Acellular pertussis vaccines—a question of efficacy

JournaZ of Hospital

Injection

(1995)

30 (Supplement),

VACCINE

Acellular

pertussis

503-507

UPDATE

vaccines-a

question

of efficacy

P. Olin

Swedish Institute for Infectious Disease Control, S-l 05 21 Stockholm, Sweden Summary:

Whole cell pertussis vaccine is considered to offer at least 80% protection against typical whooping cough. The quest for an equally effective but less reactogenic vaccine is now drawing to a close. During the forthcoming year a number of efficacy trials of acellular pertussis vaccines will be terminated. A variety of vaccines containing one, two, three or five purified pertussis antigens are being tested in Germany, Italy, Senegal and Sweden. About 30000 infants have been enrolled in placebo-controlled studies and more than 100000 in whole cell vaccine-controlled trials. The final plans for analysis of a Swedish placebo-controlled trial of whole cell and acellular vaccines is presented. Due to the unexpected high incidence of pertussis in Sweden during 1993-1994, relative risk comparisons between vaccines will be attempted in that trial, in addition to estimating absolute efficacy. A crucial issue is to what extent data may be compared between trials, given differences in design, vaccination schedules, and chosen endpoints. A primary case definition of laboratory-confirmed pertussis with at least 21 days of paroxysmal cough have been adopted in most trials. Pre-planned metaanalysis using this single endpoint will facilitate comparisons between vaccines. Serological correlates to protection in individuals will be sought in the ongoing placebo-controlled trials. The concept of a serological correlate valid for a vaccinated population but not necessarily for the vaccinated individual, as is the case with Hib vaccines, may turn out to be the only alternative to performing large efficacy trials in the future. Keywords:

Pertussis

vaccines;

efficacy

trials;

pre-planned

analysis.

Introduction

The use of acellular pertussis vaccines still seems to depend on showing acceptable safety and efficacy compared to conventional whole cell vaccines.’ This is emphasized by a report on the excellent efficacy of the whole cell vaccine presently used in the UK based on epidemiological evidence.’ Similar evidence of high efficacy was presented for the whole cell vaccines currently used in the US.3 Whole cell pertussis vaccine is thus considered to offer at least 80% protection against typical whooping cough. Such estimates should be tempered by the cautions expressed by Fine and Clarkson in their 1987 review of the efficacy of pertussis vaccines.4 They noted that whole cell pertussis vaccines protected against disease better than against infection as indicated by the following observations: 01956701/95/060503+05

$0X.00/0

0 1995 The Hospital

503

Infection

Society

P. Olin

504

clinical pertussis was less severe than in vaccinated; higher efficacy was shown for more severe case definitions; poor protection against infection itself was suggested by unchanged intervals between whooping cough epidemics. Pertussis vaccines also induced more immunoglobin G (IgG) responses than IgA responses. They also warned against case ascertainment bias giving higher efficacy estimates for culture-confirmed cases, due to differential sensitivity of pertussis culture in vaccinated and unvaccinated individuals, and in open, not blinded studies. Lower efficacy estimates would be expected for case definitions with no laboratory confirmation, due to the inclusion of nonpertussis illnesses. Such bias seems to apply to the analysis of the efficacy of acellular vaccines, as shown in the first efficacy trial of two acellular pertussis vaccines 1986-l 987.5-7 These cautionary remarks are highly relevant as the quest for equally effective but less reactogenic pertussis vaccines is drawing to a close. During the forthcoming year a number of efficacy trials of acellular pertussis vaccines will be terminated. This paper presents the tentative timetable for these trials and describes the plan for the primary analysis of one Swedish multicentre placebo-controlled efficacy trial of two acellular and one whole cell vaccine. It also discusses the problems of comparing data between trials, and the search for serological correlates of protection. Ongoing

trials

A variety of vaccines containing one, two, three or five purified pertussis antigens are being tested in Germany, Italy, Senegal and Sweden (Table I). About 30 000 infants have been enrolled in placebo-controlled studies and more than 100 000 in whole cell vaccine-controlled trials. A primary case definition of laboratory confirmed pertussis with at least 21 days of paroxysmal cough have been adopted in most trials.’ The

