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Effectiveness of a single dose of acellular pertussis vaccine to prevent pertussis in children primed with pertussis whole cell vaccine
Vaccine 19 (2001) 3004– 3008 www.elsevier.com/locate/vaccine
Effectiveness of a single dose of acellular pertussis vaccine to prevent pertussis in children primed with pertussis whole cell vaccine Gaston De Serres a,b,*, Ramak Shadmani b, Nicole Boulianne a,b, Bernard Duval a,b, Louis Rochette b, Monique Douville Fradet a,c, Scott A. Halperin d b
a Institut National de Sante´ Publique du Que´bec, Quebec, Canada G1E 7G9 Public Health Research Unit, CHUL Research Center, La6al Uni6ersity, Quebec, Canada G1V 4G2 c Ministe`re de la Sante´ et des Ser6ices Sociaux du Que´bec, Quebec, CanadaG1S 2M1 d IWK-Grace Center, Dalhousie Uni6ersity, Halifax, NS, Canada
Received 11 August 2000; received in revised form 23 November 2000; accepted 25 November 2000
Abstract We estimated the protection given by one booster dose of acellular pertussis vaccine (aP) given at 18 months or before school entry to children already primed with whole cell vaccine (wP). Case-control studies were conducted in these two age groups. In children who received or were eligible to receive their 18 months booster, the risk of pertussis was 1.4 and 3.6 times higher for those with 4 and 3 wP, respectively, compared to those with 3 wP + 1 aP. In 5 and 6 yr old children, the risk of pertussis among the subjects with 5 and 4 wP, was 1.4 and 2.1 times higher respectively than in those who received 4 wP +1 aP. A single dose of aP increased the protection against pertussis and this protection was greater than that obtained with a wP booster. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Pertussis; Pertussis vaccine; Vaccine efficacy; Prevention and control; Acellular pertussis vaccine
1. Introduction There has been a substantial resurgence of pertussis in Canada since 1990 [1,2]. Outbreak investigations estimated the effectiveness of the whole cell vaccine (wP) in Canada (Aventis Pasteur formerly Pasteur Me´rieux Connaught Laboratories Ltd, North York, Ont., Canada (PMC)) between 48 and 69% [2 – 4]. As vaccine coverage was high in the affected areas, the low efficacy of the vaccine was considered the major factor in the resurgence. The nationwide introduction of the five component acellular pertussis vaccine (aP) manufactured by Aventis Pasteur as part of the regular childhood immunization schedule brought great hopes. This study was funded by an unrestricted grant from Aventis Pasteur (formerly Pasteur Me´rieux Connaught, (Canada). * Corresponding author. Address: Centre de Sante Publique de Quebec, 2400 d’Estimauville, Beauport, Que., Canada G1E 7G9. Tel.: +1-418-666-7000, ext.: 274; fax: +1-418-666-2776. E-mail address: [email protected] (G. De Serres).
In Sweden, three doses of the same five component aP given to infants had an efficacy of 85% [5] and similar efficacy might be expected in Canadian infants who will receive three doses of this vaccine. However, for older children who had already received doses of wP, the protection given by one additional single dose of aP is unknown. Some studies have shown that, in children primed with wP, a booster dose of the five component aP increases their antibodies to levels similar to those observed in infants in whom an efficacy of 85% was demonstrated [6–9]. Other studies found that the antibody level after a booster dose of aP was lower in children primed by wP than by aP (although this was not the five component aP vaccine) [10]. Recent data indicated that there may be serological correlates of protection but this conclusion was drawn from observations in few individuals [11,12]. Because immunogenicity studies do not provide definitive support about the protection in these children, epidemiological data are necessary.
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G. De Serres et al. / Vaccine 19 (2001) 3004–3008
In Quebec, a major outbreak of pertussis occurred in 1998. The two most affected age groups were 5 –9 yr old (34% of all cases) and 0 – 4 yr old (32%), children. Less affected were 10 – 14 yr old teenagers (17%). This outbreak provided an opportunity to measure the protection added by a single booster dose of aP given at 18 months or before school entry to children primed with wP.
2. Methods
2.1. Study design and population Two case-control studies were conducted. In the first one, the study population (SP18m) included all children born between October 1, 1995 and February 1, 1997, and allowed assessment of the impact of the booster dose given at 18 months of age. In the second, the study population (SP5-6y) included all children born between October 1, 1991 and October 1, 1993 and was designed to assess the impact of the dose given prior to school entry (B5 yr). This last group corresponded to children who attended kindergarten or grade 1 in September 1998. The cases and their controls were selected from five Quebec public health units where a census of the children was available and where incidence of disease was high: Bas Saint-Laurent, Chaudie`re Appalaches, Estrie, Mauricie Bois Francs and Quebec City.
