- Email: [email protected]
Early immunization with conjugate vaccines
Vaccine, Vol. PII: SO264-410X(98)00104-2
16, No. 14/15, pp. 1433-1438, 1998 0 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0264-410X/98 $19+0.00
ELSEVIER
Early immunization with conjugate vaccines Juhani Eskola and Helena Ktiyhty Conjugate vaccines have been used during the neonatal period or in early infancy in order to test their safety and immunologic behaviour Adverse events even in neonates and premature babies have been mild and spontaneously resolving. Anticapsular antibody concentrations after first doses of Hib conjugates in early infancy are generally low, but analysis of responses clearly demonstrates active antibody production. Concentrations after the whole primary series are at or close to the level achieved in routine vaccination programmes. Noteworthy, immunologic memory seems to be induced already by first doses during newborn period. These data suggest that protection against invasive Hib infections may be achieved early in life. 0 1998 Elsevier Science Ltd. All rights reserved. Keywords: conjugate vaccines; Huemophilus in~uenzae; neonatal vaccination
Several caused
infectious diseases, including invasive infections by Haemophilus infruenzae type b (Hib) and Streptococcus pneumoniue (Pnc), have their highest incidence in early childhood. The peak incidence of invasive Hib infection is at around 9 months of age in most developed countries, but around 5-6 months in developing countries. Hib polysaccharide-protein conjugate vaccines, which have recently been introduced in general vaccination programmes in most developed countries, hlave proven highly efficacious. Hib vaccinations start generally at the age of 2-4 months, but full proteaion after primary series usually is obtained after the age of 6 months. Therefore, a small proportion of the youngest children still remain unprotected with the current vaccination schedule. This is not a public health problem in developed countries, firstly because of the relatively late occurrence of the disease, and secondly because the generally high vaccination coverage and reduction of mucosal carriage of Hib bacteria lead to herd immunity. In contrast, in developing countries where approximately 30-40s of Hib disease occurs in children younger than 6 months’, poor protection during the first months of life remains a significant problem. Prevention of invasive Hib and Pnc infections in early infancy would thus be most desirable. Another advantage for beginning vaccination earlier would be improvemenr in vaccination coverage. One motivation for the early vaccination schedule implemented in the Expanded Programme on Immunization (EPI) of the World Health Organization is the experiNational Public Health Institute, Helsinki, FIN-00300, Finland. *Author to whom all correspondence should be addressed. Current address (until September 1998): Department of Biochemistry, Imperial College of Science, Technology and Medicine, Exhibition Road, London SW7 2AY, Tel.: +44-i 71-5945230; E-mail: UK. [email protected].
ence that starting vaccinations soon after birth helps to achieve good compliance. If the implementation of an earlier schedule can guarantee higher vaccination coverage, then although individual levels of protection may be reduced, the overall efficiency of the programme could be improved. There are, however, several obstacles in the early start of vaccination. In addition to the potential safety problems during the vulnerable neonatal period, not enough is known about the regulation of immune responses in early infancy. At least two variables play a role: maternal antibodies and immaturity of the immune system. An infant has variable amounts of transplacentally acquired antibodies which can interfere with the response to immunizatior?. Different titres of maternal antibodies may lead either to low or delayed response, or they may prevent it altogether: the suppressive influence of maternal antibodies seems to be greater on B cells than T cells’. In some situations maternal antibodies do not modify the response at all, or may even enhance the immune responses-‘. Another problem is the immaturity of the newborn. Although the ability to synthesize antibodies is acquired already early in gestation, many infections that in adults recruit antigen-specific humoral or cellmediated immunity stimulate either no response or a dampened response in neonates. Impaired function of both antigen-presenting cells and T cells have been demonstrated in the neonatal period, but the most profound defect has been shown to be in the B cell compartment’. Poor antibody response may be related to the signalling, since neonatal B cells can in the presence of activated T cells be induced to secrete both IgM and IgG antibodies. First conjugate vaccines, consisting of capsular polysaccharide of Hib bacteria linked covalently with carrier protein (either diphtheria or tetanus toxoid, or
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Conjugate vaccines in neonates: J. Eskola and H. Ktiyhty CRMl97 protein, or meningococcal outer membrane protein complex), have been demonstrated to be safe, immunogenic in infants, able to induce immunologic memory, and protective against invasive Hib infections. Four Hib conjugates (PRP-D, PRP-T, HbOC, and PRP-OMP) are commercially available, and have been used to immunize tens of millions of infants worldwide. Next in the pipeline are meningococcal (groups A and C) and multivalent pneumococcal conjugates, prepared largely in the same way as Hib vaccines. Thus the experience gained in the last 10 years may be applicable to these new conjugates. One word of caution should, however, be mentioned in regard to generalization of the findings from Hib vaccines to the other conjugates. If the amount of the vaccine antigen is critical for the immune response, especially the situation with the multivalent pneumococcal vaccines where the amount of carrier protein is higher, might be different from what we see after Hib vaccinations. At present, there is no published information about the use of experimental meningococcal or pneumococcal conjugates in early infancy. Clinical trials demonstrating the good protective efficacy of Hib conjugates used either two or three doses in infancy, starting either at 2, 3, or 4 months of age. This primary series was usually followed by a booster dose in the second year of life, between the ages of 12-18 months. Schedules based on these trials have then been implemented in general vaccination programmes. Here we will review the experience with Hib conjugate vaccines when they are given in early infancy, i.e. before the age of 2 months. Our focus is on neonatal immunization, but we refer also to studies where Hib vaccines have been given either to young infants or to premature babies. The responses in these three groups will be compared with those of children receiving the same vaccines at the routinely recommended age. Although our understanding is still far from complete, preliminary evidence looks promising.
SAFETY OF HIB CONJUGATE VACCINES DURING THE NEONATAL PERIOD OR IN THE PREMATURE BABIES Hib conjugate vaccines have been given to 199 neonates in three studies’-“. In general, the vaccines have been well tolerated. No immediate reactions nor severe adverse events related to the vaccinations have been recorded. The most common reactions are local redness, soreness or swelling at the injection site. In the Finnish study, using PRP-T vaccine, mild local reactions were reported in approximately 20% of the 120 children. One child developed erythema and fever, and two were reported irritable”. In the US study where HbOC was used in 50 children, local reactions were reported in two and fever in one vaccinee’“. All the symptoms disappeared spontaneously. Infants who have been immunized as neonates are no more likely to have fever or local reactions after subsequent immunizations than infants immunized according to the routine schedule”‘~“. Two studies where Hib conjugate vaccines have been given to premature babies (at the chronological age of 2 months) report adverse events. When PRP-OMP was given to 36 children, no general
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Vaccine 1998 Volume 16 Number 14/l 5
adverse events were noticed, and only one child had mild local reaction12. In another study with extremely premature (gestational age ~29 weeks, birth weight < 1000 g) infants, 10 of 14 had no reactions to the first dose of HbOC vaccine; two infants had moderate reactions, one displayed tachypnea and one had episodes of apnea’.. It has to be noticed that these children received simultaneously their first doses of DTP vaccine, and had health problems associated with their prematurity. Therefore the reactogenicity data is difficult to interpret (the authors concluded that preterm infants seemed to have a lower incidence of adverse reactions to vaccines than full-term infants in their previous studies).
