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1.  Blood stream infection is associated with altered heptavalent pneumococcal conjugate vaccine immune responses in very low birth weight infants 
Objective
Sepsis in older children and adults modifies immune system function. We compared serotype-specific antibody responses to heptavalent pneumococcal conjugate vaccine (PCV7) in very low birth weight infants (<1500g,VLBW) with and without blood stream infection (BSI) during their birth hospitalization.
Patients and Methods
Retrospective analysis of prospectively collected data for the Neonatal Research Network study of PCV7 responses among VLBWs. Infants received PCV7 at 2, 4, and 6 months after birth with blood drawn 4–6 weeks after 3rd dose. Serotype antibodies were compared between infants with or without a history of BSI. Regression models were constructed with birth-weight groups and other confounding factors identified in the primary study.
Results
244 infants completed the vaccine series and had serum antibody available; 82 had BSI. After adjustment, BSI was not associated with reduced odds of serum antibody ≥0.35μg/mL.
Conclusions
BSI was not associated with reduced odds of WHO-defined protective PCV7 responses in VLBWs.
doi:10.1038/jp.2013.5
PMCID: PMC3722279  PMID: 23370608
VLBW; immune response; vaccine; sepsis; blood stream infection
2.  Safety and Immunogenicity of Neonatal Pneumococcal Conjugate Vaccination in Papua New Guinean Children: A Randomised Controlled Trial 
PLoS ONE  2013;8(2):e56698.
Background
Approximately 826,000 children, mostly young infants, die annually from invasive pneumococcal disease. A 6-10-14-week schedule of pneumococcal conjugate vaccine (PCV) is efficacious but neonatal PCV may provide earlier protection and better coverage. We conducted an open randomized controlled trial in Papua New Guinea to compare safety, immunogenicity and priming for memory of 7-valent PCV (PCV7) given in a 0-1-2-month (neonatal) schedule with that of the routine 1-2-3-month (infant) schedule.
Methods
We randomized 318 infants at birth to receive PCV7 in the neonatal or infant schedule or no PCV7. All infants received 23-valent pneumococcal polysaccharide vaccine (PPV) at age 9 months. Serotype-specific serum IgG for PCV7 (VT) serotypes and non-VT serotypes 2, 5 and 7F were measured at birth and 2, 3, 4, 9, 10 and 18 months of age. Primary outcomes were geometric mean concentrations (GMCs) and proportions with concentration ≥0.35 µg/ml of VT serotype-specific pneumococcal IgG at age 2 months and one month post-PPV.
Results
We enrolled 101, 105 and 106 infants, respectively, into neonatal, infant and control groups. Despite high background levels of maternally derived antibody, both PCV7 groups had higher GMCs than controls at age 2 months for serotypes 4 (p<0.001) and 9V (p<0.05) and at age 3 months for all VTs except 6B. GMCs for serotypes 4, 9V, 18C and 19F were significantly higher (p<0.001) at age 2 months in the neonatal (one month post-dose2 PCV7) than in the infant group (one month post-dose1 PCV7). PPV induced significantly higher VT antibody responses in PCV7-primed than unprimed infants, with neonatal and infant groups equivalent. High VT and non-VT antibody concentrations generally persisted to age 18 months.
Conclusions
PCV7 is well-tolerated and immunogenic in PNG neonates and young infants and induces immunologic memory to PPV booster at age 9 months with antibody levels maintained to age 18 months.
Trial Registration
ClinicalTrials.gov NCT00219401NCT00219401
doi:10.1371/journal.pone.0056698
PMCID: PMC3579820  PMID: 23451070
3.  Pneumococcal Conjugate Vaccine Given Shortly After Birth Stimulates Effective Antibody Concentrations and Primes Immunological Memory for Sustained Infant Protection 
Immunization of Kenyan newborns with 7-valent pneumococcal conjugate vaccine is safe and immunogenic. Compared with the Expanded Programme on Immunization schedule beginning at 6 weeks, it stimulates similar antibody concentrations at 18 weeks and induces equal responses to a 9-month booster dose.
Background. In developing countries, newborn immunization with pneumococcal conjugate vaccines (PCVs) could protect young infants who are at high risk of invasive pneumococcal disease (IPD) but might lead to immune tolerance.
Methods. In a randomized trial, young infants received 7-valent PCV at 6, 10, and 14 weeks (Expanded Programme on Immunization [EPI] group) or 0, 10, and 14 weeks (newborn group). Safety was monitored actively at 2–7 days and then passively. Serum samples obtained at birth and 6, 10, 14, 18, 36, and 37 weeks were assayed by enzyme-linked immunosorbent assay for anticapsular immunoglobulin G concentration and avidity. Infants were boosted with either 7-valent PCV or one-fifth dose of pneumococcal polysaccharide vaccine at 36 weeks. Nasopharyngeal swab samples were obtained at 18 and 36 weeks.
Results. Three-hundred neonates and young infants were enrolled. Newborn vaccination was well tolerated. Adverse events occurred equally in each group; none was related to immunization. One infant, immunized at birth, died of unrelated neonatal sepsis. At 18 weeks, protective concentrations (≥0.35 μg/mL) were achieved against each serotype by ≥87% of infants with no significant differences between groups. Geometric mean concentrations were higher in the EPI group for serotypes 4, 9V, 18C, and 19F at 18 weeks and for serotype 4 at 36 weeks. Avidity was greater in the newborn group for serotypes 4, 6B, and 19F at 18 weeks and for serotype 19F at 36 weeks. Booster responses and vaccine-type/nonvaccine-type carriage prevalence did not differ between groups.
Conclusions. PCV was safe, immunogenic, and primed for memory when given at birth. There was no evidence of immune tolerance. Vaccination beginning at birth offers an alternative to control IPD in vulnerable young infants.
doi:10.1093/cid/cir444
PMCID: PMC3166350  PMID: 21865175
4.  Serotype-Specific Changes in Invasive Pneumococcal Disease after Pneumococcal Conjugate Vaccine Introduction: A Pooled Analysis of Multiple Surveillance Sites 
PLoS Medicine  2013;10(9):e1001517.
In a pooled analysis of data collected from invasive pneumococcal disease surveillance databases, Daniel Feikin and colleagues examine serotype replacement after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs.
Please see later in the article for the Editors' Summary
Background
Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction.
Methods and Findings
Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥2 years before and ≥1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0·55, 95% CI 0·46–0·65) and remained relatively stable through year 7 (RR 0·49, 95% CI 0·35–0·68). Point estimates for VT IPD decreased annually through year 7 (RR 0·03, 95% CI 0·01–0·10), while NVT IPD increased (year 7 RR 2·81, 95% CI 2·12–3·71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18–49 year-olds [RR 0·52, 95% CI 0·29–0·91], 50–64 year-olds [RR 0·84, 95% CI 0·77–0·93], and ≥65 year-olds [RR 0·74, 95% CI 0·58–0·95]).
Conclusions
Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude. These findings may not represent the experience in low-income countries or the effects after introduction of higher valency PCVs. High-quality, population-based surveillance of serotype-specific IPD rates is needed to monitor vaccine impact as more countries, including low-income countries, introduce PCVs and as higher valency PCVs are used.
Please see later in the article for the Editors' Summary
Editors’ Summary
Background
Pneumococcal disease–a major cause of illness and death in children and adults worldwide–is caused by Streptococcus pneumoniae, a bacterium that often colonizes the nose and throat harmlessly. Unfortunately, S. pneumoniae occasionally spreads into the lungs, bloodstream, or covering of the brain, where it causes pneumonia, septicemia, and meningitis, respectively. These invasive pneumococcal diseases (IPDs) can usually be successfully treated with antibiotics but can be fatal. Consequently, it is better to avoid infection through vaccination. Vaccination primes the immune system to recognize and attack disease-causing organisms (pathogens) rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules that it recognizes as foreign (antigens). Because there are more than 90 S. pneumoniae variants or “serotypes,” each characterized by a different antigenic polysaccharide (complex sugar) coat, vaccines that protect against S. pneumoniae have to include multiple serotypes. Thus, the pneumococcal conjugate vaccine PCV7, which was introduced into the US infant immunization regimen in 2000, contains polysaccharides from the seven S. pneumoniae serotypes mainly responsible for IPD in the US at that time.
Why Was This Study Done?
Vaccination with PCV7 was subsequently introduced in several other high- and middle-income countries, and IPD caused by the serotypes included in the vaccine declined substantially in children and in adults (because of reduced bacterial transmission and herd protection) in the US and virtually all these countries. However, increases in IPD caused by non-vaccine serotypes occurred in some settings, presumably because of “serotype replacement.” PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes. Consequently, after vaccination, previously less common, non-vaccine serotypes can colonize the nose and throat, some of which can cause IPD. In July 2010, a World Health Organization expert consultation on serotype replacement called for a comprehensive analysis of the magnitude and variability of pneumococcal serotype replacement following PCV7 use to help guide the introduction of PCVs in low-income countries, where most pneumococcal deaths occur. In this pooled analysis of data from multiple surveillance sites, the researchers investigate serotype-specific changes in IPD after PCV7 introduction using a standardized approach.