2.2. Cases All reported cases within the defined study population (SP18m and SP5-6y) who sustained pertussis between January 1, 1998 and January 15, 1999 were eligible. To be included, cases had to meet the Canadian surveillance pertussis case definition: either a positive culture or a cough illness lasting E2 weeks with at least one pertussis-related symptom (paroxysmal cough, post-tussive vomiting or apnea, whoop) without any other apparent disease [13]. The information about the pertussis illness was collected from the investigation form completed by the public health units when the cases were reported.
2.3. Controls For each case, four controls were selected at random from the census of children residing in the case’s region of residence. For the SP5-6y, half of the controls were selected among children born between October 1, 1991 and September 30, 1992 and the other half among children born between October 1, 1992 and September 30, 1993. This stratification was necessary to ensure an equal distribution of controls in each school grade.
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2.4. Vaccines All children had received the same wP for their first three doses (SP18m) or four doses (SP5-6y; Pasteur Me´rieux Connaught). In most cases, it was given in combination with diphtheria, tetanus, Haemophilus influenzae type b and polio (DTwP-IPV-Hib). The aP was the five component aP containing 20 mg of pertussis toxoid (PT), 20 mg of filamentous hemagglutinin (FHA), 5 mg of fimbriae 2 and 3 (FIM) and 3 mg of pertactin (Pasteur Me´rieux Connaught) given as DTaPIPV-Hib (SP18m) or DTaP-IPV (SP5-6y). Children in SP18m were primed by three doses of wP and received either wP or aP for their fourth dose. In SP5-6y, children received wP for their first four doses and either wP or aP for their fifth dose. As aP was introduced in January 1998, half of children in SP18m had reached 18 months of age by December 1997 and the other half after it. In consequence, approximately half of the cohort was eligible to receive wP while aP was the vaccine available for the other half. For SP5-6y, the older half of the cohort received the preschool booster with the wP, whereas the younger half received aP.
2.5. Immunization status The vaccination data were collected from the vaccination booklet given to parents of all children in Quebec, from the regional or local computerized vaccine information system and from providers. Only written proof of vaccination was accepted both for cases and controls. To be considered an unvaccinated child, the parents had to clearly report that they never had their child vaccinated. As aP was given since January 1998, the vaccination status of children who received all their doses with wP was already determined at that time whereas for those who were given aP, their status changed during the year. To account for that, we assessed the vaccination status of children at the date of onset of the case.
2.6. Ethics This study was approved by the Ethic Committee of the Centre Hospitalier Universitaire de Que´bec (CHUQ). The collection of data was done by the public health units nurses and only denominalized questionnaires were sent to the research team.
2.7. Analysis The main analysis calculated the odds ratio (OR) to estimate the relative risk of pertussis in children who were primed with wP and had their first (18 months) or second booster (5–6 yr) with aP compared to that in children who had all their immunization with wP.
G. De Serres et al. / Vaccine 19 (2001) 3004–3008
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For children in SP18m, we calculated the OR of pertussis comparing vaccinated to unvaccinated children. The effectiveness of the vaccine was derived from these OR by the following equation: Vaccine effectiveness = (1− OR vaccinated/unvaccinated) ×100%.
The 95% CI were estimated by the approximative log normal method.
3. Results
In comparison to children who received 4 wP+1 aP, the risk of pertussis among the subjects who received 5, 4 and 3 wP was 1.4, 2.1 and 2.9 times higher, respectively. The OR between 5 wP (referent) and 4 wP was 1.5 (95% CI: 1.0 –2.3). We did not calculate the vaccine effectiveness in this age group because we considered that many of the unvaccinated controls were likely to be protected by prior disease. This is illustrated by the fact that children who received 3 wP had a risk of pertussis 2.3 times higher than unvaccinated ones. We concluded that a calculation of vaccine effectiveness in this group would not be valid.
3.1. SP18m A total of 120 cases were included of whom 34 (28%) were culture positive. Among cases, 12 (10%) were unvaccinated in contrast to 11 (2%) controls (P B 0.001; Table 1). Thirty-nine (33%) cases and 74 (16%) controls received less than four doses of vaccine against pertussis (P B0.001). The risk of pertussis among the subjects who received 4 and 3 wP was 1.4 and 3.6 times higher, respectively, than those who received 3 wP+1 aP (Table 1). Children who received 3 wP were 2.5 times (95% CI: 1.4 – 4.6) more likely to have pertussis than those who received 4 wP. The OR of pertussis comparing children who received 3 wP+1 aP to unvaccinated children was 0.13 for an effectiveness of 87%. For 4 and 3 wP the OR were 0.19 and 0.48, respectively, and the effectiveness were 81% and 52% (Table 1). No protection was observed in children who received 1 wP.
