Family Practice Vol. 17, No. 5, 435-441
© Oxford University Press 2000
Selections from Current Literature |
Recent advances in conjugated pneumococcal vaccination
Columbia University School of Nursing, Department of Family Medicine, Health Sciences Center L-4, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Dabelstein D and Cromer B. Recent advances in conjugated pneumococcal vaccination. Family Practice 2000; 17: 435–441.
Abstract
This article reviews the current literature and recent updates with regard to childhood vaccination for Streptococcus pneumonia including: studies in immunology with antibody titres, dosages of conjugated vaccines, carriage rates of Streptococcus, side effects, comparison in certain disease states and comparison between vaccines.
Molecular immunology
Ahman H, Kayhty H, Tamminen P, Vuorela A, Malinoski F, Eskola J. Pentavalent pneumococcal oligosaccharide conjugate vaccine PncCRM is well tolerated and able to induce an antibody response in infants. Pediatr Infect Dis J 1996; 15: 134–139.
This study was one of the primary investigations regarding conjugated pneumococcal vaccines. HiB vaccination is a conjugated vaccine, with the primary immunogen coupled to a carrier protein to improve immunogenicity.1 This process changes the immune response from T cell independent to T cell dependent.2 Conjugation for Pneumococcus has been attempted with 5–7 serotypes conjugated to diphtheria toxoid, tetanus toxoid and Neisseria meningitis protein.
Subjects were 30 healthy infants, who were immunized at 2, 4 and 6 months. The vaccines were composed of 10 µg of five oligosaccharides: serotypes 6B, 14, 18C, 19F and 23F. Each serotype was conjugated to CRM197, a mutant diphtheria toxin. The infants were also given routine DTP and HiB immunization. Blood samples were obtained before each immunization and at 7 months, a month after the last immunization. Controls were also taken at 2, 4 and 6 months to compare the natural induction of anti-pneumococcal antibodies. Adverse effects were recorded hours and days after immunizations, with only two children withdrawing from the study.
Between the different serotypes, an antibody response was obtained that was clinically significant at 7 months of age. The timing of the antibody response varied according to serotype, with some being more immunogenic. A comparison was made with HiB titres to compare kinetics and levels of titres. The distribution of titres was similar.
Comments
This study was well designed and demonstrated a clear response rate to the conjugated pneumococcal vaccine, and provides a basis for a working fund of knowledge regarding this vaccine. Clearly, one also needs to determine the length of immune response, to see if the titres wane with time, or are maintained. Additionally, one needs to determine clinical efficacy in prevention of disease, as well as direct comparison with the polysaccharide unconjugated pneumococcal vaccine. However, none of these future studies would be reasonable unless one can demonstrate a response in titres in healthy newborns. This study had few limitations, none of which made the results invalid. Parents and investigators were not blinded to the vaccination, which may introduce bias to the adverse events. For the comparison with the HiB titres, it is not clear if one is able to compare the levels of the titres directly, specifically with regard to the protection from disease.
Pneumococcal polysaccharide vaccines have been demonstrated to be ineffective in children. These current attempts are an effort to induce a sustained response in children <2 years old, as this is where the majority of the disease occurs. Polysaccharide vaccines contain 23 serotypes, while conjugated vaccine studies are being conducted with only five serotypes. While more serotypes have a theoretical advantage, these vaccines elicit an unpredictable immune response, which is not maintained or is unresponsive to booster doses.3 Clinical efficacy has also been studied with regard to prevention of otitis media, which has illustrated that the unconjugated vaccine is ineffective in prevention of this illness.4 Studies evaluating the effect on lower respiratory infection showed minimal benefit on morbidity.5,6 Finally, polysaccharide pneumococcal vaccination has not been shown to decrease carriage of streptococcus in the nasopharynx.7 This vaccine is clearly suboptimal for most children, and is currently indicated only in children with sickle cell disease, asplenia, nephrotic syndrome, human immunodeficiency virus and cerebrospinal fluid leaks.