problem

of unblinding

of whole

cell

vaccine

recipients

The ongoing Swedish double-blind placebo (DT)-controlled randomized efficacy trial (Stockholm 1) of one whole cell and two acellular pertussis vaccines, as diphtheria-tetanus pertussis (DTP) preparations, enroled 9829 infants born in 1992. The whole cell vaccine (Connaught Laboratories Inc., Swiftwater, USA), required vigorous shaking to suspend the sediment and differed markedly in appearance from the other preparations. A majority of the study nurses engaged in that trial could readily identify the whole cell vaccine by appearance and reactogenicity. The whole cell vaccine arm is thus unblinded in this ongoing Swedish placebo-controlled trial. However, randomization was not compromised and the estimates of absolute efficacy of the acellular vaccines will be uninfluenced by the partial unblinding of the whole cell vaccine.

Acellular Table

I.

Ongoing

phase

3 trials

Components* One-component PTi Two-component PTi f FHA

Three-component PTi + FHA PTi + FHA (genetically Five-component PTi + FHA Fimbriae

pertussis

Manufacturer

Site

Amvax

Gothenburg

SmithKline SmithKline BiocineSclavo BiocineSclavo

+ Pertactin modified) + Pertactin

+ two

pertussis fimbriae

Beecham Beecham Beecham Beecham

Lederle

toxin; FHA, filamentous 2 and 3, also known

Senegal Stockholm Stockholm Italy Germany Italy Stockholm

study

Lab Lab

Ltd Ltd

haemagglutinin; as agglutinogens

Stockholm Stockholm

site,

and

Terminated

1994

1 2

1995 1995 1996

2

1995 1994 1995 1996

Germany

Connaught Connaught * PTi, inactivated membrane protein;

505

of acellular pertussis vaccines--manufacturer, planned year of termination

PasteurMerieux SmithKline SmithKline f Pertactin

vaccines

1994 1 2

pertactin, also called 2 and 3, respectively.

199s 1996 69 kDa

outer

A second Swedish double-blinded randomized trial started in September 1993 and will enrol approximately 80 000 infants in four DTP-groups (Stockholm 2). It is aimed at demonstrating relative efficacy of three acellular vaccines compared with a control whole cell vaccine against culture-confirmed typical pertussis (21 days or more of paroxysmal cough). The British Medeva-Wellcome whole cell vaccine was chosen as this vaccine holds a good record of efficacy and safety.la2 Recent data suggested that the immediate reactogenicity might even be less pronounced when given in an accelerated schedule at two, three and four months of age, rather than with a delayed third dose.’ The appearance of this vaccine has not caused unnecessary unblinding of nurses and parents at vaccination or follow-up. Pre-planned

analysis

A high incidence of pertussis was observed in Sweden during 1993-1994. The number of cases accumulated in the Stockholm 1 trial exceeds the number of cases assumed in the sample size calculations. Already in early 1993 the number of cases fitting the primary case definition among children who have received three trial doses, had reached that expected by the planned date of termination in May 1995. Because of this, trial follow-up will be terminated ahead of time, in January 1995; the analysis of efficacy will be performed in March or April 1995 and will also include relative risk comparisons between vaccines. In the study protocol for Stockholm 1 trial, for each of the three vaccines, we wanted to test the null hypothesis