PRIMARY ANTIBODY RESPONSE TO EARLY IMMUNIZATION Young infants Vaccinations starting at 1 month (or 6 weeks) of age seem immunogenic based on the results of studies conducted in Finland, the United States, the Philippines, and the Gambia. In general, the antibody concentrations measured after the first dose are low in younger infants, but the final concentrations after the whole primary series still reach levels considered traditionally sufficient for protection. The geometric mean of antibody concentration (GMC) after the first dose of Hib conjugate at 1 or 2 months of age usually is lower than the concentration prior to the start of the vaccinations. In the Finnish study, the preimmunization GMC at 1 month was 0.20 /lg mll’, at 2 months 0.15 pg ml-‘, and at 4 months 0.08 pg mll’. Two months after the first dose of PRP-T the GMCs were 0.11, 0.13, and 0.11 pg mll’ in groups vaccinated at 1, 2, or 4 months of age, respectively’4. In spite of this decline in antibody concentrations, the authors concluded that active antibody production had taken place. When evaluating the seroresponse, one has to take into account that the concentration of passively acquired antibodies decline and that the child grows rapidly during the first months of life. Expected concentrations of maternal antibodies can be calculated from the measured preimmunization antibody concentration. The half-life of maternal IgG has been estimated as 48 days15, and the dilution factor between birth and 4 months of age (based on the growth of children) is 1.8616. Thus, the serum of the children at the age of 4 months is expected to decline to 30% of the preimmunization antibody concentration if there was no active antibody production by the infant. Taking this into account, 17% of children vaccinated at 1 month of age had at least a twofold increase in their anti-Hib antibodies (observed concentration divided by the expected one) and 6% had at least fourfold increase. Corresponding figures for the group vaccinated at 2 months were 27% and 17%, and for those vaccinated at 4 months 28% and 25%. A clear-cut response to the second dose of PRP-T can seen even in early infancy. The GMC of anti-Hib antibodies increases with increasing age of the vaccinee (GMCs 1 month after the second dose in the abovementioned groups: 1.07, 2.35, and 3.45 pg mll’), but there is less variation in the proportions of responders
C:onjugate vaccines in neonates: J. Eskola and H. Ktiyhty
(at least fourfold response was seen in 66, 77, and 89%, respectively). With HbOC the antibody concentrations seem to be even higher. When it was given at 1 and 3 months of age, the GMC of anti-Hib antibodies increased from 0.20 pg ml-’ to 0.30 pg ml-’ after the first dose, and up to 5.11 ,ug ml-’ after the second dose”. Two studies in developing countries have evaluated the immune response to Hib conjugate given in early infancy. In the Gambia children received (experimental liquid) PRP-T vaccine either at 1 and 3, or at 2 and 4 months of age. The GMC 1 month after the second dose was 0.26 ,ug ml-’ in the first group and 0.41 pg ml-.’ m ’ the second one”. Higher concentrations were reached in the Philippin’es, where GMCs after primary immunizations were 1.0’7 pg ml-’ for PRP-OMP, 1.90 pg ml-’ for HbOC, and 6.62 pg ml -’ for PRP-T, compared with 0.12 /up; ml-’ in the control group. Slight increase in antibodies could be seen already after the first dose in each group (Table I)‘“. Premature
babies
Even though premature babies are usually vaccinated according to their chronological age (i.e. at 2 months or older), their response pattern is interesting when early immunization is discussed. In all five studies where this has been evaluated, the vaccine-induced concentration of anti-Hib antibodies among the premature babies is lower than among the control chi~dren’2~13.2~-2’. The GMCs after primary immunization series in preterm infants varied from 0.68 pg ml-’ to 5.75 pg ml-‘, and in term controls from 1.40 /lg ml-’ to 6.74 pg ml-’ (Table 2:). Especially, some of the most immature infants or those chronically ill may show an inadequate antibody response to the initial immunizations, and thus re-evaluation of the immunization schedule has been suggested for them’2.2”.Most studies cited above concluded, that, in general preterm infants can benefit from Hib conjugates when immunization is started at the same chronological age as in term infants. It must, however, be remembered that a 2 months prematurely born infant at 2 months of chronological age certainly is more mature than a term Table 1
Geometric
mean colicentration
(GMC, pg ml-‘)
newborn, infant.
