Meningococcal Serogroup C Conjugate Vaccine Is Immunogenic in ...

8 downloads 0 Views 66KB Size Report
Meningococcal Serogroup C Conjugate Vaccine Is Immunogenic in Infancy and Primes for Memory. Peter Richmond, Ray Borrow, Elizabeth Miller,. Sarah Clark ...
1569

Meningococcal Serogroup C Conjugate Vaccine Is Immunogenic in Infancy and Primes for Memory Peter Richmond, Ray Borrow, Elizabeth Miller, Sarah Clark, Francesca Sadler, Andrew Fox, Norman Begg, Rhonwen Morris, and Keith Cartwright

Immunisation Division, Communicable Disease Surveillance Centre, Public Health Laboratory Service (PHLS), and Immunobiology Unit, Institute of Child Health, London; PHLS Meningococcal Reference Unit, Withington Hospital, Manchester; Public Health Laboratory, Gloucester Royal Hospital, Gloucester, United Kingdom

Meningococcal infections are an important cause of morbidity and mortality worldwide. Serogroup B and C strains are responsible for most cases in the United Kingdom (UK) and the developed world, whereas serogroup A predominates in subSaharan Africa [1]. In England and Wales, notifications of meningococcal disease rose from 1129 cases in 1994 to 2330 cases in 1996, with the proportion due to serogroup C increasing to 40% of laboratory-confirmed cases [2]. This increase was associated with the emergence of a serotype C:2a strain, documented previously in Canada and Eastern Europe, which led to highly publicized outbreaks in older children and young adults, although infants remained at highest risk [3]. Meningococcal vaccines containing purified serogroup C capsular polysaccharide induce protective serum bactericidal antibodies (SBAs) in adults but are poorly immunogenic in young children and may induce tolerance [4–6]. The immunogenicity of polysaccharides can be improved by conjugation to a protein carrier. Haemophilus influenzae type b (Hib) con-

Received 24 July 1998; revised 25 January 1999. Presented in part: Eleventh International Pathogenic Neisseria Conference, Nice, France, 1–6 November 1998 (abstract 72). Written informed consent was obtained from the parents or guardians of all study subjects, and the study protocol was approved by the west Gloucestershire local research ethics committee. Financial support: UK Department of Health (grant 121/369); Wyeth Lederle Vaccines and Pediatrics. Reprints or correspondence: Dr. Peter Richmond, Immunisation Division, PHLS Communicable Disease Surveillance Centre, 61 Colindale Ave., London NW9 5EQ, UK ([email protected]). The Journal of Infectious Diseases 1999; 179:1569–72 q1999 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/99/7906-0037$02.00

jugate vaccines induce T cell–dependent responses with higher antibody titers, increased antibody avidity, and priming for immunologic memory, leading to better protection and longlasting immunity, even in infants [7]. The widespread use of Hib conjugate vaccines also protects age groups not included in vaccination programs, as reduction in Hib carriage and transmission results in herd immunity [7]. Serogroup A and C meningococcal conjugate vaccines are immunogenic and well tolerated in infants, although serogroup C antibody levels fall significantly by age 14 months [6, 8]. Long-term immunity is improved by induction of memory, as demonstrated for the serogroup C component of meningococcal AC conjugate vaccine administered to Gambian infants [6]. Monovalent meningococcal C conjugate (MCC) vaccines were developed for countries where serogroup A disease is rare and are safe and immunogenic in adults [9]. We evaluated the reactogenicity and immunogenicity of 2 dosages of a meningococcal C oligosaccharide-CRM197 conjugate vaccine in infants and subsequent antibody persistence and response to meningococcal polysaccharide vaccine to assess immunologic memory.

Materials and Methods Study population. Infants eligible for routine primary immunizations with diphtheria-tetanus-pertussis (DTP), Hib, and oral polio vaccines were recruited between October 1995 and March 1996 from general practices in west Gloucestershire. Infants were excluded if they were immunocompromised or if there was a general contraindication to immunization [10]. Infants were immunized at ages 2, 3, and 4 months according to the UK schedule.

