Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine (MenACWY-D) in infants and children.

BACKGROUND: Menactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11-55 years of age, in 2007 for children 2-10 years of age, and in 2011 for infants/toddlers 9-23 months of age. We conducted two studies at Kaiser Permanente Northern California (KPNC), an integrated health care organization, to assess the safety of MenACWY-D in 2-10-year-olds and 9-23-month-olds receiving the vaccine during routine clinical care. METHODS: We conducted observational, retrospective studies of MenACWY-D in 2-10-year-olds (October 2007-October 2010) and in 9-23-month-olds (June 2011-June 2014). We monitored all subjects for non-elective hospitalizations, emergency department visits, and selected outpatient outcomes (specified neurological conditions, hypersensitivity reactions and new-onset autoimmune diseases) up to 6 months after vaccination, depending on the study. Using a self-control risk-interval design, we calculated incidence rate ratios (IRRs) comparing outcomes during the post-vaccination risk interval (0-30 days) with those during more remote post-vaccination comparison intervals (31-60 and 31-180 days [children] or 31-75 days [infants/toddlers]). RESULTS: There were 1421 children aged 2-10 years and 116 infants/toddlers aged 9-23 months who received MenACWY-D. Approximately 30% of the 2-10-year-olds and 67% of the 9-23-month-olds were considered at increased risk of meningococcal disease. Among 2-10-year-olds, there was 1 hospitalization on post-vaccination day 5 for fever, which was considered possibly related to vaccination. The only significantly elevated outcome among 2-10-year-olds was cellulitis/abscess (2 cases occurred during the risk interval versus 0 during comparison interval; IRR not evaluable [NE], 95% CI: 1.42, NE). After medical record review, the 2 cases were considered unrelated to vaccination. Among 9-23-month-olds, no outcomes were significantly elevated after vaccination and there were no hospitalizations. There were no deaths observed during the three-year accrual and subsequent six-month surveillance period for either study. CONCLUSIONS: Immunization of infants and young children with MenACWY-D vaccine was not associated with any new safety concerns; however, these small studies had limited power to detect rare or uncommon safety events. ClinicalTrials.gov Identifiers are NCT00728260 and NCT01689155.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting interleukins, immunoglobulins and complement factors and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Patients receiving interleukin-1 (IL-1) -targeted (anakinra, canakinumab or rilonacept) or IL-5-targeted (mepolizumab) agents have a moderate risk of infection and no specific prevention strategies are recommended. The use of IL-6/IL-6 receptor-targeted agents (tocilizumab and siltuximab) is associated with a risk increase similar to that observed with anti-tumour necrosis factor-α agents. IL-12/23-targeted agents (ustekinumab) do not seem to pose a meaningful risk of infection, although screening for latent tuberculosis infection may be considered and antiviral prophylaxis should be given to hepatitis B surface antigen-positive patients. Therapy with IL-17-targeted agents (secukinumab, brodalumab and ixekizumab) may result in the development of mild-to-moderate mucocutaneous candidiasis. Pre-treatment screening for Strongyloides stercoralis and other geohelminths should be considered in patients who come from areas where these are endemic who are receiving IgE-targeted agents (omalizumab). C5-targeted agents (eculizumab) are associated with a markedly increased risk of infection due to encapsulated bacteria, particularly Neisseria spp. Meningococcal vaccination and chemoprophylaxis must be administered 2-4 weeks before initiating eculizumab. Patients with high-risk behaviours and their partners should also be screened for gonococcal infection. IMPLICATIONS: Preventive strategies are particularly encouraged to minimize the occurrence of neisserial infection associated with eculizumab.

National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13-17 Years - United States, 2016.

The Advisory Committee on Immunization Practices (ACIP) recommends that adolescents routinely receive tetanus, diphtheria, and acellular pertussis vaccine (Tdap), meningococcal conjugate vaccine (MenACWY), and human papillomavirus (HPV) vaccine (1) at age 11-12 years. ACIP also recommends catch-up vaccination with hepatitis B vaccine, measles, mumps, and rubella (MMR) vaccine, and varicella vaccine for adolescents who are not up to date with childhood vaccinations. ACIP recommends a booster dose of MenACWY at age 16 years (1). In December 2016, ACIP updated HPV vaccine recommendations to include a 2-dose schedule for immunocompetent adolescents initiating the vaccination series before their 15th birthday (2). To estimate adolescent vaccination coverage in the United States, CDC analyzed data from the 2016 National Immunization Survey-Teen (NIS-Teen) for 20,475 adolescents aged 13-17 years.* During 2015-2016, coverage increased for ≥1 dose of Tdap (from 86.4% to 88.0%) and for each HPV vaccine dose (from 56.1% to 60.4% for ≥1 dose). Among adolescents aged 17 years, coverage with ≥2 doses of MenACWY increased from 33.3% to 39.1%. In 2016, 43.4% of adolescents (49.5% of females; 37.5% of males) were up to date with the HPV vaccination series, applying the updated HPV vaccine recommendations retrospectively.† Coverage with ≥1 HPV vaccine dose varied by metropolitan statistical area (MSA) status and was lowest (50.4%) among adolescents living in non-MSA areas and highest (65.9%) among those living in MSA central cities.§ Adolescent vaccination coverage continues to improve overall; however, substantial opportunities exist to further increase HPV-associated cancer prevention.