but less mature
than a 2-month-old
term
Neonates
The GMC of anti-Hib antibodies in Finnish newborn babies is 0.34 pg ml-’ at the age of 2 days”, approximately one fifth of the anti-Hib concentration in young adults. As discussed above, this concentration is expected to decrease rapidly if no active antibody production takes place. Indeed, GMC of children who received PRP-T at 2 days was 0.12 pg ml-’ at the age of 4 months. The concentration was, however, higher than expected on the basis of the theoretical calculations, and higher than the GMC of control children who did not receive neonatal Hib vaccination (GMC 0.08 pg ml-‘). This speaks for active immune response to Hib conjugate vaccine in the neonatal period. Immunization with PRP-T at 4 months still increased these concentrations by the aFe of 6 months (GMCs 0.97 /lg ml-’ and 0.81 /lg ml- in the study group and control group, respectively)“. In the US study, infants immunized with HbOC at birth had antibody concentrations at 2 months of age similar to those in infants not immunized at birth”‘. Furthermore, their antibody concentrations were significantly higher at 4 months of age than in infants who received their first dose of HbOC at 2 months. Antibody levels at 6 and 7 months of age in children given HbOC beginning at birth were similar to those in children immunized with HbOC beginning at 2 months of age”. The third study on neonatal immunization with Hib conjugate is reported only in abstract form’. It compares children who receive PRP-OMP vaccine at birth, and at 2 and 6 months, with children who do not receive vaccine at birth but receive three doses in infancy (at 2, 4, and 6 months). GMCs of the group which had received PRP-OMP at birth were significantly lower than of the control group at all time points when antibody concentrations were measured. The GMC of the neonatally vaccinated group at 7 months of age was 0.35 clg ml-‘, and that of the control
during primary immunization
series in Philippine children”
Pre 1st dose
Post 1st dose
Pre 2nd dose
Post 2nd dose
Vaccine
6.7 weeks
11.2 weeks
15.7 weeks
20.3 weeks
PRP-OMP HbOC PRP-T
0.37 0.28 0.32
0.72 0.33 0.37
1 .Ol 0.44 1.50
1.07 1.90 6.62
Table 2 children
Geometric
mean concentration
(GMC, pg ml-‘)
after primary
immunization
series in premature
children,
compared
with term
GMC of anti-Hib in: Vaccine
Gestational
PRP-OMP PRP-OMP HbOC PRP-T PRP-T
23-35 (28) <32 (28) <29 (26) <37 27-36
age, weeks (mean/median)
No. premature
infants
22 36 16 17 35
Vaccine
Prematures
Term infants
Reference
0.73 1.05 5.75 0.68 0.71
4.60 4.0 6.74 1.40 2.03
20 12 13 21 22
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Conjugate vaccines in neonates: J. Eskola and H. Ktiyhty
group was 1.46 pg ml-‘. The authors interpret finding as suggestive of toleranceY. Effect of pre-existing
antibodies
their
on vaccine response
Passive protection with anti-Hib antibodies can be provided to high risk infants through immune globulin injection or infusion. Studies with human hyperimmune globulin rich of anti-Hib, pneumococcal and meningococcal antibodies (BPIG) demonstrate that the levels achieved by this treatment do not impair active to concurrently administered immune responses PRP-OMP or HbOC vaccines”,“. Immunization during pregnancy leads to increased maternal antibody concentrations, and subsequently to higher amounts of antibodies transferred through placenta to the foetus. Mulholland et al. vaccinated 251 mothers in the Gambia”. The children of the vaccinated mothers had expectedly higher anti-Hib concentrations (GMC 0.35 pg ml-‘) prior to the start of their vaccination than children of the nonvaccinated mothers (GMC 0.12 pg ml-‘). Anti-Hib antibody concentrations after three doses of PRP-T at 2. 4, and 6 months did not differ significantly in these groups (GMCs 2.84 and 3.91 /cg ml-‘, respectively). The authors assessed also the relationship between 2-month and 5-month antibody levels, but did not lind any significant correlation. No relationship was noted between cord blood anti-tetanus concentrations and the infant’s anti-Hib response’8. Some impairment in the antibody response was seen in Finnish studies when the preimmunization concentration was greater than 1.0 pg mll’ (Table 3)6.“.‘4. When the preimmunization concentration exceeded 3.0 none of the children had even a twofold pg ml-‘, increase. Thus, with high concentration of maternal antibodies, the response was poor. In spite of this, there was a good response to later doses, i.e. high preimmunization antibody concentrations does not seem to affect on priming. Therefore it seems to be safe to vaccinate even when the child had high maternal anti-Hib antibody concentrations. In the Finnish studies, maternal anti-tetanus antibodies did not have any influence on anti-H& response after the first dose of Hib polysaccharidetetanus toxoid conjugate, PRP-T”. Similar GMCs and antibody distributions were detected in infants having Table 3
Influence of maternal antibodies
low or high anti-tetanus antibody titres. After the second dose of PRP-T, highest anti-Hib responses were achieved in children with highest preimmunization anti-tetanus antibody titres. In contrast, Barington et al. found a negative correlation between anti-Hib concentrations after the first dose of PRP-T and the prevaccination concentration of (maternally derived) tetanus toxoid titre?. There was a similar, though not statistically significant trend after the second dose. In a group with the highest anti-tetanus antibody titres (induced by active immunization with tetanus toxoid), no negative influence was observed. As an explanation, the authors discuss different mechanisms involved with the actively and passively acquired immunity to the carrier protein in conjugate vaccines5. EVIDENCE FOR INDUCTION OF IMMUNOLOGIC MEMORY IN EARLY IMMUNIZATION WITH CONJUGATES Certain concentrations of anticapsular antibodies after natural infection or after polysaccharide vaccination correlates well with the protection; concentrations of 0.15 /lg mll’ have been suggested as surrogates for short term and 1.0 pugml-’ for long term protection“‘. Clinical protection after conjugate vaccines seems to be better than what can be achieved with polysaccharide vaccines, and therefore these limits are less useful in predicting protection afforded by the conjugates. On the basis of the results of the efficacy trial, induction of immunologic memory has been suggested as one potential surrogate for protection’5m’7. Evidence for memory induction in early life can be obtained from studies where infants have been vaccinated at l-4 months of age. Comparison of anti-Hib antibody concentrations at the same age in children who had received one or two doses of PRP-T vaccine shows constantly a clear-cut advantage of two doses. For example, when the infants in Finnish study were 4 months old, the GMC was nearly tenfold higher in the group where Hib conjugate had been given at 1 and 3 months of age (1.07 /lg mll’), compared with the group receiving the vaccine at 2 months of age (0.13 /cg mll’)‘3. The memory induced by one dose will sustain at least to the second year of life, the age when booster vaccination is usually given’x.
on the response to the first dose of PFlP-T”,“,‘4 Preimmunization i 0.3
PRP-T at 2 days, anti-Hib at 4 months (N = 7 75) GMC % > 0.15 % > 1.0 > twofold response > fourfold response Mean fold rise PRP-T at 1-4 months, anti-Hib 2 months later (N = 156) GMC % > 0.15 %> 1.0 > twofold response > fourfold response Mean fold rise
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Vaccine 1998 Volume 16 Number 14/15
0.08 8 0 52 51 12.9
0.08 10 1
25 17 6.6
concentration 0.3-0.99
0.11
26 3 55 13 4.9
0.20 71 7 22 7 4.0
of anti-Hib 1 .o-2.99
> 3.0
All
0.25
0.67 100 55 0 0 1.2
0.12 31 4 49 31 7.4
1.39 100
0.11 28 3 24 14 5.7
100 0
50 0 2.1
0.57 100
11 22 0 1.2
67 0 0 1.3
Conjugate vaccines in neonates: J. Eskola and H. Kiiyhty Table 4 Evidence of priming by neonatal PRP-T, tested by the anti-Hib response measured 2 months given at 4 months of age”. In unprimed infants at this age, no antibody response can be detected Response to vaccination
after Hib polysaccahride
vaccine
with PRP at 4 months
% children having an increase of at least Response to neonatal PRP-T
No. of infants
Twofold
Fourfold
Tenfold
No response detected At least twofold response All
24 31 55
37 81 62
17 52 36
4 23 14
Stronger evidence of development of memory after immunization of neon,stes comes from the study where children received PRP-T at 2 days of age”. At 4 months they were randomized in two groups, either to receive the same conjugate or Hib polysaccharide vaccine. The aim of the polysaccharide vaccination was to test specifically for priming to the capsular polysaccharide, which would not elicit any antibody response in unprimed infants at this age”. The antibodies were measured 2 months later and compared with the expected anti-Hib concentration. By 6 months of age, antibodies were expected to have declined to 30% if there were no response to the Hib polysaccharide vaccine. However, at least fourfold response was seen in 36% of infants receiving Hib polysaccharide. These r#:sponses were more frequent among those classified as responders to the neonatal PRP-T (Table 4)“. Thus these children seem to benefit from neonatal vaccination with Hib conjugate, even though antibody concentrations in early infancy remain low.