Ahman H, Kayhty H, Lehtonen H, Leroy O, Froeschile 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: 211–216.
The authors of this study build on the knowledge gained from the previous study regarding antibody response rates. They recruited 125 infants randomized to four groups: three groups to receive conjugated pneumococcal vaccine at three different dosages of 1, 3 and 10 µg versus a control group which received physiological saline, all at 2, 4 and 6 months of age. The conjugated vaccine consisted of serotypes 6B, 14, 19F and 23F individually conjugated to diphtheria toxoid. The second part of the study involved an evaluation of booster dosages at 14 months of age. Fifty percent of the infants immunized with the conjugated vaccines and all of the infants in the placebo group received a booster dose of the 3 µg conjugated vaccine (PncD03). The remaining 50% of the conjugated vaccine recipients received Pneumovax—the traditional unconjugated vaccine. Standard immunizations (DtP, HiB, IPV and MMR) were given to all infants at a separate site. Similarly to the previous study, titres were drawn prior to each immunization and at 7, 15 and 24 months.
Antibody titres on average differed from placebo after the second vaccine, reaching a maximum at 7 months with 95% confidence intervals. Similarly to the previous study, titre levels varied according to serotype, with 19F being the strongest immunogen. However, by 14 months of age, the titres had decreased, but were still greater than placebo. It was at this point that the booster doses were given. The authors report no statistical difference in response to either booster (conjugated or polysaccharide vaccine) in children already primed with conjugated vaccines. In the placebo group, naïve conjugated vaccine also induced a response, but not as well as in those primed. An evaluation of vaccine concentration illustrated that the highest dose induced the strongest response to the primary series, but the greatest response to the booster dose was seen in those with the lowest initial dose.
Lastly, the authors follow the titres to 24 and 36 months. Again the titres decreased significantly, with no statistical difference between any of the groups. Specifically, there was no difference between the groups given conjugated versus polysaccharide booster or between the groups that were primed versus unprimed.
Comments
This study raises many questions regarding pneumococcal immunization. Many findings were not expected. Specifically, there was no statistically significant difference with priming, nor any difference in the response to the different booster vaccines. There was not a group kept as a true placebo. The placebo arm all received the conjugated vaccine, with none left to be able to compare the natural induction of anti-pneumococcal antibodies. Secondly, the entire placebo group received the con-jugated vaccine, with none receiving the polysaccharide vaccine. This may bias the statistical significance, as there were not four groups to compare, nor a placebo group. This study design flaw brings into question the results at 36 months. Another limitation is the fact that only four serotypes were studied, rather than the typical five common serotypes. This will make direct comparison with other studies difficult. Strong aspects of the initial study design included a true placebo group, a fair number of patients and an attempt to follow titres over time. Clearly this will be an important aspect of future trials. Without persistence of statistically significant titres, all further efforts will be in vain.
This is important research on a relevant and serious problem. One may underestimate the morbidity and mortality from S.pneumoniae. Pneumococcal pneumonia has been estimated to cause 1.2 million deaths per year, and 40% of the pneumonia deaths in children throughout the world.8 The overall mortality for pneumococcal pneumonia is 10–20%.9 Occult pneumococcal bacteraemia has been studied extensively.10 Often present in children <2 years of age, it can progress to pneumonia, cellulitis, meningitis or sepsis. With the introduction of HiB immunization, Pneumococcus is now the leading cause of bacterial meningitis in children, with a 6% mortality rate9 and is most common in children <2 years of age. Otitis media also has a peak incidence between the ages of 6 and 18 months. Again, Streptococcus is the most common cause of bacterial otitis (40%).3
Children are at further increased risk because of the lack of type-specific antibody, lowest between the ages of 12 and 17 months, even after colonization.3 Interestingly, daycare attendance places children at a 2.6 times greater risk of developing invasive disease. Recurrent otitis places children at 1.6 times the risk.11 Clearly, one cannot underestimate the pathology that Streptococcus can cause, both in children and in transmission to adults. There is a substantial benefit to be gained by eradication of childhood streptococcal disease.