Analysis of novel meningococcal vaccine formulations.

The protective effect of meningococcal vaccines targeting disease causing serogroups exemplified by the introduction of MenAfriVac™ in Africa, is well established and documented in large population-based studies. Due to the emergence of other meningococcal disease causing serogroups, novel vaccine formulations are needed. There is a high potential for novel nanotechnology-based meningococcal vaccine formulations that can provide wider vaccine coverage. The proposed meningococcal vaccine formulation contains spherical shaped micro and nanoparticles that are biological mimics of Niesseria meningitidis, therefore present to immune system as invader and elicit robust immune responses. Vaccine nanoparticles encapsulate meningococcal CPS polymers in a biodegradable material that slowly release antigens, therefore enhance antigen presentation by exerting antigen depot effect. The antigenicity of meningococcal vaccine delivered in nanoparticles is significantly higher when compared to vaccine delivered in solution. Preclinical studies are required to assess the immunogenicity of novel vaccine formulations. Therefore, implementing various in-vitro human immune cell-based assays that mimic in-vivo interactions, would provide good insight on optimal antigen dose, effective antigen presentation, facilitate screening of various vaccine and adjuvant combinations and predict in-vivo immunogenicity. This rapid approach is cost-effective and provides data required for the preclinical immunogenicity assessment of novel meningococcal vaccine formulations.

Background Paper for the update of meningococcal vaccination recommendations in Germany: use of the serogroup B vaccine in persons at increased risk for meningococcal disease.

In December 2013 Bexsero® became available in Germany for vaccination against serogroup B meningococci (MenB). In August 2015 the German Standing Committee on Vaccination (STIKO) endorsed a recommendation for use of this vaccine in persons at increased risk of invasive meningococcal disease (IMD). This background paper summarizes the evidence underlying the recommendation. Bexsero® is based on surface protein antigens expressed by about 80% of circulating serogroup B meningococci in Germany. The paper reviews available data on immunogenicity and safety of Bexsero® in healthy children and adolescents; data in persons with underlying illness and on the effectiveness in preventing clinical outcomes are thus far unavailable.STIKO recommends MenB vaccination for the following persons based on an individual risk assessment: (1) Persons with congenital or acquired immune deficiency or suppression. Among these, persons with terminal complement defects and properdin deficiency, including those under eculizumab therapy, are at highest risk with reported invasive meningococcal disease (IMD) incidences up 10,000-fold higher than in the general population. Persons with asplenia were estimated to have a ~ 20-30-fold increased risk of IMD, while the risk in individuals with other immune defects such as HIV infection or hypogammaglobulinaemia was estimated at no more than 5-10-fold higher than the background risk. (2) Laboratory staff with a risk of exposure to N. meningitidis aerosols, for whom an up to 271-fold increased risk for IMD has been reported. (3) Unvaccinated household (-like) contacts of a MenB IMD index case, who have a roughly 100-200-fold increased IMD risk in the year after the contact despite chemoprophylaxis. Because the risk is highest in the first 3 months and full protective immunity requires more than one dose (particularly in infants and toddlers), MenB vaccine should be administered as soon as possible following identification of the serogroup of the index case.

National, regional, state, and selected local area vaccination coverage among adolescents aged 13-17 years--United States, 2013.

The Advisory Committee on Immunization Practices (ACIP) recommends that adolescents routinely receive 1 dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine, 2 doses of meningococcal conjugate (MenACWY) vaccine, and 3 doses of human papillomavirus (HPV) vaccine.* ACIP also recommends administration of "catch-up"† vaccinations, such as measles, mumps, and rubella (MMR), hepatitis B, and varicella, and, for all persons aged ≥6 months, an annual influenza vaccination. ACIP recommends administration of all age-appropriate vaccines during a single visit. To assess vaccination coverage among adolescents aged 13-17 years, CDC analyzed data from the 2013 National Immunization Survey-Teen (NIS-Teen).§ This report summarizes the results of that analysis, which show that from 2012 to 2013, coverage increased for each of the vaccines routinely recommended for adolescents: from 84.6% to 86.0% for ≥1 Tdap dose; from 74.0% to 77.8% for ≥1 MenACWY dose; from 53.8% to 57.3% for ≥1 HPV dose among females, and from 20.8% to 34.6% for ≥1 HPV dose among males. Coverage varied by state and local jurisdictions and by U.S. Department of Health and Human Services (HHS) region. Healthy People 2020 vaccination targets for adolescents aged 13-15 years were reached in 42 states for ≥1 Tdap dose, 18 for ≥1 MenACWY dose, and 11 for ≥2 varicella doses. No state met the target for ≥3 HPV doses.¶ Use of patient reminder and recall systems, immunization information systems, coverage assessment and feedback to clinicians, clinician reminders, standing orders, and other interventions can help make use of every health care visit to ensure that adolescents are fully protected from vaccine-preventable infections and cancers (5), especially when such interventions are coupled with clinicians' vaccination recommendations.

