Peter C. Giardina

A randomized, double-blind trial to evaluate immunogenicity and safety of 13-valent pneumococcal conjugate vaccine given concomitantly with trivalent influenza vaccine in adults aged ≥65 years

This randomized, double-blind study evaluated concomitant administration of 13-valent pneumococcal conjugate vaccine (PCV13) and trivalent inactivated influenza vaccine (TIV) in adults aged ≥65 years who were naïve to 23-valent pneumococcal polysaccharide vaccine. Patients (N=1160) were randomized 1:1 to receive PCV13+TIV followed by placebo, or Placebo+TIV followed by PCV13 at 0 and 1 months, with blood draws at 0, 1, and 2 months. Slightly lower pneumococcal serotype-specific anticapsular polysaccharide immunoglobulin G geometric mean concentrations were observed with PCV13+TIV relative to PCV13. Concomitant PCV13+TIV demonstrates acceptable immunogenicity and safety compared with either agent given alone.

Immunogenicity, Safety, and Tolerability of 13-Valent Pneumococcal Conjugate Vaccine Followed by 23-Valent Pneumococcal Polysaccharide Vaccine in Recipients of Allogeneic Hematopoietic Stem Cell Transplant Aged ≥2 Years: An Open-Label Study

Severe Streptococcus pneumoniae infections are frequent complications after hematopoietic stem cell transplant (HSCT). A 3-dose regimen of 13-valent pneumococcal conjugate vaccine, starting 3–6 months after HSCT and followed by a booster dose, may be required for adequate protection.

Randomized, Controlled Trial of a 13-Valent Pneumococcal Conjugate Vaccine Administered Concomitantly with an Influenza Vaccine in Healthy Adults

ABSTRACT A randomized, double-blind, phase 3 trial evaluated the immunogenicity, safety, and tolerability of a 13-valent pneumococcal conjugate vaccine (PCV13) coadministered with trivalent inactivated influenza vaccine (TIV) in pneumococcal vaccine-naive adults. Participants ages 50 to 59 years (n = 1,116) received TIV with PCV13 (group 1) or placebo (group 2) (1:1 randomization); 1 month later, group 1 received placebo and group 2 received PCV13. A hemagglutination inhibition (HAI) assay for TIV and a standardized enzyme-linked immunosorbent assay for pneumococcal serotype-specific immunoglobulin G (IgG) were performed and opsonophagocytic activity (OPA) titers (assessed post hoc) were measured at baseline and 1 and 2 months postvaccination. The rises in HAI assay geometric mean titer (GMT) and percentage of participants in groups 1 and 2 with ≥4-fold increases in HAI responses (A/H1N1, 84.0% and 81.2%, respectively; A/H3N2, 71.1% and 69.5%, respectively; and B, 60.6% and 60.3%, respectively) were similar. In group 1, all serotypes met the predefined IgG geometric mean concentration (GMC) ratio noninferiority criterion relative to group 2, but GMCs were lower in group 1 than group 2. When comparing group 1 with group 2, 5 serotypes did not meet the OPA GMT ratio noninferiority criterion, and OPA GMTs were significantly lower for 10 serotypes. PCV13 injection site reactions were similar and mostly mild in both groups. Systemic events were more frequent in group 1 (86.2%) than group 2 (76.7%; P < 0.001); no vaccine-related serious adverse events occurred. Coadministration of PCV13 and TIV was well tolerated but associated with lower PCV13 antibody responses and is of unknown clinical significance. Given the positive immunologic attributes of PCV13, concomitant administration with TIV should be dictated by clinical circumstances.

A phase 1, randomized, open-label, active-controlled trial to assess the safety of a meningococcal serogroup B bivalent rLP2086 vaccine in healthy adults

Neisseria meningitidis serogroup B (MnB) is a significant cause of invasive meningococcal disease, but no broadly protective vaccine is yet approved. We assessed the safety and immunogenicity of a bivalent MnB vaccine composed of lipidated subfamily A and B variants of recombinant LP2086 (rLP2086, also known as factor H binding protein, fHBP). Forty-eight adults, ages 18–40 y, were randomized to receive 60, 120 or 200 μg of the bivalent rLP2086 vaccine or control at 0, 2 and 6 mo. Immunogenicity was assessed by rLP2086-specific immunoglobulin G (IgG) geometric mean titers for subfamily A and B proteins. Safety was determined by laboratory assessments of blood and urine and by reporting of solicited and unsolicited adverse events (AEs). The bivalent rLP2086 vaccine elicited high IgG titers following the second and third vaccination at all dose levels. In each of the four study arms, 11 of the 12 participating subjects reported ≥ 1 AE, and no serious AEs were reported. Local and systemic reactions were mainly mild to moderate. Laboratory abnormalities (including increased sodium, decreased neutrophils, and proteinuria) were not associated with clinical events and were not considered to be related to the study vaccine. Vaccinations were generally well-tolerated. Strong IgG antibody responses and the absence of clinically significant laboratory abnormalities support further development of the bivalent rLP2086 vaccine (www.clinicaltrials.gov; identifier: NCT00879814).