What Did the Researchers Do and Find?
The researchers identified 21 databases that had data about the rate of IPD for at least 2 years before and 1 year after PCV7 introduction. They estimated whether changes in IPD rates had occurred after PCV7 introduction by calculating site-specific rate ratios–the observed IPD rate for each post-PCV7 year divided by the expected IPD rate in the absence of PCV7 extrapolated from the pre-PCV7 rate. Finally, they used a statistical approach (random effects meta-analysis) to estimate summary (pooled) rate ratios. For children under 5 years old, the overall number of observed cases of IPD in the first year after the introduction of PCV7 was about half the expected number; this reduction in IPD continued through year 7 after PCV7 introduction. Notably, the rate of IPD caused by the S. pneumonia serotypes in PCV7 decreased every year, but the rate of IPD caused by non-vaccine serotypes increased annually. By year 7, the number of cases of IPD caused by non-vaccine serotypes was 3-fold higher than expected, but was still smaller than the decrease in vaccine serotypes, thereby leading to the decrease in overall IPD. Finally, smaller decreases in overall IPD also occurred among adults but occurred later than in children 2 years or more after PCV7 introduction.
What Do These Findings Mean?
These findings show that consistent, rapid, and sustained decreases in overall IPD and in IPD caused by serotypes included in PCV7 occurred in children and thus support the use of PCVs. The small increases in IPD caused by non-vaccine serotypes that these findings reveal are likely to be the result of serotype replacement, but changes in antibiotic use and other factors may also be involved. These findings have several important limitations, however. For example, PCV7 is no longer made and extrapolation of these results to newer PCV10 and PCV13 formulations should be done cautiously. On the other hand, many of the serotypes causing serotype replacement after PCV7 are included in these higher valency vaccines. Moreover, because the data analyzed in this study mainly came from high-income countries, these findings may not be generalizable to low-income countries. Nevertheless, based on their analysis, the researchers make recommendations for the collection and analysis of IPD surveillance data that should allow valid interpretations of the effect of PCVs on IPD to be made, an important requisite for making sound policy decisions about vaccination against pneumococcal disease.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001517.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination, including personal stories
Public Health England provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
The not-for-profit Immunization Action Coalition has information on pneumococcal disease, including personal stories
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
The International Vaccine Access Center at Johns Hopkins Bloomberg School of Public Health has more information on introduction of pneumococcal conjugate vaccines in low-income countries
doi:10.1371/journal.pmed.1001517
PMCID: PMC3782411  PMID: 24086113
5.  Pneumococcal Antibody Concentrations and Carriage of Pneumococci more than 3 Years after Infant Immunization with a Pneumococcal Conjugate Vaccine 
PLoS ONE  2012;7(2):e31050.
Background
A 9-valent pneumococcal conjugate vaccine (PCV-9), given in a 3-dose schedule, protected Gambian children against pneumococcal disease and reduced nasopharyngeal carriage of pneumococci of vaccine serotypes. We have studied the effect of a booster or delayed primary dose of 7-valent conjugate vaccine (PCV-7) on antibody and nasopharyngeal carriage of pneumococci 3–4 years after primary vaccination.
Methodology/Principal Findings
We recruited a subsample of children who had received 3 doses of either PCV-9 or placebo (controls) into this follow-up study. Pre- and post- PCV-7 pneumococcal antibody concentrations to the 9 serotypes in PCV-9 and nasopharyngeal carriage of pneumococci were determined before and at intervals up to 18 months post-PCV-7. We enrolled 282 children at a median age of 45 months (range, 38–52 months); 138 had received 3 doses of PCV-9 in infancy and 144 were controls. Before receiving PCV-7, a high proportion of children had antibody concentrations >0.35 µg/mL to most of the serotypes in PCV-9 (average of 75% in the PCV-9 and 66% in the control group respectively). The geometric mean antibody concentrations in the vaccinated group were significantly higher compared to controls for serotypes 6B, 14, and 23F. Antibody concentrations were significantly increased to serotypes in the PCV-7 vaccine both 6–8 weeks and 16–18 months after PCV-7. Antibodies to serotypes 6B, 9V and 23F were higher in the PCV-9 group than in the control group 6–8 weeks after PCV-7, but only the 6B difference was sustained at 16–18 months. There was no significant difference in nasopharyngeal carriage between the two groups.
Conclusions/Significance
Pneumococcal antibody concentrations in Gambian children were high 34–48 months after a 3-dose primary infant vaccination series of PCV-9 for serotypes other than serotypes 1 and 18C, and were significantly higher than in control children for 3 of the 9 serotypes. Antibody concentrations increased after PCV-7 and remained raised for at least 18 months.
doi:10.1371/journal.pone.0031050
PMCID: PMC3282700  PMID: 22363544
6.  Effects of Community-Wide Vaccination with PCV-7 on Pneumococcal Nasopharyngeal Carriage in The Gambia: A Cluster-Randomized Trial 
PLoS Medicine  2011;8(10):e1001107.
In a cluster-randomized trial conducted in Gambian villages, Anna Roca and colleagues find that vaccination of children with pneumococcal conjugate vaccines reduced vaccine-type pneumococcal carriage even among nonvaccinated older children and adults.
Background
Introduction of pneumococcal conjugate vaccines (PCVs) of limited valency is justified in Africa by the high burden of pneumococcal disease. Long-term beneficial effects of PCVs may be countered by serotype replacement. We aimed to determine the impact of PCV-7 vaccination on pneumococcal carriage in rural Gambia.
Methods and Findings
A cluster-randomized (by village) trial of the impact of PCV-7 on pneumococcal nasopharyngeal carriage was conducted in 21 Gambian villages between December 2003 to June 2008 (5,441 inhabitants in 2006). Analysis was complemented with data obtained before vaccination. Because efficacy of PCV-9 in young Gambian children had been shown, it was considered unethical not to give PCV-7 to young children in all of the study villages. PCV-7 was given to children below 30 mo of age and to those born during the trial in all study villages. Villages were randomized (older children and adults) to receive one dose of PCV-7 (11 vaccinated villages) or meningococcal serogroup C conjugate vaccine (10 control villages). Cross-sectional surveys (CSSs) to collect nasopharyngeal swabs were conducted before vaccination (2,094 samples in the baseline CSS), and 4–6, 12, and 22 mo after vaccination (1,168, 1,210, and 446 samples in CSS-1, -2, and -3, respectively).
A time trend analysis showed a marked fall in the prevalence of vaccine-type pneumococcal carriage in all age groups following vaccination (from 23.7% and 26.8% in the baseline CSS to 7.1% and 8.5% in CSS-1, in vaccinated and control villages, respectively). The prevalence of vaccine-type pneumococcal carriage was lower in vaccinated than in control villages among older children (5 y to <15 y of age) and adults (≥15 y of age) at CSS-2 (odds ratio [OR] = 0.15 [95% CI 0.04–0.57] and OR = 0.32 [95% CI 0.10–0.98], respectively) and at CSS-3 (OR = 0.37 [95% CI 0.15–0.90] for older children, and 0% versus 7.6% for adults in vaccinated and control villages, respectively). Differences in the prevalence of non-vaccine-type pneumococcal carriage between vaccinated and control villages were small.
Conclusions
Vaccination of Gambian children reduced vaccine-type pneumococcal carriage across all age groups, indicating a “herd effect” in non-vaccinated older children and adults. No significant serotype replacement was detected.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The prevention of pneumococcal disease, especially in children in developing countries, is a major international public health priority. Despite all the international attention on the UN's Millennium Development Goal 4—to reduce deaths in children under five years by two-thirds between 1990 and 2015—pneumonia, sepsis, and meningitis together compose more than 25% of the 10 million deaths occurring in children less than five years of age. Streptococcus pneumoniae is a leading bacterial cause of these diseases, and the World Health Organization estimates that approximately 800,000 children die each year of invasive pneumococcal disease.
Pneumococcal conjugate vaccines are currently available and protect against the serotypes that most commonly cause invasive pneumococcal disease in young children in North America and Europe. Such vaccines have been highly successful in reducing the incidence of invasive pneumococcal disease in both vaccinated children and in the non-vaccinated older population by reducing nasopharyngeal carriage (presence of pneumococcal bacteria in the back of the nose) in vaccinated infants, resulting in decreased transmission to contacts—the so-called herd effect. However, few countries with the highest burden of invasive pneumococcal disease, especially those in sub-Saharan Africa, have introduced the vaccine into their national immunization programs.