Downloaded from http://jid.oxfordjournals.org/ by guest on December 26, 2015

The safety, immunogenicity, and immunologic priming of 2 dosages (2 mg or 10 mg) of a meningococcal C oligosaccharide-CRM197 conjugate vaccine was evaluated in 114 infants vaccinated at ages 2, 3, and 4 months. Antibody persistence and response to boosting with 10 mg of meningococcal C polysaccharide were assessed. The meningococcal conjugate vaccine produced fewer local reactions than concurrent routine immunizations. Total serogroup C–specific immunoglobulin geometric mean concentration (GMC) increased from 0.3 mg/mL before vaccination to 13.1 mg/mL at age 5 months. Serum bactericidal antibody (SBA) geometric mean titers (GMTs) rose from !1:4 to 1:1057 at 5 months and fell by 14 months to 1: 19. Following boosting, anti–C-specific immunoglobulin GMC rose to 15.9 mg/mL and SBA GMT to 1:495. Antibody responses in the 10-mg dose cohort were significantly higher at 5 months (P ! .01) than in the 2-mg dose cohort but were lower after polysaccharide boosting (P 5 .02). This meningococcal conjugate vaccine was well tolerated and immunogenic and induced immunologic memory in infants.

1570

Richmond et al.

2a:P1.5,2). SBA titers were expressed as the reciprocal of the final serum dilution giving >50% killing at 60 min [12]. A subset of sera from each cohort were tested for IgG antibodies to diphtheria and tetanus toxoids by standardized ELISA using the World Health Organization international standard [13]. Statistical evaluation. Antibody levels were log-transformed, and geometric mean titers with 95% confidence intervals (CIs) were calculated. The Mann-Whitney U test was used to determine whether differences in antibody titers between different doses and different vaccine formulations were significant. McNemar’s test was used to evaluate the significance of differences in local reactions between DTP/Hib and meningococcal vaccines. The x2 and Fisher’s exact tests were used to determine the significance of differences in symptoms in high- and low-dose cohorts. The relationship between serogroup C–specific antibody levels and SBA titers was measured by Pearson’s correlation coefficient.

Results Study subjects. Of 115 infants recruited (60 boys, 55 girls), 114 received 3 doses of MCC vaccine (57 low and 57 high doses). The median birth weight of infants was 3.4 kg (range, 1.7–4.7), and the median age at first vaccination was 8 weeks (range, 8–12), with no differences between cohorts. Fifty infants (25 from each cohort) received a polysaccharide booster at median ages of 83 weeks (range, 63–95) and 77 weeks (range, 67–93) for low- and high-dose cohorts, respectively. Reactogenicity. Rates of local reactions and systemic symptoms up to 7 days after immunization are shown in table 1. Local reactions at the site of immunization were rare after MCC vaccine and were significantly less common than at the site of DTP/Hib immunization for all 3 doses. The high-dose cohort had more systemic symptoms than the low-dose cohort, but there was no difference in the proportion of infants with temperatures 1387C. One subject required hospitalization for a viral illness following the second vaccination, but there were no vaccine-attributable serious adverse events. One of the 2 children who received a 0.5-mL dose of meningococcal AC polysaccharide vaccine developed generalized rash, mild facial edema, cough, and coryzal symptoms 5 h after immunization. There was no local reaction or anaphylaxis symptoms. Symptoms resolved with oral antihistamines over 48 h. Specific IgE antibodies to meningococcal A and C polysaccharides and skin

Table 1. Number (%) of infants with local reactions and systemic symptoms within 7 days (unless otherwise stated) of meningococcal C-CRM197 conjugate vaccine and DTP/Hib vaccines at 2, 3, and 4 months according to vaccine formulation (results for doses 1–3 combined). Meningococcal C Low dose (2 mg) Erythema >2.5 cm Swelling >2.5 cm Fever >387C (up to 3 days) Systemic symptoms >3 in first 24 h Crying 11 h in first 24 h a