Evaluation of Approaches to Monitor Staphylococcus aureus Virulence Factor Expression during Human Disease

Staphylococcus aureus is a versatile pathogen of medical significance, using multiple virulence factors to cause disease. A prophylactic S. aureus 4-antigen (SA4Ag) vaccine comprising capsular polysaccharide (types 5 and 8) conjugates, clumping factor A (ClfA) and manganese transporter C (MntC) is under development. This study was designed to characterize S. aureus isolates recovered from infected patients and also to investigate approaches for examining expression of S. aureus vaccine candidates and the host response during human infection. Confirmation of antigen expression in different disease states is important to support the inclusion of these antigens in a prophylactic vaccine. Hospitalized patients with diagnosed S. aureus wound (27) or bloodstream (24) infections were enrolled. Invasive and nasal carriage S. aureus isolates were recovered and characterized for genotypic diversity. S. aureus antigen expression was evaluated directly by real-time, quantitative, reverse-transcriptase PCR (qRT-PCR) analysis and indirectly by serology using a competitive Luminex immunoassay. Study isolates were genotypically diverse and all had the genes encoding the antigens present in the SA4Ag vaccine. S. aureus nasal carriage was detected in 55% of patients, and in those subjects 64% of the carriage isolates matched the invasive strain. In swab samples with detectable S. aureus triosephosphate isomerase housekeeping gene expression, RNA transcripts encoding the S. aureus virulence factors ClfA, MntC, and capsule polysaccharide were detected by qRT-PCR. Antigen expression was indirectly confirmed by increases in antibody titer during the course of infection from acute to convalescent phase. Demonstration of bacterial transcript expression together with immunological response to the SA4Ag antigens in a clinically relevant patient population provides support for inclusion of these antigens in a prophylactic vaccine.

Human antibody responses to the meningococcal factor H binding protein (LP2086) during invasive disease, colonization and carriage

Recombinant forms of Neisseria meningitidis factor H binding protein (fHBP) are undergoing clinical trials in candidate vaccines against serogroup B meningococcal disease. Little is known, however, about the host response to fHBP during natural carriage and disease. Here we report a longitudinal study of the antibody response to fHBP in healthy meningococcal carriers and non-carriers, and in patients with invasive meningococcal disease. Using a highly sensitive quantitative immunoassay, anti-fHBP antibodies were detected in sera from all healthy carriers and non-carriers. Carriers had significantly higher anti-fHBP antibody concentrations than non-carriers. Antibody responses similar to those seen in non-carrier subjects were detected in the sera of patients with invasive disease upon their admission to the hospital. The serum anti-fHBP antibody concentrations in these patients generally rose to reach levels similar to those seen in carriers. No correlation between levels of surface fHBP expressed in vitro by the infecting N. meningitidis strain and the magnitude of antibody responses was observed. These data suggest that fHBP is expressed in vivo during both carriage and invasive disease at levels high enough to elicit a robust antibody response.

Immunogenicity of a combination vaccine containing diphtheria toxoid, tetanus toxoid, three-component acellular pertussis, hepatitis B, inactivated polio virus, and Haemophilus influenzae type b when given concomitantly with 13-valent pneumococcal conjugate vaccine.

Two randomized trials of 13-valent pneumococcal conjugate vaccine (PCV13) relative to PCV7 evaluated the immune responses of coadministered antigens comprising Infanrix(®) hexa/Infanrix(®)-IPV+Hib (diphtheria, tetanus, 3-component acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b). After the 3-dose infant series, immunogenic noninferiority was demonstrated for all concomitantly administered antigens between the PCV13 and PCV7 groups. All antigens elicited good booster responses after the toddler dose except pertussis toxoid; however, 99.6% subjects achieved pertussis toxoid protective antibody level ≥5EU/mL in both groups. These results support the concomitant administration of PCV13 and Infanrix hexa/Infanrix-IPV+Hib as part of routine immunization schedules.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine given to Korean children receiving routine pediatric vaccines