Dosages and concentration of pneumococcal conjugated vaccine
Daum RS, Hogerman D, Rennels MB et al. Infant immunization with pneumococcal CRM197 vaccines: effect of saccharide size on immunogenicity and interactions with simultaneously administered vaccines. J Infect Dis 1997; 176: 445–455.
These investigators studied the effect on immunogenicity of saccharide chain length and saccharide quantity between six pentavalent pneumococcal conjugate vaccines. This study consisted of 400 US infants, randomized to receive the above versus controls at 2, 4 and 6 months of age. The conjugated vaccines consisted of five prevalent serotypes (6B, 14, 18C, 19F and 23F) conjugated to CRM197, a mutant diphtheria toxin molecule. Furthermore, the researchers evaluated antibody titres of simultaneously administered vaccines for possible interference between relevant antigens.
Each serotype was synthesized to set protein lengths, oligosaccharide (OS) and polysaccharide (PS), then conjugated and divided into concentrations (0.5, 2 and 5 µg). This comprised six vaccines, with the seventh being the control group. All groups received HiB, DTP and OPV, with parents and laboratory personnel being blinded. Data were collected from blood samples prior to the three immunizations, and at 7 months of age, and adverse events were recorded.
There were increased rates of fever with increasing dose of the pneumococcal vaccine, as well as higher rates compared with those who received only HbOC/DTP. Erythema, induration and tenderness were higher at the sites of HbOC/DTP than at the site of any pneumococcal vaccine.
Irrespective of dose and chain length, after the three-dose schedule, the mean anticapsular antibody titres exceeded that found in the control group. The timing and distribution of antibody titres differed according to the serotype administered, with certain serotypes being more immunogenic; specifically, serotypes 14 and 19F had mean antibody concentrations exceeding all others.
Overall, PS formulations were more immunogenic than OS formulations at the same dose level. For the PS vaccines, the magnitude of the antibody titre was related to the concentration, with the PS 5 µg having the highest titre, though not always clinically significantly different from 2 µg.
To analyse simultaneously administered vaccines, antibody titres were compared between controls and PS 2 µg. Anti-tetanus antibodies did not differ significantly from controls. Anti-diphtheria toxoid antibody titres were higher among conjugated pneumococcal vaccines versus controls. Perhaps, as pneumococcal vaccines were conjugated to attenuated diphtheria toxoid, this would raise antibody titres secondarily to an immune response to the conjugated protein. Antibody titres to Haemophilus influenzae were higher for each group of pneumococcal vaccines compared with controls, the reason for which was unclear.
Comments
There is a considerable lack of knowledge regarding the effect of protein size, the various protein carrier molecules, linkage molecules and the amount of saccharide that should be present for optimal immunogenicity. This study provides a fair comparison between dosages of vaccine components as well as an evaluation of protein length. The material appears valid, and adds to our general understanding regarding vaccine components. This study has limitations, in that 50 patients did not complete the study, but no mention is made regarding to which group these individuals belonged. This may introduce bias, if the data were not analysed with an intention to treat model. Secondly, comparisons regarding simultaneously administered vaccines were made comparing only specific subgroups, i.e PS 2 µg, and the antibody concentration versus control was only done with the PS 5 µg subgroup. This is a limitation due to the lack of data regarding other subgroups.
The level of antibody titres needed for protection from clinical disease is not known. The concentration may vary according to disease state or various serotypes, with the less immunogenic possibly requiring higher titres. It is accepted that anti-polysaccharide antibodies are protective against pneumococcal diseases; specifically, prevention of disease with bacterial polysaccharide immune globulin (BPIG).12–15 Estimates of protective antibody concentration vary from 0.06 to 2.9 µg/ml.1,16,17 The titres obtained in this study exceed this, with a range of 1.24 µg/ml for serotype 6B to 3.87 µg/ml for serotype 14. We must await clinical trials to determine the efficacy in various disease states.