4/171 2/171 7/171 26/171 3/156

(2.3) (1.2) (4.1) (11.7) (1.9)

High dose (10 mg) 5/173 6/173 8/173 53/173 2/153

(3.9) (3.5) (4.6) (30.6) (1.3)

a

P

DTP/Hib

P

1.5

48/344 (11.6) 64/344 (18.6)

!.001

.16 1.5 !.01 1.5

!.001

P values calculated for comparison of low- and high-dose meningococcal C vaccines combined vs. Haemophilus influenza (Hib)/diptheria-tetanus-pertussis (DTP) vaccines.

Downloaded from http://jid.oxfordjournals.org/ by guest on December 26, 2015

Vaccines and immunization. The MCC study vaccine was developed by Wyeth Lederle Vaccines and Pediatrics (WLVP; Pearl River, NY). It comprises purified short-chain oligosaccharides derived from serogroup C meningococcal capsular polysaccharide, coupled to CRM197, a nontoxic mutant diphtheria toxin, with 0.5 mg of AlPO4 adjuvant, in single-dose (0.5 mL) vials. Two dosages of conjugate vaccine, containing either 2 or 10 mg of oligosaccharide and 5 or 25 mg of CRM197, respectively, were used for primary immunization in sequential cohorts of infants. The meningococcal vaccines were given by intramuscular injection into the right anterolateral thigh with a 2.54-cm, 25-gauge needle. All infants received 0.5 mL of DTP vaccine (Trivax-AD; Wellcome, Manchester, UK) with Al(OH)3 adjuvant mixed prior to injection with 0.5 mL of Hib oligosaccharide-CRM197 conjugate vaccine (HibTITER; WLVP), given by intramuscular injection into the left thigh, and oral polio vaccine. Half the infants were randomized to receive meningococcal AC polysaccharide vaccine at age 15–20 months. The rest will be vaccinated at 4 years of age. The first 2 infants received a 0.5-mL dose of meningococcal AC polysaccharide vaccine (AC Vax; SmithKline, Rixensart, Belgium), but after adverse events in 1 infant and in 3 children in another study, the dose was changed to 0.1 mL (containing 10 mg each of meningococcal A and C polysaccharides) of an alternative meningococcal AC polysaccharide vaccine (Mengivac [A1C]; Pasteur Merieux, Lyon, France). Reactogenicity was assessed by parents, who recorded axillary temperatures, local reactions, and systemic symptoms for 7 days after each vaccination, and by study nurses, who visited at 24 h and 7 days after vaccination to measure temperatures and local reactions and to complete a standard symptom questionnaire as previously done [8]. Parents were interviewed at each visit to ascertain adverse events, visits to general practitioners, and hospitalizations. Blood samples were obtained by venipuncture from each infant prior to the first immunization, at 4 weeks after each dose of vaccine, at age 14 months, and 1 month after the booster immunization. Sera were separated, stored at 2207C, and transported frozen to the Meningococcal Reference Unit for analysis. Serologic studies. Sera were tested for serogroup C–specific capsular polysaccharide antibodies by ELISA and by serum bactericidal assays against 2 serogroup C strains by standardized protocols as described [8]. ELISA antibody levels measured total immunoglobulin (IgG, IgA, and IgM isotypes) by use of CDC 1992 reference serum assigned a value of 32.0 mg/mL [11]. Meningococcal strains used in bactericidal assays were C11 (phenotype C:16: P1.7a,1) and a clinical isolate representing the epidemic strain (C:

JID 1999;179 (June)

JID 1999;179 (June)

Meningococcal C Conjugate Vaccine in Infancy

1571

and 4.48 IU/mL (95% CI, 3.0–6.7; n 5 22) for infants receiving the 2- and 10-mg doses, respectively. Tetanus antibody GMCs were 1.80 IU/mL (95% CI, 1.2–2.7) and 1.47 IU/mL (95% CI, 1.0–2.3) for the respective groups.

