Safety and Immunogenicity of Heptavalent Pneumococcal Vaccine Conjugated to CRM197 in United States Infants
Objective. To determine the safety and immunogenicity of heptavalent pneumococcal saccharide vaccine (serotypes 4, 6B, 9V, 14, 18C, 19F, 23F) individually conjugated to CRM197 (PNCRM7), administered at 2, 4, 6, and 12 to 15 months of age.
Design. Two hundred twelve healthy 2-month-old infants were equally randomized to receive four consecutive doses of PNCRM7 or an investigational meningococcal group C conjugate vaccine, which served as a control. Concomitantly administered routine vaccines were oral polio vaccine and combined diphtheria toxoid, tetanus toxoid, and whole cell pertussis vaccine/Haemophilus influenzae type b vaccine consisting of capsular oligosaccharides conjugated to CRM197 (DTP/HbOC) at 2, 4, and 6 months, and either measles-mumps-rubella vaccine or HbOC at 12 to 15 months. Active safety surveillance was conducted for 3 days after each dose. Antibody concentrations to each of the 7 pneumococcal serotypes were measured by enzyme-linked immunosorbent assay prevaccination, after doses two and three, prebooster, and postbooster.
Results. Significantly fewer children experienced local reactions at the PNCRM7 injection site than at the DTP/HbOC site. There was no increase in the incidence or severity of local reactions at the PNCRM7 site with increasing doses of vaccine. Mild to moderate postvaccination fever was common in both the PNCRM7 and control vaccine groups, however DTP/HbOC was administered concurrently. All 7 vaccine serotypes were immunogenic. The kinetics of the immune responses were serotype-specific. After three doses of PNCRM7, between 92% to 100% of children had ≥0.15 μg/mL of antibody, and 51% to 90% achieved a level of ≥1 μg/mL against specific serotypes. A booster dose of PNCRM7 resulted in a brisk anamnestic response to all 7 vaccine serotypes, demonstrating effective stimulation of T-cell memory by the primary series of vaccinations.
Conclusion. Primary immunization followed by a booster dose of PNCRM7 seemed to be acceptably safe and resulted in significant rises in antibody to all 7 serotypes.
Implications. Studies to assess vaccine efficacy of PNCRM7 for prevention of systemic disease, nasopharyngeal colonization, and acute otitis media are in progress. If PNCRM7 proves to be protective, there is the potential to prevent up to 85% of invasive pneumococcal disease occurring in US children.
- Hib =
- Haemophilus influenzae type b conjugate vaccine •
- CRM197 =
- cross-reactive material 197 •
- PNCRM5 =
- pentavalent pneumococcal saccharide vaccine conjugated to CRM197 •
- menC =
- conjugate meningococcal group C vaccine •
- PNCRM7 =
- heptavalent pneumococcal saccharide vaccine conjugated to CRM197 •
- DTP =
- combined diphtheria toxoid, tetanus toxoid, and whole cell pertussis vaccine •
- HbOC =
- Haemophilus influenzae type b vaccine consisting of capsular oligosaccharides conjugated to CRM197 •
- MMR =
- measles-mumps-rubella vaccine •
- IgG =
- immunoglobulin G •
- ELISA =
- enzyme-linked immunosorbent assay •
- GMC =
- geometric mean concentration of antibody
After the remarkable success of Haemophilus influenzae type b conjugate vaccines (Hib) in virtually eliminating disease among immunized populations of children,1 2 the same conjugate vaccine technology has been utilized to develop more effective vaccines against Streptococcus pneumoniae. Coincidentally, the alarmingly rapid emergence of strains of pneumococci resistant to both penicillin and cephalosporins3-5 has created an urgent need for pneumococcal vaccines that are effective in infants. Because there are more than 80 serotypes of S pneumoniae, development of pneumococcal conjugate vaccines is considerably more difficult and expensive than creation of the conjugate Hib vaccines. Fortunately, a vaccine that protects against the 7 most common serotypes isolated in the United States and much of the developed world has the potential to prevent up to 85% of invasive pneumococcal infections in children.6 7
Pneumococcal vaccine containing capsular polysaccharides of 5 serotypes of S pneumoniae (6B, 14, 19F, 18C, 23F) conjugated to cross-reacting molecule 197 (CRM197) is immunogenic and safe when given as a three dose series at 2, 4, and 6 months of age.8-10 Administration of a booster dose of licensed pneumococcal polysaccharide vaccine to toddlers who have received a primary series of the pentavalent CRM197 conjugate pneumococcal vaccine (PNCRM5) also has been demonstrated to stimulate a boosting in titers of antibodies to serotypes contained in the primary series vaccine.11 12 However, the addition of serotypes 4 and 19F would increase the percentage of infections prevented from approximately 65% to 85%.6 7 For practical purposes, it may be optimal to give a toddler a booster vaccination with the same conjugate vaccine administered as the primary series, as is done with Hib vaccination.
