Sylvia H. Yeh

Immunogenicity and Safety of 13-Valent Pneumococcal Conjugate Vaccine in Infants and Toddlers

BACKGROUND: 7-Valent pneumococcal conjugate vaccine (PCV7 [Prevnar, Wyeth Pharmaceuticals Inc, Philadelphia, PA], serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) is effective in preventing vaccine-serotype pneumococcal disease. 13-Valent pneumococcal conjugate vaccine (PCV13) (PCV7 serotypes plus 1, 3, 5, 6A, 7F, and 19A) was designed to provide broader pneumococcal disease coverage. We evaluated the immunogenicity and safety of PCV13 compared with PCV7. METHODS: Infants received PCV13 or PCV7 at ages 2, 4, 6, and 12 to 15 months with routine pediatric vaccinations. Pneumococcal anticapsular polysaccharide-binding immunoglobulin G responses and functional antipneumococcal opsonophagocytic activity were assessed 1 month after dose 3, before the toddler dose, and 1 month after the toddler dose. Safety and tolerability were also assessed. RESULTS: For the 7 common serotypes, PCV13-elicited immunoglobulin G titers were noninferior to those elicited by PCV7, although PCV13 responses were generally somewhat lower. PCV13 also elicited functional opsonophagocytic activity comparable with that elicited by PCV7. For the 6 additional serotypes in PCV13, PCV13 elicited binding and functional antibody levels notably greater than those in PCV7 recipients. After PCV13 immunization, concordance between antipolysaccharide and opsonophagocytic responses was noted for all 13 serotypes. The PCV13 toddler dose resulted in higher immune responses compared with infant-series doses. Safety and tolerability were comparable; reactogenicity was generally mild. CONCLUSIONS: PCV13 will be as effective as PCV7 in the prevention of pneumococcal disease caused by the 7 common serotypes and could provide expanded protection against the 6 additional serotypes. The PCV13 safety profile was comparable to that of PCV7.

Safety and immunogenicity of a pentavalent diphtheria, tetanus, pertussis, hepatitis B and polio combination vaccine in infants.

Introduction. The objectives of this study were to evaluate the safety and immunogenicity of a new combination vaccine (DTaP-HB-IPV) containing diphtheria, tetanus, acellular pertussis and hepatitis B (HB) and a new inactivated poliovirus vaccine (IPV) manufactured by GlaxoSmithKline (GSK). This vaccine was given in an all IPV or sequential IPV and oral polio vaccine (OPV) schedule. Another combination vaccine, DTaP-HB (GSK), was similarly evaluated given with OPV or IPV. Methods. Four hundred infants were randomized into one of four study groups and immunized at 2, 4 and 6 months of age. Group A received three doses of DTaP-HB-IPV; Group B received DTaP-HB-IPV at 2 and 4 months and DTaP-HB with OPV (Orimune) at 6 months; Group C received three doses of DTaP-HB with licensed IPV (IPOL) administered separately; Group D received separate doses of OPV, DTaP (Infanrix; GSK) and HB (Engerix; GSK). All subjects received conjugate Haemophilus influenzae type b vaccine (Hib) (OmniHIB) at 2, 4 and 6 months of age given at a separate injection site. Subjects who returned at 12 to 18 months of age (229) received booster immunization with DTaP and Hib. Safety was evaluated after each vaccine dose. Blood was drawn before the first dose and one month after the third dose as well as before and after the booster dose. Results. There were no vaccine-related serious adverse events in any group after any vaccine dose. Minor systemic and local adverse events were also not significantly different among the four groups after any dose. There were no differences in the immune response rates for Hib, HB, polio (types 1, 2 and 3), diphtheria, tetanus or pertussis antigens (pertussis toxin, filamentous hemagglutinin, pertactin) among groups, although there were some quantitative differences in specific antibody titers among groups. DTaP-HB-IPV and DTaP-HB combination vaccines had safety and immunogenicity equivalent to those of standard individually administered vaccines. The new IPV was not inferior to IPOL. Conclusion. Use of the pentavalent combination vaccine would greatly reduce the number of required injections during the first 2 years of life, thereby simplifying the immunization schedule, enhancing compliance and facilitating acceptance of additional injections engendered by introduction of newer vaccines.

The Bordetella type III secretion system effector BteA contains a conserved N-terminal motif that guides bacterial virulence factors to lipid rafts

The Bordetella type III secretion system (T3SS) effector protein BteA is necessary and sufficient for rapid cytotoxicity in a wide range of mammalian cells. We show that BteA is highly conserved and functionally interchangeable between Bordetella bronchiseptica, Bordetella pertussis and Bordetella parapertussis. The identification of BteA sequences required for cytotoxicity allowed the construction of non‐cytotoxic mutants for localization studies. BteA derivatives were targeted to lipid rafts and showed clear colocalization with cortical actin, ezrin and the lipid raft marker GM1. We hypothesized that BteA associates with the cytoplasmic face of lipid rafts to locally modulate host cell responses to Bordetella attachment. B. bronchiseptica adhered to host cells almost exclusively to GM1‐enriched lipid raft microdomains and BteA colocalized to these same sites following T3SS‐mediated translocation. Disruption of lipid rafts with methyl‐β‐cyclodextrin protected cells from T3SS‐induced cytotoxicity. Localization to lipid rafts was mediated by a 130‐amino‐acid lipid raft targeting domain at the N‐terminus of BteA, and homologous domains were identified in virulence factors from other bacterial species. Lipid raft targeting sequences from a T3SS effector (Plu4750) and an RTX‐type toxin (Plu3217) from Photorhabdus luminescens directed fusion proteins to lipid rafts in a manner identical to the N‐terminus of BteA.