3.2. SP5 -6y A total of 197 cases were included among whom 70 (36%) were culture positive. Four (2%) cases and 18 (2%) controls were unvaccinated (Table 2). Among cases and controls, 72 (37%) and 198 (25%), respectively, received less than five doses of vaccine against pertussis.
4. Discussion The administration of a single dose of aP increased the protection against pertussis in children primed by wP. This confirms the hypothesis derived from immunogenicity studies that a single booster dose provides effective protection [6–9,14,15]. In SP18m, our estimate of vaccine effectiveness for 3 wP+ 1 aP was 87% which is similar to estimates found in clinical trials in infants who received 3 aP. Children who received aP as booster at 18 months old or pre-school had a reduction of 40% of their risk of pertussis in comparison to children who were boosted with wP. While these results did not reach statistical significance, it is likely that this is a true increase in protection considering the same improvement in both cohorts and the strong trends with the increasing number of doses. Although increasing the sample size by merging the data from both cohorts would achieve statistical significance, it could introduce a bias as the intensity of exposure to pertussis may have been different in the two cohorts. Nevertheless, the ORs were the same in both cohorts (1.4) and there was a statistically significant improvement when children who
Table 1 Odds ratio of pertussis and vaccine effectiveness according to the number of doses and type of vaccine in children born between October 1, 1995 and February 1, 1997 (SP18m) 3 wP+1 aP
4 wP
3 wP
2 wP
1 wP
Unvaccinated
Total
Cases Controls
25 174
44 215
28 54
2 9
9 6
12 11
120 469a
Odds ratio Referent 3 wP+1 aP CI (95%)
Referent –
1.4 (0.8, 2.5)
3.6 (1.9, 7.0)
1.6 (0.2, 8.1)
10.4 (3.0, 38.2)
7.6 (2.8, 21.0)
Referent unvaccinated CI (95%)
0.13 (0.1–0.4)
0.19 (0.1–0.5)
0.48 (0.2–1.3)
0.20 (0.02, 1.4)
1.38 (0.3, 6.3)
Referent –
Vaccine effectiveness CI (95%)
87% (60, 90)
81% (50, 90)
52% (−30, 80)
80% (−40, 98)
−38% (−500, 70)
– –
a
Excludes 11 controls with other vaccine combinations (e.g. 2 wp+1 ap) or missing information.
G. De Serres et al. / Vaccine 19 (2001) 3004–3008
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Table 2 Odds ratio of pertussis according to the number of doses and type of vaccine in children born between October 1, 1991 and October 1, 1993 (SP5-6y) 4 wP+1 aP
5 wP
4 wP
3 wP
2 wP
1 wP
Unvaccinated
Total
Cases Controls
38 221
83a 351
55 153
10 20
1 3
6 10
4 18
197 776b
Odds ratio Referent 4 wP+1 aP CI (95%)
Referent –
1.4 (0.9–2.1)
2.1 (1.3–3.4)
2.9 (1.2–7.2)
1.9 (0.04, 24.8)
3.5 (1.0, 11.3)
1.3 (0.3, 4.2)
a b
One case had received six doses of wP. Excludes 12 controls with other vaccine combinations.
received aP were compared to those who had no booster (SP18m: OR=3.6; 95% CI: (1.9 – 7.1) and SP56y: OR= 2.1; 95% CI: (1.3 – 3.4)). The ideal design to compare the efficacy (or effectiveness) of two vaccines is through clinical trials; however, such trials will never be done because of the cost involved. An epidemiological study using the opportunity given by the programatic change from wP to aP is the only possible design to assess this question but it has the limitations associated with such designs. In this study, we used reported cases. The fact that not all cases were diagnosed or reported does not bias the results as long as the proportion of reported cases was similar regardless of which vaccine was used. A selection bias could exist for cases if the diagnosis of pertussis was less likely with one vaccine as might happen if one vaccine decreases the symptomatology more than the other vaccine. There were no data suggesting this might have occurred and reporting is unlikely to change with the type of vaccine administered. Moreover, if this had happened, one could argue that the decreased severity of disease is in fact a measure of vaccine efficacy. Controls who had pertussis prior to the study period were not excluded because only a small proportion of children with pertussis are diagnosed [16]. For the main comparisons between children who received an aP and those who were given wP as booster, this should not bias the results because the proportion of vulnerable children before the administration of the booster dose was likely to be equal whatever the type of vaccine used for the booster. However, not excluding controls with a history of pertussis might impact on the estimate of vaccine effectiveness because it is more likely to affect the unvaccinated children. Because the incidence of pertussis in the 2 yr preceding the study period was low, the non-exclusion of children with prior episode of pertussis would have a minimal impact in the 18 months old cohort. For SP5-6y, the bias is likely to be much greater because the incidence of pertussis during 1993, 1994 and 1995 was high and many unvaccinated children may have acquired pertussis as previously described in the results section.
