An MD wrote me and chided me for not posting this study which 'proves'
vaccines work. I have highlighted some areas in the study that I find
interesting. Take a look and tell me what you think.
Abstract
Background.
Concern about both safety and efficacy has made the use of whole-cell pertussis
vaccines controversial. In some European countries, including Italy, the rate of
vaccination against pertussis is low.
Methods.
We conducted a double-blind trial in Italy in which infants were randomly
assigned to vaccination at two, four, and six months of age with an acellular
Pertussis vaccine together with diphtheria and tetanus toxoids (DTP); a DTP
vaccine containing whole-cell Pertussis (manufactured by Connaught
Laboratories); or diphtheria and tetanus toxoids without pertussis (DT). The
acellular DTP vaccine was either one containing filamentous hemagglutinin,
pertactin, and pertussis toxin inactivated with formalin and glutaraldehyde
(SmithKline Beecham) or one with filamentous hemagglutinin, pertactin, and
genetically detoxified pertussis toxin (Chiron Biocine). Pertussis was defined
as 21 days or more of paroxysmal cough, with infection confirmed by culture or
serologic testing.
Results.
The efficacy of each vaccine, given in three doses, against pertussis was
determined for 14,751 children over an average of 17 months, with cases included
in the analysis if cough began 30 days or more after the completion of
immunization. For both of the acellular DTP vaccines, the efficacy was 84
percent (95 percent confidence intervals, 76 to 89 percent for SmithKline DTP
and 76 to 90 percent for Biocine DTP), whereas the efficacy of the whole-cell
DTP vaccine was only 36 percent (95 percent confidence interval, 14 to 52
percent).
(If they worked wouldn't this be 100%?)
The antibody responses were greater to the acellular vaccines than to
the whole-cell vaccine. Local and systemic adverse events were significantly
more frequent
(adverse events? Like what? Seizures? Death?)
after the administration of the whole-cell vaccine. For the acellular vaccines, the frequency of adverse events was similar to that in the
control (DT) group.
Conclusions.
The two acellular DTP vaccines we studied were safe, immunogenic, and
efficacious against pertussis, whereas the efficacy of the whole-cell DTP
vaccine was unexpectedly low.
( You mean all this time it hasn't really worked?)
(N Engl J Med 1996;334: 341-8.) In pediatrics the
routine use of whole-cell vaccines against Bordetella pertussis has been a
matter of continuous debate. 1-4 Acellular vaccines, consisting of purified
proteins, have been in use for the primary immunization of two-year-old children
in Japan since 1981. 5,6 Two acellular vaccines were evaluated in a randomized
clinical trial in Sweden, 7 but the results left unanswered questions about the
efficacy of the vaccines in infants, particularly in relation to that of
whole-cell vaccines. In Italy, vaccination of infants against diphtheria,
tetanus, poliomyelitis, and hepatitis B is mandatory, but vaccination against
pertussis is not. The rate of vaccination against pertussis varies greatly
according to year of birth and geographic area. 8 In 1991, the national average
rate of vaccination against pertussis was estimated at 40 percent for children
less than five years of age 9 ;this low level of coverage can be attributed to
the perception that there is an unacceptably high frequency of adverse events
after the administration of the wholecell vaccine. 8 In 1992, we initiated the
present randomized, double-blind, controlled clinical trial of three Pertussis
vaccines. The pertussis vaccines we studied were combined with diphtheria and
tetanus toxoids and included a whole-cell vaccine currently used in the United
States and two acellular vaccines, each containing inactive pertussis toxin,
filamentous hemagglutinin, and pertactin. These proteins are involved in the
pathogenesis of B. Pertussis infection, and animal studies have suggested that
they confer active immunity. 10,11 Pertussis toxin has various biologic actions;
because of its toxicity in animals, inactivation is required before it can
beused as an immunogen. The main objective of the trial was to examine the
efficacy of each vaccine, given at two, four, and six months of age, in
preventing laboratory-confirmed clinical pertussis.