Why Was This Study Done?
The features of pneumococcal nasopharyngeal carriage and invasive pneumococcal disease in sub-Saharan Africa are different than in other regions. Therefore, careful evaluation of the immune effects of vaccination requires long-term, longitudinal studies. As an alternative to such long-term observational studies, and to anticipate the potential long-term effects of the introduction of pneumococcal conjugate vaccination in sub-Saharan Africa, the researchers conducted a cluster-randomized (by village) trial in The Gambia in which the whole populations of some villages were immunized with the vaccine PCV-7, and other villages received a control.
What Did the Researchers Do and Find?
With full consent from communities, the researchers randomized 21 similar villages in a rural region of western Gambia to receive pneumococcal conjugate vaccine or a control—meningococcal serogroup C conjugated vaccine, which is unlikely to affect pneumococcal carriage rates. For ethical reasons, the researchers only randomized residents aged over 30 months—all young infants received PCV-7, as a similar vaccine had already been shown to be effective in young infants. Before immunization began, the researchers took nasopharyngeal swabs from a random selection of village residents to determine the baseline pneumococcal carriage rates of both the serotypes of pneumococci covered by the vaccine (vaccine types, VTs) and the serotypes of pneumococci not covered in the vaccine (non-vaccine types, NVTs). The researchers then took nasopharyngeal swabs from a random sample of 1,200 of village residents in both groups of villages in cross-sectional surveys at 4–6, 12, and 22 months after vaccination. Villagers and laboratory staff were unaware of which vaccine was which (that is, they were blinded).
Before immunization, the overall prevalence of pneumococcal carriage in both groups was high, at 71.1%, and decreased with age. After vaccination, the overall prevalence of pneumococcal carriage in all three surveys was similar between vaccinated and control villages, showing a marked fall. However, the prevalence of carriage of VT pneumococci was significantly lower in vaccinated than in control villages in all surveys for all age groups. The prevalence of carriage of NVT pneumococci was similar in vaccinated and in control villages, except for a slightly higher prevalence of NVT pneumococci among vaccinated communities in adults at 4–6 months after vaccination. The researchers also found that the overall prevalence of pneumococcal carriage fell markedly after vaccination and reached minimum levels at 12 months in both study arms and in all age groups.
What Do These Findings Mean?
These findings show that vaccination of young Gambian children reduced carriage of VT pneumococci in vaccinated children but also in vaccinated and non-vaccinated older children and adults, revealing a potential herd effect from vaccination of young children. Furthermore, the immunological pressure induced by vaccinating whole communities did not lead to a community-wide increase in carriage of NVT pneumococci during a two-year period after vaccination. The researchers plan to conduct more long-term follow-up studies to determine nasopharyngeal carriage in these communities.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001107.
The World Health Organization has information about pneumococcus
The US Centers for Disease Control and Prevention provides information about pneumococcal conjugate vaccination
doi:10.1371/journal.pmed.1001107
PMCID: PMC3196470  PMID: 22028630
7.  Immunogenicity following the first and second doses of 7-valent pneumococcal conjugate vaccine in HIV-infected and -uninfected infants☆,☆☆ 
Vaccine  2012;31(5):777-783.
Background
The immunogenicity of pneumococcal conjugate vaccine (PCV) has not been evaluated in HIV-infected infants following the first and second PCV-doses. We studied antibody kinetics of serotypes included in 7-valent PCV in HIV-infected and HIV-uninfected infants prior to and following each of three PCV-doses.
Methods
HIV-uninfected infants born to HIV-uninfected (HUU) and HIV-infected mothers (HEU); and perinatal HIV-infected children with CD4+ < 25% randomized to initiate antiretroviral treatment (ART) when clinically and/or immunologically indicated (ART−) or immediately (ART+) were enrolled. Vaccination occurred at approximately 7.4, 11.5 and 15.5 weeks of age. Serotype-specific antibody was measured by ELISA following each PCV-dose and opsonophagocytic activity (OPA) to three serotypes following the second and third doses.
Results
Pre-vaccination, antibody geometric mean concentrations (GMCs) were higher in HUU compared to HIV-exposed groups for most serotypes. GMCs and proportion of infants with antibody ≥0.35 μg/ml were similar in HUU compared to other groups following the second PCV-dose. In all groups, GMCs were greater following the third compared to post-second dose; and a higher proportion within each group had antibody ≥0.35 μg/ml to 6B and 23F. OPA GMTs increased after the third compared to post-second dose for studied-serotypes; as did the proportion with OPA ≥8 to 23F.
Conclusion
A two-dose primary-series of PCV probably confers similar protection against invasive pneumococcal disease in HIV-infected compared to HUU children. The inferior response to serotypes 6B and 23F, and lower GMCs and OPA GMTs, following two compared to after three PCV-doses may have implications in the prevention of pneumococcal disease in high-burden countries.
doi:10.1016/j.vaccine.2012.11.076
PMCID: PMC3646262  PMID: 23228814
Streptococcus pneumoniae; Pneumococcal conjugate vaccine; Dosing schedules; HIV; Opsonophagocytic assay
8.  Immunogenicity of Seven-Valent Pneumococcal Conjugate Vaccine Administered at 6, 14 and 40 Weeks of Age in South African Infants 
PLoS ONE  2013;8(8):e72794.
Background
The high cost of pneumococcal conjugate vaccine (PCV) and local epidemiological factors contributed to evaluating different PCV dosing-schedules. This study evaluated the immunogenicity of seven-valent PCV (PCV7) administered at 6-weeks; 14-weeks and 9-months of age.
Methods
250 healthy, HIV-unexposed infants were immunized with PCV7 concurrently with other childhood vaccines. Serotype-specific anti-capsular IgG concentrations were measured one-month following the 1st and 2nd PCV-doses, prior to and two-weeks following the 3rd dose. Opsonophagocytic killing assay (OPA) was measured for three serotypes following the 2nd and 3rd PCV7-doses. Immunogenicity of the current schedule was compared to a historical cohort of infants who received PCV7 at 6, 10 and 14 weeks of age.
Results
The proportion of infants with serotype-specific antibody ≥0.35 µg/ml following the 2nd PCV7-dose ranged from 84% for 6B to ≥89% for other serotypes. Robust antibody responses were observed following the 3rd dose. The proportion of children with OPA ≥8 for serotypes 9V, 19F and 23F increased significantly following the 3rd PCV7-dose to 93.6%; 86.0% and 89.7% respectively. The quantitative antibody concentrations following the 2nd PCV7-dose were comparable to that after the 3rd -dose in the 6-10-14 week schedule. Geometric mean concentrations (GMCs) following the 3rd PCV7-dose were higher for all serotypes in this study compared to the historical cohort.
Conclusions
The studied PCV7 dosing schedule induced good immune responses, including higher GMCs following the 3rd-dose at 9-months compared to when given at 14-weeks of age. This may confer longer persistence of antibodies and duration of protection against pneumococcal disease.
doi:10.1371/journal.pone.0072794
PMCID: PMC3755982  PMID: 24015277
9.  Decreased Bone Mineral Density in Adults Born with Very Low Birth Weight: A Cohort Study 
PLoS Medicine  2009;6(8):e1000135.
Petteri Hovi and colleagues evaluate skeletal health in 144 adults born preterm with very low birth weight and show that as adults these individuals have significantly lower bone mineral density than do their term-born peers.
Background
Very-low-birth-weight (VLBW, <1,500 g) infants have compromised bone mass accrual during childhood, but it is unclear whether this results in subnormal peak bone mass and increased risk of impaired skeletal health in adulthood. We hypothesized that VLBW is associated with reduced bone mineral density (BMD) in adulthood.
Methods and Findings
The Helsinki Study of Very Low Birth Weight Adults is a multidisciplinary cohort study representative of all VLBW births within the larger Helsinki area from 1978 to 1985. This study evaluated skeletal health in 144 such participants (all born preterm, mean gestational age 29.3 wk, birth weight 1,127 g, birth weight Z score 1.3), and in 139 comparison participants born at term, matched for sex, age, and birth hospital. BMD was measured by dual energy X-ray absorptiometry at age 18.5 to 27.1 y. Adults born with VLBW had, in comparison to participants born at term, a 0.51-unit (95% confidence interval [CI] 0.28–0.75) lower lumbar spine Z score and a 0.56-unit (95% CI 0.34–0.78) lower femoral neck Z score for areal BMD. These differences remained statistically significant after adjustment for the VLBW adults' shorter height and lower self-reported exercise intensity.