A Bovine Parainfluenza Virus Type 3 Vaccine Is Safe and Immunogenic in Early Infancy

BACKGROUND A phase 2 trial was conducted to assess in young infants the safety, tolerability, infectivity, and immunogenicity of multiple doses of an intranasal vaccine using bovine parainfluenza virus type 3 (bPIV3). METHODS One hundred ninety-two healthy 2-month-old infants were randomized 1 : 1 : 1 to receive 1x10(5) median tissue culture infective dose (TCID(50)) bPIV3 vaccine, 1x10(6) TCID(50) bPIV3 vaccine, or placebo at 2, 4, 6, and 12-15 months of age. Safety information was collected by use of diary sheets and telephone interviews. Nasal wash and serum specimens were collected for assessment of infectivity and immunogenicity. RESULTS The safety profiles of both dosages of bPIV3 were similar to that of placebo, with the exception of fever with temperature of >/=38.1 degrees C after dose 2 only, occurring in 34% of the 1x10(5) TCID(50) group, 35% of the 1x10(6) TCID(50) group, and 12% of the placebo group (P<.01). No vaccine-related serious adverse events were reported. The cumulative vaccine infectivity (isolation of bPIV3 and/or bPIV3 seroconversion) after dose 3 was similar in the 2 vaccine groups (87% in the 1x10(5) TCID(50) group and 77% in the 1x10(6) TCID(50) group) (P=.46). Seroconversion rates after dose 3, assessed by means of hemagglutination inhibition assay, after adjustment for decrease in maternal antibody titers, were 67% in the 1x10(5) TCID(50) group, 57% in the 1x10(6) TCID(50) group, and 12% in the placebo group (P<.01). Isolation of bPIV3 was common after dose 1, dose 2, or dose 3, but only 1 of 51 participants in the vaccine groups had bPIV3 isolated after dose 4. CONCLUSIONS Multiple doses of bPIV3 vaccine were well tolerated and immunogenic in young infants.

Antibody Responses to Bovine Parainfluenza Virus Type 3 (PIV3) Vaccination and Human PIV3 Infection in Young Infants

A phase 2 clinical trial was conducted to evaluate the antibody responses to bovine parainfluenza virus type 3 (bPIV3) vaccination in young infants. Three groups were tested as follows: placebo (n=66) and 10(5) (n=64) or 10(6) (n=62) TCID(50) of bPIV3. The vaccine or placebo was administered intranasally at ages 2, 4, 6, and 12-15 months, and serum specimens were collected at ages 2, 6, 7, 12-15, and 13-16 months. Serum hemagglutination inhibition (HI) and IgA antibody titers against bPIV3 and human PIV3 (hPIV3) were measured. The results indicate that antibody responses to bPIV3 vaccination are more likely to be detected by the bPIV3 IgA and HI assays than by the hPIV3 IgA and HI assays, that bPIV3-induced antibody response can be differentiated from hPIV3-induced antibody response most reliably by comparing bPIV3 and hPIV3 HI titers, and that bPIV3 vaccine prevents vaccine recipients from developing antibody profiles of hPIV3 primary infection.

Heptavalent pneumococcal vaccine conjugated to outer membrane protein of Neisseria meningitidis serogroup b and nasopharyngeal carriage of Streptococcus pneumoniae in infants

BACKGROUND Streptococcus pneumoniae (Sp) is an important bacterial pathogen in children. Nasopharyngeal (NP) colonization of S. pneumoniae is necessary for person-to-person transmission and often precedes invasive disease. METHODS NP carriage of Sp was studied in 49 infants following administration of a heptavalent pneumococcal conjugate vaccine (PCV) conjugated to the outer membrane protein of serogroup b Neisseria meningitidis (vaccine serotypes: 4, 6B, 9V, 14, 18C, 19F, 23F). The vaccine was administered at 2, 4, 6, and 12 months of age and carriage rates were compared to a concurrent group of 32 infants not given PCV and evaluated over the first 15 months of life. RESULTS Overall, Sp was isolated in 86/367 (23%) of NP cultures and 49% of infants. Serotype 23F was significantly less prevalent in the PCV group (1.9%) than the control group (16.1%) (P<0.05). Analysis of the proportion of children with prevalent carriage or acquisition of carriage did not differ between groups when evaluated by age or serotype. We noted, however, decreased acquisition and carriage in the vaccine group 1 month following the 12 month dose of PCV for vaccine serotypes (76 and 52% reduction, respectively), but this did not reach statistical significance (P=0.3). Adjustment for age, daycare and antibiotic use by multivariate modeling revealed no difference in carriage of vaccine containing serotypes or non-vaccine serotypes between groups. CONCLUSION We did not show a significant effect of this heptavalent PCV on NP carriage. Further study of this issue, including a larger population size, is needed.