There may be safety limitations and/or immunologic limitations on the number of serotypes of polysaccharide-protein conjugated vaccine that can be combined into a single dose of vaccine. It must be demonstrated that the addition of 2 more serotypes does not result either in decreased immunogenicity, or in an unacceptable increase in reactions. Severe local reactions have occurred after revaccination with the polysaccharide pneumococcal vaccine within a few years of the first immunization.13 Therefore, it is important to establish not only that a toddler dose of the heptavalent conjugate vaccine given to previously primed children will result in anamnestic antibody responses, but also that it will not cause serious side effects. Herein is the first report of the safety and immunogenicity of four consecutive doses of the heptavalent pneumococcal vaccine, containing serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, each independently conjugated to CRM197.
Healthy 2-month-old infants (±10 days) were enrolled into the trial through four centers located in Atlanta, GA; Baltimore, MD; Nashville, TN; and Pittsburgh, PA. The study was approved by institutional review boards at each center and written informed consent was obtained from a parent or guardian before enrollment.
Vaccine and Vaccine Administration
Infants were randomized equally to receive either the heptavalent conjugate pneumococcal vaccine or a meningococcal group C conjugate vaccine (menC), which served as a control. The pneumococcal vaccine is composed of polysaccharides of serotypes 4, 6B, 9V, 14, 19F, 23F, and oligosaccharides of 18C. Each serotype is independently coupled to CRM197 via reductive amination and combined into the 7-valent formulation (PNCRM7). This pneumococcal vaccine is formulated at 2 μg of serotype 4, 9V, 14, 18C, 19F, and 23F, and 4 μg of serotype 6B. It contains approximately 20 μg CRM197 per dose. Vaccine was administered at 2, 4, and 6 months of age (±2 weeks) in a double-blind manner. Study vaccines (PNCRM7 or menC) were administered intramuscularly into the left anterolateral thigh in a volume of 0.5 mL. At the primary series visits, children were given oral polio vaccine, and the Wyeth-Lederle combined whole cell pertussis-tetanus-diphtheria, and Hib vaccine (DTP/HbOC, Tetramune) was administered in the right thigh. After completion of the primary trial, parents were invited to have their child receive, at 12 to 15 months of age, a booster dose of the same vaccine they received as infants (menC, or PNCRM7). Toddlers were randomized to receive simultaneously with the experimental vaccine either HbOC or measles-mumps-rubella vaccine (MMR) in the opposite thigh at 12 to 15 months of age. No other vaccines were given within 4 weeks of the study vaccines.
At the first vaccination, parents were given a digital thermometer and a diary card on which to record possible reactions for 3 days after each dose of vaccine. Information collected about systemic symptoms included evening rectal temperature, the presence or absence of abnormal fussiness, sleepiness, anorexia, vomiting, high-pitched cry, prolonged crying (>3 hours), difficulty breathing, convulsions, or hives. Parents were instructed to examine the injection sites on both thighs and to record: 1) the presence or absence of tenderness and whether it interfered with movement of the leg; and 2) the presence or absence of erythema and induration, and whether it was larger than a US quarter-dollar coin (>2.4 cm).
Blood for antibody assays was drawn immediately predose one (age 2 months), predose three (age 6 months), postdose three (age 7 to 8 months), and before and 1 month after the booster dose. Standard enzyme-linked immunosorbent assay (ELISA) was used to quantitate serum quantities of immunoglobulin G (IgG) to each of the 7 serotypes contained in the PNCRM7 vaccine.14 Antibodies to C-polysaccharide were blocked by preincubation with a pneumococcal absorbent prepared by Wyeth-Lederle. ELISA units were converted to μg/mL of IgG by use of standard reference serum 89SF. Serologic assays were performed in the laboratories of Wyeth-Lederle Vaccines and Pediatrics.