DISCUSSION Studies evaluating the safety and immunogenic@ of early conjugate vaccinations are relatively few, and the number of children in them limited. No studies on clinical efficacy have been conducted in neonates or very young infants. In spite of this, analysis of available data gives valuable information for future studies and eventually for the use of conjugate vaccines in early childhood. Hib conjugate vaccines have proven, as early studies suggested, safe in wide scale use. The same seems to apply also among young infants. No serious adverse events have been documented, and reported reactions have been mild, resolving spontaneously. Due to the limited power of the studies, it is clear that careful follow-up of potential adverse events in the future trials has to be continued. Of special importance is to look for the possibility of development of immunologic tolerance which might happen after early immunization with polysaccharide antigen’“. Whether it occurs after conjugate vaccination is still open. Results from published studies are contradictory: preliminary findings in one study’ have not been confirmed in others”‘.“. One explanatilon to the discrepancy might be the different characteristics of the PRP-OMP vaccine compared with the PRP-T and HbOC vaccines. More information is definitely needed. Anti-Hib antibody concentrations after first dose of Hib conjugates in early immunization schedules are generally low. However, if the efficacy of the vaccination programme is evaluated after the completed
series-as is the routine with other childhood vaccines-the results of the neonatal or early infancy vaccinations look promising. In particular, the data from developing countries where vaccinations with Hib conjugates have been adjusted to the EPI schedule are encouraging: antibody concentrations are high enough to predict good protection. As pointed out above, the induction of the immunologic memory could be at least as important as the actual concentrations. Several findings support the idea that a boostable memory starts early, to develop even after neonatal immunizations. One could anticipate that if neonatal vaccinations were a common practice, vaccination schedules most probably would include another dose relatively early. This would help in achievement of higher antibody concentrations in the first few months of life. If induction of immunologic priming really is a valid surrogate for clinical protection, most children vaccinated even at neonatal age with Hib conjugates are protected against invasive Hib disease.
REFERENCES Bijlmer, H.A. Epidemiology of Haemophilus influenzae invasive disease in developing countries and intervention strategies. In: Development and Uses of Haemophilus b Conjugate Vaccines (Eds Ellis, R.W. and Granoff, D.M.). Marcel Dekker, New York, 1994, pp. 247-264 Claesson, B.A., Schneerson, R. and Robbins, J.B. et al. Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide tetanus toxoid conjugate. J. Pediatr. 1989, 114,97-100 Halsey, N.A. and Klein, D. Maternal immunization. Pediafr. Infect. Dis. J. 1990, 9, 574-581 Sarvas, H., Kurikka, S., Sepp%, I.J.T., M&kel& P.H. and MakeI& 0. Maternal antibodies partly inhibit an active antibody response to routine tetanus toxoid immunization in infants. J. infect. Dis. 1992, 165, 977-979 Barington, T., Gyhrs, A., Kristensen, K. and Heilman, C. Opposite effects of actively and passively acquired immunity to the carrier on responses of human infants to a Haemophi/us influenzae type b conjugate vaccine. lnfecfion and immunity 1994,,,62, 9-l 4 Kurikka, S., Olander, R.-M., Eskola, J. and Ktiyhty, H. Passively acquired anti-tetanus and anti-Haemophilus antibodies and the response to Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infancy. Pediatr. Infect. Dis. J. 1996,15,530-535 Siegrist, CA. and Lambert, P.H. Maternal immunity and infant responses to immunization: factors influencing infant responses. Developments in Biological Standardization (in press) Fisher, G.W., Ottolini, M.G. and Mond, J.J. Prospects for vaccines during pregnancy and in the newborn period. Clinics in Perinatology 1997, 24, 231-249 Ward, J.I., Bulkow, L., Wainwright, R. and Chang, S. Immune tolerance and lack of booster responses to Haemophilus influenzae (Hib) conjugate vaccination in infants immunized begin-
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conjugate vaccine in chronically ill premature infants. J. Pediatr. 1993, 123, 791-794 Greenberg, D.P., Vadheim, C.M., Prtridge, S., Chang, S.-J., Chiu, C.-Y., Ward, J.I. and the Kaiser-UCLA Vaccine Study Group. lmmunogenicity of Haemophilus influenzae type b tetanus toxoid conjugate vaccine in young infants. J. Infect. Dis. 1994,170,76-81 Kristensen, K., Gyhrs, A., Lausen, B, Barington, T. and Heilman, C. Antibody response to Haemophilus influenzae type b capsular polysaccharide conjugated to tetanus toxoid in.preterm infants. Pediatr. infect. Di.&. i 1996, 15, 525-529 Siber. G.R.. Thomoson. C. and Reid, G.R. et a/. Evaluation of bacterial polysaccharide immune globulin for the treatment or prevention of Haemophilus influenzae type b and pneumococcal disease. J. infect. Dis. 1992, 165, S129-S133 Kayhty, H., Peltola, H., Karanko, V. and Makela, P.H. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J. infect. Dis. 1983, 147,llOO Eskola, J., Kayhty, H. and Takala, A.K. et al. A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children agaist invasive Haemophilus influenzae type b disease. A/. Engl. J. Med. 1990, 323, 1381-1387 Granoff, D.M., Holmes, S.J. and Osterholm, M.T. et al. Induction of immunologic memory in infants primed with Haemophilus influenzae type b conjugate vaccines. J. infect. Dis. 1993,168,663-671 Kayhty, H. Difficulties in establishing a serological correlate of protection after immunization with Haemophilus influenzae type b conjugate vaccines. Biologicals 1994, 22, 397-402 Kurikka, S., Kayhty, H., Saarinen, L., Ronnberg, P.-R., Eskola, J. and Make@ P.H. Immunologic priming by one dose of Haemophilus influenzae type b conjugate vaccine in infancv. J. /nfe&. Dis. 1995, 172, i268-1272. Peltola. H.. Kavhtv. H.. Virtanen. M. and Make& P.H. Prevention of. Haemobhks kfluenzae’ type b bacteremic infections with the polysaccharide vaccine. N. Engl. J. Med. 1984, 310, 156661569 Mosier, D.E., Freeney, A.J. and Shcerle, P. The physiology of B lymphocytes capable of generating anti-polysaccharide antibody responses. In: Towards Better Carbohydrate Vaccines (Eds Bell, R. and Torrigiani, G.). Wiley, Chichester, 1987, pp. 243-261
16, No. 14/15, pp. 1433-1438, 1998 0 1998 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0264-410X/98 $19+0.00
ELSEVIER
Early immunization with conjugate vaccines Juhani Eskola and Helena Ktiyhty Conjugate vaccines have been used during the neonatal period or in early infancy in order to test their safety and immunologic behaviour Adverse events even in neonates and premature babies have been mild and spontaneously resolving. Anticapsular antibody concentrations after first doses of Hib conjugates in early infancy are generally low, but analysis of responses clearly demonstrates active antibody production. Concentrations after the whole primary series are at or close to the level achieved in routine vaccination programmes. Noteworthy, immunologic memory seems to be induced already by first doses during newborn period. These data suggest that protection against invasive Hib infections may be achieved early in life. 0 1998 Elsevier Science Ltd. All rights reserved. Keywords: conjugate vaccines; Huemophilus in~uenzae; neonatal vaccination
Several caused