In children, exposure to pertussis is likely to increase with age because of the increased frequency of contact with other people. In fact, observations suggest that this did not occur within each cohort. First, results of a stratified analysis of OR for the first 6 months of 1998 were similar to that for the second half (data not shown). Second, children who had not received their booster dose (3 wP in SP18 and 4 wP in SP5-6y) were generally in the younger half of the cohorts and their risk of pertussis was greater than in older children who had received a full regimen of wP doses. The fact that the risk of pertussis was greater among children with 3 wP than in those with 4 wP in SP18m may have two explanations. First, the protection was optimal after the first three doses but waned with time and the fourth dose brought the protection back to the level obtained after three doses. Second, the protection after three doses was not optimal and the booster increased it. A combination of these two phenomena may have also occurred. This also applies to the observation between 4 and 5 wP in SP5-6y. In any case this poses a problem. It indicates either that waning occurs rapidly with wP or that the number of doses to obtain the optimal protection is large. The 81% effectiveness we observed with 4 wP was greater than anticipated from previous studies [2–4]. In these studies, E 4 doses gave a protection ranging from 48% to 61%, which is similar to what we observed with 3 wP. This may be explained by the fact that the study period was soon after the administration of the booster dose, suggesting that rapid waning is the predominant factor. From our study we cannot derive information about the duration of protection of aP but the Swedish study of infants who received three doses showed that protection is maintained for at least 2 yr [17]. The confirmation of the effectiveness of a single booster dose of aP by our study is important. An adolescent and adult formulation of aP is now available in Canada and immunogenicity studies showed good antibody responses. While efficacy data would be important, they are not likely to be available soon. In the meantime, extrapolation of the results from this study
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G. De Serres et al. / Vaccine 19 (2001) 3004–3008
in 18 month old and 5 – 6 yr old children suggests that a single booster dose in adolescents and adults will increase their protection. The question, which remains, is the duration of protection after these booster doses.
Acknowledgements We are grateful to Daniel Bolduc, Jacques Blais and Geanine Tourgeon from the Bas Saint-Laurent region, Suzanne Me´nard from Estrie region, Gabrielle Vermette and Chantal Dumont from Chaudie`re Appalaches, Fernand Guillemette and Guylaine Prud’homme from Mauricie Bois Franc, Colette Couture, Sophie Auger, Claude Boulianne, Manon Loisel and Ste´phanie Michaud from Que´bec.
References [1] De Serres G, Boulianne N, Douville Fradette M, Duval B. Pertussis in Quebec: ongoing epidemic since the late 1980s. Can Com Dis Rep 1995;21:45–7. [2] Bentsi-Enchill AD, Halperin SA, Scott J, MacIsaac K, Duclos P. Estimates of the effectiveness of a whole-cell pertussis vaccine from an outbreak in an immunized population. Vaccine 1997;15:301– 6. [3] Halperin SA, Bortolussi R, MacLean D, Chisholm N. Persistence of pertussis in an immunized population: results of the Nova Scotia enhanced pertussis surveillance program. J Pediatr 1989;115:686– 93. [4] De Serres G, Boulianne N, Duval B, et al. Effectiveness of a whole cell pertussis vaccine in child-care centers and schools. Ped Infect Dis J 1996;15:519–24. [5] Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996;334:349– 55. [6] Halperin SA, Barreto L, Eastwood BJ, et al. Safety and immunogenicity of a five-component acellular pertussis vaccine with varying antigen quantities. Arch Ped Adolesc Med 1994;148:1220– 4.
