La vacunación antineumocócica en Cuba. Retos y desafíos

El desarrollo de la Medicina ha reflejado la necesidad de prevenir enfermedades trasmisibles a través de vacunas. Después de la descripción del papel que juega el neumococo en la génesis de enfermedades, se inició una carrera destinada a prevenirlas. En el presente siglo se licenció la primera vacuna conjugada contra el Streptococcus pneumoniae para ser utilizada en niños. En Cuba, a pesar de los esfuerzos realizados, no se ha introducido la vacuna antineumocócica y desde hace más de una década se trabaja en un candidato vacunal conjugado heptavalente, actualmente en evaluación clínica avanzada. En este trabajo se hacen consideraciones al respecto.

Medicine development has shown the need of preventing transmissible diseases by means of Vaccines. After a description of the role of pneumococcus in the origin of diseases, a career towards preventing them was started. In the current century, the first conjugated vaccine was certified against Streptococcus pneumonia to be used in children. In Cuba, in spite of the efforts, the anti-pneumococcal vaccine has not been introduced and for more of a decade time scientists have been working in a heptavalent conjugated vaccine, currently in an advanced clinical evaluation. In this work, considerations in this regard are made.

Impact of IgM Antibodies on Cross-Protection against Pneumococcal Serogroups 6 and 19 after Immunization with 7-Valent Pneumococcal Conjugate Vaccine in Children.

Although it is well known that pneumococcal conjugate vaccines provide cross-protection against some vaccine-related serotypes, these mechanisms are still unclear. This study was performed to investigate the role of cross-protective IgM antibodies against vaccine-related serotypes 6A, 6C, and 19A induced in children aged 12-23 months after immunization with 7-valent pneumococcal conjugate vaccine (PCV7). We obtained serum samples from 18 Korean children aged 12-23 months after a PCV7 booster immunization. The serum IgG and IgM concentrations of serotypes 6B and 19F were measured by enzyme-linked immunosorbent assay (ELISA) in serum. The opsonic indices (OIs) against vaccine serotypes 6B and 19F and vaccine-related serotypes 6A, 6C, and 19A were determined by an opsonophagocytic killing assay (OPA) in IgM-depleted and control serum. Both IgG and IgM antibodies in ELISA and opsonic indices in OPA against serotypes 6B and 19F were demonstrated in the immune serum. IgM depletion decreased the OIs against vaccine serotypes 6B (geometric means of OIs (GMIs) of 3,009 vs. 1,396, 38% reduction) and 19F (1,117 vs. 750, 36% reduction). In addition, IgM depletion markedly decreased the OIs against vaccine-related serotypes 6A (GMIs of 961 vs. 329, 70% reduction), 6C (432 vs. 185, 72% reduction), and 19A (301 vs. 166, 58% reduction). The booster immunization PCV7 induced protective antibodies in the form of both IgG and IgM isotypes. IgM antibodies contributed to eliciting cross-protection against vaccine-related serotypes as well as against vaccine serotypes.

Impact of IgM Antibodies on Cross-Protection against Pneumococcal Serogroups 6 and 19 after Immunization with 7-Valent Pneumococcal Conjugate Vaccine in Children

Although it is well known that pneumococcal conjugate vaccines provide cross-protection against some vaccine-related serotypes, these mechanisms are still unclear. This study was performed to investigate the role of cross-protective IgM antibodies against vaccine-related serotypes 6A, 6C, and 19A induced in children aged 12-23 months after immunization with 7-valent pneumococcal conjugate vaccine (PCV7). We obtained serum samples from 18 Korean children aged 12-23 months after a PCV7 booster immunization. The serum IgG and IgM concentrations of serotypes 6B and 19F were measured by enzyme-linked immunosorbent assay (ELISA) in serum. The opsonic indices (OIs) against vaccine serotypes 6B and 19F and vaccine-related serotypes 6A, 6C, and 19A were determined by an opsonophagocytic killing assay (OPA) in IgM-depleted and control serum. Both IgG and IgM antibodies in ELISA and opsonic indices in OPA against serotypes 6B and 19F were demonstrated in the immune serum. IgM depletion decreased the OIs against vaccine serotypes 6B (geometric means of OIs (GMIs) of 3,009 vs. 1,396, 38% reduction) and 19F (1,117 vs. 750, 36% reduction). In addition, IgM depletion markedly decreased the OIs against vaccine-related serotypes 6A (GMIs of 961 vs. 329, 70% reduction), 6C (432 vs. 185, 72% reduction), and 19A (301 vs. 166, 58% reduction). The booster immunization PCV7 induced protective antibodies in the form of both IgG and IgM isotypes. IgM antibodies contributed to eliciting cross-protection against vaccine-related serotypes as well as against vaccine serotypes.