Conclusions
Young adults born with VLBW, when studied close to the age of peak bone mass, have significantly lower BMD than do their term-born peers. This suggests that compromised childhood bone mass accrual in preterm VLBW children translates into increased risk for osteoporosis in adulthood, warranting vigilance in osteoporosis prevention.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Most pregnancies last 40 weeks but some babies arrive earlier than expected. Sadly, babies born before 37 weeks of pregnancy—premature babies—are more likely to die than full-term babies, although recent improvements in neonatal care have increased their chances of survival. Premature babies also often have serious long-term health problems, particularly those born before 32 weeks of pregnancy. Such extremely premature babies have poorly developed internal organs and are usually very small—babies whose birth weight is less than 1,500 g are called very-low-birth-weight (VLBW) babies; the average full-term birth weight is about 3,500 g. Furthermore, their bones are not as well developed as those of full-term babies. The human skeleton initially consists of a soft fibrous material called cartilage. This is gradually transformed into bone by a process called bone mineralization. The last third of pregnancy is a crucial period for bone mineralization although the process continues throughout infancy and childhood. Thus, VLBW babies often have subnormal skeletal mineralization and their accrual of bone mass during childhood is frequently compromised.
Why Was This Study Done?
It is not known whether the childhood bone deficits of VLBW babies persist into adulthood because the first generation of these infants not to die soon after birth is only just reaching adulthood. Peak bone mass is reached in early adulthood (bone mass begins to decrease from the age of 35 years onward) and is an important indicator of whether an individual will develop osteoporosis (thinning of the bones) and be susceptible to bone fractures later in life. If adults with VLBW (about 1% of live births in high-income countries are now VLBW births) do have a subnormal peak bone mass and reduced bone mineral density (BMD), they may be able reduce their risk of developing osteoporosis by eating a healthy diet and exercising regularly. In this study (part of the Helsinki Study of Very Low Birth Weight Adults), the researchers investigate the skeletal health of people who were born with VLBW in the Helsinki area between 1978 and 1985.
What Did the Researchers Do and Find?
The researchers compared the skeletal health of 144 young adults who were born prematurely with VLBW and subnormal BMD with that of 139 age- and sex-matched individuals who were born at term. They measured the BMD of the participants (average age 22.6 years) using “dual energy X-ray absorptiometry” and determined a “Z score” for the spine in the lower back (the lower lumbar spine) and the hip (two sites that are routinely examined in assessments of skeletal health). Z scores indicate whether an individual's BMD is significantly different from the average BMD of healthy age- and sex-matched people; in this study, reduced BMD was defined as a Z score of −1.0 or less. The researchers found that adults born with VLBW had an average Z score of −0.51 at the lower lumbar spine and −0.56 at the hip when compared with the adults born at term. Furthermore, 44% of the VLBW participants but only 26% of the term-born participants had a lumbar spine Z score of −1.0 or less. Adjustment for the shorter height of the VLBW participants slightly reduced these differences in BMD but the differences remained statistically significant.
What Do These Findings Mean?
These findings show that, when studied close to the age of peak bone mass, young adults born with VLBW have a significantly lower BMD than their term-born peers and a 2-fold greater risk of having a lumbar spine Z score of below −1.0; a unit decrease in Z score approximately doubles the risk of bone fractures. Because BMD measurements were only taken at one age, it remains possible, however, that the BMD of the VLBW adults might eventually match that of their full-term peers. Recently born VLBW babies still have a lower than average BMD during their childhood, note the researchers, even though their care has changed since the people included in this study were born. Thus, these findings suggest that people who were VLBW infants should be encouraged to eat food rich in vitamin D and calcium and to do regular weight-bearing exercise throughout their lives to improve their bone health and reduce their risk of developing osteoporosis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000135.
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
The Nemours Foundation, another nonprofit organization for child health, also provides information on premature babies (in English and Spanish)
MedlinePlus provides links to other information on premature babies and to information on osteoporosis (in English and Spanish)
The US National Institute of Arthritis and Musculoskeletal and Skin Diseases and the UK National Health Service also provide detailed information on all aspects of osteoporosis
Further details about the Helsinki Study of Very Low Birth Weight Adults are available
doi:10.1371/journal.pmed.1000135
PMCID: PMC2722726  PMID: 19707270
10.  Immunogenicity of Trivalent Influenza Vaccine in Extremely-Low-Birth-Weight, Premature versus Term Infants 
Background
Influenza vaccine immunogenicity in premature infants is incompletely characterized.
Objective
To assess the immunogenicity of trivalent, inactivated influenza vaccine (TIV) in extremely low-birth-weight (ELBW, ≤1000 grams birth weight), premature (<30 weeks gestation) infants. We hypothesized that geometric mean titers (GMT) of influenza antibody would be lower in premature than in full-term (≥37 week) infants.
Design/Methods
In this prospective, multicenter study, former premature and full-term infants ages, 6–17 months, received 2 doses of TIV during the 2006–7 or 2007–8 influenza seasons. Sera were drawn before dose 1 and 4–6 weeks after dose 2. Antibody was measured by hemagglutination inhibition.
Results
Over two years, 41 premature and 42 full-term infants were enrolled; 36 and 33 of these infants, respectively, had post-vaccination titers available. Premature infants weighed less (mean 1.3 – 1.8 kg difference) at the time of immunization than full-term infants. Pre-vaccination titers did not differ between groups. Premature infants had higher post-vaccination antibody GMT than full-term infants to H1 (2006–7, 1:513 v. 1:91, P=0.03; 2007–8, 1:363 v. 1:189, P=0.02) and B/Victoria (2006–7, 1:51 v. 1:10, P=0.02). More premature than full-term infants had antibody titers ≥ 1:32 to B/Victoria (85% v. 60%, p=0.04) in 2007–8. Two (5%) premature and 8 (19%) full-term infants had adverse events, primarily fever, within 72 hours after vaccination. No child had medically-diagnosed influenza.
Conclusions
Former premature infants had antibody responses to two TIV doses greater than or equal to those of full-term children. Two TIV doses are immunogenic and well tolerated in ELBW, premature infants 6–17 months old.
doi:10.1097/INF.0b013e31820c1fdf
PMCID: PMC3090695  PMID: 21273938
Premature infant; very low birth weight infant; influenza vaccines; immunization; vaccines
11.  Safety and Immunogenicity of a 13-Valent Pneumococcal Conjugate Vaccine Compared to Those of a 7-Valent Pneumococcal Conjugate Vaccine Given as a Three-Dose Series with Routine Vaccines in Healthy Infants and Toddlers ▿ †  
A 13-valent pneumococcal conjugate vaccine (PCV13) has been developed to improve protection against pneumococcal disease beyond that possible with the licensed 7-valent vaccine (PCV7). This study compared the safety and immunogenicity of PCV13 with those of PCV7 when given as part of the pediatric vaccination schedule recommended in Italy. A total of 606 subjects were randomly assigned to receive either PCV13 or PCV7 at 3, 5, and 11 months of age; all subjects concomitantly received diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type B (DTaP-HBV-IPV/Hib) vaccine. Vaccine reactions were monitored. Antibody responses to DTaP-HBV-IPV/Hib antigens, serotype-specific anticapsular polysaccharide IgG responses, and antipneumococcal opsonophagocytic assay (OPA) activity were measured 1 month after the two-dose primary series and 1 month after the toddler dose. Overall, the safety profile of PCV13 was similar to that of PCV7. The response to DTaP-HBV-IPV/Hib antigens was substantially the same with both PCV13 and PCV7. PCV13 elicited antipneumococcal capsular IgG antibodies to all 13 vaccine serotypes, with notable increases in concentrations seen after the toddler dose. Despite a lower immunogenicity for serotypes 6B and 23F after the primary series of PCV13, responses to the seven common serotypes were comparable between the PCV13 and PCV7 groups when measured after the toddler dose. PCV13 also elicited substantial levels of OPA activity against all 13 serotypes following both the infant series and the toddler dose. In conclusion, PCV13 appeared comparable to PCV7 in safety profile and immunogenicity for common serotypes, demonstrated functional OPA responses for all 13 serotypes, and did not interfere with immune responses to concomitantly administered DTaP-HBV-IPV/Hib vaccine.
doi:10.1128/CVI.00062-10
PMCID: PMC2884425  PMID: 20427630
12.  Pneumococcal Serotype-Specific Antibodies Persist through Early Childhood after Infant Immunization: Follow-Up from a Randomized Controlled Trial 
PLoS ONE  2014;9(3):e91413.
Background
In a previous UK multi-center randomized study 278 children received three doses of 7-valent (PCV-7) or 13-valent (PCV-13) pneumococcal conjugate vaccine at 2, 4 and 12 months of age. At 13 months of age, most of these children had pneumococcal serotype-specific IgG concentrations ≥0.35 µg/ml and opsonophagocytic assay (OPA) titers ≥8.