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[7] Halperin SA, Eastwood B, Barreto L, Law B, Roberts EA. Safety and immunogenicity of two acellular pertussis vaccines with different pertussis toxoid and filamentous hemagglutinin content in infants 2 – 6 months old. Scand J Infect Dis 1995;27:279– 87. [8] Pichichero ME, Deloria MA, Rennels MB, et al. A safety and immunogenicity comparison of 12 acellular pertussis vaccines and one whole-cell pertussis vaccine given as a fourth dose in 15to 20-month-old children. Pediatrics 1997;100:772– 88. [9] Halperin SA, Davies D, Barreto L, et al. Safety and immunogenicity of two inactivated poliovirus vaccines in combination with an acellular pertussis vaccine and diphtheria and tetanus toxoids in seventeen- to nineteen-month-old infants. J Pediatr 1997;130:525– 31. [10] Podda A, Bona G, Canciani G, et al. Effect of priming with diphtheria and tetanus toxoids combined with whole-cell pertussis vaccine or with acellular pertussis vaccine on the safety and immunogenicity of a booster dose of an acellular pertussis vaccine containing a genetically inactivated pertussis toxin in fifteen- to twenty-one-month-old children. J Pediatr 1995; 127:238– 43. [11] Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998;16:1901– 6. [12] Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998;16:1907–16. [13] National Advisory Committee on Immunization, the Advisory Committee on Epidemiology and the Canadian Pediatric Society. Statement on management of persons exposed to pertussis and pertussis outbreak control. Can Com Dis Rep 1994;20: 193– 9. [14] Schmitt H-J, Beutel K, Schuind A, et al. Reactogenicity and immunogenicity of a booster dose of a combined diphtheria, tetanus, and tricomponent acellular pertussis vaccine at fourteen to twenty-eight months of age. J Pediatr 1997;130:616–23. [15] Pichichero ME, Badgett JT, Rodgers GC, McLinn S, TrevinoScatterday B, Nelson JD. Acellular pertussis vaccine: immunogenicity and safety of an acellular pertussis vs. a whole cell pertussis vaccine combined with diphtheria and tetanus toxoids as a booster in 18- to 24-month old children. Pediatr Infect Dis J 1987;6:352– 63. [16] Deeks S, De Serres G, Boulianne N, et al. Failure of physicians to consider the diagnosis of pertussis in children. Clin Infect Dis 1999;28:840– 6. [17] Taranger J, Trollfors B, Lagergard T, et al. Unchanged efficacy of a pertussis toxoid vaccine throughout the two years after third vaccination of infants. Pediatr Infect Dis J 1997;16:180–4.
Effectiveness of a single dose of acellular pertussis vaccine to prevent pertussis in children primed with pertussis whole cell vaccine Gaston De Serres a,b,*, Ramak Shadmani b, Nicole Boulianne a,b, Bernard Duval a,b, Louis Rochette b, Monique Douville Fradet a,c, Scott A. Halperin d b
a Institut National de Sante´ Publique du Que´bec, Quebec, Canada G1E 7G9 Public Health Research Unit, CHUL Research Center, La6al Uni6ersity, Quebec, Canada G1V 4G2 c Ministe`re de la Sante´ et des Ser6ices Sociaux du Que´bec, Quebec, CanadaG1S 2M1 d IWK-Grace Center, Dalhousie Uni6ersity, Halifax, NS, Canada
Received 11 August 2000; received in revised form 23 November 2000; accepted 25 November 2000
Abstract We estimated the protection given by one booster dose of acellular pertussis vaccine (aP) given at 18 months or before school entry to children already primed with whole cell vaccine (wP). Case-control studies were conducted in these two age groups. In children who received or were eligible to receive their 18 months booster, the risk of pertussis was 1.4 and 3.6 times higher for those with 4 and 3 wP, respectively, compared to those with 3 wP + 1 aP. In 5 and 6 yr old children, the risk of pertussis among the subjects with 5 and 4 wP, was 1.4 and 2.1 times higher respectively than in those who received 4 wP +1 aP. A single dose of aP increased the protection against pertussis and this protection was greater than that obtained with a wP booster. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Pertussis; Pertussis vaccine; Vaccine efficacy; Prevention and control; Acellular pertussis vaccine
1. Introduction There has been a substantial resurgence of pertussis in Canada since 1990 [1,2]. Outbreak investigations estimated the effectiveness of the whole cell vaccine (wP) in Canada (Aventis Pasteur formerly Pasteur Me´rieux Connaught Laboratories Ltd, North York, Ont., Canada (PMC)) between 48 and 69% [2 – 4]. As vaccine coverage was high in the affected areas, the low efficacy of the vaccine was considered the major factor in the resurgence. The nationwide introduction of the five component acellular pertussis vaccine (aP) manufactured by Aventis Pasteur as part of the regular childhood immunization schedule brought great hopes. This study was funded by an unrestricted grant from Aventis Pasteur (formerly Pasteur Me´rieux Connaught, (Canada). * Corresponding author. Address: Centre de Sante Publique de Quebec, 2400 d’Estimauville, Beauport, Que., Canada G1E 7G9. Tel.: +1-418-666-7000, ext.: 274; fax: +1-418-666-2776. E-mail address: [email protected] (G. De Serres).