METHODS
Participants
Infants were enrolled from September 1992 to September 1993 at 62 public health
clinics operated by the National Health System, located in 4 of the 20 regions
of Italy: Piemonte, Veneto, Friuli–Venezia Giulia, and Puglia. Nurses were hired
and trained specifically to enroll and follow study children and to record
information on standardized forms and in customized computerized data bases. The
inclusion criteria for the study are shown in Table 1. The parents of each
eligible newborn were invited to enter the trial; those who agreed gave written,
informed consent. The study was approved by the Italian National Committee for
Bioethics and the institutional review board of the U.S. National Institute of
Allergy and Infectious Diseases (NIAID).
Vaccination
The composition of the study vaccines is shown in Table 2. The acellular
diphtheria–tetanus–pertussis (DTP) vaccine manufactured by Chiron Biocine
(Siena, Italy) contains genetically detoxified Pertussis toxin, 12 filamentous
hemagglutinin, and pertactin. The acellular DTP vaccine manufactured by
SmithKline Beecham Biologicals (Rixensart, Belgium) contains pertussis toxin
inactivated with formalin and glutaraldehyde, filamentous hemagglutinin, and
pertactin. The heat- inactivated whole-cell DTP manufactured by Connaught
Laboratories (Swiftwater, Pa.) belonged to a commercial lot licensed in the
United States; this same lot was used concurrently in Sweden in a randomized
clinical trial of two other acellular vaccines. A commercial diphtheria– tetanus
(DT) preparation (Biocine) was used for the control group. Three doses were
administered when the infants were 6 to 12, 13 to 20, and 21 to 28 weeks of age,
with a period of 4 to 12 weeks between successive doses. Criteria for
discontinuing vaccination are included in Table 1. A booster dose of DT was
given to all children six months after the third dose. The first two doses of
the trial vaccine could be administered simultaneously with oral poliomyelitis
vaccine and hepatitis B vaccine. The study vaccines were injected
intramuscularly in the buttock or thigh.
Medical: Age 6–12 weeks
Weight: 3rd percentile for age
No history of seizures or other central nervous system disease, including
perinatal brain damage
No major congenital abnormalities, failure to thrive, or renal failure
No known or suspected immunologic deficit, including having a
mother known to be positive for the human immunodeficiency virus
No prior illness compatible with pertussis
No prior vaccination against pertussis
Practical
Italian-speaking mother
Family accessible by telephone
Family planning to remain in the area for at least 12 months
CRITERIA CONTRAINDICATIONS TO FURTHER DOSES
Rectal temperature 40 C within 48 hours
Persistent crying for 3 hours within 48 hours
Hypotonic, hyporesponsive episode or collapse within 48 hours
Generalized cyanosis within 48 hours
Anaphylaxis within 24 hours
Seizure, encephalitis, encephalopathy, or other serious central nervous system
disease at any time
*5.7 IU per dose by mouse intracerebral challenge test, as determined by the
manufacturer.
Sample Size, Randomization, and Vaccine Masking
Assuming a true vaccine efficacy of 80 percent and a 5 percent incidence of
laboratory-confirmed pertussis in unvaccinated children for the mean observation
period, we calculated that a sample of 3300 children receiving each pertussis
vaccine and 1100 receiving DT would provide an 85 percent probability that the
lower limit of a two sided
95 percent confidence interval for vaccine efficacy would be greater than 60
percent. 13 Enrollment was augmented to compensate for attrition and potential
overestimation of the incidence of pertussis. Ten sets of three doses each of
vaccine were boxed together (three sets of each of the three DTP vaccines and
one set of the DT vaccine, all in identical vials); the sets were consecutively
numbered according to randomization lists provided by the NIAID. Infants were
assigned to one of the four study groups at each clinic when they received the
first dose of vaccine from the next available set of vials. Regular clinical
personnel prepared and administered the vaccine. Neither parents nor
investigators knew the infants’ vaccine assignments.