infectious diseases, including invasive infections by Haemophilus infruenzae type b (Hib) and Streptococcus pneumoniue (Pnc), have their highest incidence in early childhood. The peak incidence of invasive Hib infection is at around 9 months of age in most developed countries, but around 5-6 months in developing countries. Hib polysaccharide-protein conjugate vaccines, which have recently been introduced in general vaccination programmes in most developed countries, hlave proven highly efficacious. Hib vaccinations start generally at the age of 2-4 months, but full proteaion after primary series usually is obtained after the age of 6 months. Therefore, a small proportion of the youngest children still remain unprotected with the current vaccination schedule. This is not a public health problem in developed countries, firstly because of the relatively late occurrence of the disease, and secondly because the generally high vaccination coverage and reduction of mucosal carriage of Hib bacteria lead to herd immunity. In contrast, in developing countries where approximately 30-40s of Hib disease occurs in children younger than 6 months’, poor protection during the first months of life remains a significant problem. Prevention of invasive Hib and Pnc infections in early infancy would thus be most desirable. Another advantage for beginning vaccination earlier would be improvemenr in vaccination coverage. One motivation for the early vaccination schedule implemented in the Expanded Programme on Immunization (EPI) of the World Health Organization is the experiNational Public Health Institute, Helsinki, FIN-00300, Finland. *Author to whom all correspondence should be addressed. Current address (until September 1998): Department of Biochemistry, Imperial College of Science, Technology and Medicine, Exhibition Road, London SW7 2AY, Tel.: +44-i 71-5945230; E-mail: UK. [email protected].
ence that starting vaccinations soon after birth helps to achieve good compliance. If the implementation of an earlier schedule can guarantee higher vaccination coverage, then although individual levels of protection may be reduced, the overall efficiency of the programme could be improved. There are, however, several obstacles in the early start of vaccination. In addition to the potential safety problems during the vulnerable neonatal period, not enough is known about the regulation of immune responses in early infancy. At least two variables play a role: maternal antibodies and immaturity of the immune system. An infant has variable amounts of transplacentally acquired antibodies which can interfere with the response to immunizatior?. Different titres of maternal antibodies may lead either to low or delayed response, or they may prevent it altogether: the suppressive influence of maternal antibodies seems to be greater on B cells than T cells’. In some situations maternal antibodies do not modify the response at all, or may even enhance the immune responses-‘. Another problem is the immaturity of the newborn. Although the ability to synthesize antibodies is acquired already early in gestation, many infections that in adults recruit antigen-specific humoral or cellmediated immunity stimulate either no response or a dampened response in neonates. Impaired function of both antigen-presenting cells and T cells have been demonstrated in the neonatal period, but the most profound defect has been shown to be in the B cell compartment’. Poor antibody response may be related to the signalling, since neonatal B cells can in the presence of activated T cells be induced to secrete both IgM and IgG antibodies. First conjugate vaccines, consisting of capsular polysaccharide of Hib bacteria linked covalently with carrier protein (either diphtheria or tetanus toxoid, or
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Conjugate vaccines in neonates: J. Eskola and H. Ktiyhty CRMl97 protein, or meningococcal outer membrane protein complex), have been demonstrated to be safe, immunogenic in infants, able to induce immunologic memory, and protective against invasive Hib infections. Four Hib conjugates (PRP-D, PRP-T, HbOC, and PRP-OMP) are commercially available, and have been used to immunize tens of millions of infants worldwide. Next in the pipeline are meningococcal (groups A and C) and multivalent pneumococcal conjugates, prepared largely in the same way as Hib vaccines. Thus the experience gained in the last 10 years may be applicable to these new conjugates. One word of caution should, however, be mentioned in regard to generalization of the findings from Hib vaccines to the other conjugates. If the amount of the vaccine antigen is critical for the immune response, especially the situation with the multivalent pneumococcal vaccines where the amount of carrier protein is higher, might be different from what we see after Hib vaccinations. At present, there is no published information about the use of experimental meningococcal or pneumococcal conjugates in early infancy. Clinical trials demonstrating the good protective efficacy of Hib conjugates used either two or three doses in infancy, starting either at 2, 3, or 4 months of age. This primary series was usually followed by a booster dose in the second year of life, between the ages of 12-18 months. Schedules based on these trials have then been implemented in general vaccination programmes. Here we will review the experience with Hib conjugate vaccines when they are given in early infancy, i.e. before the age of 2 months. Our focus is on neonatal immunization, but we refer also to studies where Hib vaccines have been given either to young infants or to premature babies. The responses in these three groups will be compared with those of children receiving the same vaccines at the routinely recommended age. Although our understanding is still far from complete, preliminary evidence looks promising.
SAFETY OF HIB CONJUGATE VACCINES DURING THE NEONATAL PERIOD OR IN THE PREMATURE BABIES Hib conjugate vaccines have been given to 199 neonates in three studies’-“. In general, the vaccines have been well tolerated. No immediate reactions nor severe adverse events related to the vaccinations have been recorded. The most common reactions are local redness, soreness or swelling at the injection site. In the Finnish study, using PRP-T vaccine, mild local reactions were reported in approximately 20% of the 120 children. One child developed erythema and fever, and two were reported irritable”. In the US study where HbOC was used in 50 children, local reactions were reported in two and fever in one vaccinee’“. All the symptoms disappeared spontaneously. Infants who have been immunized as neonates are no more likely to have fever or local reactions after subsequent immunizations than infants immunized according to the routine schedule”‘~“. Two studies where Hib conjugate vaccines have been given to premature babies (at the chronological age of 2 months) report adverse events. When PRP-OMP was given to 36 children, no general
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adverse events were noticed, and only one child had mild local reaction12. In another study with extremely premature (gestational age ~29 weeks, birth weight < 1000 g) infants, 10 of 14 had no reactions to the first dose of HbOC vaccine; two infants had moderate reactions, one displayed tachypnea and one had episodes of apnea’.. It has to be noticed that these children received simultaneously their first doses of DTP vaccine, and had health problems associated with their prematurity. Therefore the reactogenicity data is difficult to interpret (the authors concluded that preterm infants seemed to have a lower incidence of adverse reactions to vaccines than full-term infants in their previous studies).