In Sweden, three doses of the same five component aP given to infants had an efficacy of 85% [5] and similar efficacy might be expected in Canadian infants who will receive three doses of this vaccine. However, for older children who had already received doses of wP, the protection given by one additional single dose of aP is unknown. Some studies have shown that, in children primed with wP, a booster dose of the five component aP increases their antibodies to levels similar to those observed in infants in whom an efficacy of 85% was demonstrated [6–9]. Other studies found that the antibody level after a booster dose of aP was lower in children primed by wP than by aP (although this was not the five component aP vaccine) [10]. Recent data indicated that there may be serological correlates of protection but this conclusion was drawn from observations in few individuals [11,12]. Because immunogenicity studies do not provide definitive support about the protection in these children, epidemiological data are necessary.
0264-410X/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 0 ) 0 0 5 4 5 - 4
G. De Serres et al. / Vaccine 19 (2001) 3004–3008
In Quebec, a major outbreak of pertussis occurred in 1998. The two most affected age groups were 5 –9 yr old (34% of all cases) and 0 – 4 yr old (32%), children. Less affected were 10 – 14 yr old teenagers (17%). This outbreak provided an opportunity to measure the protection added by a single booster dose of aP given at 18 months or before school entry to children primed with wP.
2. Methods
2.1. Study design and population Two case-control studies were conducted. In the first one, the study population (SP18m) included all children born between October 1, 1995 and February 1, 1997, and allowed assessment of the impact of the booster dose given at 18 months of age. In the second, the study population (SP5-6y) included all children born between October 1, 1991 and October 1, 1993 and was designed to assess the impact of the dose given prior to school entry (B5 yr). This last group corresponded to children who attended kindergarten or grade 1 in September 1998. The cases and their controls were selected from five Quebec public health units where a census of the children was available and where incidence of disease was high: Bas Saint-Laurent, Chaudie`re Appalaches, Estrie, Mauricie Bois Francs and Quebec City.
2.2. Cases All reported cases within the defined study population (SP18m and SP5-6y) who sustained pertussis between January 1, 1998 and January 15, 1999 were eligible. To be included, cases had to meet the Canadian surveillance pertussis case definition: either a positive culture or a cough illness lasting E2 weeks with at least one pertussis-related symptom (paroxysmal cough, post-tussive vomiting or apnea, whoop) without any other apparent disease [13]. The information about the pertussis illness was collected from the investigation form completed by the public health units when the cases were reported.
2.3. Controls For each case, four controls were selected at random from the census of children residing in the case’s region of residence. For the SP5-6y, half of the controls were selected among children born between October 1, 1991 and September 30, 1992 and the other half among children born between October 1, 1992 and September 30, 1993. This stratification was necessary to ensure an equal distribution of controls in each school grade.
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2.4. Vaccines All children had received the same wP for their first three doses (SP18m) or four doses (SP5-6y; Pasteur Me´rieux Connaught). In most cases, it was given in combination with diphtheria, tetanus, Haemophilus influenzae type b and polio (DTwP-IPV-Hib). The aP was the five component aP containing 20 mg of pertussis toxoid (PT), 20 mg of filamentous hemagglutinin (FHA), 5 mg of fimbriae 2 and 3 (FIM) and 3 mg of pertactin (Pasteur Me´rieux Connaught) given as DTaPIPV-Hib (SP18m) or DTaP-IPV (SP5-6y). Children in SP18m were primed by three doses of wP and received either wP or aP for their fourth dose. In SP5-6y, children received wP for their first four doses and either wP or aP for their fifth dose. As aP was introduced in January 1998, half of children in SP18m had reached 18 months of age by December 1997 and the other half after it. In consequence, approximately half of the cohort was eligible to receive wP while aP was the vaccine available for the other half. For SP5-6y, the older half of the cohort received the preschool booster with the wP, whereas the younger half received aP.
2.5. Immunization status The vaccination data were collected from the vaccination booklet given to parents of all children in Quebec, from the regional or local computerized vaccine information system and from providers. Only written proof of vaccination was accepted both for cases and controls. To be considered an unvaccinated child, the parents had to clearly report that they never had their child vaccinated. As aP was given since January 1998, the vaccination status of children who received all their doses with wP was already determined at that time whereas for those who were given aP, their status changed during the year. To account for that, we assessed the vaccination status of children at the date of onset of the case.
2.6. Ethics This study was approved by the Ethic Committee of the Centre Hospitalier Universitaire de Que´bec (CHUQ). The collection of data was done by the public health units nurses and only denominalized questionnaires were sent to the research team.
