Tamara Pilishvili

Sustained Reductions in Invasive Pneumococcal Disease in the Era of Conjugate Vaccine

BACKGROUND Changes in invasive pneumococcal disease (IPD) incidence were evaluated after 7 years of 7-valent pneumococcal conjugate vaccine (PCV7) use in US children. METHODS Laboratory-confirmed IPD cases were identified during 1998-2007 by 8 active population-based surveillance sites. We compared overall, age group-specific, syndrome-specific, and serotype group-specific IPD incidence in 2007 with that in 1998-1999 (before PCV7) and assessed potential serotype coverage of new conjugate vaccine formulations. RESULTS Overall and PCV7-type IPD incidence declined by 45% (from 24.4 to 13.5 cases per 100,000 population) and 94% (from 15.5 to 1.0 cases per 100,000 population), respectively (P< .01 all age groups). The incidence of IPD caused by serotype 19A and other non-PCV7 types increased from 0.8 to 2.7 cases per 100,000 population and from 6.1 to 7.9 cases per 100,000 population, respectively (P< .01 for all age groups). The rates of meningitis and invasive pneumonia caused by non-PCV7 types increased for all age groups (P< .05), whereas the rates of primary bacteremia caused by these serotypes did not change. In 2006-2007, PCV7 types caused 2% of IPD cases, and the 6 additional serotypes included in an investigational 13-valent conjugate vaccine caused 63% of IPD cases among children <5 years-old. CONCLUSIONS Dramatic reductions in IPD after PCV7 introduction in the United States remain evident 7 years later. IPD rates caused by serotype 19A and other non-PCV7 types have increased but remain low relative to decreases in PCV7-type IPD.

Population Snapshot of Emergent Streptococcus pneumoniae Serotype 19A in the United States, 2005

BACKGROUND Serotype 19A invasive pneumococcal disease (IPD) increased annually in the United States after the introduction of the 7-valent conjugate vaccine (PCV7). To understand this increase, we characterized serotype 19A isolates recovered during 2005. METHODS IPD cases during 1998-2005 were identified through population-based surveillance. We performed susceptibility testing and multilocus sequence typing on 528 (95%) of 554 serotype 19A isolates reported in 2005. RESULTS The incidence of IPD due to serotype 19A increased from 0.8 to 2.5 cases per 100,000 population between 1998 and 2005 (P < .05), whereas the overall incidence of IPD decreased from 24.4 to 13.8 cases per 100,000 population (P < .05). Simultaneously, the incidence of IPD due to penicillin-resistant 19A isolates increased from 6.7% to 35% (P < .0001). Of 151 penicillin-resistant 19A isolates, 111 (73.5%) belonged to the rapidly emerging clonal complex 320, which is related to multidrug-resistant Taiwan(19F)-14. The remaining penicillin-resistant strains were highly related to other clones of PCV7 serotypes or to isolates within major 19A clonal complex 199 (CC199). In 1999, only CC199 and 3 minor clones were apparent among serotype 19A isolates. During 2005, 11 multiple-isolate clonal sets were detected, including capsular switch variants of a serotype 4 clone. CONCLUSIONS PCV7 ineffectiveness against serotype 19A, antibiotic resistance, clonal expansion and emergence, and capsular switching have contributed to the genetic diversity of 19A and to its emergence as the predominant invasive pneumococcal serotype in the United States.

Postvaccine Genetic Structure of Streptococcus pneumoniae Serotype 19A from Children in the United States

BACKGROUND The introduction of the 7-valent conjugate pneumococcal vaccine (PCV7) in children may result in serotype replacement. We estimated the rate of increase of invasive pneumococcal disease (IPD) caused by serotype 19A in children <5 years old and determined the genetic composition of these isolates. METHODS Cases of IPD between July 1999 and June 2004 were identified through the Active Bacterial Core Surveillance. Serotype 19A isolates obtained from children <5 years old between January 2003 and June 2004 were characterized by serotyping, antibiotic susceptibility testing, and pulsed-field gel electrophoresis (PFGE). Select isolates representing homologous PFGE clusters were subjected to multilocus sequence typing, and eBURST was used to delineate clonal groups. RESULTS Between July 1999 and June 2004, the overall rate of IPD decreased from 23.3 to 13.1 cases/100,000 population (P<.00001). In children <5 years old, the rate decreased from 88.7 to 22.4 cases/100,000 population (P<.00001), whereas the rate in persons > or =5 years old decreased from 18.4 to 12.4 cases/100,000 population (P<.0001). The rate of serotype 19A IPD in children <5 years old increased significantly from 2.6 cases/100,000 population in 1999-2000 to 6.5 cases/100,000 population in 2003-2004; this was accompanied by significant increases in penicillin nonsusceptibility (P=.008) and multidrug resistance (P=.002) among serotype 19A isolates. As was observed during the pre-PCV7 era, clonal complex (CC) 199 predominated within serotype 19A, representing approximately 70% of invasive serotype 19A isolates from children <5 years old during 2003-2004. New serotype 19A genotypes were observed during 2003-2004, including 6 CCs that were not found among pneumococcal serotype 19A isolates during surveillance in 1999. CONCLUSION Serotype 19A is, at present, the most important cause of IPD by replacement serotypes, and it is increasingly drug resistant. CC199 is the predominant CC among type 19A serotypes in children <5 years old. Our data suggest that some of the increase in rates of infection with serotype 19A may be due to serotype switching within certain vaccine type strains.

Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years or older - United States, 2014.

In October 2015, the Advisory Committee on Immunization Practices (ACIP)* approved the Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States, 2016. This schedule provides a summary of ACIP recommendations for the use of vaccines routinely recommended for adults aged 19 years or older in two figures, footnotes for each vaccine, and a table that describes primary contraindications and precautions for commonly used vaccines for adults. Although the figures in the adult immunization schedule illustrate recommended vaccinations that begin at age 19 years, the footnotes contain information on vaccines that are recommended for adults that may begin at age younger than age 19 years. The footnotes also contain vaccine dosing, intervals between doses, and other important information and should be read with the figures.

Differential Effects of Pneumococcal Vaccines against Serotypes 6A and 6C

BACKGROUND Because classic pneumococcal serotyping methods cannot distinguish between serotypes 6A and 6C, the effects of pneumococcal vaccines against serotype 6C are unknown. Pneumococcal vaccines contain serotype 6B but not serotypes 6A and 6C. METHODS We used a phagocytic killing assay to estimate the immunogenicity of the 7-valent conjugate vaccine (PCV7) in children and the 23-valent polysaccharide vaccine (PPV23) in adults against serotypes 6A and 6C. We evaluated trends in invasive pneumococcal disease (IPD) caused by serotypes 6A and 6C in the United States, using active surveillance. RESULTS Serum specimens from PCV7-immunized children had median opsonization indices of 150 and < 20 for serotypes 6A and 6C, respectively. Similarly, only 52% of adults (25 of 48) vaccinated with PPV23 showed opsonic indices of > 20 against serotype 6C. During 1999--2006, the incidence of serotype 6A IPD decreased by 91% (from 4.9 to 0.46 cases per 100,000 persons; P < .05) among individuals aged < 5 years and by 58% (from 0.86 to 0.36 cases per 100,000 persons; P < .05) among those aged > or = 5 years. Although the incidence of 6C IPD showed no consistent trend (range, 0-0.6 cases per 100,000 persons) among individuals aged < 5 years, it increased from 0.25 to 0.62 cases per 100,000 persons (P < .05) among those aged > or = 5 years. CONCLUSIONS PCV7 introduction has led to reductions in serotype 6A IPD but not serotype 6C IPD in the United States.

PCR-Based Quantitation and Clonal Diversity of the Current Prevalent Invasive Serogroup 6 Pneumococcal Serotype, 6C, in the United States in 1999 and 2006 to 2007

Following introduction of the 7-valent pneumococcal conjugate vaccine to the United States, rates of invasive pneumococcal disease (IPD) caused by serotype 6A declined among all age groups, while rates of IPD caused by newly identified serotype 6C increased slightly among persons 5 years of age and older. Conventionally serotyped 6A isolates (CS6As) from active population-based surveillance during 1999 and 2006 to 2007 were classified as serotypes 6A and 6C by an expedient and highly accurate serotype 6C-specific PCR assay developed during this study. PCR testing of 636 year 1999, 2006, and 2007 CS6As revealed 6C proportions of 35/214 (16.4%), 141/218 (64.7%), and 141/204 (69.1%), respectively. These results agreed with those from a previously devised monoclonal antibody-based serotyping system (346 CS6As compared). Type 6C IPD incidence significantly increased during 2006 and 2007 compared to during 1999 (0.57 to 0.58 cases per 100,000 and 0.22 cases per 100,000, respectively; 164% increase from 1999 to 2007 [95% confidence interval, 87 to 270%]), while rates of IPD due to types 6A and 6B markedly decreased. In 2007, 31.2% of 6C isolates were not susceptible to penicillin. Serotype 6C is now the predominant serotype associated with serogroup 6 IPD in the United States and is often penicillin nonsusceptible. We performed multilocus sequence typing (MLST) on a limited sampling of 6C isolates with different antimicrobial susceptibility profiles. MLST of 42 6C isolates revealed 12 genotypes distributed among six distinct genetic groups. Fifteen 6C isolates shared one of four different MLST types with 6C-negative CS6As. MLST results suggest 6C strains arose from independent recombination events involving only serotype 6A and 6C parental strains.

Intervals Between PCV13 and PPSV23 Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP).