The analyses of serum antibody titers was based on logarithms of the antibody concentrations. Geometric mean concentrations of antibody (GMC) and 95% confidence intervals were determined for antibody to each pneumococcal serotype in both vaccine groups. The confidence intervals of GMCs were determined based on normal distributions on the logarithmic scale. Comparisons of the GMCs between the two study vaccine groups were made using analysis of covariance, with study vaccine and study site as the classification variables and the prevaccination titers as the covariate. Reverse cumulative distribution plots15 were used to display the percentage of children achieving different concentrations of antibody to each of the 7 pneumococcal serotypes. Comparisons of local reactions between the injection sites of DTP/HbOC and PNCRM7 within subjects were made using the sign test. Comparisons of the systemic reaction rates and fever rates between the two treatment groups were made using the χ2 test. All statistical tests were performed based on two-sided P values with type 1 error rate α < .05.
The sample sizes were chosen to have at least 80% power to detect a ≥1.88-fold difference between the two treatment groups in postdose three GMC of antibody against any of the 7 pneumococcal serotypes, and a 14% to 21% difference in the rates of common reactions. The statistical power in the booster portion of the study was lower because of the smaller sample sizes. At 80% power, the smallest detectable difference after dose four in GMCs was 2.2 fold, and the difference in reactions rates that could be demonstrated ranged from 18% to 25%.
A total of 212 infants were enrolled; 106 received PNCRM7 and 106 were given menC. There were no demographic differences between the PNCRM7 and menC recipients. In both groups, 90.6% were Caucasian and 7.6% were black. The percentage of boys in the PNCRM7 and menC groups was 55.7% and 53.8%, respectively. Ninety-five (89.6%) of the PNCRM7 recipients and 99 (93.3%) of those given menC completed the primary series study. The reasons for withdrawal were: adverse experiences (n = 5), lost to follow-up (n = 4), parent request (n = 3), and protocol violations (n = 6). Fifty-eight percent (122) of the original cohort received the booster; 58 of the boosted children were in the PNCRM7 group and 64 children were in the menC group.
The incidence of any local reaction (erythema, induration, and/or tenderness combined) at the injection site of PNCRM7 was significantly lower than that at the DTP/HbOC injection site for all three primary doses: dose one, 35.9% versus 56.3% (P < .001); dose two, 42.9% versus 58.2% (P < .001); dose three, 34.7% versus 45.8% (P = .019). After the booster, or fourth dose, the incidence of any local reactions at the PNCRM7 site was 32.8%; it was 24.1% at the Hib or MMR site (P = .302). Moderate local reactions, defined as greater than the size of a quarter (>2.4 cm) area of erythema or induration, or pain that interfered with leg movement, occurred after doses one, two, and three in 4.9%, 6.1%, and 5.3% of children at the PNCRM7 injection site, as compared with 11.7% 11.2%, and 5.2% of children at the DTP/HbOC injection site. After the booster dose, a moderate local reaction was observed in 2 children (3.4%) at the PNCRM7 site and in 2 children (3.4%) at the control (MMR or HbOC) injection site (Fig 1). Local reactions did not increase in frequency or severity with repeated doses of the conjugate pneumococcal vaccine, and there were no local reactions severe enough to require medical attention. The rates of febrile responses (>38°C) were somewhat higher in the PNCRM7 than in the menC group: 25% versus 17% after dose one, 28% versus 24% after dose two, 38% and 32% postdose three, and 22% versus 19% postdose four (Fig 1). Fevers occurred during the 48 hours after the primary series of vaccinations and resolved by day 3. Children with temperature ≥38°C had higher rates of fussiness and drowsiness in both groups; no other systemic or local symptoms were associated with fevers. There were no significant differences between these fever rates between the two vaccine groups, nor were there significant differences in rates of lethargy, irritability, anorexia, or vomiting. Three children experienced fever higher than 39.6°C; 1 child was in the PNCRM7 group and 2 children were in the menC group.
Five children were withdrawn from the study because of adverse events, all of which resolved without consequences. One child had a febrile seizure 32 days after receipt of the menC vaccine. Prolonged or unusual crying was the reason for withdrawal of the other 4 children; 3 infants had received PNCRM7 and DTP/HbOC and 1 had been given menC and DTP/HbOC. Five other infants were hospitalized during the study period for reasons judged to be unrelated to study vaccine (bronchiolitis, pneumonia, cleft palate repair, rule out bacteremia, and gastroenteritis in 2 children). There were four transient adverse events that were thought by the investigator to be possibly, or probably, related to a study vaccine: fever in 1 PNCRM7 recipient and in 1 menC vaccinee on the day of vaccination; irritability, decreased appetite, and vomiting 1 day after vaccination in a menC recipient; and a hypotonic-hyporesponsive episode on the day of the third vaccination was reported to have occurred in 1 PCRM7 child. These adverse events could not be definitively attributed to the PNCRM7 or menC because routine vaccines were administered concurrently.