2.7. Analysis The main analysis calculated the odds ratio (OR) to estimate the relative risk of pertussis in children who were primed with wP and had their first (18 months) or second booster (5–6 yr) with aP compared to that in children who had all their immunization with wP.
G. De Serres et al. / Vaccine 19 (2001) 3004–3008
3006
For children in SP18m, we calculated the OR of pertussis comparing vaccinated to unvaccinated children. The effectiveness of the vaccine was derived from these OR by the following equation: Vaccine effectiveness = (1− OR vaccinated/unvaccinated) ×100%.
The 95% CI were estimated by the approximative log normal method.
3. Results
In comparison to children who received 4 wP+1 aP, the risk of pertussis among the subjects who received 5, 4 and 3 wP was 1.4, 2.1 and 2.9 times higher, respectively. The OR between 5 wP (referent) and 4 wP was 1.5 (95% CI: 1.0 –2.3). We did not calculate the vaccine effectiveness in this age group because we considered that many of the unvaccinated controls were likely to be protected by prior disease. This is illustrated by the fact that children who received 3 wP had a risk of pertussis 2.3 times higher than unvaccinated ones. We concluded that a calculation of vaccine effectiveness in this group would not be valid.
3.1. SP18m A total of 120 cases were included of whom 34 (28%) were culture positive. Among cases, 12 (10%) were unvaccinated in contrast to 11 (2%) controls (P B 0.001; Table 1). Thirty-nine (33%) cases and 74 (16%) controls received less than four doses of vaccine against pertussis (P B0.001). The risk of pertussis among the subjects who received 4 and 3 wP was 1.4 and 3.6 times higher, respectively, than those who received 3 wP+1 aP (Table 1). Children who received 3 wP were 2.5 times (95% CI: 1.4 – 4.6) more likely to have pertussis than those who received 4 wP. The OR of pertussis comparing children who received 3 wP+1 aP to unvaccinated children was 0.13 for an effectiveness of 87%. For 4 and 3 wP the OR were 0.19 and 0.48, respectively, and the effectiveness were 81% and 52% (Table 1). No protection was observed in children who received 1 wP.
3.2. SP5 -6y A total of 197 cases were included among whom 70 (36%) were culture positive. Four (2%) cases and 18 (2%) controls were unvaccinated (Table 2). Among cases and controls, 72 (37%) and 198 (25%), respectively, received less than five doses of vaccine against pertussis.
4. Discussion The administration of a single dose of aP increased the protection against pertussis in children primed by wP. This confirms the hypothesis derived from immunogenicity studies that a single booster dose provides effective protection [6–9,14,15]. In SP18m, our estimate of vaccine effectiveness for 3 wP+ 1 aP was 87% which is similar to estimates found in clinical trials in infants who received 3 aP. Children who received aP as booster at 18 months old or pre-school had a reduction of 40% of their risk of pertussis in comparison to children who were boosted with wP. While these results did not reach statistical significance, it is likely that this is a true increase in protection considering the same improvement in both cohorts and the strong trends with the increasing number of doses. Although increasing the sample size by merging the data from both cohorts would achieve statistical significance, it could introduce a bias as the intensity of exposure to pertussis may have been different in the two cohorts. Nevertheless, the ORs were the same in both cohorts (1.4) and there was a statistically significant improvement when children who
Table 1 Odds ratio of pertussis and vaccine effectiveness according to the number of doses and type of vaccine in children born between October 1, 1995 and February 1, 1997 (SP18m) 3 wP+1 aP
4 wP
3 wP
2 wP
1 wP
Unvaccinated
Total
Cases Controls
25 174
44 215
28 54
2 9
9 6
12 11
120 469a
Odds ratio Referent 3 wP+1 aP CI (95%)
Referent –
1.4 (0.8, 2.5)
3.6 (1.9, 7.0)
1.6 (0.2, 8.1)
10.4 (3.0, 38.2)
7.6 (2.8, 21.0)
Referent unvaccinated CI (95%)
0.13 (0.1–0.4)
0.19 (0.1–0.5)
0.48 (0.2–1.3)
0.20 (0.02, 1.4)
1.38 (0.3, 6.3)
Referent –
Vaccine effectiveness CI (95%)
87% (60, 90)
81% (50, 90)
52% (−30, 80)
80% (−40, 98)
−38% (−500, 70)
– –
a
Excludes 11 controls with other vaccine combinations (e.g. 2 wp+1 ap) or missing information.
