Conjugate pneumococcal vaccine and antibiotic-resistant Streptococcus pneumoniae : herd immunity and reduction of otitis morbidity (2000)

Respiratory infections are the most common cause of morbidity in childhood. Bacterial respiratory infections can occur either as primary infections or as a secondary complication of viral infections. Streptococcus pneumoniae is one of the most important bacterial pathogens in respiratory tract infections. Together with untypable Haemophilus influenzae, it is one of the two most common causes of acute otitis media (AOM). In addition it is the most frequent cause of bacterial community-acquired pneumonia and one of the leading organisms causing sinusitis, sepsis and meningitis. The main reservoir of S. pneumoniae is the nasopharynx. From there the organism can: (1) enter the bloodstream to cause invasive infections such as sepsis, meningitis and infections in remote foci such as joints, bones and soft tissues; (2) spread to adjacent mucosal tissues to cause mucosal infections such as otitis, sinusitis and pneumonia; and (3) be transmitted by direct contact and through aerosols to other individuals. It is established that acquisition and carriage of S. pneumoniae are associated with the occurrence of AOM, 1–3 bacteremia 4–7 and pneumonia. 8 Therefore studying pneumococcal carriage and the influence of antibiotic treatment on carriage rates and antibiotic resistance is important. Most children are colonized by S. pneumoniae during the first years of life. This colonization, which may be detected in early infancy, peaks toward the second to the third year of life. 9, 10 In the developing world colonization rates can be as high as 60% or greater at 2 months of age, 11, 12 and in more developed, less crowded populations, carriage rates can be as low as <15% for those younger than 3 months of age. 7, 13–17 Resistance of pneumococci to antimicrobial agents, which was first reported in the mid-1960s, 18, 19 is increasing worldwide and has an enormous impact on clinicians, microbiologists, drug manufacturers and public health authorities. 20–23 In another article in this supplement we reviewed extensively the contribution of S. pneumoniae to AOM and the implication of the increasing antibiotic resistance to bacteriologic and clinical failure. 24 Also reviewed in detail within the article was the detrimental effect of antibiotic treatment on nasopharyngeal carriage of antibiotic-resistant S. pneumoniae and the extensive spread of this organism in infants and young children. The aim of this article is to evaluate the potential role of the newly designed pneumococcal conjugate vaccines in reducing carriage and spread of S. pneumoniae in general and antibiotic-resistant S. pneumoniae in particular. If indeed such a reduction occurs, it implies that widespread immunization with conjugate pneumococcal vaccines will have two main consequences: (1) unvaccinated individuals (mainly young infants) may be protected if others are vaccinated (herd immunity); and (2) the choice of antibiotics for the treatment of bacterial respiratory infections such as AOM may be altered if the frequency of antibiotic-resistant S. pneumoniae is reduced. RELATION OF CARRIAGE OF S. PNEUMONIAE TO ANTIBIOTIC-RESISTANT AOM Acquisition and carriage of S. pneumoniae is associated with the occurrence of AOM. 1–3 We recently examined the correlation of nasopharyngeal carriage and AOM using several approaches. The first approach was to examine pairs of isolates from middle ear fluid (MEF) and the nasopharynx obtained simultaneously from patients with AOM. During the last 4 years our group studied a total of 357 such pairs (R Dagan, M.D., unpublished data, 1999). Of the 357 middle ear isolates 244 (69%) were penicillin-nonsusceptible. In 323 of 357 (90%) of the cases identical antibiotic serotypes were isolated from both samples, and in 320 of 357 (90%) identical susceptibility patterns were observed. The main serotypes were (by descending order) 23F, 14, 19F, 19A, 6B and 9V (Fig. 1). Fig. 1: Serotype distribution and susceptibility of acute otitis media pneumococcal isolates and the correlation between middle ear fluid and nasopharyngeal isolates during acute otitis media in regard to serotypes and penicillin susceptibility. Pen-s, penicillin-susceptible strains;Pen-ns, penicillin-nonsusceptible strains.Another way to examine the predictability of susceptibility of causative agents of AOM by the patterns of nasopharyngeal isolates is to compare the patterns between nasopharyngeal isolates in healthy children and those isolated from MEF in children of the same age with AOM. We have been studying this issue