PRIMARY ANTIBODY RESPONSE TO EARLY IMMUNIZATION Young infants Vaccinations starting at 1 month (or 6 weeks) of age seem immunogenic based on the results of studies conducted in Finland, the United States, the Philippines, and the Gambia. In general, the antibody concentrations measured after the first dose are low in younger infants, but the final concentrations after the whole primary series still reach levels considered traditionally sufficient for protection. The geometric mean of antibody concentration (GMC) after the first dose of Hib conjugate at 1 or 2 months of age usually is lower than the concentration prior to the start of the vaccinations. In the Finnish study, the preimmunization GMC at 1 month was 0.20 /lg mll’, at 2 months 0.15 pg ml-‘, and at 4 months 0.08 pg mll’. Two months after the first dose of PRP-T the GMCs were 0.11, 0.13, and 0.11 pg mll’ in groups vaccinated at 1, 2, or 4 months of age, respectively’4. In spite of this decline in antibody concentrations, the authors concluded that active antibody production had taken place. When evaluating the seroresponse, one has to take into account that the concentration of passively acquired antibodies decline and that the child grows rapidly during the first months of life. Expected concentrations of maternal antibodies can be calculated from the measured preimmunization antibody concentration. The half-life of maternal IgG has been estimated as 48 days15, and the dilution factor between birth and 4 months of age (based on the growth of children) is 1.8616. Thus, the serum of the children at the age of 4 months is expected to decline to 30% of the preimmunization antibody concentration if there was no active antibody production by the infant. Taking this into account, 17% of children vaccinated at 1 month of age had at least a twofold increase in their anti-Hib antibodies (observed concentration divided by the expected one) and 6% had at least fourfold increase. Corresponding figures for the group vaccinated at 2 months were 27% and 17%, and for those vaccinated at 4 months 28% and 25%. A clear-cut response to the second dose of PRP-T can seen even in early infancy. The GMC of anti-Hib antibodies increases with increasing age of the vaccinee (GMCs 1 month after the second dose in the abovementioned groups: 1.07, 2.35, and 3.45 pg mll’), but there is less variation in the proportions of responders
C:onjugate vaccines in neonates: J. Eskola and H. Ktiyhty
(at least fourfold response was seen in 66, 77, and 89%, respectively). With HbOC the antibody concentrations seem to be even higher. When it was given at 1 and 3 months of age, the GMC of anti-Hib antibodies increased from 0.20 pg ml-’ to 0.30 pg ml-’ after the first dose, and up to 5.11 ,ug ml-’ after the second dose”. Two studies in developing countries have evaluated the immune response to Hib conjugate given in early infancy. In the Gambia children received (experimental liquid) PRP-T vaccine either at 1 and 3, or at 2 and 4 months of age. The GMC 1 month after the second dose was 0.26 ,ug ml-’ in the first group and 0.41 pg ml-.’ m ’ the second one”. Higher concentrations were reached in the Philippin’es, where GMCs after primary immunizations were 1.0’7 pg ml-’ for PRP-OMP, 1.90 pg ml-’ for HbOC, and 6.62 pg ml -’ for PRP-T, compared with 0.12 /up; ml-’ in the control group. Slight increase in antibodies could be seen already after the first dose in each group (Table I)‘“. Premature
babies
Even though premature babies are usually vaccinated according to their chronological age (i.e. at 2 months or older), their response pattern is interesting when early immunization is discussed. In all five studies where this has been evaluated, the vaccine-induced concentration of anti-Hib antibodies among the premature babies is lower than among the control chi~dren’2~13.2~-2’. The GMCs after primary immunization series in preterm infants varied from 0.68 pg ml-’ to 5.75 pg ml-‘, and in term controls from 1.40 /lg ml-’ to 6.74 pg ml-’ (Table 2:). Especially, some of the most immature infants or those chronically ill may show an inadequate antibody response to the initial immunizations, and thus re-evaluation of the immunization schedule has been suggested for them’2.2”.Most studies cited above concluded, that, in general preterm infants can benefit from Hib conjugates when immunization is started at the same chronological age as in term infants. It must, however, be remembered that a 2 months prematurely born infant at 2 months of chronological age certainly is more mature than a term Table 1
Geometric
mean colicentration
(GMC, pg ml-‘)
newborn, infant.
but less mature
than a 2-month-old
term
Neonates
The GMC of anti-Hib antibodies in Finnish newborn babies is 0.34 pg ml-’ at the age of 2 days”, approximately one fifth of the anti-Hib concentration in young adults. As discussed above, this concentration is expected to decrease rapidly if no active antibody production takes place. Indeed, GMC of children who received PRP-T at 2 days was 0.12 pg ml-’ at the age of 4 months. The concentration was, however, higher than expected on the basis of the theoretical calculations, and higher than the GMC of control children who did not receive neonatal Hib vaccination (GMC 0.08 pg ml-‘). This speaks for active immune response to Hib conjugate vaccine in the neonatal period. Immunization with PRP-T at 4 months still increased these concentrations by the aFe of 6 months (GMCs 0.97 /lg ml-’ and 0.81 /lg ml- in the study group and control group, respectively)“. In the US study, infants immunized with HbOC at birth had antibody concentrations at 2 months of age similar to those in infants not immunized at birth”‘. Furthermore, their antibody concentrations were significantly higher at 4 months of age than in infants who received their first dose of HbOC at 2 months. Antibody levels at 6 and 7 months of age in children given HbOC beginning at birth were similar to those in children immunized with HbOC beginning at 2 months of age”. The third study on neonatal immunization with Hib conjugate is reported only in abstract form’. It compares children who receive PRP-OMP vaccine at birth, and at 2 and 6 months, with children who do not receive vaccine at birth but receive three doses in infancy (at 2, 4, and 6 months). GMCs of the group which had received PRP-OMP at birth were significantly lower than of the control group at all time points when antibody concentrations were measured. The GMC of the neonatally vaccinated group at 7 months of age was 0.35 clg ml-‘, and that of the control
during primary immunization
series in Philippine children”
Pre 1st dose
Post 1st dose
Pre 2nd dose
Post 2nd dose
Vaccine
6.7 weeks
11.2 weeks
15.7 weeks
20.3 weeks
PRP-OMP HbOC PRP-T
0.37 0.28 0.32
0.72 0.33 0.37
1 .Ol 0.44 1.50
1.07 1.90 6.62
Table 2 children
Geometric
mean concentration
(GMC, pg ml-‘)
after primary
immunization
series in premature
children,
compared
with term
GMC of anti-Hib in: Vaccine
Gestational
PRP-OMP PRP-OMP HbOC PRP-T PRP-T