prick test to the vaccine were negative. Independent assessment concluded that this adverse event was not vaccine related. Immunogenicity. The results of serogroup C–specific total immunoglobulin and bactericidal antibody responses are shown in table 2. Before vaccination, 88% of infants had detectable serogroup C antibody by ELISA, but only 9% had bactericidal antibody. Significant increases in total immunoglobulin concentrations were seen after the first and second doses of meningococcal vaccine for both formulations (P ! .01 ). All infants achieved antibody levels 12 mg/mL after 2 doses of vaccine. The increase after the third immunization was not significant (P 5 .11). Antibody concentrations decreased significantly by age 14 months (P ! .001). After boosting with polysaccharide vaccine, all children achieved antibody levels 12 mg/mL. Antibody levels were significantly higher in infants given the 10-mg formulation after the second and third doses of meningococcal vaccine (P ! .01). The differences in antibody levels between high- and low-dose cohorts persisted at 14 months of age, but following boosting, children who had received the lowdose vaccine in infancy had higher total immunoglobulin geometric mean concentrations (GMCs; P 5 .02). The antibody responses to boosting in the 2 children given a 0.5-mL dose of polysaccharide vaccine were higher (63.9 and 278.9 mg/mL) than in those receiving the 0.1-mL booster dose. SBAs. Because bactericidal titers to the 2 serogroup C strains did not differ significantly, only the C11 results are shown. SBA was detectable after a single dose of MCC vaccine, with 72% of infants achieving a titer of >1:8. The titer increased significantly after first and second doses with 4-fold or greater rises in 74% and 95% of infants, respectively, compared with results after the previous dose. There was a lesser response to the third dose, with only 22% of infants achieving a 4-fold or greater rise. SBA titers declined at age 14 months but were boosted in response to polysaccharide vaccine (mean rise, 27fold; 86% had a rise >4-fold). SBA titers correlated with total antibody levels at age 5 months (r 5 0.57, P ! .001 ) and after boosting (r 5 0.78, P ! .001). Diphtheria and tetanus antibody responses did not differ between high- and low-dose cohorts. After dose 3, diphtheria antibody GMCs were 4.53 IU/mL (95% CI, 3.2–6.4; n 5 21)

Discussion

Table 2. Meningococcal serogroup C–specific antibody concentrations before and 1 month after meningococcal C conjugate vaccine at 2, 3, and 4 months of age and after boosting with 10 mg of serogroup C polysaccharide according to vaccine formulation. Total immunoglobulin GMC (95% CI) Sample timing Before dose 1 After dose 1 After dose 2 After dose 3 At 14 months After polysaccharide a boosting

Low dose (2 mg) 0.3 (0.2–0.4) 3.7 (2.9–4.7) 7.8 (6.4–9.5) 10 (8.5–11.6) 1.2 (1.0–1.5) 19.0 (17.4–20.5)

High dose (10 mg) 0.3 5.4 15.7 17.6 2.4 12.1

(0.2–0.4) (4.0–7.2) (12.9–19.2) (14.7–21.0) (2.0–3.0) (10.3–13.9)

No. (%) of infants with 12 mg/mL Low dose (2 mg)

High dose (10 mg)

2/55 41/56 54/54 56/56 15/53 23/23

3/54 39/50 56/56 52/53 31/53 20/20

(3.6) (73) (100) (100) (28) (100)

(5.6) (78) (100) (98) (58) (100)

Serum bactericidal antibody GMT (95% CI) Low dose (2 mg)

High dose (10 mg)

2.3 (1.9–2.8) 32.8 (19.6–55.0) 553.8 (376–815) 1102.9 (804–1513) 21.5 (12.7–36.1) 581 (322–2047)

1.3 (1.1–1.6) 30.3 (17–55) 766.3 (500–1174) 1011 (702–1455) 13.5 (7.3–25) 256 (108–610)

No. (%) of infants with SBA reciprocal titer >8 Low dose (2 mg)

High dose (10 mg)

2/55 42/55 53/53 56/56 35/52 22/22

2/54 34/50 54/55 52/53 28/53 19/20

NOTE. CI, confidence interval; GMC, geometric mean concentration; GMT, geometric mean titer; SBA, serum bactericidal antibody. a Children receiving 0.5-mL booster dose of meningococcal polysaccharide vaccine were not included in this analysis.