Background: The immunogenicity and safety of 13-valent and 7-valent pneumococcal conjugate vaccines (PCV13 and PCV7) were compared when administered with routine vaccines in Korea. Methods: Healthy infants (n = 180) were randomly assigned (1:1) to receive PCV13 or PCV7 at 2, 4, 6 (infant series) and 12 months (toddler dose). Immune responses 1 month after the infant series and toddler dose were measured by enzyme-linked immunosorbent assay and opsonophagocytic activity (OPA) assay. IgG antibody geometric mean concentrations and OPA functional antibody geometric mean titers were calculated. Safety was assessed. Results: After the infant series, for the 7 common serotypes, proportions of responders with IgG concentrations ≥0.35 µg/mL were comparable (≥97.6%) between groups; IgG geometric mean concentrations and OPA geometric mean titers were generally similar, but tended to be lower in the PCV13 group for some serotypes. For the 6 serotypes unique to PCV13, IgG geometric mean concentrations and OPA geometric mean titers were notably higher in the PCV13 group. Importantly, although PCV7 elicited IgG antibodies to PCV13 serotypes 5 and 19A, OPA responses were minimal, whereas serotype 6A elicited both IgG and OPA responses. These observations are consistent with at least some protection by PCV7 against 6A-mediated invasive pneumococcal disease, but no cross-protection for serotypes 5 and 19A. The toddler dose elicited higher IgG and OPA responses than postinfant series responses for most serotypes; however, for serotypes 3 and 14 only OPA responses were increased posttoddler dose. Vaccine safety profiles were similar. Conclusions: PCV13 is safe and immunogenic in Korean children. PCV13 should provide broader protection than PCV7.

13-Valent Pneumococcal Conjugate Vaccine (PCV13) in Preterm Versus Term Infants

OBJECTIVES: This study evaluated the immune response and safety profile of 13-valent pneumococcal conjugate vaccine (PCV13) in preterm infants compared with term infants. METHODS: This Phase IV, open-label, 2-arm, multicenter, parallel-group study enrolled 200 healthy infants (preterm, n = 100; term, n = 100) aged 42 to 98 days. All subjects received PCV13 at ages 2, 3, 4 (infant series), and 12 (toddler dose [TD]) months, together with routine vaccines (diphtheria-tetanus-acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b vaccine and meningococcal group C conjugate vaccine). RESULTS: Most subjects achieved an anticapsular immunoglobulin G (IgG) antibody concentration ≥0.35 μg/mL for all serotypes: >85% after the infant series (except preterm infants for serotypes 5, 6A, and 6B) and >97% after TD (except for serotype 3). Preterm infants had overall lower IgG geometric mean concentrations compared with term infants; however, geometric mean fold increases after TD were similar for all serotypes. Opsonophagocytic activity results were consistent with IgG results and titers increased after TD in both groups for all serotypes, including serotype 3. PCV13 was generally well tolerated, with similar safety profiles in all preterm subgroups. CONCLUSIONS: Immune responses were lower in preterm infants than in term infants. However, the majority of subjects in both groups achieved both pneumococcal serotype-specific IgG antibody levels after the infant series that exceeded the World Health Organization–established threshold of protection and functional antibody responses. Responses were uniformly higher after TD, reinforcing the importance of a timely booster dose. PCV13 was well tolerated regardless of gestational age.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in healthy infants in Japan.

Background: A 13-valent pneumococcal conjugate vaccine (PCV13) containing 6 additional serotypes not included in the 7-valent PCV has been developed to broaden protection against Streptococcus pneumoniae, which is responsible for over 500,000 deaths annually worldwide in children <5 years of age. This study in Japanese infants evaluated the immunogenicity and safety of PCV13 given subcutaneously, the standard route for infant vaccination in Japan. Methods: This phase 3, single-arm, open-label study was conducted at 25 sites. Subjects received PCV13 as a 3-dose infant series and a toddler dose. Parents/legal guardians recorded local reactions and systemic events after each vaccination. The proportion of subjects with serotype-specific antipneumococcal polysaccharide immunoglobulin (Ig)G antibody concentrations ≥0.35 µg/mL was calculated before and 1 month after the infant series and toddler dose. Results: A total of 193 subjects enrolled. The proportion of subjects achieving pneumococcal IgG antibody concentrations ≥0.35 µg/mL was ≥97.2% for all 13 pneumococcal serotypes 1 month after the infant series and 98.9–100% after the toddler dose. IgG geometric mean concentrations were 2.57–14.69 µg/mL after the infant series and 2.06–16.33 µg/mL after the toddler dose. IgG geometric mean concentrations increased from pre- to posttoddler dose by ≥2.8-fold, demonstrating a booster effect. Local reactions and fever were generally mild or moderate in severity. Conclusions: PCV13 was immunogenic for all serotypes and had a favorable safety profile when administered subcutaneously to Japanese infants. PCV13 should offer broader serotype protection than 7-valent PCV in preventing pneumococcal disease in Japanese children.