Data Collection and Analysis
Efficacy
Nurses performed active surveillance by means of routine monthly telephone
calls. Parents were instructed to note each of the child’s episodes of coughing
and report them to the study nurse. As soon as an illness characterized by cough
lasting more than seven days was identified, samples of acute-phase serum and
nasopharyngeal mucus were obtained; convalescent-phase serum was obtained six to
eight weeks after the onset of cough. Parents recorded details of the illness
and of treatment daily in a standardized diary; a nurse telephoned each week to
review and record this information. The episode of coughing was considered over
when the child had had no cough for two full days. Surveillance was conducted
for coughing illnesses that began as late as December 31, 1994. Each child
contributed time at risk for Pertussis through the date of onset of
laboratory-confirmed disease, the last date of contact with a study nurse, or
the end of the surveillance period. Vaccine efficacy was estimated for two
periods, one beginning 30 days after the third dose of study vaccine and the
other beginning immediately after the first dose. A case of pertussis was
defined as an illness with 21 days or more of paroxysmal cough and evidence of
B. Pertussis infection on culture or diagnostic serologic testing, as defined
below. Vaccine efficacy after three doses was also estimated with the use of
other clinical end points, according to the same laboratory criteria.
Immunogenicity
Paired capillary-blood samples were collected at each health center before the
first dose of vaccine was given and one month after the third dose from a
subsample of 10 percent of the children. Geometric mean titers of antibody to
each pertussis antigen were measured before and after vaccination in each study
group. A serologic response to each pertussis antigen was defined by a
postvaccination titer at least four times higher than both the titer before
vaccination and the minimal level of detection of the assay. Response to the
diphtheria and tetanus toxoids was defined by a postvaccination antibody titer
exceeding 0.01 IU per milliliter.
Safety
Parents recorded information on local and systemic symptoms in a standardized
diary for the eight consecutive evenings after each vaccine dose was given.
After the eighth day, nurses collected this information by telephone. If a
serious illness occurred at any time, the study pediatricians verified the
clinical history and reviewed all available documentation. Common side effects
occurring during the two evenings after each dose were analyzed. Adverse events
that were considered serious were anaphylaxis within 24 hours of vaccination;
persistent crying (for 3 hours or more), a rectal temperature 40 C, hypotonic,
hyporesponsive episodes, generalized cyanosis, or convulsions within 48 hours;
and encephalopathy within 7 days.
Laboratory Procedures
Culture
Nasopharyngeal mucus was collected with an 8-French DeLee suction catheter
(Sherwood Medical, St. Louis) and cultured on charcoal agar containing 10
percent defibrinated horse blood and 20 mg of cephalexin per liter (lot CM119,
Unipath, Milan, Italy) in the regional laboratories. Isolates were identified by
biochemical assay and by agglutination with specific antiserum (Murex
Diagnostics, Dartford, England). All strains of bordetella were confirmed at the
Istituto Superiore di Sanità in Rome.
Serologic Testing
Capillary blood was collected with Microtainer vials (Becton Dickinson,
Rutherford, N. J.). All serologic assays were performed by personnel who had no
knowledge of the infants’ vaccine assignments or the order of collection of the
specimens; the samples were tested against pertussis antigens with reference
serum calibrated against reference serum samples provided by the U.S. Food and
Drug Administration (serum lot 3 or 4, Bethesda, Md.). Standardized
enzyme-linked immunoassays (EIAs) were used to evaluate IgG and IgA antibodies
to pertussis toxin and filamentous hemagglutinin and IgG antibodies to pertactin,
14 with antigens provided by SmithKline Beecham. The reference-line method was
used to calculate EIA units with standardized software (Unitcalc, Biosys inova,
Stockholm, 1992). The minimal level of detection was set at 2 units per
milliliter for IgG antibody to pertussis toxin and filamentous hemagglutinin, 3
units per milliliter for both IgG antibody to pertactin and IgA antibody to
filamentous hemagglutinin, and 10 units per milliliter for IgA antibody to
Pertussis toxin. Any value below this minimum was recorded as half of the
minimal value. The Chinese-hamster-ovary (CHO) assay of pertussis-toxin–
neutralizing antibodies was performed only when sufficient serum was available.