(3.6) (76) (100) (100) (67) (100)

(4) (68) (98) (98) (53) (95)

Downloaded from http://jid.oxfordjournals.org/ by guest on December 26, 2015

Prevention of meningococcal C disease requires vaccines that are effective in young children, as they bear the greatest burden of disease [3]. We have demonstrated that a candidate MCC vaccine is well tolerated and immunogenic in infants when given at ages 2, 3, and 4 months. Local reactions to the vaccine were significantly less than with routine immunizations. The incidence of systemic symptoms was similar to UK infants receiving DTP and Hib vaccines alone, using the same follow-up procedures [13]. Protection against serogroup C meningococcal disease correlates with the presence of anticapsular antibodies that have bactericidal activity [14]. Total antibody levels required for protection against serogroup C disease are not known but are estimated to be 1–2 mg/mL for serogroup A disease [15]. In our study, all infants achieved 2 mg/mL by age 4 months after 2 doses of MCC vaccine. Of importance, bactericidal activity was detectable after a single dose. Levels of bactericidal antibodies were much higher than after meningococcal polysaccharide vaccines [16]. We would expect this vaccine to induce protection in infants after 2 doses. Outbreaks of meningococcal C disease with a high morbidity have occurred in adolescents and university students. It is important that a vaccine given in infancy provide long-term protection. Antibody levels fell rapidly by 14 months, as noted previously [8]. Experience with Hib conjugate vaccines shows that induction of immunologic memory provides long-term protection despite low antibody levels [7]. Infants primed with MCC vaccine mounted an anamnestic antibody response when vaccinated with 10 mg of meningococcal C polysaccharide 12 months later. Total antibody and SBA responses were similar to levels after the primary series but higher than in children given 50 mg of meningococcal C polysaccharide at the same age [16]. This confirms the generation of memory B cells, which

1572

Richmond et al.

3. 4.

5.

6.

7. 8.

9.

10.

11.

Acknowledgments 12.

We are grateful to the study nurses in Gloucester (Diane Webb, Gail Breeze, Wendy Nedoma, and Anne Maher) who conducted the study, Marie Rush (Communicable Disease Surveillance Centre, Colindale) for data entry and analysis, Moya Burrage and Carol Thornton (CAMR, Porton Down) for doing the diphtheria and tetanus ELISAs, and George Carlone (CDC, Atlanta) for providing reference serum CDC 1992 and for help in establishing standardized ELISA and bactericidal assays. We also thank Steve Lockhart and Jane Clarke (WLVP) for assistance in this study and David Salisbury, Department of Health, for support of the study.

13.

14.

15.

16. References 1. Achtman M. Global epidemiology of meningococcal disease. In: Cartwright K, ed. Meningococcal disease. Chichester, UK: John Wiley & Sons, 1995: 159–75. 2. Ramsay M, Collins M, Rush M, Kaczmarski E. The epidemiology of me-

17.