506

P. Olin

that true vaccine efficacy is below 70%, against the alternative hypothesis that the true efficacy is at least 70%. A desired statistical power of O-8 should be reached for an assumed true efficacy of 80%. Comparisons between acellular vaccines and the whole cell vaccine will test the corresponding null hypothesis RR>l*S. The comparison between the two acellular vaccines aims at detecting a significant difference of efficacy. The null hypothesis in that case would be RR = 1. The pre-planned analysis of absolute and relative efficacy is outlined below (personal communication Storsaeter, Gustafsson): 1. One primary analysis, including children who received three doses of the same trial vaccine and during follow-up had a clinical episode with 21 days or more of spasmodic coughing in connection with either a culture confirmed Bordetella pertussis, a significant enzyme-linked immunosorbent assay (ELISA) IgG or IgA antibody rise against PT or FHA in paired sera or a contact with culture-confirmed B. pertussis in the household. 2. One primary per protocol analysis, including children as defined above, but excluding children with defined protocol violations. 3. The pre-planned secondary analysis will include a range of clinical severity (cough for one day or more; for seven days or more; for 21 days or more; for 30 days or more. Spasmodic cough for 14 days or more; and 21 days or more) in laboratory-confirmed pertussis among children who have received three trial doses. 4. Intention to treat analysis will be performed for all secondary endpoints above, including all randomized children. A clinical-only diagnosis will not be included in the efficacy analysis because of the high risk of false-positive diagnosis and of the recent opportunity to include polymerase chain reaction as confirmatory evidence of pertussis.i’ Life-table analysis will be used and the duration of follow-up will be divided into three month intervals. Exploratory analysis will be directed to the question of whether protection varies with time. Meta-analysis A crucial issue will be to determine to what extent data may be compared between ongoing trials described in Table I. The trials differ in design, vaccination schedules and chosen endpoints. Neither trigger criteria, timing of laboratory samples, no sampling techniques have been standardized between trials. Pooling data for meta-analysis may be severely criticized. However, it still seems prudent to use the primary case definition of laboratory-confirmed pertussis with at least 21 days of paroxysmal cough as suggested at a World Health Organization working group in January 1992 for a pre-planned meta-analysis of the results from trials in Germany,

Acellular

pertussis

vaccines

507

Italy, Senegal and Sweden. Such a universally agreed single endpoint would facilitate comparisons between vaccines tested in different trials. Serological

correlates

to protection

Serological correlates to protection in individuals will be sought in the ongoing placebo-controlled trials. In the Stockhom 1 trial, such an analysis will focus on study children with known exposure within the household, and for which pre-exposure sera is available. Sera have been collected from nearly all participating children at 12 months of age and will be collected at either 2 or 2.5-3 years of age, and the study households are actively surveyed for culture-confirmed pertussis. About 150 exposed children will be available for the analysis of serological correlates to protection by the end of the trial. Pending these results, a serological correlate valid for a vaccinated population but not necessarily for the vaccinated individual, may turn out to be the only alternative to performing large efficacy trials also in the future. A better understanding of the cellular immunological response to pertussis infection and vaccination is still needed. This work is supported through Allergy and Infectious Diseases, following vaccine manufacturers: Kline Beecham.

contract NO1 -Al-l 5125 by the National Institute for Bethseda, Maryland, USA, and by contracts with the BiocineSclavo, Connaught Laboratories Ltd, and Smith-

References 1. Anon. Pertussis: adults, infants and herds. Lancet 1992; 339: 526-527. 2. Miller E, Vurdien JE, White JM. The epidemiology of pertussis in England and Wales. CDR review 1992; 2: 152-154. 3. Onorato IM, Wassilak SG, Meade B. Efficacy of whole-cell pertussis vaccine in preschool children in the United States. JAMA 1992; 267: 2745-2749. 4. Fine PEM, Clarkson JA. Reflections on the efficacy of pertussis vaccines. Rev Infect Dis 1987; 9: 866-883. J, Olin P. Efficacy of two acellular pertussis vaccines during three years of 5. Storsaeter passive surveillance. Vaccine 1992; 10: 142-144. J, Hallander H, Farrington CP, Olin P, Mollby R, Miller E. Secondary 6. Storsaeter analyses of the efficacy of two acellular pertussis vaccines in a Swedish phase III trial. Vaccine 1990; 8: 457-461. WC, Storsaeter J, Olin P, Hallander HO. Acellular pertussis vaccines: 7. Blackwelder Efficacy and evaluation of clinical case definitions. AmJ Dis Child 1991; 145: 1285-1289. 8. World Health Organisation meeting on case definition of pertussis. Geneva, lo-11 January 1991. MINIEpIIPERTj91.1 1991; 4-5. 9. Ramsay MEB, Rao M, Begg NT. Symptoms after accelerated immunisation. BMJ 1992; 304: 1534-1536. 10. Meade BD, Bollen A. Recommendations for use of the polymerase chain reaction in the diagnosis of Bordetella pertussis infections. J Med Microbial 1994; 41: 51-55.