The development of 13-valent pneumococcal conjugate vaccine and its possible use in adults.

Introduction: Worldwide, Streptococcus pneumoniae causes significant morbidity and mortality. The 23-valent pneumococcal polysaccharide vaccine (PPSV23) has been recommended for use in persons aged 65 years and over and in adults with certain chronic medical conditions. Pneumococcal conjugate vaccines (PCVs) have been developed for use in infants and children aged less than 5 years, and are being studied for use in adult populations. Areas covered: The different types of pneumococcal vaccines are discussed. Studies comparing PPSV23 and PCVs, as well as the results of the widespread use of 7-valent PCV are covered. The possible extension of the use of 13-valent PCV to adults, particularly to vulnerable populations, is discussed. The MEDLINE database was used to identify relevant studies from literature published in English between January 1977 and January 2011. All studies of adults aged over 18 years were considered for the review. Expert opinion: Elderly individuals and adults with chronic medical conditions who are at increased risk for pneumococcal disease would benefit from more effective prevention than is provided by the currently recommended PPSV23.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine in children previously immunized with 7-valent pneumococcal conjugate vaccine.

Background: The 7-valent pneumococcal conjugate vaccine (PCV7) has proven highly effective in preventing diseases caused by Streptococcus pneumoniae; however, in some regions, serotype coverage is limited. A recently licensed 13-valent PCV (PCV13) was developed to provide additional coverage globally. Children previously vaccinated with PCV7 could benefit from supplemental vaccination with PCV13 to provide protection against the 6 additional serotypes in PCV13. This open-label study evaluated the immunogenicity and safety of administering PCV13 to healthy children previously vaccinated with PCV7. Methods: Children between 15 months and 2 years of age (group 1) received 2 doses of PCV13; children between 2 and 5 years (group 2) received 1 dose. Antibodies (immunoglobulin G) against the polysaccharide antigens in PCV13 were measured before vaccination and 1 month after the final dose. Solicited local and systemic adverse events (AEs) were collected for 7 days postvaccination. Unsolicited and serious AEs were collected throughout. Results: A total of 284 subjects (group 1: n = 109; group 2: n = 175) had blood available for testing. Antipneumococcal immunoglobulin G geometric mean fold rises ranged from 2- to 19-fold for the PCV7 serotypes and from approximately 2- to 124-fold for the 6 additional serotypes. Additionally, postvaccination titers in excess of 0.35 &mgr;g/mL, the serologic correlate of immunity against pneumococcus for children, occurred in ≥98% of subjects in both groups for 12 of the 13 serotypes in PCV13. Slightly lower percentage of subjects, 94.5% and 92% of subjects in group 1 and group 2, respectively, had postvaccine titers for serotype 3 exceeding the serologic correlate of immunity. Reactogenicity was typically mild and self-limited, and unsolicited AEs reported were generally consistent with common childhood illnesses. Conclusion: PCV13 was safe and immunogenic when administered to children who had previously received PCV7, and can be used for supplemental vaccination to provide additional protection against the 6 additional serotypes.

Pertussis: persistent pathogen, imperfect vaccines.

Routine use of pertussis vaccines has diminished the incidence of this disease but has not eliminated the pathogen. Pertussis remains a significant cause of disease in both very young infants and in the adolescent and adult populations. Acellular pertussis vaccines have fewer adverse reactions compared with whole-cell pertussis vaccines. Although efficacious against severe disease, current vaccines may not be as efficacious against milder forms of infection. New methodologies for understanding disease pathogenesis, immune responses and vaccine development are needed to effectively interrupt continued transmission of this pathogen.

Strategies for development of combination vaccines.

Background. The increasing complexity of the recommended childhood immunization schedule has resulted in the need for combination vaccines. Methods. Through an extensive review of the current literature, various strategies and issues related to the development of combination vaccines are discussed. Results. Issues that should be considered when combining vaccine components include the current childhood immunization schedule, compatibility of components, availability of antigens for targeted diseases, safety, efficacy, immunogenicity and route of delivery. When choosing an appropriate combination of antigen(s)/serotype(s) for a global or national formulation, careful consideration must be made when selecting serotypes to combine depending on the market or area of use. It is important to know that potential interactions can involve other components of the vaccines, including buffers, adjuvants and preservatives. The Food and Drug Administration requires that the combination not only have immunogenicity comparable with those of the component vaccines, but that its safety profile be comparable with the most reactogenic component. The Food and Drug Administration also recommends that a test of noninferiority be performed, such that the combination performs similarly to the separate components with regard to antibody titers. Conclusions. Combination vaccines are critical to the success of vaccination programs, and each new combination must be carefully studied to ensure comparable safety and immunogenicity of the individual components.