Methods
Children who had participated in the original study were enrolled again at 3.5 years of age. Persistence of immunity following infant immunization with either PCV-7 or PCV-13 and the immune response to a PCV-13 booster at pre-school age were investigated.
Results
In total, 108 children were followed-up to the age of 3.5 years and received a PCV-13 booster at this age. At least 76% of children who received PCV-7 or PCV-13 in infancy retained serotype-specific IgG concentrations ≥0.35 µg/ml against each of 5/7 shared serotypes. For serotypes 4 and 18C, persistence was lower at 22–42%. At least 71% of PCV-13 group participants had IgG concentrations ≥0.35 µg/ml against each of 4/6 of the additional PCV-13 serotypes; for serotypes 1 and 3 this proportion was 45% and 52%. In the PCV-7 group these percentages were significantly lower for serotypes 1, 5 and 7F. A pre-school PCV-13 booster was highly immunogenic and resulted in low rates of local and systemic adverse effects.
Conclusion
Despite some decline in antibody from 13 months of age, these data suggest that a majority of pre-school children maintain protective serotype-specific antibody concentrations following conjugate vaccination at 2, 4 and 12 months of age.
Trial Registration
ClinicalTrials.gov NCT01095471
doi:10.1371/journal.pone.0091413
PMCID: PMC3950188  PMID: 24618837
13.  Inferior quantitative and qualitative immune responses to pneumococcal conjugate vaccine in infants with nasopharyngeal colonization by Streptococcus pneumoniae during the primary series of immunization 
Vaccine  2011;29(40):6994-7001.
Background
Heightened immunogenicity, measured one month after the primary series of pneumococcal conjugate vaccine (PCV), in African children was previously hypothesized to be due to increased rates of nasopharyngeal pneumococcal colonization during early infancy.
Methods
We analyzed the effect of selected vaccine-serotype (6B, 19F and 23F) nasopharyngeal colonization prior to the first PCV dose or when colonized for the first time prior to the second or third (2nd/3rd) PCV dose on serotype quantitative and qualitative antibody responses.
Results
Colonization prior to receiving the first PCV was associated with lower geometric mean antibody concentrations (GMCs) one month after the third dose of PCV and six months later to the colonizing-serotype. Colonized infants also had lower geometric mean titers (GMTs) on opsonophagocytosis activity assay (OPA) and a lower proportion had titers ≥8 against the colonizing serotypes (19F and 23F) post vaccination. Colonization occurring only prior to the 2nd/3rd PCV dose was also associated with lower GMCs and OPA GMTs to the colonizing-serotype. The effect of colonization with serotypes 19F and 23F prior to PCV vaccination had a greater effect on a lower proportion of colonized infants having OPA titers ≥8 than the effect of colonization on the lower proportion with antibody ≥0.35 μg/ml.
Conclusion
Infant nasopharyngeal colonization at any stage before completing the primary series of PCV vaccination was associated with inferior quantitative and qualitative antibody responses to the colonizing-serotype.
doi:10.1016/j.vaccine.2011.07.035
PMCID: PMC3167924  PMID: 21787822
Streptococcus pneumoniae; pneumococcal conjugate vaccine; HIV; immunogenicity; colonization; hypo-responsiveness
14.  The Differential Impact of Coadministered Vaccines, Geographic Region, Vaccine Product and Other Covariates on Pneumococcal Conjugate Vaccine Immunogenicity 
The Pediatric Infectious Disease Journal  2013;33(Suppl 2 Optimum Dosing of Pneumococcal Conjugate Vaccine For Infants 0 A Landscape Analysis of Evidence Supportin g Different Schedules):S130-S139.
Background:
Antipneumococcal capsular polysaccharide antibody concentrations are used as predictors of vaccine efficacy against vaccine serotype (ST) pneumococcal disease among infants. While pneumococcal conjugate vaccines (PCV) are recommended globally, factors associated with optimal PCV immune response are not well described. We aimed to systematically assess local setting factors, beyond dosing schedule, which may affect PCV antibody levels.
Methods:
We conducted a literature review of PCV immunogenicity, abstracting data from published reports, unpublished sources, and conference abstracts from 1994 to 2010 (and ad hoc 2011 reports). Studies included in this analysis evaluated ≥ 2 primary doses of PCV before 6 months of age in non–high-risk populations, used 7-valent or higher PCV products (excluding Aventis-Pasteur and Merck products) and provided information on geometric mean concentration (GMC) for STs 1, 5, 6B, 14, 19F or 23F. Using random effects meta-regression, we assessed the impact of geographic region, coadministered vaccines and PCV product on postprimary GMC, adjusting for dosing schedule and ELISA laboratory method.
Results:
Of 12,980 citations reviewed, we identified 103 vaccine study arms for this analysis. Children in studies from Asia, Africa and Latin America had significantly higher GMC responses compared with those in studies from Europe and North America. Coadministration with acellular pertussis DTP compared with whole-cell DTP had no effect on PCV immunogenicity except for ST14, where GMCs were higher when coadministered with acellular pertussis DTP. Vaccine product, number of PCV doses, dosing interval, age at first dose and ELISA laboratory method also affected the GMC.
Conclusions:
PCV immunogenicity is associated with geographic region and vaccine product; however, the associations and magnitude varied by ST. Consideration of these factors is essential when comparing PCV immunogenicity results between groups and should be included in the evidence base when selecting optimal PCV vaccine schedules in specific settings.
doi:10.1097/INF.0000000000000081
PMCID: PMC3944480  PMID: 24336055
pneumococcal conjugate vaccine; immunogenicity; immunization
15.  Immune Response in Infants to the Heptavalent Pneumococcal Conjugate Vaccine against Vaccine-Related Serotypes 6A and 19A ▿  
The currently available 7-valent pneumococcal conjugate vaccine (PCV7) elicits good immune response to and is effective against vaccine serotypes. However, its effectiveness against vaccine-related serotypes is variable. Serum samples were obtained 1 month after the last vaccination from 31 infants immunized with PCV7 at 2, 4, and 6 months of age. The sera were used to determine immunoglobulin G antibody levels to eight serotypes (seven vaccine serotypes and serotype 19A) with enzyme-linked immunosorbent assay (ELISA) and opsonic capacity against 11 serotypes (seven vaccine serotypes, serotypes 19A and 6A, and nonvaccine serotypes 5 and 7F) using a multiplexed opsonization assay. ELISA results showed antibody concentrations varied between 1.84 and 10.49 μg/ml, and all subjects had antibody concentrations of ≥0.35 μg/ml for all serotypes, including serotype 19A. In contrast, the opsonic index was detectable (i.e., opsonic index ≥ 8) in all children for the seven vaccine serotypes, 81% for serotype 6A, and merely 19% for serotype 19A. PCV7 shows good immunogenicity for vaccine serotypes in infants after a primary series. PCV7 does not elicit opsonic antibodies to serotype 19A. ELISA may thus be an inadequate surrogate assay for evaluating the response for cross-reactive serotypes in infants.
doi:10.1128/CVI.00344-08
PMCID: PMC2650865  PMID: 19144787
16.  Maternal Influenza Immunization and Reduced Likelihood of Prematurity and Small for Gestational Age Births: A Retrospective Cohort Study 
PLoS Medicine  2011;8(5):e1000441.
In an analysis of surveillance data from the state of Georgia (US), Saad Omer and colleagues show an association between receipt of influenza vaccination among pregnant women and reduced risk of premature births.
Background
Infections during pregnancy have the potential to adversely impact birth outcomes. We evaluated the association between receipt of inactivated influenza vaccine during pregnancy and prematurity and small for gestational age (SGA) births.
Methods and Findings
We conducted a cohort analysis of surveillance data from the Georgia (United States) Pregnancy Risk Assessment Monitoring System. Among 4,326 live births between 1 June 2004 and 30 September 2006, maternal influenza vaccine information was available for 4,168 (96.3%). The primary intervention evaluated in this study was receipt of influenza vaccine during any trimester of pregnancy. The main outcome measures were prematurity (gestational age at birth <37 wk) and SGA (birth weight <10th percentile for gestational age). Infants who were born during the putative influenza season (1 October–31 May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature compared to infants of unvaccinated mothers born in the same period (adjusted odds ratio [OR] = 0.60; 95% CI, 0.38–0.94). The magnitude of association between maternal influenza vaccine receipt and reduced likelihood of prematurity increased during the period of at least local influenza activity (adjusted OR = 0.44; 95% CI, 0.26–0.73) and was greatest during the widespread influenza activity period (adjusted OR = 0.28; 95% CI, 0.11–0.74). Compared with newborns of unvaccinated women, newborns of vaccinated mothers had 69% lower odds of being SGA (adjusted OR = 0.31; 95% CI, 0.13–0.75) during the period of widespread influenza activity. The adjusted and unadjusted ORs were not significant for the pre-influenza activity period.
