Lindsey Ashton

Antibody Responses to Nasopharyngeal Carriage of Streptococcus pneumoniae in Adults: A Longitudinal Household Study

BACKGROUND Natural immunity to Streptococcus pneumoniae is thought to be induced by exposure to S. pneumoniae or cross-reactive antigens. No longitudinal studies of carriage of and immune responses to S. pneumoniae have been conducted using sophisticated immunological laboratory techniques. METHODS We enrolled 121 families with young children into this study. Nasopharyngeal (NP) swabs were collected monthly for 10 months from all family members and were cultured in a standard fashion. Cultured S. pneumoniae isolates were serotyped. At the beginning (month 0) and end (month 10) of the study, venous blood was collected from family members >18 years old. Serotype-specific antipolysaccharide immunoglobulin G (IgG) and functional antibody and antibodies to pneumolysin, pneumococcal surface protein A (PspA), and pneumococcal surface antigen A (PsaA) were measured in paired serum samples. RESULTS Levels of anticapsular IgG increased significantly after carriage of serotypes 9V, 14, 18C, 19F, and 23F by an individual or family member. For serotype 14, a higher level of anticapsular IgG at the beginning of the study was associated with reduced odds of carriage (P = .006). There was a small (approximately 20%) but significant increase in titers of antibodies to PsaA and pneumolysin but no change in titers of antibody to PspA. CONCLUSIONS Adults respond to NP carriage by mounting anticapsular and weak antiprotein antibody responses, and naturally induced anticapsular IgG can prevent carriage.

Immunogenicity and boosting after a reduced number of doses of a pneumococcal conjugate vaccine in infants and toddlers.

Background: The minimum number of doses of pneumococcal conjugate vaccine required for protection is not known. We studied the immunogenicity of a reduced schedule in infants and toddlers. Methods: U.K. infants were given either 2 or 3 doses (at 2 and 4 or 2/3/4 months of age) of a 9-valent pneumococcal conjugate vaccine (9VPCV) followed by boosting at 12 months of age. In a separate study, toddlers (12 months) received 1 or 2 doses (2 months apart) of 9VPCV followed by pneumococcal polysaccharide vaccine at 18 months of age. Results: For infants, serotype-specific IgG geometric mean concentrations were similar post-primary immunization between the groups with both showing avidity maturation and similar booster responses. For toddlers, the primary response to 4 of the 9 serotypes was lower in the 1- compared with the 2-dose group (type 6B, 0.77 versus 7.1; type 14, 4.67 versus 14.98; type 19F, 5.05 versus 7.75; type 23F, 2.48 versus 5.05), although for all serotypes booster responses were similar between groups, and the postprimary responses in the 1-dose group were at least as high as those after infant immunization. Conclusions: The 2-dose infant priming schedule of 9VPCV is comparable with the 3-dose schedule and may thus be equally protective, whereas 1 dose in toddlers may suffice for a catch-up.

The immunogenicity of 7-valent pneumococcal conjugate vaccine versus 23-valent polysaccharide vaccine in adults aged 50-80 years.

BACKGROUND Infections with pneumococci are a major cause of morbidity and mortality in the elderly population. Although 23-valent pneumococcal polysaccharide vaccine (PPV) is recommended for elderly persons, the potential benefits of conjugate vaccine use in this age group remain unclear. METHODS We performed an open-label, randomized study that compared 7-valent pneumococcal conjugate vaccine (7vPnC) with PPV in 599 adults aged 50-80 years. Vaccinees received either 1 dose of 7vPnC or PPV or 1 dose of 7vPnC followed by a dose of 7vPnC or PPV 6 months later. Groups were stratified so they contained similar numbers of individuals aged 50-59, 60-69, and 70-80 years. Concentrations of immunoglobulin G specific for the serotypes in 7vPnC were measured before and 4-6 weeks after each vaccination and 1 year after enrollment. RESULTS Although baseline antibody levels were slightly lower in the older age groups, responses (fold rises) to either vaccine did not depend on age. Single-dose 7vPnC was superior for only 3 serotypes. Administration of a second dose of PPV or 7vPnC was similarly immunogenic in adults primed with 7vPnC, and titers after a second dose were similar to the first. CONCLUSIONS Pneumococcal vaccines retain their immunogenicity when administered into the eighth decade of life, but a second dose, when assessed by antibody titers alone, has little utility. 7vPnC vaccines do not lead to subsequent hyporesponsiveness. CLINICAL TRIALS REGISTRATION http://www.clinicaltrials.gov/NCT00197821.