15 Neutralization titers were expressed as the reciprocal of the highest serum
dilution that caused complete inhibition of typical clustering; the minimal
level of detection was the first dilution tested (1:40), and undetectable values
were recorded as 1:20. For a serologic test to be considered positive, we
required an increase in the antibody titer between acute-phase and
convalescentphase serum samples that was equivalent to one of the following: (1)
an increase in the level of IgG or IgA antibody to pertussis toxin to twice the
initial value; (2) an increase in the level of IgG or IgA antibody to
filamentous hemagglutinin to twice the initial value, provided culture and the
polymerase-chain-reaction (PCR) assay were negative forB. parapertussis; or (3)
an increase in the level of pertussis-toxin– neutralizing antibodies to four
times the initial value. A diagnostic doubling of the value on the EIA required
the convalescent-phase antibody level to be at least four times the minimal
level of detection. Diphtheria antitoxin was assayed by toxin neutralization in
Vero cells and tetanus antitoxin by a modified passive-hemagglutination assay
16,17 ; titers were converted to international units per milliliter with the use
of an international reference serum.
B. parapertussis PCR
The PCR for the detection of B. parapertussis in aspirates
involved the use of a specific insertion-sequence element IS1001.
18,19
Statistical Analysis
Vaccine efficacy was estimated as 1 _ R, where R is the ratio of the incidence
of pertussis (ratio of cases to total person-time of follow-up) among the
recipients of each DTP vaccine to the incidence among the control infants. 20
Confidence intervals were estimated by exact calculation, 21 on the basis of the
conditional binomial distribution of cases in one vaccine group and the total
number of cases.continuous variables were compared by means of the Kruskal–Wallis
test. Differences between proportions were assessed by the chi-square test or
Fisher’s exact test. No adjustment of P values was made for multiple
comparisons. The Wilcoxon rank-sum test was used to compare mean log antibody
titers.
RESULTS
A total of 15,601 infants (49.6 percent girls and 50.4 percent boys), making up
about 25 percent of the eligible newborns, received the first study dose at a
mean age of 10.5 weeks; 15,101 received the second dose (mean age, 17.8 weeks);
and 14,832 received the third (mean age, 24.9 weeks). In each vaccine group, 89
percent of the doses were injected into the buttocks. At the time the first two
trial doses were given, 92 percent of each vaccine group also received hepatitis
B vaccine and 94 percent received oral poliomyelitis vaccine.22
Efficacy
Of the 15,601 enrolled children, 769 did not receive three doses of study
vaccine. The reported reasons for the failure to administer the three-dose
series were similar among the study groups, except for withdrawals due to side
effects of the vaccine, which were more frequent after receipt of the whole-cell
DTP vaccine; 135 children were withdrawn because of side effects after receiving
the whole-cell DTP vaccine, 14 the SmithKline acellular DTP vaccine,
17 the Biocine acellular DTP vaccine, and 6 the DT vaccine. Of the 14,832 children who
received three doses, 19 received doses of different products, 3 received
partial doses, and 59 were excluded from further observation within 29 days
after the administration of the third dose (13 because they had laboratory-
confirmed illness and 46 who were lost to followup); (well, you did
inject it into them!) therefore, 14,751 children
(94.6 percent of those who were randomly assigned to groups) were included in
the analysis of the efficacy of three doses of vaccine. No significant
differences were detected among these 14,751 children according to study group
in terms of sex, age at vaccination, household size, number of children less
than 13 years of age in the same household, or mean number of days of
observation. The mean length of follow-up for these children was 523 days (17.2
months), beginning 30 days after the third dose of vaccine. A total of 5147
episodes of cough lasting more than seven days were reported, and biologic
specimens were collected for 4942 (96.0 percent) of these episodes, after a
median of eight days of cough. Of 474 episodes of cough that were confirmed by
laboratory testing to be associated with B. pertussis, 288 were defined as cases