Conclusions
This study demonstrates an association between immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. However, no associations were found for the pre-influenza activity period. Moreover, during the period of widespread influenza activity there was an association between maternal receipt of influenza vaccine and reduced likelihood of SGA birth.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Maternal infections during pregnancy can have harmful effects on both mother and baby. For example, influenza is associated with increased morbidity and mortality among pregnant women compared to women who are not pregnant or who acquire influenza infection after delivery. And some respiratory infections, especially those that can cause maternal pneumonia such as influenza virus, are known to be associated with the baby being small—below the 10th percentile—for gestational age and with an increased risk of preterm birth—birth before 37 weeks of gestation. Previous studies have shown that inactivated influenza vaccination during pregnancy provides protection against influenza virus for both mother and baby. As there has been an increase in the rate of preterm birth the United States from 9.5% in 1981 to 12.8% in 2006, the impact of maternal influenza immunization on birth outcomes has important public health implications and is of particular interest during influenza pandemics.
Why Was This Study Done?
Given that maternal vaccination can protect babies from influenza virus, it is plausible that influenza vaccination in pregnancy could mitigate adverse birth outcomes such as prematurity and the baby being small for gestational age. The researchers of this study set out to evaluate this hypothesis by investigating whether there was an association between women receiving inactivated influenza vaccine during pregnancy and positive birth outcomes for their babies in the population of the state of Georgia, in the United States.
What Did the Researchers Do and Find?
The researchers conducted a retrospective cohort analysis of a large surveillance dataset (the Georgia Pregnancy Risk Assessment Monitoring System) to analyze the relationship between receipt of inactivated influenza vaccine during any trimester of pregnancy by mothers of infants born between June 1, 2004, and September 30, 2006, and their baby being premature or small for gestational age. The study period encompassed the 2004–2005 and 2005–2006 influenza seasons—the two most recent seasons for which the data were available. The researchers did a stratified analysis for the overall study period, and various periods during it, and also weighted their analysis to adjust for possible oversampling. They used logistic regression to evaluate the association of maternal influenza vaccine and (a) prematurity and (b) small for gestational age, and also used linear regression to evaluate the statistical significance of differences between vaccinated and unvaccinated women for mean gestational age at first antenatal visit and mean birth weight.
During the study period, 4,168 mother–baby pairs were included in the analysis. Local influenza activity was detected during 27 weeks (22.1%), and 578 women (14.9% [weighted]) had received the influenza vaccine during pregnancy, giving a vaccination coverage of 19.2% (weighted) among mothers of infants born during the assumed influenza season. In the study sample, 1,547 babies (10.6% [weighted]) were born premature, and 1,186 babies (11.2% [weighted]) were small for gestational age. Infants who were born during the assumed influenza season (October–May) and whose mothers were vaccinated against influenza during pregnancy were less likely to be premature than infants of unvaccinated mothers born in the same period, with an adjusted odds ratio of 0.60. The effect of maternal influenza vaccine on reducing prematurity was the highest for infants born during the period of widespread influenza activity, with 72% lower odds of prematurity in infants of vaccinated mothers than infants of unvaccinated mothers. Compared with newborns of unvaccinated women, babies of vaccinated mothers also had 69% lower odds of being small for gestational age during the period of widespread influenza activity, but the adjusted and unadjusted odd ratios were not significant for the pre-influenza activity period.
What Do These Findings Mean?
These results show that there was an association between maternal immunization with the inactivated influenza vaccine during pregnancy and reduced likelihood of prematurity during local, regional, and widespread influenza activity periods. In addition, during the period of widespread influenza activity there was an negative association between maternal receipt of influenza vaccine and small for gestational age birth.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000441.
More information about influenza vaccination during pregnancy is available from the World Health Organization and the UK National Health Service
More information about the Georgia Pregnancy Risk Assessment Monitoring System is also available
doi:10.1371/journal.pmed.1000441
PMCID: PMC3104979  PMID: 21655318
17.  Effect of Pneumococcal Conjugate Vaccination on Serotype-Specific Carriage and Invasive Disease in England: A Cross-Sectional Study 
PLoS Medicine  2011;8(4):e1001017.
A cross sectional study by Stefan Flasche and coworkers document the serotype replacement of Streptococcus pneumoniae that has occurred in England since the introduction of PCV7 vaccination.
Background
We investigated the effect of the 7-valent pneumococcal conjugate vaccine (PCV7) programme in England on serotype-specific carriage and invasive disease to help understand its role in serotype replacement and predict the impact of higher valency vaccines.
Methods and Findings
Nasopharyngeal swabs were taken from children <5 y old and family members (n = 400) 2 y after introduction of PCV7 into routine immunization programs. Proportions carrying Streptococcus pneumoniae and serotype distribution among carried isolates were compared with a similar population prior to PCV7 introduction. Serotype-specific case∶carrier ratios (CCRs) were estimated using national data on invasive disease. In vaccinated children and their contacts vaccine-type (VT) carriage decreased, but was offset by an increase in non-VT carriage, with no significant overall change in carriage prevalence, odds ratio 1.06 (95% confidence interval 0.76–1.49). The lower CCRs of the replacing serotypes resulted in a net reduction in invasive disease in children. The additional serotypes covered by higher valency vaccines had low carriage but high disease prevalence. Serotype 11C emerged as predominant in carriage but caused no invasive disease whereas 8, 12F, and 22F emerged in disease but had very low carriage prevalence.
Conclusion
Because the additional serotypes included in PCV10/13 have high CCRs but low carriage prevalence, vaccinating against them is likely to significantly reduce invasive disease with less risk of serotype replacement. However, a few serotypes with high CCRs could mitigate the benefits of higher valency vaccines. Assessment of the effect of PCV on carriage as well as invasive disease should be part of enhanced surveillance activities for PCVs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Pneumococcal diseases—major causes of illness and death in children and adults worldwide—are caused by Streptococcus pneumoniae, a bacterium that often colonizes the nasopharynx (the area of the throat behind the nose). Carriage of S. pneumoniae bacteria does not necessarily cause disease. However, these bacteria can cause local, noninvasive diseases such as ear infections and sinusitis and, more rarely, they can spread into the lungs, the bloodstream, or the covering of the brain, where they cause pneumonia, septicemia, and meningitis, respectively. Although these invasive pneumococcal diseases (IPDs) can be successfully treated if administered early, they can be fatal. Consequently, it is better to protect people against IPDs through vaccination than risk infection. Vaccination primes the immune system to recognize and attack disease-causing organisms (pathogens) rapidly and effectively by exposing it to weakened or dead pathogens or to pathogen molecules (antigens) that it recognizes as foreign.
Why Was This Study Done?
There are more than 90 S. pneumoniae variants or “serotypes” characterized by different polysaccharide (complex sugar) coats, which trigger the immune response against S. pneumoniae and determine each serotype's propensity to cause IPD. The pneumococcal conjugate vaccine PCV7 contains polysaccharides (linked to a protein carrier) from the seven serotypes mainly responsible for IPD in the US in 2000 when routine childhood PCV7 vaccination was introduced in that country. PCV7 prevents both IPD caused by the serotypes it contains and carriage of these serotypes, which means that, after vaccination, previously uncommon, nonvaccine serotypes can colonize the nasopharynx. If these serotypes have a high invasiveness potential, then “serotype replacement” could reduce the benefits of vaccination. In this cross-sectional study (a study that investigates the relationship between a disease and an intervention in a population at one time point), the researchers investigate the effect of the UK PCV7 vaccination program (which began in 2006) on serotype-specific carriage and IPD in England to understand the role of PCV7 in serotype replacement and to predict the likely impact of vaccines containing additional serotypes (higher valency vaccines).
What Did the Researchers Do and Find?
The researchers examined nasopharyngeal swabs taken from PCV7-vaccinated children and their families for S. pneumoniae, determined the serotype of any bacteria they found, and compared the proportion of people carrying S. pneumoniae (carrier prevalence) and the distribution of serotypes in this study population and in a similar population that was studied in 2000/2001, before the PCV vaccination program began. Overall, there was no statistically significant change in carrier prevalence, but carriage of vaccine serotypes decreased in vaccinated children and their contacts whereas carriage of nonvaccine serotypes increased. The serotype-specific case-to-carrier ratios (CCRs; a measure of serotype invasiveness that was estimated using national IPD data) of the replacing serotypes were generally lower than those of the original serotypes, which resulted in a net reduction in IPD in children. Moreover, before PCV7 vaccination began, PCV7-included serotypes were responsible for similar proportions of pneumococcal carriage and disease; afterwards, the additional serotypes present in the higher valency vaccines PVC10 and PVC13 were responsible for a higher proportion of disease than carriage. Finally, three serotypes not present in the higher valency vaccines with outstandingly high CCRs (high invasiveness potential) are identified.