Primary Series (Doses One, Two, and Three of Vaccine)
There were no significant differences in immunogenicity results among study sites; therefore, the results were pooled. GMCs attained by the pneumococcal vaccine recipients to each of the 7 pneumococcal serotypes contained in PNCRM7 are shown in the Table and Fig2. After three doses of vaccine, the GMCs in the PNCRM7 groups were significantly higher (P < .001) for each serotype than in the menC vaccine group. The GMC of antibody in the PNCRM7 recipients ranged from 0.98 to 3.48 μg/mL, with the highest against serotypes 14 and 19F, and the lowest against serotype 9V. Kinetics of the antibody responses to the pneumococcal capsular polysaccharides were serotype specific. After two vaccine doses, GMCs were >1 μg/mL to serotypes 4, 14, and 19F, whereas three doses were required for any response to serotype 6B. The third vaccination induced a further rise in GMC greater than the postdose two level (1.6-fold to 5.5-fold) to all serotypes except 4. Children vaccinated with PNCRM7 showed a 4-fold to 27-fold rise in GMC, depending upon the serotype, from prevaccination to after dose three of vaccine.
In the menC control group, 61% to 79% of children experienced a 2-fold or greater decrease in antibodies to the 7 pneumococcal serotypes from age 2 to 7 months. In contrast, the percentages of PNCRM7 recipients with at least a 2-fold rise in antibody concentration to each serotype from prevaccination to 1 month postdose three was: 97% to serotype 4, 69% to serotype 6B, 83% to serotype 9V, 83% to serotype 14, 86% to serotype 18C, 86% to serotype 19F, and 87% to serotype 23F. Contained in Fig 3 are reverse distribution curves demonstrating the percentage of pneumococcal vaccinees achieving varying levels of antibody to each vaccine serotype. After three PNCRM7 vaccinations, between 92% (6B, 23F) to 100% (4) of children had ≥0.15 μg/mL of postvaccination antibody, and 51% (9V) to 90% (19F) achieved a level of ≥1 μg/mL.
Antibody concentrations declined substantially from 1 month after the third dose of vaccine (0.98 to 3.48 μg/mL) to the prebooster dose (0.20 to 1.81 μg/mL) at age 12 to 15 months of age (Table 1, Fig 2). However, these prebooster antibody levels were significantly higher (P < .001) than the baseline concentrations for each serotype at 2 months of age (0.05 to 0.31 μg/mL), and were also significantly higher (P < .001) than those of the prebooster titers of the control menC group (Table 1, Fig 2). One month after the fourth or booster dose of the PNCRM7 vaccine, a rapid rise in antibody was noted, demonstrating a brisk anamnestic response to each of the 7 capsular serotypes contained in the vaccine. The GMC of antibody against every serotype was significantly higher (P < .001) after the booster dose (2.39 to 9.74 μg/mL) than after dose three (0.98 to 3.45 μg/mL). The fold rises of GMC per serotype from prebooster to postbooster dose varied from 5.4 (type 14) to 15.0 (type 23F). As was the case after the first three doses, antibody concentration to serotype 14 was the highest after the booster dose. The second highest antibody concentration after the booster dose was to serotype 6B (8.36 μg/mL). Displayed in Fig4 are the reverse cumulative distribution curves demonstrating that after the booster dose, 100% of children have at least 0.15 μg/mL of antibody to 6 of the vaccine serotypes; 96% children had ≥0.15 μg/mL to 23F. Depending upon the serotype, 84% (type 4) to 100% (type 14) children attain antibody concentrations ≥1 μg/mL. The percentages of PNCRM7 vaccinees experiencing at least a 2-fold rise in antibody concentration from prebooster dose to 1 month after the booster were: serotype 4, 95%; serotype 6B, 93%; serotype 9V, 93%; serotype 14, 89%; serotype 18C, 96%; serotype 19F, 81%; and serotype 23F, 95%.