in an ongoing research project conducted in Beer-Sheva. The results of our interim analysis are show in Figure 2. The nasopharyngeal isolates were obtained from healthy children attending Maternal Children Health Centers for vaccination and day-care centers attendees, and the MEF isolates were obtained from children from the same area with AOM visiting pediatric clinics and the Pediatric Emergency Room at the Soroka University Medical Center. Resistance in general and penicillin resistance in particular peaked at ages 12 to 17 months but was frequent among S. pneumoniae isolates in all ages. A clear correlation between the prevalence of penicillin-resistant isolates and isolates resistant to ≥1 antibiotic drugs among nasopharyngeal isolates from healthy children and the prevalence in isolates from MEF of children with AOM was found. The somewhat higher resistance rate among the MEF isolates is most probably due to the more frequent selection of treatment failures among these patients in whom tympanocentesis is performed. Fig. 2: Relation of antibiotic resistance between nasopharyngeal isolates from healthy infants and young children and resistance among middle ear fluid pneumococcal isolates obtained during acute otitis media episodes, by age.We therefore can conclude that at least for AOM, carriage of resistant S. pneumoniae in the community correlates with disease caused by these resistant organisms. This is important because it suggests that reduction of carriage of S. pneumoniae in general, and antibiotic-resistant S. pneumoniae in particular, not only may prevent AOM caused by these organisms in the individuals but also can reduce such a disease among their contacts. Administration of antibiotics selects for carriage of resistant S. pneumoniae, which in turn predisposes to AOM with resistant pneumococci. 3, 17, 24–39 It is recognized worldwide that most of the resistance among pneumococci is found among the serotypes most likely to cause disease in children. 40–44 This was clearly demonstrated in a recent study in southern Israel, in which a total of >800 MEF pneumococcal isolates obtained from patients with AOM were examined. 37 The most common serotypes causing diseases (23F, 19F, 14, 19A, 9V, 6A and 6B) had higher drug resistance and multiple drug resistance rates than the isolates less frequently associated with diseases (Fig. 3). When the five most commonly resistant serotypes (i.e. 6B, 9V, 14, 19F and 23F) were examined, a striking association was found between their presence in the MEF and recent antibiotic treatment (Fig. 4A). Similarly these serotypes were present more often in the MEF of children with recurrent AOM (more than three cases in last year) than in those with less frequently occurring AOM (Fig. 4B). Fig. 3: Serotype distribution and antibiotic resistance patterns of the various serotypes of S. pneumoniae causing acute otitis media in southern Israel (all isolates were middle ear fluid isolates). A, serotypes distribution of the most common serotypes;B, proportion of S. pneumoniae isolates that were susceptible to ≥1 antibiotic drug(s) and multiresistant (resistant to ≥3 antibiotic classes) among middle ear fluid isolates.Fig. 4: The relation between S. pneumoniae serotypes 6B, 9V, 14, 19F and 23F and the timing of previous antibiotic treatment (A) and number of occurrences of acute otitis media during 1999 (B) in 837 children with pneumococcal acute otitis media in southern Israel.Thus frequent antibiotic treatment selects for AOM caused by antibiotic-resistant S. pneumoniae, which exhibit a limited repertoire of serotypes. The relatively limited number of serotypes that express resistance and the fact that most are also the ones that cause frequent disease has led to the fact that the candidate pneumococcal conjugate vaccines have better coverage against antibiotic-resistant pneumococcal strains than against antibiotic-susceptible ones. We recently examined the vaccine coverage of 821 pneumococcal MEF isolates from children with AOM in southern Israel. The 7-valent vaccine (serotypes 4, 6B, 9V, 14, 19F and 23F), 9-valent vaccine (same as 7-valent with the addition of serotypes 1 and 5) and 11-valent vaccines (same as 9-valent with the addition of serotypes 3 and 7F) covered in total 24, 30 and 45%, respectively, of isolates susceptible to all antibiotics but 69, 73 and 73%, respectively, of those resistant to ≥1 drug and 87, 87 and 88%, respectively, of the multiply resistant isolates (Table 1). Furthermore even among penicillin-nonsusceptible S. pneumoniae isolates, all 3 candidate vaccines had higher coverage when penicillin MIC was >1.0 μg/ml (defined as highly