Nasopharyngeal carriage of Streptococcus pneumoniae
Dagan R, Muallem M, Melamed R, Leroy O, Yagupsky P. Reduction of pneumococcal nasopharyngeal carriage in early infancy after immunization with tetravalent pneumococcal vaccines conjugated to either tetanus toxoid or diphtheria toxoid. Pediatr Infect Dis J 1997; 16: 1060–1064.
This study is a transition and link between the above noted immunology studies and clinical trials to demonstrate efficacy. The authors demonstrated a decreased carriage rate of Pneumococcus with immunization. Three groups were devised, with two groups receiving polysaccharide serotypes 6B, 14, 19F and 23F conjugated to tetanus toxoid (Pnc-T) or diphtheria toxoid (Pnc-D) at 2, 4 and 6 months. The remaining group of infants (25) received placebo. At 12 months, a booster was given of unconjugated polysaccharide. Outcome measures included serum antibody titres as well as nasopharyngeal swabs done after each immunization and booster.
The results demonstrated an increase in titres, as expected with Pnc-T and Pnc-D as compared with placebo. The carriage rate increased 10–30%with placebo, with no similar increase in the Pnc-T or Pnc-D groups. No difference was seen in the placebo group after the polysaccharide booster at 12 months. When the cultures for each group were compared, a 10 and 5% carriage rate was seen in the Pnc-T and Pnc-D groups, respectively. The placebo group had a 27% carriage rate. The study was strengthened further when non-vaccine serotypes were compared. No pattern was distinguishable between the groups.
Comments
This study was well designed and executed. There were a small number of patients, but this provides a pilot on which to base larger scale studies. It was unclear when calculating titres and carriage why the entire population was not studied. Only 17 out of 25 were used to report serum titres, and 19 out of 25 were used to calculate carriage rates. This is in excess of the four patients that did not complete the study. Another limitation is the length of the study being only 13 months. Conceivably the passage of time may influence pharyngeal carriage rates.
A previous study carried out by the authors of this study has also demonstrated reduced carriage of pneumococcus that was conjugated to the outer membrane protein of Neisseria meningitidis.18
Nasopharyngeal carriage rates provide a link to actual disease states. In theory, if one can decrease carriage, one may decrease transmission as well as progression to disease. Pneumococcal carriage in the nasopharynx has been estimated at 60% in pre-school children, 35% in children at senior school and 25% in high school students.3,19 Carrier rates for adults in the household with children are 18–29% compared with 6% in adults without children.3 Daycare attendance places children, and younger siblings of these children, at an even higher risk of carriage of resistant pneumococci.20,21
Protection from disease has already been proven with H.influenzae immunization, also a conjugated vaccine. The reduction in nasopharyngeal carriage provides protection to more than just those immunized through herd immunity.22 A decreased rate of carriage in those immunized correlated with decreased Haemophilus morbidity in adults and disease in siblings.22 Until specific disease states are studied, one may be able to extrapolate these findings to include Streptococcus.
Side effects of pneumococcal vaccination
Nichol KL, MacDonald R, Hauge M. Side effects associated with pneumococcal vaccination. Am J Infect Control 1997; 25: 223–228.
This article addresses the low rates of vaccination in those eligible to receive the pneumococcal vaccine. Despite recommendations for pneumococcal immunization, 
70% of those eligible have not received the vaccine.23,24 The study was conducted at a VA hospital vaccination clinic; 1006 patients of the first 2049 patients were enrolled. A questionnaire was administered 1 week pre- and post-immunization to determine side effects. The mean age of the subjects was 69.9 years, and the average time to the interview was 14.9 days. For all systemic symptoms evaluated, patients reported lower rates in the post-vaccination period as compared with the pre-vaccination period. Local symptoms were 27.1% with soreness, 5.7% with redness and 5% with swelling. Of these, 90% were listed as mild to moderate, with 50% lasting <48 hours. In an attempt to assess for non-respondent bias, a sample (50 patients) of the 1043 patients not originally surveyed were questioned as well. The results did not differ significantly from those of the original survey respondents.