(with 21 days or more of paroxysmal cough) (Table 3). The average age at the
onset of pertussis in these 288 cases was 551 days (18.2 months). The only
complication noted after pertussis was a seizure in a recipient of the DT
vaccine, who recovered without sequelae. The proportion of cases confirmed by
culture was 73 percent for the whole-cell DTP vaccine, 82 percent for theDT
vaccine, 7 6 percent f or t he SmithKline a cellular DTP vaccine, and 67 percent
for the Biocine acellular vaccine; the remaining cases were confirmed by
serologic assays. Each of the two types of acellular vaccine was 84 percent
efficacious after three doses, whereas the efficacy of the whole-cell DTP
vaccine was 36 percent (Table 3). Estimates of vaccine efficacy based on only
the 216 culture-confirmed cases were 85 percent for the SmithKline acellular DTP
vaccine, 87 percent for the Biocine acellular vaccine, and 43 percent for the
whole-cell DTP vaccine. Examination of alternative clinical criteria for
confirmed B. pertussis infection indicates that the vaccine efficacy after three
doses increased for illnesses with increasingly longer durations of cough, but
it nonetheless remained low for the wholecell DTP vaccine (Table 4). For the
entire group of 15,601 children randomly assigned to vaccine groups, biologic
specimens were collected for 5152 episodes of cough over an average of 21.6
months of follow-up after the first dose. There were 531 episodes of cough
laboratory-confirmed as associated with B. pertussis, of which 343 were cases
with paroxysmal cough lasting 21 days or more (Table 3); for each vaccine,
vaccine efficacy after the first dose was similar to that after three doses.
A total of 24 cases occurred from randomization through the 29 days after the
third dose (8 in recipients f the SmithKline acellular vaccine, 1 in a recipient
of the Biocine acellular vaccine, 12 in recipients of the whole-cell DTP
vaccine, and 3 in recipients of the DT vaccine) — an insufficient number to
permit meaningful estimates of the incremental efficacy of each dose. Another
analysis was based on cumulative periods from 30 days after the first dose to
either 29 days after the third dose or 231 days of age, if fewer than three
doses were received (this corresponded to 29 days after the maximal age at which
the third dose could be given). In this period, 5 cases occurred in recipients
of the SmithKline acellular vaccine (for an incidence of 0.39 per 100
person-years), 1 in a recipient of the Biocine acellular vaccine (0.08 per 100
person-years), 10 in recipients of the whole-cell DTP vaccine (0.79 per 100
person-years), and 2 in recipients of the DT vaccine (0.48 per 100
person-years). In pairwise comparisons, the incidence in recipients of the
Biocine acellular DTP vaccine differed significantly from that in recipients of
the whole-cell DTP vaccine (exact P_0.006, assuming the binomial
distribution).23
Immunogenicity
Serum specimens were obtained both before and after vaccination from 1572
children; 808 were tested by the CHO assay (Table 5). Antibody titers in the
specimens obtained before immunization did not differ significantly among the
groups. Each acellular vaccine elicited significantly higher titers of IgG and
neutralizing antibody to pertussis toxin than did the whole-cell vaccine; the
Biocine acellular DTP vaccine induced higher titers than the SmithKline
acellular vaccine. In each group given an acellular DTP vaccine, the rate of
serologic response on EIA was 94 percent or higher; the proportion with a
serologic response by CHO assay was significantly higher for the Biocine
acellular vaccine than for the SmithKline product. For the whole-cell DTP
vaccine, the proportion of children with a serologic response to pertussis toxin
by EIA or by CHO assay was minimal. Geometric mean titers of IgG antibody to
filamentous hemagglutinin and pertactin were much higher after vaccination with
the acellular DTP vaccine than with the whole-cell vaccine; in recipients of the
SmithKline acellular DTP vaccine, titers were significantly higher than in
recipients of the Biocine acellular DTP vaccine. The proportions of children
with a serologic response to filamentous hemagglutinin differed significantly
among the vaccine groups. For the two acellular DTP vaccines, the serologic
response to pertactin was more than 95 percent, whereas it was significantly
lower after the administration of the whole-cell DTP vaccine.