Pneumonia in Elderly Australians: Reduction in Presumptive Pneumococcal Hospitalizations but No Change in All-Cause Pneumonia Hospitalizations Following 7-Valent Pneumococcal Conjugate Vaccination.

BACKGROUND: Studies evaluating long-term trends in hospitalizations coded as pneumonia following introduction of the 7-valent pneumococcal vaccine (PCV7) are sparse, especially in adults. We extended our previous analysis to 6.5 years after the "3 + 0" PCV7 schedule was introduced in Australia in 2005. METHODS: We estimated vaccine impact on hospitalizations coded as pneumonia (pneumococcal/lobar, other specified, unspecified, and all-cause) using a multivariate negative binomial regression model of monthly hospitalization rates by age group for the pre-PCV7 (July 1998 to December 2004) and post-PCV7 (January 2005 to June 2011) periods, adjusting for vaccination coverage. Changes in pneumonia hospitalizations were measured as incidence rate ratios. RESULTS: A total of 791 000 hospitalizations coded as pneumonia were identified; unspecified causes accounted for >85%. Reductions in pneumonia coded as pneumococcal/lobar were statistically significant in all age groups and greatest in children. Significant reductions in all-cause pneumonia were seen only in children aged <2 years (32%; 95% confidence interval [CI], 28%-37%) and 2-4 years (20%; 95% CI, 14%-27%), with no significant changes in other age groups, including adults aged 65-74 (4%; 95% CI, -3% to 10%), 75-84 (2%; 95% CI, -4% to 9%), and ≥85 years (3%; 95% CI, -3% to 10%). CONCLUSIONS: We could not replicate reductions of 23% in all-cause pneumonia 7-9 years post-PCV7 introduction reported for adults aged ≥85 years in the United States. This could be attributable to vaccine program factors, differing proportions of pneumonia due to pneumococci, or data limitations. More data from countries with differing PCV schedules and from the PCV13 era are needed to inform vaccination strategies for elderly adults.

Immunogenicity and safety of 23-valent pneumococcal polysaccharide vaccine as a booster dose in 12- to 18-month-old children primed with 3 doses of 7-valent pneumococcal conjugate vaccine.

The current study examined the safety and immunogenicity of 23-valent pneumococcal capsular polysaccharide vaccine (Pneumo23(®) [PPV23], Sanofi Pasteur) as a booster dose in 12- to 18-month-old children primed with heptavalent pneumococcal vaccine (PCV7; Prevnar(®), Pfizer). This was a randomized, observer-blinded, 2-arm, controlled, multicenter phase III study performed in Thailand to assess and describe the immunogenicity and safety of PPV23 as a booster dose in children who had received the 3 primary doses of PCV7, the pneumococcal vaccine available during the study period. Children primed with 3 doses of PCV7 were randomized 1:1 to receive a booster immunization with PPV23 or PCV7. Pneumococcal antibody concentrations were measured by enzyme-linked immunosorbent assay and functional antibody levels by multiplex opsonophagocytosis assay on day 30. A total of 339 children were enrolled. Geometric mean serum antibody concentrations against serotypes common to PCV7 and PPV23 (4, 6B, 9V, 14, 18C, 19F, and 23F) increased in both groups but they were higher for serotypes 4, 9V, 18C, and 19F in the PPV23 group. Opsonization indices increased in both groups for all measured serotypes (1, 6B, 14, 19A, and 23F) and were higher for serotypes 6B, 14, and 23F in the PCV7 group and for serotypes 1 and 19A in PPV23 group. Solicited reactions and unsolicited adverse events were similar in the 2 groups and generally mild and transient. No treatment-related serious adverse events were reported. These results confirm that boosting with PPV23 is immunogenic and well tolerated in healthy toddlers primed with PCV7.