penicillin-resistant S. pneumoniae). In fact all candidate vaccines covered >90% of all highly penicillin-resistant S. pneumoniae. Table 1: Coverage by valent conjugate vaccines of pneumococcal middle ear fluid isolates (n = 821) during acute otitis media episode by antibiotic susceptibility patternsIf administration of the conjugate pneumococcal vaccines results in reduction not only of disease but also of pneumococcal carriage, immunization could be expected to reduce both disease and transmission of S. pneumoniae in general and of antibiotic-resistant S. pneumoniae in particular. CONJUGATE PNEUMOCOCCAL VACCINES AND THEIR POTENTIAL EFFECT ON NASOPHARYNGEAL CARRIAGE AND SPREAD OF ANTIBIOTIC-RESISTANT PNEUMOCOCCUS Part of the dramatic success of the recently introduced H. influenzae type b conjugate vaccines was based on its ability to reduce carriage and spread, thus causing a clear herd immunity effect. 45–49 One would hope that the pneumococcal conjugate vaccines could exert the same effect. The first report to show that conjugate pneumococcal vaccines might reduce the carriage of S. pneumoniae in general and that of resistant S. pneumoniae in particular was published by our group in 1996. 50 In this study we examined the effect of a 7-valent pneumococcal conjugate vaccine, serotypes 4, 6B, 9V, 14, 18C, 19F and 23F conjugated to the outer membrane protein complex of Neisseria meningitis group B, on carriage of S. pneumoniae and resistant S. pneumoniae belonging to the serotypes included in the vaccine. Children ages 12 to 18 months were randomized to receive one dose of a conjugate heptavalent pneumococcal vaccine, two doses of the same vaccine, or one dose of a 23-valent native polysaccharide vaccine. Before immunization pneumococcal serotypes included in the conjugate vaccine were isolated from 24% of the children, and an antibiotic-resistant pneumococcus was isolated from 22%. The vaccines had no effect on carriage of non-vaccine-type pneumococci. In contrast there was a significant reduction in carriage of vaccine-type pneumococci 3 months after one dose and 1 month after a second dose of conjugate vaccine (from 25% to 9 and 7%, respectively;P < 0.001). No effect was seen after vaccination with the nonconjugated vaccine. One year after immunization, carriage of antibiotic-resistant vaccine-type pneumococci in children receiving conjugate vaccine was still lower than that in children receiving the nonconjugated vaccine (4%vs. 14%, P = 0.042). A second report was published by our group comparing the effect of tetravalent (serotypes 6B, 14, 19F and 13F) vaccine in which the polysaccharides were conjugated to diphtheria toxoid (Pnc-D) or tetanus toxoid (Pnc-T) to the effect of placebo when administered to infants in a randomized double blind study. 51 The vaccines or placebo were injected at 2, 4 and 6 months of age. At 12 months of age a native (nonconjugated) polysaccharide vaccine was administered as a booster. Nasopharyngeal cultures were obtained at 2, 4, 6, 7, 12 and 13 months of age. In general carriage of all pneumococcal serotypes (vaccine- and non-vaccine-related) was low at age 2 months and increased with age. However, for the vaccine-related serotypes (6A, 6B, 14, 19F and 23F), carriage did not increase with age in Pnc-D or Pnc-T recipients. Of all cultures obtained after the full primary series, 7 of 72 (10%), 3 of 62 (5%) and 19 of 70 (27%) were positive for the vaccine-related pneumococcal serotypes among the Pnc-D, Pnc-T and placebo recipients, respectively (P = 0.001 for Pnc-D vs. placebo;P = 0.014 for Pnc-T vs. placebo). Most of the antibiotic-resistant isolates from the nasopharynx belonged to the vaccine-related serotypes. These studies showed clearly that conjugate pneumococcal vaccines could reduce the carriage of S. pneumoniae and resistant S. pneumoniae of the serotypes included in the vaccines. In a letter to the editor Obaro et al. 52 raised an important issue regarding the effect of conjugate pneumococcal vaccines on carriage. The research group in The Gambia studied the effect of a pentavalent pneumococcal vaccine, serotypes 6B, 14, 18C, 19F and 23F conjugated to CRM197 (a nontoxic mutant of diphtheria toxin), on S. pneumoniae carriage in infants. In The Gambia simultaneous carriage of multiple serotypes was common. Under these circumstances the investigators observed two opposite effects of the vaccine on carriage: (1) the serotypes included in the vaccine were commonly found in children age 21 months who had not received any pneumococcal vaccine previously; the carriage rate was 83 to 90%. In contrast children who had received the pentavalent conjugate vaccine at 