Comments
The authors do a fair job in assessing side effects from polysaccharide pneumococcal vaccination. There have been minimal large-scale studies done in assessing side effects from the conjugated vaccine. While we await those trials, it is reassuring that the side effects are minimal from the polysaccharide vaccine. These data, however, are limited in two major aspects. First, there is a possible selection bias, in that the patients were selected, not randomly, but from the first 1006 patients. Secondly, there were no data on the number or percentage of patients that responded to the survey. The survey response rate would strengthen the validity of the study especially given the fact that they conducted an evaluation to account for non-response. The study does, however, underline the lack of a reason not to vaccinate. Patients are aware of and concerned about side effects. Providers play a pivotal role in offering this vaccine to patients, as well as providing accurate information regarding vaccine risk.
Comparison of pneumococcal and conjugated vaccine in otitis media
Allen C, Barnett ED, Cabral HJ et al. Immune response to pneumococcal conjugate and polysaccharide vaccines in otitis-prone and otitis-free children. Clin Infect Dis 1999; 29: 191–192.
In an attempt to understand the role of two different vaccines in preventing pneumococcal infection in children, specifically otitis media, the authors compare the antibody concentrations to common S.pneumoniae serotypes 6B, 14, 19F and 23F before and after receiving either pneumococcal polysaccharide (PP) or conjugated (PC) vaccine. Both vaccines contained seven common pathogenic S.pneumoniae serotypes (4, 6B, 9, 14, 18, 19F and 23F). The PC vaccine was conjugated to detoxified diphtheria toxoid (CRM197). Enrolled in the study were 48 otitis-free children (<1 acute otitis media per year of life) and 64 otitis-prone children (with ventilation tubes) from private paediatric and otolaryngology practices, respectively. Using a double-blind prospective design, the authors randomly assigned individuals within both groups to receive either PP or PC vaccinations. Children with immunodeficiency, malignancy or previous pneumococcal vaccination were excluded. Pre-vaccination antibody titres were obtained at zero days for both groups. Post-vaccination titres were obtained at 38 days in the otitis-free group and at 25 days in the otitis-prone group.
In the otitis-free group, the PC vaccine demonstrated a significant increase in antibody response to serotype 6B versus vaccination with PP (pre-PC = 0.57 µg/ml and post-PC = 1.43 µg/ml versus pre-PP = 0.28 µg/ml and post-PP = 0.47 µg/ml, P = 0.01). However, the response to serotypes 14, 19F and 23F was not significant between the two vaccines for the otitis-free group. In the otitis-prone group, vaccination with the PC vaccine elicited a significantly higher rise in antibody titres (1 µg/ml) to all four serotypes versus vaccination with the PP. Vaccination with PC resulted in comparable antibody responses in both otitis-free and otitis-prone children, with children in both groups achieving titre concentrations of 1 µg/ml to all four serotypes. In contrast, vaccination with PP achieved antibody concentrations of 1 µg/ml to subtypes 14 and 19F in otitis-free children and to subtype19F in otitis-prone children.
Comments
It is difficult to formulate any conclusions from this study due to its limitations. Baseline demographic and prognostic features of a control and experimental group were not reported. This makes it difficult to formulate clinically relevant conclusions with regard to a relationship between the population under investigation and the predicted response. Additionally, it is important to remember that certain strains of S.pneumoniae are more prevalent in specific geographic locations and age groups (6–18 months). Unfortunately, these two key variables were not reported, leaving the reader to wonder if the response was affected by these confounding variables.
The authors raise an important question—does prophylactic immunization with a pneumococcal conjugate vaccine in children prone to otitis media reduce the incidence of this condition? This study is one of the first to evaluate pneumococcal vaccines in specific disease states; specifically with regard to efficacy of vaccination in children at risk, rather than prevention of disease. Overall, based on titre levels, the results suggest that children respond better to the conjugated vaccine than to polysaccharide vaccine. This response was significant for all serotypes when comparing conjugate and polysaccharide vaccine in otitis-prone children. However, as mentioned previously, it is unknown what antibody levels are needed for each serotype to confer protection in both otitis-free and otitis-prone children.