23-35 (28) <32 (28) <29 (26) <37 27-36
age, weeks (mean/median)
No. premature
infants
22 36 16 17 35
Vaccine
Prematures
Term infants
Reference
0.73 1.05 5.75 0.68 0.71
4.60 4.0 6.74 1.40 2.03
20 12 13 21 22
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Conjugate vaccines in neonates: J. Eskola and H. Ktiyhty
group was 1.46 pg ml-‘. The authors interpret finding as suggestive of toleranceY. Effect of pre-existing
antibodies
their
on vaccine response
Passive protection with anti-Hib antibodies can be provided to high risk infants through immune globulin injection or infusion. Studies with human hyperimmune globulin rich of anti-Hib, pneumococcal and meningococcal antibodies (BPIG) demonstrate that the levels achieved by this treatment do not impair active to concurrently administered immune responses PRP-OMP or HbOC vaccines”,“. Immunization during pregnancy leads to increased maternal antibody concentrations, and subsequently to higher amounts of antibodies transferred through placenta to the foetus. Mulholland et al. vaccinated 251 mothers in the Gambia”. The children of the vaccinated mothers had expectedly higher anti-Hib concentrations (GMC 0.35 pg ml-‘) prior to the start of their vaccination than children of the nonvaccinated mothers (GMC 0.12 pg ml-‘). Anti-Hib antibody concentrations after three doses of PRP-T at 2. 4, and 6 months did not differ significantly in these groups (GMCs 2.84 and 3.91 /cg ml-‘, respectively). The authors assessed also the relationship between 2-month and 5-month antibody levels, but did not lind any significant correlation. No relationship was noted between cord blood anti-tetanus concentrations and the infant’s anti-Hib response’8. Some impairment in the antibody response was seen in Finnish studies when the preimmunization concentration was greater than 1.0 pg mll’ (Table 3)6.“.‘4. When the preimmunization concentration exceeded 3.0 none of the children had even a twofold pg ml-‘, increase. Thus, with high concentration of maternal antibodies, the response was poor. In spite of this, there was a good response to later doses, i.e. high preimmunization antibody concentrations does not seem to affect on priming. Therefore it seems to be safe to vaccinate even when the child had high maternal anti-Hib antibody concentrations. In the Finnish studies, maternal anti-tetanus antibodies did not have any influence on anti-H& response after the first dose of Hib polysaccharidetetanus toxoid conjugate, PRP-T”. Similar GMCs and antibody distributions were detected in infants having Table 3
Influence of maternal antibodies
low or high anti-tetanus antibody titres. After the second dose of PRP-T, highest anti-Hib responses were achieved in children with highest preimmunization anti-tetanus antibody titres. In contrast, Barington et al. found a negative correlation between anti-Hib concentrations after the first dose of PRP-T and the prevaccination concentration of (maternally derived) tetanus toxoid titre?. There was a similar, though not statistically significant trend after the second dose. In a group with the highest anti-tetanus antibody titres (induced by active immunization with tetanus toxoid), no negative influence was observed. As an explanation, the authors discuss different mechanisms involved with the actively and passively acquired immunity to the carrier protein in conjugate vaccines5. EVIDENCE FOR INDUCTION OF IMMUNOLOGIC MEMORY IN EARLY IMMUNIZATION WITH CONJUGATES Certain concentrations of anticapsular antibodies after natural infection or after polysaccharide vaccination correlates well with the protection; concentrations of 0.15 /lg mll’ have been suggested as surrogates for short term and 1.0 pugml-’ for long term protection“‘. Clinical protection after conjugate vaccines seems to be better than what can be achieved with polysaccharide vaccines, and therefore these limits are less useful in predicting protection afforded by the conjugates. On the basis of the results of the efficacy trial, induction of immunologic memory has been suggested as one potential surrogate for protection’5m’7. Evidence for memory induction in early life can be obtained from studies where infants have been vaccinated at l-4 months of age. Comparison of anti-Hib antibody concentrations at the same age in children who had received one or two doses of PRP-T vaccine shows constantly a clear-cut advantage of two doses. For example, when the infants in Finnish study were 4 months old, the GMC was nearly tenfold higher in the group where Hib conjugate had been given at 1 and 3 months of age (1.07 /lg mll’), compared with the group receiving the vaccine at 2 months of age (0.13 /cg mll’)‘3. The memory induced by one dose will sustain at least to the second year of life, the age when booster vaccination is usually given’x.
on the response to the first dose of PFlP-T”,“,‘4 Preimmunization i 0.3
PRP-T at 2 days, anti-Hib at 4 months (N = 7 75) GMC % > 0.15 % > 1.0 > twofold response > fourfold response Mean fold rise PRP-T at 1-4 months, anti-Hib 2 months later (N = 156) GMC % > 0.15 %> 1.0 > twofold response > fourfold response Mean fold rise
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Vaccine 1998 Volume 16 Number 14/15
0.08 8 0 52 51 12.9
0.08 10 1
25 17 6.6
concentration 0.3-0.99
0.11
26 3 55 13 4.9
0.20 71 7 22 7 4.0
of anti-Hib 1 .o-2.99
> 3.0
All
0.25
0.67 100 55 0 0 1.2
0.12 31 4 49 31 7.4
1.39 100
0.11 28 3 24 14 5.7
100 0
50 0 2.1
0.57 100
11 22 0 1.2
67 0 0 1.3
Conjugate vaccines in neonates: J. Eskola and H. Kiiyhty Table 4 Evidence of priming by neonatal PRP-T, tested by the anti-Hib response measured 2 months given at 4 months of age”. In unprimed infants at this age, no antibody response can be detected Response to vaccination
after Hib polysaccahride
vaccine
with PRP at 4 months
% children having an increase of at least Response to neonatal PRP-T
No. of infants
Twofold
Fourfold
Tenfold
No response detected At least twofold response All
24 31 55
37 81 62
17 52 36
4 23 14
Stronger evidence of development of memory after immunization of neon,stes comes from the study where children received PRP-T at 2 days of age”. At 4 months they were randomized in two groups, either to receive the same conjugate or Hib polysaccharide vaccine. The aim of the polysaccharide vaccination was to test specifically for priming to the capsular polysaccharide, which would not elicit any antibody response in unprimed infants at this age”. The antibodies were measured 2 months later and compared with the expected anti-Hib concentration. By 6 months of age, antibodies were expected to have declined to 30% if there were no response to the Hib polysaccharide vaccine. However, at least fourfold response was seen in 36% of infants receiving Hib polysaccharide. These r#:sponses were more frequent among those classified as responders to the neonatal PRP-T (Table 4)“. Thus these children seem to benefit from neonatal vaccination with Hib conjugate, even though antibody concentrations in early infancy remain low.