[Emergence of invasive pneumococcal disease caused by non-vaccine serotypes in the era of the 7-valent conjugate vaccine]. / Serotipos no vacunales emergentes causantes de enfermedad neumocócica invasora en la era de la vacuna 7-valente.

INTRODUCTION: There has been an increased incidence in invasive pneumococcal disease (IPD) produced by non-vaccine serotype (NVS) of Streptococcus pneumoniae after the introduction of PCV7. Our objective was to describe the epidemiological, clinical and microbiological characteristics of IPD caused by NVS in a tertiary hospital in Madrid. PATIENTS AND METHODS: Retrospective (1998-2004) and prospective (2005-2009) study evaluating IPD caused by NVS in children. The study was divided into three periods: P1 (1998-2001) when PCV7 was not commercialized; P2 (2002-2005) with 40% vaccine coverage among children; and P3 (2006-2009) when the vaccine was added to the Childhood Immunization Schedule in Madrid. RESULTS: We analyzed 155 cases of IPD. One hundred and fifty of these isolates were serotyped (100 were NVS). There was an increase in the prevalence of IPD from P1 (31%) to P2 (54%) and P3 (91%). The most relevant emerging serotypes were 19A, 7F, 1, 5, 3 and 15C. The most significant clinical syndromes produced by some specific serotypes were as follows: lower respiratory tract infection (LRTI) by serotypes 1, 3, 5 and 15C; LRTI, primary bacteremia and meningitis by serotype 19A; and primary bacteremia by serotype 7F (66%). The large majority (83.8%) of NVS were sensitive to penicillin. CONCLUSIONS: There has been an increased prevalence of IPD caused by NVS since the introduction of PCV7. These changes should prompt the introduction of new pneumococcal vaccines, which include most of the NVS, in the childhood immunization calendar to prevent IPD in children.

Prevalence of Heptavalent Vaccine-related Pneumococcal Serotypes in Nasopharyngeal carrier in children under five years old in Shahrekord, Iran by Multiplex-PCR during 2010- 2011.

BACKGROUND: Heptavalent pneumococcal vaccine which included pneumococcal serotypes 4, 6B, 9V,14, 18C, 19F and 23F has been regularly used and is effective on preventing invasive pneumococcal infection. This study aimed to determine vaccine-related serotype distribution in nasopharyngeal carrier and healthy children under five years old. MATERIALS AND METHODS: In this cross-sectional study from September 2010 to September 2011, 363 nasopharyngeal specimens were collected from healthy children in day care centers. In positive cultures of streptococcus pneumoniae (S. pneumonia) distribution, serotypes were detected by Multiplex polymerase chain reaction (PCR). Electrophoresis of PCR products was used for detection of serotypes of S. pneumoniae. RESULTS: The carrier rate of S. pneumoniae was 29.5% with 95% confidence interval as 24.8- 34.5%. Electrophoresis of PCR products for detection of serotypes of S. pneumonia revealed 430, 220, 753, 189, 573, 304, and 384 bp (s) for 4, 6B, 9V, 14, 18C, 19F, and 23F serotypes of S. pneumoniae, respectively. The frequency of 23F, 6B, 19F, and 18C serotypes were 43%, 34%, 18%, and 5% respectively, but other serotypes (4, 9V and 14) were not detected. CONCLUSION: Based on the 30% carrier rate and high prevalence of most of heptavalent pneumococcal conjugate vaccine serotypes in our study, this vaccine should be used for prevention of invasive infection in Iranian children.

Functionality of the pneumococcal antibody response in Down syndrome subjects.

We investigated the anti-polysaccharide antibody responses in subjects with Down syndrome (DS) because DS subjects show decreased peripheral B-lymphocyte numbers in all age groups, and a clinical picture of recurrent respiratory tract infections and increased incidence of autoimmune diseases which is reminiscent of common variable immunodeficiency disorders (CVID)-like disease. We determined titers and opsonophagocytosis in response to conjugated and unconjugated pneumococcal serotypes in 18 DS subjects aged 6-24 years. The results show adequate serotype-specific antibody titers in response to all conjugated and almost all unconjugated serotypes used. Opsonophagocytosis activity as measured against pneumococcal serotypes 9N, 19F and 23F was also found to be intact. We conclude that DS subjects do not have a clear defect in their anti-polysaccharide antibody response.