Two pneumococcal vaccines are currently licensed for use in the United States: the 13-valent pneumococcal conjugate vaccine (PCV13 [Prevnar 13, Wyeth Pharmaceuticals, Inc., a subsidiary of Pfizer Inc.]) and the 23-valent pneumococcal polysaccharide vaccine (PPSV23 [Pneumovax 23, Merck and Co., Inc.]). The Advisory Committee on Immunization Practices (ACIP) currently recommends that a dose of PCV13 be followed by a dose of PPSV23 in all adults aged ≥65 years who have not previously received pneumococcal vaccine and in persons aged ≥2 years who are at high risk for pneumococcal disease because of underlying medical conditions (Table) (1-4). The recommended intervals between PCV13 and PPSV23 given in series differ by age and risk group and the order in which the two vaccines are given (1-4).

Comparison of an Opsonophagocytic Assay and IgG ELISA to Assess Responses to Pneumococcal Polysaccharide and Pneumococcal Conjugate Vaccines in Children and Young Adults with Sickle Cell Disease

Children with sickle cell disease were immunized with either 2 doses of 7-valent pneumococcal conjugate vaccine followed by 1 dose of 23-valent pneumococcal polysaccharide vaccine or a single dose of 23-valent vaccine. Functional antibodies to 7 vaccine serotypes were measured by a flow cytometric opsonophagocytic assay (OPA) and compared with IgG anticapsular polysaccharide antibody concentrations measured by ELISA. Moderate correlations were found between OPA and ELISA antibody titers for all 7 serotypes (r values, 0.41-0.70; P<.001 for all serotypes). After immunization with 23-valent vaccine, geometric mean antibody titers by OPA were significantly higher in the combined schedule group for 5 of 7 vaccine serotypes but were significantly higher for only 2 of 7 serotypes as measured by ELISA. The ability of OPA to show a greater differential response to the 2 immunization schedules used in this study suggests that it may be useful in the evaluation of immunization regimens involving pneumococcal conjugate vaccines.

Pneumococcal disease prevention among adults: Strategies for the use of pneumococcal vaccines

Use of the pneumococcal conjugate vaccines among children in the US since 2000 has dramatically reduced pneumococcal disease burden among adults. Significant vaccine-preventable morbidity and mortality from pneumococcal infections still remains, especially among older adults. The US Advisory Committee on Immunization Practices (ACIP) has recently recommended the routine use of both pneumococcal conjugate (PCV13) and polysaccharide vaccines (PPSV23) for adults ≥65 years. These recommendations were based on the remaining burden of illness among adults and the importance of non-bacteremic pneumonia prevention in light of new evidence confirming the efficacy of PCV13 to prevent pneumococcal pneumonia among older adults. This paper reviews the evidence that led the ACIP to make recommendations for PCV13 and PPSV23 use among adults, and highlights potential gaps to be addressed by future studies to inform adult vaccination policy. The changing epidemiology of invasive pneumococcal disease and pneumonia should be closely monitored to evaluate the effectiveness and continued utility of the current vaccination strategy, and to identify future directions for pneumococcal disease prevention among older adults.

Use of surveillance data to estimate the effectiveness of the 7-valent conjugate pneumococcal vaccine in children less than 5 years of age over a 9 year period.

BACKGROUND Case-control studies evaluating post-licensure effectiveness of conjugate vaccines can be laborious and costly. We applied an indirect cohort method to evaluate the effectiveness of seven-valent pneumococcal conjugate vaccine (PCV7) against invasive pneumococcal disease (IPD) and compared the results to the effectiveness measured using a standard case-control study conducted during the same time period. METHODS IPD cases among children 2-59 months old were identified through the Active Bacterial Core surveillance system during 2001-2009. We used logistic regression to calculate the odds ratio of vaccination (versus no vaccination) among cases (PCV7-type IPD cases) and non-cases (non-PCV7-type IPD cases), controlling for the presence of underlying conditions. Vaccine effectiveness (VE) was calculated as one minus the adjusted odds ratio. RESULTS Among 4225 IPD cases reported during 2001-2009, 2680 (63%) had serotype information and vaccine history. Effectiveness of ≥ 1 dose of PCV7 against PCV7-types was 88% (95% confidence interval (CI) 78-94%) among children with comorbid conditions and 97% (95% CI 92-98%) among healthy children. Among healthy children, VE was higher in 2001-2003 (97%, 95% CI 95-98%) compared to 2004-2009 (81%, 95% CI 64-90%). The annual estimates of VE in 2004-2009 showed great variability and wide confidence intervals due to the small number of PCV7-type cases. CONCLUSIONS An indirect cohort design using IPD surveillance data confirms the findings of the case-control study and, therefore, appears suitable for estimating PCV7 effectiveness. This method would be most useful shortly after vaccine introduction, and less useful in a setting of very high vaccine coverage and fewer vaccine-type cases.