Comparison of various conjugated vaccines
Anttila M, Eskola J, Ahman H, Kayhty H. Differences in the avidity of antibodies evoked by four different pneumococcal conjugate vaccines in early childhood. Vaccine 1999; 17: 1970–1977.
Since avidity of antibody for antigen may play a role in preventing disease, the authors compared the avidity of antibodies produced in response to priming children with one of four S.pneumoniae (Pnc) vaccines. Each vaccine was conjugated to diphtheria toxin (CRM197), diphtheria toxoid (PncD), tetanus toxoid (PncT) or meningococcal protein complex (PncOMPC). Each vaccine contained serotypes 6B, 14, 19F and 23F in varying concentrations. The authors also investigated the effects of boosting with S.pneumoniae capsular polysaccharide (PncPS) versus the conjugate priming vaccine. In a prospective design, 176 infants were immunized at 2, 4 and 6 months of age with one of the four vaccines. At 14 or 15 months of age, children in the PncCRM197 group received a booster dose of either PncCRM197 or PncPS. Children in the PncD group received either PncD or PncPS as a booster. The PncT group also received PncPS as a booster, but no PncT. The PncOMPC group received no booster dose. Blood samples were obtained at 7 (post-vaccination), 14 (pre-booster) and 15 (post-booster) months of age. Avidity was determined using an enzyme-linked immunabsorbent assay.
Overall, at 7 and 14 months of age, infants primed with PncCRM197 or PncOMPC had significantly higher concentrations of serum IgG antibodies to four common pathogenic S.pneumoniae serotypes (6B, 14, 19F and 23F) versus those primed with PncD or PncT. Additionally, the concentration of IgG decreased from 7 to 14 months for every serotype, except 6B in children primed with PncT, which increased. At 15 months (post-booster), antibody concentrations to all serotypes increased significantly. Children primed with PncCRM197 and boosted with either PncCRM197 or PncPS responded with similar antibody concentrations to all serotypes. Furthermore, children primed with PncD and boosted with PncD or PncPS responded with similar antibody concentrations to all serotypes. No data were available to compare post-booster IgG concentrations in those children primed with PncT or PncOMPC and boosted with either the priming vaccine or PncPS. The reason for this is unclear.
From 7 to 14 months, the avidity of IgG to all serotypes increased for all vaccine groups. PncT and PncCRM197 induced significantly higher avidity to serotype 6B when compared with PncD or PncOMPC at 14 months (pre-booster). Additionally, after priming, PncCRM197 induced a significantly higher avidity to serotype 23F when compared with all other vaccine groups. With the exception of the PncD group serotypes 14 and 23F, IgG avidity decreased in all other groups after PncPS booster was administered. In contrast, when children were given a conjugate booster, IgG avidity to all serotypes increased significantly. This suggests that booster vaccination with a conjugate vaccine induces a superior response when compared with PncPS booster. Overall, IgG avidity to all serotypes was highest in children primed and boosted with PncCRM197.
The authors observed a weak positive correlation between antibody concentration and avidity, with the best correlation existing in the post-booster samples. There was a statistically significant and positive correlation in the group primed and boosted with PncCRM197 for serotypes 6B and 23F, in the PncD primed and boosted group for serotype 6B, in PncD primed and PncPS boosted group for all serotypes, and in PncT primed and PncPS boosted group for serotypes 6B and 23F. In addition, it appears that each serotype induces variable degrees of antibody avidity. Serotype 14 induced the greatest avidity, followed by 19F, 23F and 6B. The differences for each serotype were significant except for 23F and 6B. Furthermore, the authors report that the differences in avidity between serotypes diminish as age increased. This suggests that each serotype is unique in that some induce higher avidity more quickly than others.