Results from this study indicate that four consecutive doses of this heptavalent conjugate pneumococcal vaccine, containing serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, can be safely administered to children at 2, 4, 6, and 12 to 15 months of age. Local reactions to PNCRM7 were generally mild and occurred at a significantly lower rate than after vaccination with the licensed DTP/HbOC vaccine in the primary series. The percentage of children experiencing local reactions was similar to that seen in previous studies with the pentavalent pneumococcal vaccine conjugated to CRM197, PNCRM5.8-10 An important observation is that there was not an increasing rate, or severity, of local reactions with subsequent doses of vaccine. This has been a concern because administration of a second dose of licensed polysaccharide vaccines within a few years of the first immunization occasionally has been associated with clinically significant local erythema, swelling, and pain,13 which is thought to be attributable to a combination of circulating antibody with antigen at the injection site.16 A possible explanation for the different local reactogenicity profiles is that the licensed polysaccharide vaccines contain 573 μg of total polysaccharide per dose versus only 16 μg of total polysaccharide in each dose of PNCRM7.
Mild to moderate febrile reactions occurred, depending upon the dose, in 25% to 38% of PNCRM7 recipients and in 16% to 30% of recipients of the conjugate meningococcal control vaccine. Only 1 child experienced a temperature greater than 39.6°C. These fever rates are higher than have been observed after vaccination with concurrent PNCRM5 and or DTP/HbOC vaccines.8-10 Children in this study received DTP/HbOC simultaneously with the first three doses of the study vaccines. Because there was not a group of infants in this evaluation who were given only DTP/HbOC, it is not possible to determine whether these fevers were attributable to the study vaccine, the DTP/HbOC vaccine, or concurrent viral infections at the time the study was conducted. The percentage of children perceived by their parents to have experienced fever after vaccination with DTP/HbOC in prelicensure studies was similar to the rate of febrile reactions in children receiving concurrent PNCRM7 and DTP/HbOC in this evaluation.17
Every serotype contained in this 7-valent conjugate pneumococcal vaccine was immunogenic after three doses. Depending upon the serotype, there was a 4-fold to 27-fold rise in GMC of antibody from age 2 months to postdose three (Table 1). At 7 months of age, the GMC of antibody to the various serotypes ranged from 0.98 to 3.48 μg/mL; the highest was against serotypes 14 and 19F, and the lowest against serotype 9V. The percentage of children who had ≥0.15 μg/mL of antibody to each serotype was 92% (6B) to 100%,4 and a level of ≥1 μg/mL was achieved by 51% (9V) to 90% (19F) of vaccinees at age 7 months (Fig 2). As previously demonstrated,10 the kinetics of the antibody responses to the pneumococcal capsular polysaccharides are serotype specific. GMCs were ≥1 μg/mL to serotypes 4, 14, and 19F after two doses of PNCRM7, whereas three doses were required for any response to 6B.
Five of the 7 serotypes in this heptavalent PNCRM7 vaccine were also included in the previously studied PNCRM5 vaccine. It is not possible to accurately compare immune responses to these 5 serotypes between studies, because there were differences in the population evaluated and in the dosage and/or chain length of the pneumococcal saccharide given. Also, the serologic assays were performed in three different laboratories. There is general consistency in the immunogenicity of the shared 5 serotypes among studies, however. Serotype 14 was the most immunogenic serotype and serotype 6B was the least immunogenic in the majority of studies.8-10 Comparison of the GMCs achieved after the three-dose primary series in this study with those observed after the most comparable PNCRM5 previously evaluated10suggests that the addition of 2 more serotypes (4 and 9V) to the pentavalent vaccine did not result in a biologically meaningful decrease in immunogenicity. A direct comparison study of immune responses to the pentavalent and heptavalent vaccines has not been conducted, however.
Antibody concentrations to each serotype waned substantially from age 7 months to 12 to 15 months. The administration of a booster dose of the PNCRM7 vaccine resulted in an increase in GMC of antibody to each serotype to greater than that achieved after the primary three-dose series. The fold rises in GMCs from prebooster to postbooster dose varied from 5.4 (type 14) to 15 (type 23F). After the booster dose, 96% of PNCRM7 recipients had ≥0.15 μg/mL of antibody and 84% to 100% of children attained ≥1 μg/mL against different vaccine serotypes. Interestingly, there was not always a correlation between the relative immunogenicity of each serotype in the primary series with the strength of the booster responses. Most notably, serotype 6B has consistently been one of the least immunogenic serotypes after a primary series of vaccinations, but the GMC of antibody to 6B postbooster was the second highest of the 7 types. One can conclude that PNCRM7 effectively stimulates T cell memory and thus primes for an anamnestic response to all 7 vaccine serotypes. To our knowledge, this is the first published study to demonstrate the immunologic effectiveness of using the same PNCRM7 vaccine for the booster dose. These results have important practical implications. It will be logistically easier to use the conjugate vaccine for all doses, rather than to maintain stocks of both the conjugate and polysaccharide vaccines.