Safety
Table 6 shows the incidence of adverse events within the first two days
(anything after two days is ignored?) after
vaccination. The common events we investigated were significantly more frequent
in the group given the whole-cell DTP vaccine; overall, the frequency of these
events in the two groups given acellular DTP vaccine was similar to that in
DT-vaccine recipients. Swelling was more frequently reported after the
administration of the acellular DTP vaccine than after the administration of the
DT vaccine; it was somewhat more frequent in the children who received Smith-
Kline acellular DTP vaccine than in those who received the Biocine acellular
vaccine. Rectal temperatures _38C were infrequent after vaccination with either
of the acellular DTP vaccines but occurred significantly more often than in the
DT-vaccine recipients; such temperatures were more frequent in recipients of the
SmithKline vaccine than in recipients of the Biocine vaccine. In all but the
recipients of the whole-cell DTP vaccine, the frequency of temperatures _38C
and local symptoms increased with each dose in the series. Rectal temperature
_40C, crying for three hours or more, and hypotonic, hyporesponsive episodes
were rarely reported after the administration of the DT vaccine or the acellular
DTP vaccines; (Rarely?) the frequency of these symptoms after the administration of the wholecell DTP vaccine was greater than in all the other groups. Although the
frequency of temperatures _40C increased with each additional dose, persistent
crying for three hours or more and hypotonic, hyporesponsive episodes were more
frequently reported after the first dose. No episodes of anaphylaxis or
encephalopathy were observed. All children who had severe events within 48 hours
of vaccination recovered without sequelae. (Severe events?)
DISCUSSION
In this study, primary vaccination in infancy with either of two types of
three-component acellular DTP vaccine was found to be highly effective in
preventing clinical, laboratory-confirmed pertussis. Virtually all recipients of
the DT vaccine who had confirmed disease had cough for 21 days or more (89 of 92
children), whereas the corresponding proportions in the recipients of the
acellular DTP vaccines were lower (Smith- Kline, 58 of 84 children; Biocine,
63 of 82 children). Inclusion of a randomly assigned control group given only the
DT vaccine provided precise estimates of absolute vaccine efficacy, without
which estimates of efficacy in relation to that of the whole-cell vaccine could
have been uninformative. The use of a U.S.- licensed whole-cell vaccine that was
also included in the clinical trial conducted by the Swedish Institute for
Infectious Disease Control24 provided a solid basis for interpreting the results
of both trials. In the Swedish trial, the observed efficacy of the same
whole-cell DTP vaccine was 48 percent (95 percent confidence interval, 37 to 58
percent); a five-component vaccine containing 10 mg of pertussis toxin
inactivated with glutaraldehyde, 5 mg each of filamentous hemagglutinin and
fimbrial antigens (serotypes 2 and 3), and 3mg of pertactin was highly
efficacious (85 percent), whereas a two-component vaccine containing 25 mg each
of filamentous hemagglutinin and pertussis toxin inactivated with formalin and
glutaraldehyde had inferior efficacy (59 percent).24 In another
placebo-controlled, randomized clinical trial in Sweden, 40 mg of peroxide-
inactivated pertussis toxin administered at 3, 5, and 12 months of age was found
to be 71 percent effective (95 percent confidence interval, 63 to 78 percent) in
preventing laboratory-confirmed disease characterized by 21 days or more of
paroxysmal coughing.25 The results of our trial are supported by a case–contact
study of secondary transmission in households, in which the same three-component
acellular DTP vaccine (SmithKline) was administered at two, four, and six months
of age, with an estimated efficacy of 89 percent (95 percent confidence
interval, 77 to 95 percent).26 Results of other studies of acellular vaccines
are expected shortly.27,28 Different vaccine preparations, vaccination