Comments
Even though the authors selected to begin immunizations in 2-month-old infants, they failed to identify their target population, indicate exclusion criteria or randomize subjects to each treatment group. This would inherently produce selection bias and possibly place non-equivalent subjects in the same group. Along with the small sample size, the demographic characteristics of these patients were not stated. As a result, children with a history of S.pneumoniae infection may have different antibody responses from those of children with no history of infection. Additionally, neither the investigators nor the mothers were blinded to the treatment modalities. This lends itself to recording bias, i.e. maybe the investigators looked more critically for a response to one vaccine and not to others. Because the investigators did not use a control group, it is difficult to determine how much of the response is due to the vaccination and how much to environmental exposure. This limitation could have been modified if pre-immunization titres were reported. By determining pre-immunization titres, the investigators could have evaluated the immunization response with more accuracy. Also, even though the authors present the graphs of avidity as linear, it may be that maximum avidity is obtained at another time between 7 and 14 months. Without serial sera analysis, we only know about the avidity at 7, 14 and 15 months. Perhaps the avidity increases or decreases before or after this time period. This would be clinically relevant if in fact antibody avidity is correlated positively with protection. Finally, the authors fail to indicate the route and location of delivery of the vaccines. Perhaps the injections were given in different sites with varying techniques, which could possibly effect the absorption of the vaccine.
Since the authors selected an age group with a high risk of S.pneumoniae infection (6–18 months), the data may be used to build on the limited data on pneumococcal vaccination in this group. From these results, it appears that all of the conjugate vaccines are effective in producing a primary and secondary immune response in infants <2 years old. Since the avidity to all serotypes increases with time, it appears that these vaccines may induce affinity maturation and therefore memory. This is important, since previous attempts to vaccinate with pneumococcal polysaccharide were ineffective in inducing a significant secondary immune response in children <2 years. Another interesting observation is that infants receiving the conjugate vaccine as a booster responded with significantly higher antibody avidity than those who received the polysaccharide as a booster. Vaccination with a protein-conjugated vaccine induces the potential for a secondary response and therefore is T-cell dependent. As a result, high affinity antibodies are produced and quickly attach and eliminate antigens. Yet it is difficult to reach any conclusions as to which vaccine provides the best protection because we do not know what levels of avidity or titres are needed to prevent infection. The necessity of booster vaccinations may not be warranted if priming at 2, 4 and 6 months of age is proven to reduce the incidence S.pneumoniae infection.
These data illustrate the many barriers in evaluating vaccine efficacy against bacteria with many common pathogenic serotypes. As illustrated in this investigation, certain S.pneumoniae serotypes are more or less immunogenic; therefore, it is difficult to determine the optimal vaccine concentration and dosing. This vaccine hopefully will play a role in the ever growing problem of drug resistance. Up to 15% of pneumococci are intermediately resistant to penicillin, and another 15% are highly resistant.3 Serotypes included in the vaccine will not only be the most likely to cause disease, but also the most commonly resistant serotypes. As previously illustrated, if one can reduce the carriage of vaccine-related serotypes, one can therefore reduce the carriage of resistant pneumococci. Pneumococcus is unique with regard to its 83 different serotypes. To complicate matters, the serotypes that cause clinical disease in adults vary from the disease caused in children, as well as varying throughout the world.3 The serotypes 6B, 14, 18C, 19F and 23F have been isolated in 67.9% of isolates in California from 1992 to 1994.25 These same five serotypes are estimated to cause 46% of cases of otitis media in children.26 Vaccination to specific serotypes may cause emergence of serotypes that presently do not cause major illness. The authors speculate that the vaccine may need to be modified continuously in order to account for common serotypes, or even to vary content throughout the world.
Summary
As illustrated, S.pneumoniae causes significant morbidity and mortality worldwide. Successful immunization programmes have all but eradicated many infectious diseases. However, S.pneumoniae with its numerous serotypes provides a challenge to immunization potential. Conjugated vaccine technology provides a possible solution to immunogenicity. Ongoing research is attempting to expand current knowledge regarding protection from the numerous manifestations of S.pneumoniae. A critical area of research will involve the evaluation of specific disease states. A vaccine would be clinically useful for children, if proven to decrease the number of cases of otitis media, pharyngitis or pneumonia, for example. The studies evaluated in this review provide a basis for this research.
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