One should exercise caution in assuming that antibody concentrations of ≥0.15 μg and ≥1.0 μg/mL are those required for short-term and long-term protection, respectively, against serotypes of pneumococci. These antibody levels were extrapolated from studies of protection against H influenzae type b.18-20 It is not known if the same levels are associated with protection against pneumococcal serotypes. Also, it is quite feasible that immune priming for an anamnestic response, and not any particular antibody level, is the most important determinate of protection. The anamnestic response is characterized by a rapid and vigorous increase in antibody concentrations upon reexposure to the organism, resulting in long-term immunity. Stimulation of a T-cell-dependent antibody response has been proposed as the mechanism for the apparent prolonged protection after immunization with the conjugate Hib vaccines. It is reasonable to presume that this is also an important mechanism for immunity againstS pneumoniae.
The ultimate test of vaccine protection is a prospective, controlled trial in which children are randomized to receive either the PNCRM7 vaccine or a control vaccine and are then followed to compare the incidence of pneumococcal disease caused by the vaccine serotypes. Two such studies are underway in Finland and in northern California to determine the efficacy of this PNCRM7 vaccine against otitis media and against invasive disease, respectively. It is hoped that serologic correlates of protection will be defined to aid in the evaluation of possible future-generation conjugate pneumococcal vaccines. There is preliminary evidence that conjugate pneumococcal vaccines, like the Hib vaccines, will reduce carriage of vaccine serotypes;21larger trials are underway to further evaluate this finding. Thus, there is reason to believe that widespread use of pneumococcal conjugate vaccine may result in some degree of herd immunity by reducing spread of the organisms. Postvaccination epidemiologic studies of serotypes causing both colonization and invasion will be important, however, to determine if serotypes not covered in the vaccine become more prevalent. Conceivably, this could occur either by the reduction of competition by vaccine serotypes22 or by antibody selection for different capsular types through the process of in vivo capsular transformation.23 If PNCRM7 conjugate pneumococcal vaccine proves to be as protective as the conjugate Hib vaccines, there may be the potential to prevent the approximately 85% of invasive pneumococcal disease and 65% of pneumococcal otitis media currently caused by these 7 vaccine serotypes in the United States.7This is particularly important because of the rapid emergence of antibiotic resistance among S pneumoniae strains.
This study was funded by Wyeth-Lederle Vaccines and Pediatrics.
The authors express appreciation to the children in this study and their families and to the following physicians: Janet Blackwell, Mark Blatter, David Bromberg and his colleagues, William Davidson, Dwight Fortier and his colleagues, and Mary Keown. The study nurses whose dedication and hard work made this trial possible are Jane Baker, Teresa Ball, Barbara Culley, Laminade Padrick, Lynn Regina, Linda Wadsworth, and Nancy Wymer.
- Received April 24, 1997.
- Accepted August 1, 1997.
Reprint requests to (M.B.R.) University Hospital, N5W70, 22 South Greene St, Baltimore, MD 21201.
↵# Formerly Wyeth-Lederle Vaccines and Pediatrics, currently NABI, Rockville, Maryland.
This study was presented in part at the 106th Annual Academic Pediatric Societies meeting, Washington, DC, May 8, 1996.
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- ↵Steinhoff M, Reisinger K, Keyserling H, Block S, Malinoski F, Daum RS. Immunologic priming of infants by S pneumoniae oligo- and polysaccharide-CRM197 vaccines. In: Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–20, 1996; San Francisco, CA: American Society for Microbiology; 1996:151
- ↵Käyhty H, Chman H, Vuorela A, Malinosky F, Eskola J. Response at 24 months to a booster dose of pneumococcal (Pnc) polysaccharide vaccine in children immunized with pentavalent Pnc conjugate vaccine (PncCRM) in infancy. In: Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–20, 1996; San Francisco, CA: American Society for Microbiology; 1996:162
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- Copyright © 1998 American Academy of Pediatrics