2, 3 and 4 months of age carried the vaccine-related serotypes significantly less frequently (50%;P < 0.005 vs. control); (2) contrary to the effect observed with the serotypes included in the vaccine, the other pneumococcal serotypes were carried significantly more often by the vaccine recipients than by the controls (77%vs. 43%;P < 0.005). This preliminary observation on the promotion of carriage of S. pneumoniae serotype not included in the vaccine by conjugate vaccine was provocative and raised several questions and concerns. Shortly after the observation from The Gambia, reduction of the serotypes included in the conjugate vaccine and replacement by other serotypes after immunization was confirmed by South African researchers, who immunized infants at ages 6, 10 and 14 weeks with a 9-valent (serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23F) pneumococcal vaccine conjugated to CRM197. 53 Our group undertook an extensive study to determine whether carriage in toddlers attending day-care centers, which are probably the main location associated with amplification and spread of resistant S. pneumoniae in the community, is affected by immunization. In a double blind prospective randomized study involving 264 toddlers during their second and third years of life, we immunized 132 toddlers with the same 9-valent pneumococcal vaccine conjugated to CRM197. 54 A nasopharyngeal culture was obtained before and once monthly after immunization for 1 year and bimonthly during the second year. At the recent completion of the study a total of 4237 cultures was obtained and 2829 of them (67%) were positive. As expected the majority of the antibiotic resistance was confined to the serotypes included in the vaccine. When the 9 serotypes included in the vaccine (i.e. 1, 4, 5, 6B, 9V, 14, 18C, 19F and 23), in addition to serotype 6A (which shows cross-protection by serotype 6B), were examined for antibiotic resistance, 72% were resistant to at least 1 antibiotic, 46% to ≥2 antibiotic classes and 15% to ≥3 antibiotic classes (defined as multiply resistant strains). The respective figures for the serotypes not included in the vaccine were 38, 8 and 4%, respectively (P < 0.001) (Fig. 5). Fig. 5: Antibiotic resistance patterns among 9-valent vaccine-associated (n = 1249) and nonvaccine serotype (n = 1580) carried by children attending day-care centers.An interim analysis to evaluate the effect of the vaccine and carriage was conducted after 18 months of the study by a person not involved in the study, thus permitting its continuation as a double blind study. 54, 55 This study revealed several important points. 1. The conjugate vaccine had a marked effect on the carriage of pneumococci of the serotypes included in the vaccine when compared with the controls (Fig. 6A). Fig. 6: Results of interim analysis of a study examining the effect of a conjugate 9-valent pneumococcal vaccine (Pnc-CRM-9) on pneumococcal carriage in day-care center attendees. Carriage of vaccine types 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F (A) and of other types (6A excluded) (B) during the first 18 months of follow-up. Between 66 and 132 cultures were performed at each point of the graph.2. As observed in The Gambia and in South Africa, an increase in carriage of S. pneumoniae belonging to the serotypes not in the vaccine could be clearly observed (Fig. 6B). 3. The carriage of both vaccine type and non-vaccine type pneumococci was age-dependent (Fig. 7). In the control group a reduction of the carriage of vaccine-type pneumococci with time (and thus with age) could be clearly observed and, at the same time, a parallel increase in non-vaccine-type pneumococci with time was observed. This phenomenon could be explained by the “maturation” phenomenon that is observed in infants and toddlers with regard to immune response to polysaccharide antigens and concords with the results of previous studies performed in the community that document reduction of pneumococcal carriage with age and replacement of the “infantile serotypes” (mainly 6A, 6B, 9V, 14, 19F and 23F) by other serotypes. Fig. 7: Effect of a conjugate 9-valent pneumococcal vaccine (PncCRM-9) on pneumococcal carriage of the vaccine type, serotype 6A, total pneumococcal carriage and antibiotic-resistant pneumococci, by age at vaccination. Results of the interim analysis of a study examining an effect of the vaccine on carriage of S. pneumoniae in day-care centers attendees (after 18 months of follow-up). VT, serotypes included in the vaccine;6A, S. pneumoniae serotype 6A;PncCRM, carriage of any S. pneumoniae;R ≥1 drug, S. pneumoniae resistant to at least one antibiotic