Cross-reaction of 6B and 19F Specific Antibodies to Serotypes 6A, 6C, and 19A after Immunization with 7-valent Pneumococcal Conjugate Vaccine in Korean Children Aged 12-23 Months / 소아감염

PURPOSE: The cross-protection of 7-valent pneumococcal conjugate vaccine (PCV7) against vaccine-related serotypes has been controversial. We investigated the serological properties of cross-protective antibodies against vaccine-related serotypes 6A, 6C, and 19A induced in young children aged 12-23 months after booster immunization of PCV7. METHODS: IgG and IgM antibody concentrations and opsonic index (OI) against vaccine serotypes 6B and 19F and vaccine-related serotypes 6A, 6C, and 19A were measured by ELISA and opsonophagocytic killing assay (OPA) in 4 selected immunesera. The serological properties and antigenic specificity of protective antibodies were determined by IgM depletion of immunesera, OPA, and competitive OPA against serogroup 6 and 19 pneumococci. RESULTS: Compared to pre-IgM depleted immunesera, OI of IgM-depleted immunesera against 6B and 19F decreased and OI against 6A, 6C, and 19A decreased, too. In competition OPA, free 6B and 19F polysaccharide completely inhibited the immune protection against vaccine-related serotypes 6A, 6C, and 19A as well as vaccine types 6B and 19F. CONCLUSIONS: The booster immunization of PCV7 certainly induced cross-protective antibodies against vaccine-related serotypes 6A, 6C, and 19A with both IgG and IgM isotypes. Furthermore, IgM antibodies are more highly contributed to opsonophagocytic activity against vaccine-related serotypes as well as most of vaccine types than do IgG antibodies. Further studies are needed for the more immunized sera in the children as well as adults.

Immune response to 19A serotype after immunization of 19F containing pneumococcal conjugate vaccine in Korean children aged 12-23 months.

PURPOSE: The purpose of this study was to evaluate the immune response to serotype 19A in children aged 12-23 months after immunization of the 19F containing 7-valent pneumococcal conjugate vaccine (PCV7). METHODS: Blood samples from a total of 45 subjects (age 12-23 months) were included in the study. Subjects were categorized according to immunization status into three groups as follows: 18 subjects with 3 primary doses and 1 booster dose of PCV7 (booster group), 21 subjects with 3 primary doses before 12 months of age (primary group), and 6 subjects with no vaccination history of PCV7 (control group). An ELISA and opsonophagocytic killing assay (OPKA) was done to evaluate the immune responses against serotypes 19F and 19A. RESULTS: According to the ELISA, all subjects had antibody titers ≥0.35 µg/mL for serotypes 19F and 19A in the booster and primary group and 83.0% and 66.7% in the control group, respectively. According to the OPKA, subjects with opsonic activity (≥20) against serotypes 19F and 19A were 100% and 61.1% of the subjects in the booster group and 66.7% and 19.0% in the primary group, respectively. No subjects in the control group had opsonic antibodies against both serotypes. CONCLUSION: In conclusion, in children 12-23 months age who were previously vaccinated with PCV7, a cross-reactive immune response is elicited against serotype 19A after a primary series of 3 doses in a small proportion of subjects, and this response is amplified after booster vaccination.

Nasopharyngeal pneumococcal carriage of children attending day care centers in Korea: comparison between children immunized with 7-valent pneumococcal conjugate vaccine and non-immunized.