Antibody Persistence and Immunological Memory at Age 4 Years after Meningococcal Group C Conjugate Vaccination in Children in the United Kingdom

Antibody persistence and immunological priming for 2 formulations of a meningococcal group C (menC) conjugate (MCC) vaccine (containing 2 or 10 microg of menC polysaccharide) administered at 2, 3, and 4 months of age was investigated by boosting vaccine recipients at age 13-16 months or 4 years with 10 microg of unconjugated menC polysaccharide. At age 4 years, geometric mean titers (GMTs) and concentrations of menC-specific immunoglobulin G and serum bactericidal antibody (SBA) had decreased to prevaccination levels. Geometric mean avidity indices increased after the primary vaccination until age 13-16 months and then remained constant until age 4 years. One month after boosting at age 4 years, menC immunoglobulin G and SBA levels increased significantly. The postbooster SBA GMT for the 2-microg vaccination (2181.2; 95% confidence interval [CI], 975.9-4875.1) was 2-fold higher than that for the 10-microg vaccination (931.6; 95% CI, 338.0-2568.1). This is the first demonstration of immunological memory at 4 years of age in children receiving MCC vaccine on the United Kingdoms 2/3/4-month immunization schedule.

Immunogenicity of, and immunologic memory to, a reduced primary schedule of meningococcal C-tetanus toxoid conjugate vaccine in infants in the United kingdom.

ABSTRACT It has been previously shown that one of the three meningococcal C conjugate (MCC) vaccines introduced in the United Kingdom proved highly immunogenic after the first dose of a three-dose schedule, with evidence of immune memory after dose 3. Thus, in infants a one- or two-dose schedule of this MCC vaccine, conjugated to tetanus toxoid (TT), may suffice. Healthy infants (n = 586) were randomized to receive either one (group 1), two (group 2), or three (group 3) doses of MCC-TT vaccine with a 10-μg polysaccharide booster given at 13 to 14 months of age. Serum bactericidal antibody (SBA) levels were measured by utilizing rabbit complement (rSBA), meningococcal C-specific immunoglobulin G (IgG), and avidity indices (AIs). For groups 1, 2, and 3, the percentages of infants with an rSBA level of ≥8 against strain C11 were 98.4, 100, and 99.4%, respectively. Infants in group 1 with prevaccination rSBA titers of ≥8 had post-primary MCC rSBA geometric mean titers (GMTs) significantly lower than those infants with prevaccination rSBA titers of <8. One dose of MCC-TT vaccine given to infants at 2 months of age yielded significantly lower SBA GMTs and geometric mean AIs (GMAIs) than two or three doses but elicited a significantly greater response after boosting, as reflected by rSBA levels and GMAI. This study provides the first evidence that the number of doses of MCC-TT used in infant immunization schedules could be decreased.

Critical Differences between Pneumococcal Polysaccharide Enzyme-Linked Immunosorbent Assays with and without 22F Inhibition at Low Antibody Concentrations in Pediatric Sera

ABSTRACT A comparative study was conducted between two laboratories in order to evaluate the differences between two enzyme-linked immunosorbent assay (ELISA) techniques for the detection of pneumococcal anti-capsular polysaccharide antibodies. One laboratory used an assay including heterologous 22F polysaccharide inhibition, and the other laboratory employed a non-22F reference assay. After conjugate immunization, 30 pediatric post-primary immunization sera with antipolysaccharide concentrations ranging from <0.05 to 15 μg/ml were analyzed. Aggregate reverse cumulative distribution curves combining concentrations of antibodies against serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F revealed similar results for both methods at antibody levels of >1 μg/ml. However, at antibody levels of <1 μg/ml, the distribution curve measured with the 22F inhibition ELISA shifted toward lower levels. This observation suggests that the 22F inhibition assay is more specific at low antibody concentrations, which was confirmed by heterologous polysaccharide inhibition experiments. Translation of low antibody levels suggested that the proposed threshold concentration of 0.35 μg/ml determined with the non-22F ELISA corresponded to a concentration of 0.20 μg/ml with the 22F inhibition ELISA. Pneumococcal antipolysaccharide ELISA including 22F inhibition can be recommended as a reference method.

