, the child was to be referred to a central investigator. For
this report we analyzed study physician evaluation rates and rates of
referral to the central investigators. Physician practices were
separated into three compliance categories: high, intermediate, and
low. We analyzed vaccine efficacy of an acellular pertussis component
DTP vaccine (DTaP) and a whole cell pertussis component DTP vaccine
(DTP) by compliance category. Bordetella pertussis infection was documented by culture of the organism in the study child
or in a household contact or by a significant antibody response to
pertussis toxin determined by enzyme-linked immunosorbent assay.
Results. Using a clinical case definition that included
both mild and typical pertussis (cough illness 7 days duration)
efficacy of DTaP vaccine was 40% (95% confidence interval [CI] = 
3-65) in the high compliance category and 78% (95% CI = 65-86) and 75% (95% CI = 53-87) in the intermediate and low
compliance groups, respectively. Similar, but less marked, differences
in efficacy were noted with DTP vaccine recipients. Using a clinical
case definition that required 21 days of cough with paroxysms, whoop, or vomiting (typical pertussis) the efficacy of DTaP vaccine was 69%
(95% CI = 41-83) in the high compliance category and 86% (95% CI = 76-92) and 84% (95% CI = 64-93) in the intermediate
and low compliance groups, respectively. In contrast, the efficacy of DTP vaccine did not vary by compliance category using this case definition. The attack rate in children vaccinated with diphtheria and
tetanus toxoids vaccine (DT) was twofold less in low compliance physician practices when compared with the rates in high and
intermediate groups. The DT/DTaP and DT/DTP fold-change differences
were less in the high compliance group compared with the intermediate
and low compliance groups.
Conclusions. Our data suggest that observer compliance (observer bias), can significantly inflate calculated vaccine efficacy. It is likely that all recently completed efficacy trials have been effected by this type of observer bias and all vaccines have considerably less efficacy against mild disease than published data suggest. Key words: observer bias, vaccine efficacy, acellular pertussis vaccine, whole cell pertussis vaccine, investigation compliance.
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