To confirm the effect of 7-valent pneumococcal conjugate vaccine (PCV7), pneumococcal nasopharyngeal (NP) carriage was compared between vaccinated (3 + 1 doses PCV7) and non-vaccinated children. Vaccinated subjects were recruited from highly vaccinated regions (≥ 60%), Seoul and Incheon whereas control subjects were recruited from Jeju Island where vaccination rates are low (< 15%). NP swabs were obtained from 400 children aged 18-59 months. Serotype and antibiotic susceptibility was analyzed. Pneumococcal carriage rate was 18.0% (36/200) and 31.5% (63/200) for the vaccinated and control group, respectively. Among those vaccinated, 41.7% (15/36) of the serotypes were vaccine-related type (VRT: 6A, 6C, 19A) with the most common serotype 6C. The next common type was non-typable/non-capsule 30.6% (11/36) followed by non-vaccine type 16.7% (6/36) and vaccine type (VT) serotypes were found in only 11.1% (4/36). In contrast, 52.4% (33/63) of the isolates in the control group were VT. Resistance rates for penicillin and erythromycin were lower in the vaccine group (vaccine vs control; penicillin 45.2% vs 71.4%, erythromycin 74.2% vs 90.5%, P < 0.05). Multi-drug resistance was also lower in vaccinated subjects (vaccine vs control; 45.2% vs 69.8%, P < 0.05). PCV7 reduces carriage in VT which leads to replacement of pneumococci by antibiotic susceptible VRT or non-vaccine type strains.

Nasopharyngeal Pneumococcal Carriage of Children Attending Day Care Centers in Korea: Comparison between Children Immunized with 7-valent Pneumococcal Conjugate Vaccine and Non-immunized

To confirm the effect of 7-valent pneumococcal conjugate vaccine (PCV7), pneumococcal nasopharyngeal (NP) carriage was compared between vaccinated (3 + 1 doses PCV7) and non-vaccinated children. Vaccinated subjects were recruited from highly vaccinated regions (> or = 60%), Seoul and Incheon whereas control subjects were recruited from Jeju Island where vaccination rates are low (< 15%). NP swabs were obtained from 400 children aged 18-59 months. Serotype and antibiotic susceptibility was analyzed. Pneumococcal carriage rate was 18.0% (36/200) and 31.5% (63/200) for the vaccinated and control group, respectively. Among those vaccinated, 41.7% (15/36) of the serotypes were vaccine-related type (VRT: 6A, 6C, 19A) with the most common serotype 6C. The next common type was non-typable/non-capsule 30.6% (11/36) followed by non-vaccine type 16.7% (6/36) and vaccine type (VT) serotypes were found in only 11.1% (4/36). In contrast, 52.4% (33/63) of the isolates in the control group were VT. Resistance rates for penicillin and erythromycin were lower in the vaccine group (vaccine vs control; penicillin 45.2% vs 71.4%, erythromycin 74.2% vs 90.5%, P < 0.05). Multi-drug resistance was also lower in vaccinated subjects (vaccine vs control; 45.2% vs 69.8%, P < 0.05). PCV7 reduces carriage in VT which leads to replacement of pneumococci by antibiotic susceptible VRT or non-vaccine type strains.

Immune response to 19A serotype after immunization of 19F containing pneumococcal conjugate vaccine in Korean children aged 12-23 months / 소아과

PURPOSE: The purpose of this study was to evaluate the immune response to serotype 19A in children aged 12-23 months after immunization of the 19F containing 7-valent pneumococcal conjugate vaccine (PCV7). METHODS: Blood samples from a total of 45 subjects (age 12-23 months) were included in the study. Subjects were categorized according to immunization status into three groups as follows: 18 subjects with 3 primary doses and 1 booster dose of PCV7 (booster group), 21 subjects with 3 primary doses before 12 months of age (primary group), and 6 subjects with no vaccination history of PCV7 (control group). An ELISA and opsonophagocytic killing assay (OPKA) was done to evaluate the immune responses against serotypes 19F and 19A. RESULTS: According to the ELISA, all subjects had antibody titers > or =0.35 microg/mL for serotypes 19F and 19A in the booster and primary group and 83.0% and 66.7% in the control group, respectively. According to the OPKA, subjects with opsonic activity (> or =20) against serotypes 19F and 19A were 100% and 61.1% of the subjects in the booster group and 66.7% and 19.0% in the primary group, respectively. No subjects in the control group had opsonic antibodies against both serotypes. CONCLUSION: In conclusion, in children 12-23 months age who were previously vaccinated with PCV7, a cross-reactive immune response is elicited against serotype 19A after a primary series of 3 doses in a small proportion of subjects, and this response is amplified after booster vaccination.