Immunogenicity of a Reduced Schedule of Pneumococcal Conjugate Vaccine in Healthy Infants and Correlates of Protection for Serotype 6B in the United Kingdom

Background: Pneumococcal conjugate vaccine (PCV) was introduced in the United Kingdom immunization schedule in September 2006. This study was conducted to establish the immunogenicity of licensed PCV (Prevenar) at a reduced, 2 priming dose schedule (2+1) and to evaluate functional responses in the context of vaccine effectiveness. Methods: Infants were randomized to receive PCV at 2 and 3 months or 2 and 4 months of age. Boosters were administered at the same time as Haemophilus influenzae type B/meningococcal C conjugate and Measles, Mumps and Rubella or with Measles, Mumps and Rubella alone (www.ClinicalTrials.gov NCT00197808). Results: PCV at 2/3 months of age was poorly immunogenic and recruitment to this arm was terminated. PCV at 2/4 months of age resulted in lower than expected responses to serotypes 6B and 23F. Functional analysis of serotype 6B by OPA revealed that an enzyme-linked immunosorbent assay cutoff of 0.2 &mgr;g/mL was a better predictor of OPA positivity than a cut off of 0.35 &mgr;g/mL. PCV booster responses were excellent and no interference from concomitant vaccines was noted. Conclusions: An interval of at least 8 weeks is required when starting PCV vaccination at 2 months of age although not all serotypes are equally immunogenic. Correlates of protection derived from enzyme-linked immunosorbent assay values may not be equally appropriate for all serotypes as illustrated by results for 6B in this study.

Effects of Prior Polysaccharide Vaccination on Magnitude, Duration, and Quality of Immune Responses to and Safety Profile of a Meningococcal Serogroup C Tetanus Toxoid Conjugate Vaccination in Adults

ABSTRACT Extensive use of meningococcal AC polysaccharide (MACP) vaccines has raised concerns about induction of immunologic hyporesponsiveness to C polysaccharide. We investigated the immunogenicity and safety of a meningococcal C-tetanus conjugate (MCC-TT) vaccine in naïve adults and prior MACP vaccinees. Laboratory staff (n = 113) were recruited; 73 were naïve to meningococcal vaccination, and 40 had previously received ≥1 dose of MACP vaccine. Blood was taken prior to MCC-TT vaccination and 1 week, 1 month, and 6 months later. At each time point, proportions of subjects with serum bactericidal antibody (SBA) titers of ≥8 or ≥128 were similar (P > 0.46); >94% of subjects achieved titers of ≥128 at 1 month. However, the geometric mean titer (GMT) of SBA at 1 month was higher in the naïve (1,757; 95% confidence interval [95% CI], 1,102 to 2,803) than in the previously vaccinated (662; 95% CI, 363 to 1,207) group (P = 0.02), and similarly at 6 months (P < 0.001). Conversely, geometric mean concentrations (GMCs) of serogroup C-specific immunoglobulin G (IgG) were significantly higher in the previously vaccinated group pre-MCC-TT and at 1 week; the groups were similar at 1 month, and there was some evidence that the GMC for the previously vaccinated group was higher at 6 months. Qualitative differences in antibodies between groups were demonstrated by using the SBA/IgG ratio, though avidity measures were similar for the two groups throughout the study. MCC-TT was well tolerated, with similar safety profiles in the two groups. Pain in the arm and headache were the most frequently reported events following vaccination. The study shows that MCC-TT is safe and immunogenic in naïve and previously MACP-vaccinated adults, though the magnitude and persistence of postvaccination SBA responses in the latter group were lower.

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.

Pediatric invasive pneumococcal disease caused by vaccine serotypes following the introduction of conjugate vaccination in Denmark.

A seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the Danish childhood immunization program (2+1 schedule) in October 2007, followed by PCV13 starting from April 2010. The nationwide incidence of IPD among children younger than 5 years nearly halved after the introduction of PCV7 in the program, mainly due to a decline in IPD caused by PCV7-serotypes. We report the results from a nationwide population-based cohort study of laboratory confirmed IPD cases in children younger than 5 years during October 1, 2007 to December 31, 2010 and describe the characteristics of children suspected to present with a vaccine failure. The period between April 19 and December 31, 2010 was considered a PCV7/PCV13 transitional period, where both vaccines were offered. We identified 45 episodes of IPD caused by a PCV7 serotype (23% of the total number) and 105 (55%) caused by one of the 6 additional serotypes in PCV13. Ten children had received at least one PCV7 dose before the onset of IPD caused by a PCV7 serotype. Seven children were considered to be incompletely vaccinated before IPD, but only three cases fulfilled the criteria of vaccine failure (caused by serotypes 14, 19F and 23F). One case of vaccine failure was observed in a severely immunosuppressed child following three PCV7 doses, and two cases were observed in immunocompetent children following two infant doses before they were eligible for their booster. None of the IPD cases caused by the additional PCV13 serotypes had been vaccinated by PCV13 and there were therefore no PCV13-vaccine failures in the first 8-months after PCV13 introduction in Denmark.