What Do These Findings Mean?
These findings document the serotype replacement of S. pneumoniae that has occurred in England since the introduction of PCV7 vaccination and highlight the importance of assessing the effects of pneumococcal vaccines on carriage as well as on IPDs. Because the additional serotypes included in PCV10 and PCV13 have high CCRs but low carriage prevalence and because most of the potential replacement serotypes have low CCRs, these findings suggest that the introduction of higher valency vaccines should further reduce the occurrence of invasive disease with limited risk of additional serotype replacement. However, the emergence of a few serotypes that have high CCRs but are not included in PCV10 and PCV13 might mitigate the benefits of higher valency vaccines. In other words, although the recent introduction of PCV13 into UK vaccination schedules is likely to have an incremental benefit on the reduction of IPD compared to PCV7, this benefit might be offset by increases in the carriage of some high CCR serotypes. These serotypes should be considered for inclusion in future vaccines.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001017.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination
The US National Foundation for Infectious Diseases has a fact sheet on pneumococcal diseases
The UK Health Protection Agency provides information on pneumococcal disease and on pneumococcal vaccines
The World Health Organization also provides information on pneumococcal vaccines
MedlinePlus has links to further information about pneumococcal infections (in English and Spanish)
doi:10.1371/journal.pmed.1001017
PMCID: PMC3071372  PMID: 21483718
18.  Economic evaluation of pneumococcal conjugate vaccination in The Gambia 
BMC Infectious Diseases  2010;10:260.
Background
Gambia is the second GAVI support-eligible country to introduce the 7-valent pneumococcal conjugate vaccine (PCV7), but a country-specific cost-effectiveness analysis of the vaccine is not available. Our objective was to assess the potential impact of PCVs of different valences in The Gambia.
Methods
We synthesized the best available epidemiological and cost data using a state-transition model to simulate the natural histories of various pneumococcal diseases. For the base-case, we estimated incremental cost (in 2005 US dollars) per disability-adjusted life year (DALY) averted under routine vaccination using PCV9 compared to no vaccination. We extended the base-case results for PCV9 to estimate the cost-effectiveness of PCV7, PCV10, and PCV13, each compared to no vaccination. To explore parameter uncertainty, we performed both deterministic and probabilistic sensitivity analyses. We also explored the impact of vaccine efficacy waning, herd immunity, and serotype replacement, as a part of the uncertainty analyses, by assuming alternative scenarios and extrapolating empirical results from different settings.
Results
Assuming 90% coverage, a program using a 9-valent PCV (PCV9) would prevent approximately 630 hospitalizations, 40 deaths, and 1000 DALYs, over the first 5 years of life of a birth cohort. Under base-case assumptions ($3.5 per vaccine), compared to no intervention, a PCV9 vaccination program would cost $670 per DALY averted in The Gambia. The corresponding values for PCV7, PCV10, and PCV13 were $910, $670, and $570 per DALY averted, respectively. Sensitivity analyses that explored the implications of the uncertain key parameters showed that model outcomes were most sensitive to vaccine price per dose, discount rate, case-fatality rate of primary endpoint pneumonia, and vaccine efficacy against primary endpoint pneumonia.
Conclusions
Based on the information available now, infant PCV vaccination would be expected to reduce pneumococcal diseases caused by S. pneumoniae in The Gambia. Assuming a cost-effectiveness threshold of three times GDP per capita, all PCVs examined would be cost-effective at the tentative Advance Market Commitment (AMC) price of $3.5 per dose. Because the cost-effectiveness of a PCV program could be affected by potential serotype replacement or herd immunity effects that may not be known until after a large scale introduction, type-specific surveillance and iterative evaluation will be critical.
doi:10.1186/1471-2334-10-260
PMCID: PMC2944347  PMID: 20815900
19.  Immunogenicity of a Heptavalent Conjugate Pneumococcal Vaccine Administered Concurrently with a Combination Diphtheria, Tetanus, Five-Component Acellular Pertussis, Inactivated Polio, and Haemophilus influenzae Type b Vaccine and a Meningococcal Group C Conjugate Vaccine at 2, 3, and 4 Months of Age ▿  
The immunogenicities of conjugate pneumococcal vaccines have been demonstrated when they are administered at 2, 3, and 4 months of age. There is a paucity of data on the immunogenicity of this vaccine when it is administered concurrently with other vaccines in the primary immunization schedule of the United Kingdom. We immunized 55 term infants at 2, 3, and 4 months of age with the seven-valent pneumococcal conjugate vaccine (PCV7), the meningococcal group C conjugate (MCC) vaccine, and the diphtheria, tetanus, five-component acellular pertussis, inactivated polio, and Haemophilus influenzae type b (DTaP5/IPV/Hib-TT) vaccine. The immune responses to the H. influenzae type b (Hib), MCC, and tetanus vaccines were measured at 2, 5, and 12 months of age; and the immune responses to PCV7 were measured at 2 and 5 months and then either at 12 months or following a 4th dose of PCV7. There were increases in the geometric mean concentrations (GMCs) of all antigens postimmunization. Greater than or equal to 90% of the infants achieved putatively protective levels postimmunization for all vaccine antigens except pneumococcal serotype 6B and Hib. The GMCs of the PCV7 serotypes increased following a 4th dose, although one infant had not reached putative levels of protection against serotype 6B. In conclusion, when infants were vaccinated according to the schedule described above, they had lower postprimary immunization responses to Hib, meningococcus group C capsular polysaccharide, and pneumococcal serotype 6B than the responses demonstrated by use of the other schedules. Despite this finding, there was a good response following a 4th dose of PCV7.
doi:10.1128/CVI.00315-09
PMCID: PMC2837965  PMID: 20042517
20.  Pneumococcal conjugate vaccination at birth in a high-risk setting: No evidence for neonatal T-cell tolerance 
Vaccine  2011;29(33-19):5414-5420.
Concerns about the risk of inducing immune deviation-associated “neonatal tolerance” as described in mice have restricted the widespread adoption of neonatal vaccination. The aim of this study was to demonstrate the immunological feasibility of neonatal pneumococcal conjugate vaccination (PCV) which could potentially protect high-risk infants in resource poor countries against severe pneumococcal disease and mortality in the early critical period of life. Papua New Guinean infants were randomized to be vaccinated with the 7-valent PCV (7vPCV) at birth, 1 and 2 months (neonatal group, n = 104) or at 1, 2 and 3 months of age (infant group, n = 105), or to not receive 7vPCV at all (control group, n = 109). Analysis of vaccine responses at 3 and 9 months of age demonstrated persistently higher type-1 (IFN-γ) and type-2 (IL-5 and IL-13) T-cell responses to the protein carrier CRM197 and IgG antibody titres to 7vPCV serotypes in children vaccinated with 7vPCV according to either schedule as compared to unvaccinated children. In a comprehensive immuno-phenotypic analysis at 9 months of age, no differences in the quantity or quality of vaccine-specific T cell memory responses were found between neonatal vaccinations versus children given their first PCV dose at one month. Hospitalization rates in the first month of life did not differ between children vaccinated with PCV at birth or not. These findings demonstrate that neonatal 7vPCV vaccination is safe and not associated with immunological tolerance. Neonatal immunisation schedules should therefore be considered in high-risk areas where this may result in improved vaccine coverage and the earliest possible protection against pneumococcal disease and death.
doi:10.1016/j.vaccine.2011.05.065
PMCID: PMC3146700  PMID: 21645573
Immunisation; Newborn; Pneumococcal conjugate vaccine; Safety; Immunogenicity
21.  Responses to a Conjugate Pneumococcal Vaccine in Preterm Infants Immunized at 2, 3, and 4 Months of Age▿  
Clinical and Vaccine Immunology : CVI  2010;17(11):1810-1816.