schedules, study designs, or determinations of outcome variables can limit the
comparability of study results, however. The potential for bias exists in the
laboratory confirmation of cases, since confirmation may be more limited in
vaccinated children.29 However, with clinical Pertussis defined as 21 days or
more of paroxysmal coughing, there appears to be no substantial bias; point
estimates of vaccine efficacy were minimally altered when we considered only
culture-confirmed cases. In the present trial, the efficacy of the two acellular
DTP vaccines was similar despite differences in the methods of inactivating
pertussis toxin and the amounts of the various antigens included in the
vaccines. Although antibody responses to each acellular vaccine were high,
differences in geometric mean antibody titers were observed between the two
acellular vaccines. Antibody responses to the other antigens reflected the
quantity of vaccine per dose, but titers of antibody to pertussis toxin did not
correspond with the weight of antigens in each dose; this is consistent with
other reports that the genetically inactivated pertussis toxin induces a
stronger antibody response than chemically detoxified toxin.30 The weak antibody
response to pertussis toxin and filamentous hemagglutinin induced by the
Connaught wholecell DTP vaccine has been reported in other studies.31,32 The
level of protection conferred by the whole-cell vaccine was lower than we
anticipated. Caution must be used in interpreting differences in serologic
responses to vaccines, however, since serologic responses to specific pertussis
antigens have not been shown to be correlated with clinical protection.7 Despite
this fact, and although responses were measured only to the antigens contained
in the acellular DTP vaccines, these results suggest that the protective
effectiveness of whole-cell vaccines should be questioned if their
immunogenicity is low.33,34 Studies of whole-cell pertussis vaccines in general
report a higher level of protective efficacy than we found, albeit with
differences in methods and the possible influence of other factors, such as the
administration of booster doses. 28,35,36 The frequencies of common and uncommon
adverse events after the administration of the whole-cell DTP vaccine were
similar to the rates previously reported for whole-cell vaccines and much higher
than those observed in recipients of the acellular vaccines.37-39 There were
only minimal differences between the two acellular DTP vaccines and the DT
vaccine in this respect. Because of the high observed efficacy and the improved
safety profile of the acellular DTP vaccines, their use for the immunization of
infants appears highly preferable to the continued use of the whole-cell
vaccines.
We are indebted to V. Rafti and his staff for their full
engagement in the administrative management of the trial; to M. Kanieff for
valuable assistance throughout the study; to the staff of the NIAID for
technical support; to the members of the Steering Committee and the Data Safety
Monitoring Committee, in particular to Professor G.M. Fara, who acted as safety
officer; and to the staff members of the participating local health units, who
actively contributed to the conduct
of the study.
APPENDIX
The members of the Progetto Pertosse Working Group in Italy were as follows:
Laboratory of Bacteriology and Medical Mycology — P. Stefanelli, M. Bottone, and
T. Sofia; Laboratory of Epidemiology and Biostatistics — S. Luzi, G. Bellomi, F.
Cobianchi, G. Canganella, and F. Meduri; Laboratory of Immunology, Istituto
Superiore di Sanità, Rome — G. Scuderi; Department of Hygiene and Microbiology,
University of Palermo, Palermo — A. Chiarini, M. Maggio, S. Taormina, and M.
Genovese; Piemonte region — A. Moiraghi, A. Barale, S. Di Tommaso, S. Malaspina,
and E. Vasile; Veneto region — P. Ferraro, P. Dal Lago, L. De Marzi, L. Robino,
and E. Giraldo; Friuli–Venezia Giulia region — N. Coppola, P. Materassi, G.
Tarabini Castellani, and F. Basso; and Puglia region — S. Barbuti, M. Quarto, P.
Lopalco, P. D’Orazio, and A. Sanguedolce.
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