DISCUSSION Studies evaluating the safety and immunogenic@ of early conjugate vaccinations are relatively few, and the number of children in them limited. No studies on clinical efficacy have been conducted in neonates or very young infants. In spite of this, analysis of available data gives valuable information for future studies and eventually for the use of conjugate vaccines in early childhood. Hib conjugate vaccines have proven, as early studies suggested, safe in wide scale use. The same seems to apply also among young infants. No serious adverse events have been documented, and reported reactions have been mild, resolving spontaneously. Due to the limited power of the studies, it is clear that careful follow-up of potential adverse events in the future trials has to be continued. Of special importance is to look for the possibility of development of immunologic tolerance which might happen after early immunization with polysaccharide antigen’“. Whether it occurs after conjugate vaccination is still open. Results from published studies are contradictory: preliminary findings in one study’ have not been confirmed in others”‘.“. One explanatilon to the discrepancy might be the different characteristics of the PRP-OMP vaccine compared with the PRP-T and HbOC vaccines. More information is definitely needed. Anti-Hib antibody concentrations after first dose of Hib conjugates in early immunization schedules are generally low. However, if the efficacy of the vaccination programme is evaluated after the completed
series-as is the routine with other childhood vaccines-the results of the neonatal or early infancy vaccinations look promising. In particular, the data from developing countries where vaccinations with Hib conjugates have been adjusted to the EPI schedule are encouraging: antibody concentrations are high enough to predict good protection. As pointed out above, the induction of the immunologic memory could be at least as important as the actual concentrations. Several findings support the idea that a boostable memory starts early, to develop even after neonatal immunizations. One could anticipate that if neonatal vaccinations were a common practice, vaccination schedules most probably would include another dose relatively early. This would help in achievement of higher antibody concentrations in the first few months of life. If induction of immunologic priming really is a valid surrogate for clinical protection, most children vaccinated even at neonatal age with Hib conjugates are protected against invasive Hib disease.
REFERENCES Bijlmer, H.A. Epidemiology of Haemophilus influenzae invasive disease in developing countries and intervention strategies. In: Development and Uses of Haemophilus b Conjugate Vaccines (Eds Ellis, R.W. and Granoff, D.M.). Marcel Dekker, New York, 1994, pp. 247-264 Claesson, B.A., Schneerson, R. and Robbins, J.B. et al. Protective levels of serum antibodies stimulated in infants by two injections of Haemophilus influenzae type b capsular polysaccharide tetanus toxoid conjugate. J. Pediatr. 1989, 114,97-100 Halsey, N.A. and Klein, D. Maternal immunization. Pediafr. Infect. Dis. J. 1990, 9, 574-581 Sarvas, H., Kurikka, S., Sepp%, I.J.T., M&kel& P.H. and MakeI& 0. Maternal antibodies partly inhibit an active antibody response to routine tetanus toxoid immunization in infants. J. infect. Dis. 1992, 165, 977-979 Barington, T., Gyhrs, A., Kristensen, K. and Heilman, C. Opposite effects of actively and passively acquired immunity to the carrier on responses of human infants to a Haemophi/us influenzae type b conjugate vaccine. lnfecfion and immunity 1994,,,62, 9-l 4 Kurikka, S., Olander, R.-M., Eskola, J. and Ktiyhty, H. Passively acquired anti-tetanus and anti-Haemophilus antibodies and the response to Haemophilus influenzae type b-tetanus toxoid conjugate vaccine in infancy. Pediatr. Infect. Dis. J. 1996,15,530-535 Siegrist, CA. and Lambert, P.H. Maternal immunity and infant responses to immunization: factors influencing infant responses. Developments in Biological Standardization (in press) Fisher, G.W., Ottolini, M.G. and Mond, J.J. Prospects for vaccines during pregnancy and in the newborn period. Clinics in Perinatology 1997, 24, 231-249 Ward, J.I., Bulkow, L., Wainwright, R. and Chang, S. Immune tolerance and lack of booster responses to Haemophilus influenzae (Hib) conjugate vaccination in infants immunized begin-
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conjugate vaccine in chronically ill premature infants. J. Pediatr. 1993, 123, 791-794 Greenberg, D.P., Vadheim, C.M., Prtridge, S., Chang, S.-J., Chiu, C.-Y., Ward, J.I. and the Kaiser-UCLA Vaccine Study Group. lmmunogenicity of Haemophilus influenzae type b tetanus toxoid conjugate vaccine in young infants. J. Infect. Dis. 1994,170,76-81 Kristensen, K., Gyhrs, A., Lausen, B, Barington, T. and Heilman, C. Antibody response to Haemophilus influenzae type b capsular polysaccharide conjugated to tetanus toxoid in.preterm infants. Pediatr. infect. Di.&. i 1996, 15, 525-529 Siber. G.R.. Thomoson. C. and Reid, G.R. et a/. Evaluation of bacterial polysaccharide immune globulin for the treatment or prevention of Haemophilus influenzae type b and pneumococcal disease. J. infect. Dis. 1992, 165, S129-S133 Kayhty, H., Peltola, H., Karanko, V. and Makela, P.H. The protective level of serum antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J. infect. Dis. 1983, 147,llOO Eskola, J., Kayhty, H. and Takala, A.K. et al. A randomized, prospective field trial of a conjugate vaccine in the protection of infants and young children agaist invasive Haemophilus influenzae type b disease. A/. Engl. J. Med. 1990, 323, 1381-1387 Granoff, D.M., Holmes, S.J. and Osterholm, M.T. et al. Induction of immunologic memory in infants primed with Haemophilus influenzae type b conjugate vaccines. J. infect. Dis. 1993,168,663-671 Kayhty, H. Difficulties in establishing a serological correlate of protection after immunization with Haemophilus influenzae type b conjugate vaccines. Biologicals 1994, 22, 397-402 Kurikka, S., Kayhty, H., Saarinen, L., Ronnberg, P.-R., Eskola, J. and Make@ P.H. Immunologic priming by one dose of Haemophilus influenzae type b conjugate vaccine in infancv. J. /nfe&. Dis. 1995, 172, i268-1272. Peltola. H.. Kavhtv. H.. Virtanen. M. and Make& P.H. Prevention of. Haemobhks kfluenzae’ type b bacteremic infections with the polysaccharide vaccine. N. Engl. J. Med. 1984, 310, 156661569 Mosier, D.E., Freeney, A.J. and Shcerle, P. The physiology of B lymphocytes capable of generating anti-polysaccharide antibody responses. In: Towards Better Carbohydrate Vaccines (Eds Bell, R. and Torrigiani, G.). Wiley, Chichester, 1987, pp. 243-261