ningococcal disease in England and Wales, 1996 and 1997. Eurosurveillance 1997; 2:74–6. Kaczmarski EB. Meningococcal disease in England and Wales: 1995. Commun Dis Rep CDR Rev 1997; 7:R55–9. Gold R, Lepow ML, Goldschneider I, Draper TL, Gotschlich EC. Clinical evaluation of group A and group C meningococcal polysaccharide vaccines in infants. J Clin Invest 1975; 56:1536–47. Taunay AE, Galvao JS, de Morais EC, Gotschlich EC. Disease prevention by meningococcal serogroup C polysaccharide vaccine in pre-school children: results after eleven months in Sao Paulo, Brazil [abstract]. Pediatr Res 1974; 8:429. Leach A, Twumasi PA, Greenwood BM, et al. Induction of immunologic memory in Gambian children by vaccination in infancy with a group A plus group C meningococcal polysaccharide-protein conjugate vaccine. J Infect Dis 1997; 175:200–4. Eskola J, Kayhty H. Ten years’ experience with Haemophilus influenzae type b (Hib) conjugate vaccines in Finland. Rev Med Microbiol 1996; 7:231–41. Fairley CK, Begg N, Borrow R, Fox AJ, Jones DM, Cartwright K. Conjugate meningococcal serogroup A and C vaccine: reactogenicity and immunogenicity in United Kingdom infants. J Infect Dis 1996; 174:1360–3. Kimura A, Ginsberg D, Hogerman D, Nonenmacher J, Eby R, Malinoski F. Clinical evaluation of a meningococcal group C oligosaccharideCRM197 conjugate vaccine in adults [abstract]. Clin Infect Dis 1995; 21: 790. Department of Health, Welsh Office, Scottish Home and Health Department. Immunisation against infectious disease. 2nd ed. London: Her Majesty’s Stationery Office, 1992. Gheesling LL, Carlone GM, Pais L, et al. Multicenter comparison of Neisseria meningitidis serogroup C anti-capsular polysaccharide antibody levels measured by a standardized enzyme-linked immunosorbent assay. J Clin Microbiol 1994; 32:1475–82. Anderson EL, Bowers T, Mink CM, et al. Safety and immunogenicity of meningococcal A and C polysaccharide conjugate vaccine in adults. Infect Immun 1994; 62:3391–5. Begg NT, Miller E, Fairley CK, et al. Antibody responses after DTP and either tetanus or diphtheria Haemophilus influenzae type b conjugate vaccines given for primary immunisation by separate or mixed injection. Vaccine 1995; 13:1547–50. Goldschneider I, Gotschlich E, Artenstein MS. Humoral immunity to the meningococcus. I. The role of humoral antibodies. J Exp Med 1969; 129: 1307–26. Peltola H, Ma¨kela¨ H, Ka¨yhty H, et al. Clinical efficacy of meningococcus group A capsular polysaccharide vaccine in children less than three months to five years of age. N Engl J Med 1977; 297:686–91. King WJ, MacDonald NE, Wells G, et al. Total and functional antibody response to a quadrivalent meningococcal polysaccharide vaccine among children. J Pediatr 1996; 128:196–201. Ahman H, Kahyhty H, Lehtonen H, Leroy O, Froeschele J, Eskola J. Streptococcus pneumoniae capsular polysaccharide-diphtheria toxoid conjugate vaccine is immunogenic in early infancy and able to induce immunologic memory. Pediatr Infect Dis J 1998; 17:211–6.

Downloaded from http://jid.oxfordjournals.org/ by guest on December 26, 2015

secrete high avidity antibody on subsequent challenge. The persistence of memory will be tested by vaccinating the remaining children at age 4 years. The dose of conjugate influenced meningococcal antibody responses. The 10-mg formulation induced higher total antibody levels after the primary series but similar levels of bactericidal antibody. In contrast to the initial antibody response, responses to polysaccharide boosting were higher in infants who received the low-dose formulation for the primary series. Increased amounts of carrier protein may interfere with immunologic priming with other conjugate vaccines [17]. This should not affect protection induced by this vaccine but may be important in combination conjugate vaccines using the same carrier proteins. The dose of carrier protein did not affect the response to the diphtheria component of concurrent DTP vaccine. Diphtheria antibody levels were similar to those in infants receiving mixed DTP and Hib vaccine under the same schedule [13]. Both dosages of MCC vaccine in this study were well tolerated, immunogenic, and primed for immunologic memory when given to infants with routine immunizations. Meningococcal C conjugate vaccines should induce long-term protection from meningococcal C disease and be considered for introduction into the routine infant immunization schedule where there is a high prevalence of disease.

JID 1999;179 (June)