G. De Serres et al. / Vaccine 19 (2001) 3004–3008
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Table 2 Odds ratio of pertussis according to the number of doses and type of vaccine in children born between October 1, 1991 and October 1, 1993 (SP5-6y) 4 wP+1 aP
5 wP
4 wP
3 wP
2 wP
1 wP
Unvaccinated
Total
Cases Controls
38 221
83a 351
55 153
10 20
1 3
6 10
4 18
197 776b
Odds ratio Referent 4 wP+1 aP CI (95%)
Referent –
1.4 (0.9–2.1)
2.1 (1.3–3.4)
2.9 (1.2–7.2)
1.9 (0.04, 24.8)
3.5 (1.0, 11.3)
1.3 (0.3, 4.2)
a b
One case had received six doses of wP. Excludes 12 controls with other vaccine combinations.
received aP were compared to those who had no booster (SP18m: OR=3.6; 95% CI: (1.9 – 7.1) and SP56y: OR= 2.1; 95% CI: (1.3 – 3.4)). The ideal design to compare the efficacy (or effectiveness) of two vaccines is through clinical trials; however, such trials will never be done because of the cost involved. An epidemiological study using the opportunity given by the programatic change from wP to aP is the only possible design to assess this question but it has the limitations associated with such designs. In this study, we used reported cases. The fact that not all cases were diagnosed or reported does not bias the results as long as the proportion of reported cases was similar regardless of which vaccine was used. A selection bias could exist for cases if the diagnosis of pertussis was less likely with one vaccine as might happen if one vaccine decreases the symptomatology more than the other vaccine. There were no data suggesting this might have occurred and reporting is unlikely to change with the type of vaccine administered. Moreover, if this had happened, one could argue that the decreased severity of disease is in fact a measure of vaccine efficacy. Controls who had pertussis prior to the study period were not excluded because only a small proportion of children with pertussis are diagnosed [16]. For the main comparisons between children who received an aP and those who were given wP as booster, this should not bias the results because the proportion of vulnerable children before the administration of the booster dose was likely to be equal whatever the type of vaccine used for the booster. However, not excluding controls with a history of pertussis might impact on the estimate of vaccine effectiveness because it is more likely to affect the unvaccinated children. Because the incidence of pertussis in the 2 yr preceding the study period was low, the non-exclusion of children with prior episode of pertussis would have a minimal impact in the 18 months old cohort. For SP5-6y, the bias is likely to be much greater because the incidence of pertussis during 1993, 1994 and 1995 was high and many unvaccinated children may have acquired pertussis as previously described in the results section.
In children, exposure to pertussis is likely to increase with age because of the increased frequency of contact with other people. In fact, observations suggest that this did not occur within each cohort. First, results of a stratified analysis of OR for the first 6 months of 1998 were similar to that for the second half (data not shown). Second, children who had not received their booster dose (3 wP in SP18 and 4 wP in SP5-6y) were generally in the younger half of the cohorts and their risk of pertussis was greater than in older children who had received a full regimen of wP doses. The fact that the risk of pertussis was greater among children with 3 wP than in those with 4 wP in SP18m may have two explanations. First, the protection was optimal after the first three doses but waned with time and the fourth dose brought the protection back to the level obtained after three doses. Second, the protection after three doses was not optimal and the booster increased it. A combination of these two phenomena may have also occurred. This also applies to the observation between 4 and 5 wP in SP5-6y. In any case this poses a problem. It indicates either that waning occurs rapidly with wP or that the number of doses to obtain the optimal protection is large. The 81% effectiveness we observed with 4 wP was greater than anticipated from previous studies [2–4]. In these studies, E 4 doses gave a protection ranging from 48% to 61%, which is similar to what we observed with 3 wP. This may be explained by the fact that the study period was soon after the administration of the booster dose, suggesting that rapid waning is the predominant factor. From our study we cannot derive information about the duration of protection of aP but the Swedish study of infants who received three doses showed that protection is maintained for at least 2 yr [17]. The confirmation of the effectiveness of a single booster dose of aP by our study is important. An adolescent and adult formulation of aP is now available in Canada and immunogenicity studies showed good antibody responses. While efficacy data would be important, they are not likely to be available soon. In the meantime, extrapolation of the results from this study
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in 18 month old and 5 – 6 yr old children suggests that a single booster dose in adolescents and adults will increase their protection. The question, which remains, is the duration of protection after these booster doses.
Acknowledgements We are grateful to Daniel Bolduc, Jacques Blais and Geanine Tourgeon from the Bas Saint-Laurent region, Suzanne Me´nard from Estrie region, Gabrielle Vermette and Chantal Dumont from Chaudie`re Appalaches, Fernand Guillemette and Guylaine Prud’homme from Mauricie Bois Franc, Colette Couture, Sophie Auger, Claude Boulianne, Manon Loisel and Ste´phanie Michaud from Que´bec.
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