Safety monitoring in vaccine development and immunization.

The development of vaccines has been one of the most important achievement in preventive medicine. As the incidence of vaccine-preventable diseases is reduced by immunization, general public becomes increasingly concerned about the safety associated with vaccine. Vaccine safety is extensively evaluated through animal safety studies, clinical trials, during manufacturing processes, and postlicensure surveillance. Safety monitoring in postlicensure surveillance has relied on passive reporting system and epidemiological studies, including Vaccine Adverse Event Reporting System (VARES), Vaccine Safety Datalink (VSD) Project and others. Approximately 10,000 reports per year are submitted to VAERS. About 15% of these describe serious events and 85% of reports are classified as not-serious events. The system analyzed frequently reported adverse reactions, rare events, intussusception after rotavirus vaccine, cases of sudden infant death syndrome (SIDS), and safety of various vaccines. The evidence for a causal relationship with vaccines can be classified into five categories: no evidence, evidence was inadequate to accept or reject, evidence favors rejection, evidence favors a causal relationship, and evidence established. Future challenges involve improving survey and monitoring system of adverse events after immunization, enhancing vaccine safety research and vaccine risk communication, and possibility of increased reactogenicity in new and combined vaccines.

Mucosal immunity induced by pneumococcal glycoconjugate.

Host defenses against Streptococcus pneumoniae involve opsonophagocytosis mediated by antibodies and complement. Because the pneumococcus is a respiratory pathogen, mucosal immunity may play an important role in the defense against infection. The mechanism for protection in mucosal immunity consists of induction of immunity by the activation of lymphocytes within the mucosal-associated lymphoid tissues, transport of antigen-specific B and T cells from inductive sites through bloodstream and distribute to distant mucosal effector sites. Secretory IgA is primarily involved in protection of mucosal surfaces. Mucosal immunization is an effective way of inducing immune responses at mucosal surfaces. Several mucosal vaccines are in various stages of development. A number of mucosal adjuvants have been proposed. CpG oligodeoxynucleotide (ODN) has been shown to be an effective mucosal adjuvant for various antigens. Mucosal immunity induced by intranasal immunization was studied with a pneumococcal glycoconjugate, using CpG ODN as adjuvant. Mice immunized with type 9V polysaccharide (PS) conjugated to inactivated pneumolysin (Ply) plus CpG produced high levels of 9V PS IgG and IgA antibodies compared to the group that received the conjugate alone. High levels of subclasses of IgGI, IgG2 and IgG3 antibodies were also observed in sera of mice immunized with 9V PS-Ply plus CpG. In addition, high IgG and IgA antibody responses were observed in sera of young mice immunized with 9V PS-Ply plus CpG or the conjugate plus non-CpG compared with the group received the conjugate alone. These results reveal that mucosal immunization with pneumococcal glycoconjugate using CpG as adjuvant can confer protective immunity against pneumococcal infection.

Protective immunity of pneumococcal glycoconjugates.

Pneumococcal polysaccharides (PSs), designated as T-cell independent type 2 (TI-2) antigens, induce poor immune responses in young children. Splenic marginal zone B cells, associated with CD21, CD19 and C3d, play an important role in TI-2 antibody responses, and provide host defense against bacterial pathogens. Antibody response, avidity, and opsonophagocytic activity of antisera were examined in mice immunized with type 9V PS conjugated to inactivated pneulmolysin (Ply) or to autolysin (Aly). Compared to mice given 9V PS alone, serum IgG and IgM concentrations against the 9V PS were higher in mice immunized with conjugates. High concentrations of serum antibodies were maintained for over 12 weeks. The relative avidities of IgG and IgM antibodies and opsonophagocytic activity against 9V pneumococci were high in mice immunized with conjugates. Thus, conjugate vaccines can induce high as well as long duration of antibody response and effective functional activity. In another study, mice received intranasal immunization with type 9V conjugate or 9V PS. These animals produced 9V PS IgG and IgA antibodies in their serum, spleen, intestine, lung, Peyer's patch and fecal extract samples. Mice immunized with these glycoconjugates exhibited opsonophagocytic activity and rapid bacterial clearance from blood and provided homologous and cross-protection against challenge with virulent pneumococci. These results indicate that intranasal immunization with glycoconjugate vaccines may serve as an alternative and convenient approach for prevention of pneumococcal infection.

Quality control of polyvalent pneumococcal polysaccharide-protein conjugate vaccine by nephelometry.

A nephelometric method was used for quantitative analysis of individual polysaccharides (PSs) in a polyvalent pneumococcal conjugate vaccine using CRM(197) as carrier protein. Using this method, the individual types 4, 6B, 9V, 14, 18C, 19F and 23F PSs were found to range between 82.3 to 119% of the manufacturer's indicated values. During conjugation using reductive amination, pneumococcal PS was first oxidized to introduce aldehyde groups. Higher or lower levels of antigen-antibody reaction were observed in periodate activated and then reduced PS of some serotypes compared to non-treated PS. Use of oxidized and reduced PS may provide an early indication of change in conjugation process. Furthermore, since the final monovalent and polyvalent conjugate vaccines gradually change during the storage period, the nephelometry provides an useful analytical method for stability study of these vaccines.

Development and evaluation of pneumococcal conjugate vaccines: clinical trials and control tests.

Streptococcus pneumoniae is a major cause of pneumonia, meningitis, and otitis media and is responsible for disease in young children, the elderly, and immunocompromised individuals. Emerging high-level resistance to penicillin, multiple antibiotics, and tolerance to vancomycin emphasizes the importance of preventing pneumococcal infection by alternative methods such as immunization. The development of pneumococcal conjugate vaccines using the same carrier proteins as those used in Hemophilus influenzae type b vaccines has enhanced the immune response in infants and children compared with polysaccharide vaccines and has significantly improved the ability to prevent pneumococcal disease in this population worldwide. Here we review the clinical trials of multivalent pneumococcal conjugate vaccines under evaluation, identify potential carrier proteins considered for development of future pneumococcal conjugate vaccines, discuss issues regarding licensure of new candidate vaccines from a clinical trial and quality control perspective, and alternative vaccine strategies for the prevention of pneumococcal disease.