class;Pen-R, S. pneumoniae-nonsusceptible; MDR, multidrug penicillin-resistant S. pneumoniae.4. As a result of the “maturation” phenomenon of the immune system, one expects that the effect of pneumococcal conjugate vaccines would be most apparent in the young age group. Our results were indeed consistent with the expectation (Fig. 7). The main effect of the vaccine was found among children vaccinated during the second year of life, whereas the difference between vaccine and control recipients for those vaccinated during the third year of life (and thus followed by the fourth and fifth year of life) was at best minimal. THEORETICAL CONSIDERATIONS The conjugate vaccines have a dramatic effect on carriage of S. pneumoniae and antibiotic S. pneumoniae in infants and toddlers. What is the significance of the effect observed thus far of conjugate vaccines on pneumococcal carriage? It is certain that is 1. The reduction of carriage of S. pneumoniae and resistant S. pneumoniae of the vaccine types suggests a potential for marked herd immunity permitting reduction of spread of the serotypes most commonly associated with disease and antibiotic resistance in the 2. The mucosal effect of the vaccine by the reduction of nasopharyngeal carriage suggests that children may also be protected from and thus one to be and to hope that the high against invasive pneumococcal infections showed recently with one conjugate vaccine not only may be confined to invasive infections but also may show in the against the more common mucosal infections. preliminary results from the a significant reduction in the occurrence of AOM. 3. The effect of the vaccines on carriage may in the to reduction of carriage as an important of if no studies are after of pneumococcal conjugate vaccines to the immunization However, have been raised which be in the 1. the increase in the carriage of the serotypes not included in the vaccine a In other will it be associated with increased pneumococcal disease with these 2. resistance spread to the serotypes not included in the vaccine that will be carried more 3. In because AOM is a bacterial complication of an often by viral could the reduction of nasopharyngeal vaccine-type pneumococci to a to AOM than a in the of those questions are important and be in the However, it is to that the replacement of carriage will not be associated with a replacement in at least to the same The serotypes included in the vaccines and the ones most resistant to antibiotics are also most often less in children and can therefore be carried for This phenomenon them to be to antibiotics for a of time and thus to more It can be that the serotypes not included in the vaccine, which are also more and therefore are carried for a of time, will have less to However, antibiotic resistance also among serotypes not included in the vaccine, in serotypes such as 6A and 19A, which are also important pathogens causing we of cross-protection between 6B and 6A, such cross-protection may not occur between 19F and still with regard to the effect of the conjugated vaccines on the pneumococcal nasopharyngeal and it is that in the serotypes that are antibiotic-resistant and cause disease will be to the conjugate vaccine. In the candidate conjugate pneumococcal vaccines have potential in reducing both disease caused by S. pneumoniae and transmission of S. pneumoniae in general and antibiotic-resistant pneumococci in particular. A is to whether our are and the potential effect of the vaccines on nasopharyngeal not to the rate of carriage in children attending carriage of nonvaccine serotypes among vaccinated children, but the carriage of vaccine serotypes in control children. this due to a of nonvaccine carriage affected by the It may be affected in the vaccine group. We have to show that children are vaccine serotypes and nonvaccine serotypes. children are still vaccine serotypes. This may be a effect. this be a herd In a study in children attending a herd effect was but it may not be the study that compared polysaccharide vaccine with conjugate vaccine carried in children attending The study compared children from all children were in and were We were to show a difference in carriage between children who and those who did During the second year of life, if the was at the rate of pneumococcal carriage and carriage of resistant strains was observed. In of to 6 children, a higher rate of carriage was but there was no increase in carriage of resistant In children attending day-care centers no if the number of children were 6 to or the number of children pneumococci increased but an double increase in carriage of resistant strains was observed.