Preterm infants are at an increased risk of invasive pneumococcal disease infection and, additionally, have a diminished response to Haemophilus influenzae type b (Hib) conjugate vaccines. There are little data examining the response of preterm infants to a seven-valent pneumococcal conjugate vaccine (PCV7). We examined the responses of preterm infants immunized at 2, 3, and 4 months of age to PCV7. A total of 133 preterm and 54 term infants were immunized with PCV7 and the Neisseria meningitidis group C (MCC), diphtheria, tetanus, pertussis, polio, and Hib vaccines. Pneumococcal serotype-specific IgG was measured by enzyme-linked immunosorbent assay (ELISA) pre- and postimmunization and at 12 months or following a booster of PCV7. Term and preterm responses were compared using linear and logistic regression analyses. Term infants had higher preimmunization geometric mean concentrations (GMCs) for all serotypes. Preterm infants had lower postimmunization GMCs for serotype 23F. Gestational age affected postimmunization GMCs for serotypes 4, 6B, and 23F. Preterm infants were as likely to have levels of ≥0.35 μg/ml as term infants for all serotypes except 23F. The proportions of infants with titers of ≥0.35 μg/ml for all 7 serotypes were comparable between groups. A total of 28 of 29 term infants who received a booster had levels of ≥0.35 μg/ml for all serotypes. One infant had undetectable levels for serotype 6B. Of the 32 preterm infants boosted, 9 had levels of <0.35 μg/ml for 1 serotype, and 1 had levels of <0.35 μg/ml for 2 serotypes. In nonboosted infants, GMCs for all serotypes except 6B had fallen by 12 months of age. These results support the need for a booster dose in the second year of life.
doi:10.1128/CVI.00214-10
PMCID: PMC2976084  PMID: 20861323
22.  Functional Antibodies Elicited by Two Heptavalent Pneumococcal Conjugate Vaccines in the Finnish Otitis Media Vaccine Trial▿  
Infection and Immunity  2007;75(4):1794-1800.
In the Finnish Otitis Media Vaccine Trial, the now-licensed pneumococcal conjugate vaccine containing polysaccharides conjugated to protein CRM197 (PncCRM) and the experimental pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine (PncOMPC), showed similar efficacy profiles against acute otitis media despite different antibody concentrations in sera. We now report the opsonophagocytic activities (OPA) in these sera. OPA, antibody concentration, and avidity for serotypes 6B, 19F, and 23F were determined in sera of infants who received either pneumococcal conjugate (PCV) or control vaccine at 2, 4, and 6 months of age and either the homologous or pneumococcal polysaccharide vaccine at 12 months of age. OPA varied by vaccine and serotype. The majority of PCV recipients had positive OPA after the fourth dose, while OPA was undetectable in the control group. Coinciding with the efficacy data, the concentration of antibodies required for 50% killing was low for 6B and high for 19F for both PCVs. Contradictory to the efficacy data, PncOMPC induced lower functional capacity to 23F than PncCRM. OPA correlated with antibody concentration, while avidity and functional capacity of antibodies showed no correlation. The OPA data provide valuable additional information for serotype-specific differences in protection and when evaluating serotype-specific immunogenicity and should thus be considered when defining serological correlates of protection.
doi:10.1128/IAI.01673-06
PMCID: PMC1865725  PMID: 17261612
23.  Invasive Pneumococcal Disease in Infants Younger Than 90 Days Before and After Introduction of PCV7 
Pediatrics  2013;132(1):e17-e24.
BACKGROUND:
Introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) changed the epidemiology of invasive pneumococcal disease (IPD). We evaluated the changes that occurred after PCV7 introduction among Utah infants aged 1 to 90 days, too young to be fully immunized.
METHODS:
We identified children <18 years with culture-confirmed IPD from 1997–2010. We analyzed demographic, clinical, and serotype data for infants aged 1–90 days. The pre– and post–vaccine introduction periods spanned 1997–2000 and 2001–2010, respectively.
RESULTS:
Of 513 children with IPD, 36 were 1 to 90 days and accounted for 7% of IPD cases in both the pre– and post–vaccine introduction period. The pre–vaccine IPD incidence rate was 5.0 per 100 000 live births, and was unchanged in the post–vaccine introduction period. IPD caused by PCV7 serotypes decreased by 74% (from 2.2 to 0.58 per 100 000), whereas non-vaccine serotype IPD increased by 57% (from 2.8 to 4.4 per 100 000). Sixteen infants (44%) required intensive care, and 3 (8%) died. Bacteremia without focus (56%) and meningitis (44%) were the predominant syndromes in the pre– and post–vaccine introduction periods, respectively. In the post–vaccine introduction period, serotype 7F was the most common serotype among infants and was responsible for 50% of meningitis.
CONCLUSIONS:
The incidence of IPD in Utah infants aged 1 to 90 days caused by PCV7 serotypes decreased after PCV7 introduction, but overall incidence was unchanged. In the post–vaccine introduction period, serotype 7F predominated in this age group and was associated with meningitis.
doi:10.1542/peds.2012-3900
PMCID: PMC3691535  PMID: 23733800
invasive pneumococcal disease; Streptococcus pneumoniae; infant; pneumococcal conjugate vaccine
24.  Differences in neonatal and postneonatal mortality by race, birth weight, and gestational age. 
Public Health Reports  1987;102(2):182-192.
In recent decades, neonatal and postneonatal mortality rates have declined overall in the United States. Yet, the mortality rates for black infants continue to be approximately twice those for white infants. With the use of data from 45 of the 53 vital statistics reporting areas that participated in the 1980 National Infant Mortality Surveillance project, we extended previous State analyses to describe differences, nationally, in neonatal and postneonatal mortality risks for black and white infants according to gestational age and birth weight. After restricting our analysis to single-delivery infants with known and plausible combinations of gestational age of 26 or more weeks and birth weights of 500 grams (g) or more, the neonatal mortality risk (NMR)--that is, the number of deaths to infants less than 28 days of life per 1,000 live births--for black infants was 1.6 times higher than the NMR for whites. This difference was largely explained by two findings: First, although the NMR was lower for black than for white infants with gestational ages of less than 38 weeks and birth weights less than 3,000 g, that advantage was heavily outweighed by the higher percentage of such births among blacks, accounting for roughly two-thirds of the overall difference in NMR between blacks and whites. Second, most of the remaining difference in NMR was accounted for by higher NMRs among black infants with gestational ages of 38 or more weeks and birth weights of 3,000 g or more. A comparison of the lowest mortality risk for any combination of birth weight and gestational age showed that the black NMR was 1.89 times higher than the white NMR. The postneonatal mortality risk (PNMR)--PNMR equals the number of deaths to infants 28 days to less than 1 year of life per 1,000 neonatal survivors--for black infants was 2.09 times the PNMR for white infants. Black infants had higher PNMRs than white infants for nearly all combinations of birth weight and gestational age. Higher PNMRs among infants with gestational ages of 38 or more weeks and birth weights of 2,500 g or more accounted for 43 percent of the difference in PNMR between black infants and white infants. Eliminating the U.S. black-white infant mortality disparity will require not only reducing the higher frequency of prematurity and low birth weight among black infants, but also improving the survival during both the neonatal and postneonatal periods of term black infants with normal birth weights.
PMCID: PMC1477813  PMID: 3104975
25.  The 13-valent pneumococcal conjugate vaccine (PCV13) elicits cross-functional opsonophagocytic killing responses in humans to Streptococcus pneumoniae serotypes 6C and 7A 
Vaccine  2011;29(41):7207-7211.
The introduction of a 7-valent pneumococcal conjugate vaccine (PCV7) in 2000 dramatically reduced the incidence of invasive pneumococcal disease (IPD) caused by the seven serotypes covered by the vaccine. Following the introduction of PCV7, which contains a serotype 6B conjugate, some decrease in IPD due to serotype 6A was noted suggesting that the serotype 6B conjugate provided some partial cross-protection against serotype 6A. However, no effect on serotype 6C was observed. In 2010, a pneumococcal conjugate vaccine with expanded serotype coverage (PCV13) was introduced that expanded the serotype coverage to 13 serotypes including serotype 6A. To assess whether the 6A conjugate in PCV13 could potentially induce functional anti-6C antibody responses, an opsonophagocytic assay (OPA) for serotype 6C was developed. Randomly chosen subsets of immune sera collected from infants receiving three doses of PCV7 or PCV13 were tested in OPA assays for serotype 6A, 6B and 6C. PCV7 immune sera demonstrated strong OPA responses, defined as percentage of subjects having an OPA titer ≥ 1:8, to serotype 6B (100% responders), partial responses to serotype 6A (70% responders) but only minimal responses to serotype 6C (22% responders). In contrast, PCV13 immune sera showed strong OPA responses to serotypes 6A (100% responders), 6B (100% responders) and 6C (96% responders). Furthermore, during pre-clinical work it was observed that serotype 7F (included in PCV13) and serotype 7A (not included in PCV13) shared serogroup-specific epitopes. To determine whether such epitopes also may be eliciting cross-functional antibody, PCV13 immune sera were also tested in serotype 7A and 7F OPA assays. All PCV13 immune sera demonstrated OPA responses to both of these serotypes. Taken together these results suggest that immunization with PCV13 has the potential to induce cross-protective responses to related serotypes not directly covered by the vaccine.
doi:10.1016/j.vaccine.2011.06.056
PMCID: PMC3170457  PMID: 21689707
Streptococcus pneumonia; opsonophagocytic killing assay; OPA; PCV13

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