Preclinical immunogenicity and functional activity studies of an A+W meningococcal outer membrane vesicle (OMV) vaccine and comparisons with existing meningococcal conjugate- and polysaccharide vaccines.

Meningococci of serogroups A and W (MenA and MenW) are the main causes of epidemic bacterial meningitis outbreaks in sub-Saharan Africa. In this study we prepared a detergent extracted outer membrane vesicle (dOMV) vaccine from representative African MenA and MenW strains, and compared the immunogenicity of this vaccine with existing meningococcal conjugate and polysaccharide (PS) vaccines in mice. NMRI mice were immunized with preclinical batches of the A+W dOMV vaccine, or with commercially available vaccines; a MenA conjugate vaccine (MenAfriVac(®), Serum Institute of India), ACYW conjugate vaccine (Menveo(®), Novartis) or ACYW PS vaccine (Mencevax(®), GlaxoSmithKline). The mice received 2 doses of 1/10 or 1/50 of a human dose with a three week interval. Immune responses were tested in ELISA, serum bactericidal activity (SBA) and opsonophagocytic activity (OPA) assays. High levels of IgG antibodies against both A and W dOMV were detected in mice receiving the A+W dOMV vaccine. High SBA titers against both MenA and MenW vaccine strains were detected after only one dose of the A+W dOMV vaccine, and the titers were further increased after the second dose. The SBA and OPA titers in mice immunized with dOMV vaccine were significantly higher than in mice immunized with the ACYW-conjugate vaccine or the PS vaccine. Furthermore, the A+W dOMV vaccine was shown to induce SBA and OPA titers against MenA of the same magnitude as the titers induced by the A-conjugate vaccine. In conclusion, the A+W dOMV vaccine induced high levels of functional antibodies to both MenA and MenW strains, levels that were shown to be higher or equal to the levels induced by licensed meningococcal vaccines. Thus, an A+W dOMV vaccine could potentially serve as an alternative or a supplement to existing conjugate and PS vaccines in the African meningitis belt.

Preclinical evaluation of MenB vaccines: prerequisites for clinical development.

Despite the widespread use of polysaccharide and conjugate vaccines against disease caused by several serogroups of Neisseria meningitidis, vaccines targeting meningococci expressing the serogroup B capsule (MenB) have focused on subcapsular antigens, due to crossreactivity of the polysaccharide with human glycoproteins. Protein vaccines composed of outer membrane vesicles have been used successfully to control epidemics of MenB disease in several countries; however, these are specific for epidemic strains. Currently, a single serogroup B vaccine, aiming to provide comprehensive coverage, has been approved for use, and several others are undergoing clinical trials. Data on potential new vaccine candidates, from discovery to initial preclinical evaluation, are regularly published. In this review, the data required to progress from preclinical to clinical development of MenB vaccines are outlined, with reference to relevant regulatory guidelines. The issues caused by a lack of reliable animal models, particularly with respect to determination of protective efficacy, are also discussed.

Cost-effectiveness analysis of a universal infant immunization program with meningococcal C conjugate vaccine in Brazil.

OBJECTIVE: To analyze the cost-effectiveness of a meningococcal C vaccination program in Brazil. METHODS: A hypothetical cohort of 3,194,038 children born in Brazil in 2006 was followed for 10 years. A decision tree model was developed using the TreeAge Pro 2007 software program to compare universal infant vaccination with the current program. Epidemiological and cost estimates were based on data retrieved from National Health Information Systems and the literature. The analysis was conducted from the public health care system and societal perspectives. Costs are expressed in 2006 Brazilian reals (R$). RESULTS: At 94% coverage, the program would avoid 1,218 cases, 210 deaths, and 14,473 life-years lost, a reduction of, respectively, 45%, 44%, and 44%, for the 10-year period. Vaccination costs of R$320.9 million would not be offset by R$4 to R$7.9 million decreases in disease treatment costs. A national vaccination program would cost R$21,620 per life-year saved from the perspective of the health-care system and R$21,896 per life-year saved from society's perspective. Results were most sensitive to case fatality rate, disease incidence, and vaccine cost. CONCLUSIONS: A universal childhood vaccination program against meningococcal C proved to be a cost-effective strategy, supporting the recent decision of the Brazilian government. These results could contribute to defining the most favorable price of the vaccine and to monitoring its impact on the population.

Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial.

CONTEXT: Immunization with a meningococcal tetravalent (serogroup ACWY) glycoconjugate vaccine is recommended for all US adolescents. However, the currently licensed vaccine is poorly immunogenic in infancy, when the highest rates of disease are observed. OBJECTIVE: To determine the immunogenicity of a novel tetravalent CRM(197)-conjugated meningococcal vaccine (MenACWY) in infants. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, controlled study of 225 UK and 196 Canadian 2-month-olds from August 2004 to September 2006. INTERVENTION: UK infants received a primary course of MenACWY (at 2, 3, and 4 months or 2 and 4 months) or Neisseria meningitidis serogroup C monovalent meningococcal glycoconjugate vaccine (MenC) (at 2 and 4 months). All received MenACWY at 12 months. Canadian infants received MenACWY at 2, 4, and 6 months or 2 and 4 months; at 12 months they received MenACWY, a plain tetravalent polysaccharide vaccine, or no vaccine. MAIN OUTCOME MEASURE: Percentage of infants with a human complement serum bactericidal activity (hSBA) titer >or=1:4 after a primary course of MenACWY and after a 12-month booster. Safety and reactogenicity of MenACWY were also assessed. RESULTS: According to the prespecified per-protocol analysis, the percentages (95% CIs) of MenACWY 2-, 3-, and 4-month recipients with hSBA titers >or=1:4 after primary immunization were serogroup A, 93% (84%-98%); C, 96% (89%-99%); W-135, 97% (90%-100%); and Y, 94% (86%-98%). With a post hoc intention-to-treat analysis with imputed values for missing data, these values were unchanged for serogroups C and Y; for serogroup A, values were 92% (84%-97%), and for W-135, 97% (91%-99%). For the per-protocol analysis of MenACWY 2-, 4-, and 6-month recipients, the percentages (95% CIs) of responders were A, 81% (71%-89%); C, 98% (92%-100%); W-135, 99% (93%-100%); and Y, 98% (92%-100%). With the imputed value analysis, these values were A, 83% (74%-89%); C, 98% (93%-99%); W-135, 99% (94%-100%); and Y, 98% (92%-99%). At least 84% of MenACWY 2- and 4-month recipients achieved hSBA titers >or=1:4 for serogroups C, W-135, and Y after primary immunization, as did at least 60% for serogroup A (per-protocol and imputation analysis). At least 95% of primary and booster MenACWY recipients achieved hSBA titers >or=1:4 for serogroups C, W-135, and Y at 13 months, as did at least 84% for serogroup A (per-protocol and imputation analysis). During the primary immunization course, postimmunization pain on leg movement was observed in 2% of UK MenACWY 2- and 4-month recipients and 4% of MenC 2- and 4-month recipients; a temperature of 38 degrees C or greater was observed in 4% and 2% in these groups, respectively. CONCLUSION: MenACWY is well tolerated and immunogenic in infancy. Trial Registration clinicaltrials.gov Identifier: NCT00262002.

New vaccines require potent adjuvants like AFPL1 and AFCo1.

Neisseria meningitidis B proteoliposome (AFPL1 when used as adjuvant) and its derivative-Cochleate (AFCo1) contain immunopotentiating and immunomodulating properties and delivery system capacities required for a good adjuvant. Additionally, they contain meningococcal protective antigens and permit packaging of other antigens and pathogen-associated molecular patterns (PAMP). Consequently, we hypothesized that they would function as good vaccine adjuvants for their own antigens and also for non-related antigens. AFPL1 is a detergent-extracted outer membrane vesicle of N. meningitidis B transformed into AFCo1 in calcium environment. Both are produced at Finlay Institute under good manufacture practices (GMP) conditions. We show their exceptional characteristics: combining in the same structure, the potentiator activity, polarizing agents and delivery system capacities; presenting multimeric protein copies; containing multiprotein composition and multi and synergistic PAMP components; acting with incorporated or co-administrated antigens; inducing type I IFN-gamma and IL-12 cytokines suggesting the stimulation of human plasmocytoid precursor and conventional dendritic cells, respectively, inducing a preferential Th1 immune response with TCD4(+), TCD8(+), cross-presentation and cytotoxic T-lymphocyte (CTL) in vivo responses; and functioning by parenteral and mucosal routes. AFPL1-AFCo1 protective protein constitutions permit per se their function as a vaccine. In addition to Phase IV Men BC vaccine, AFPL1 has ended the preclinical stage in an allergy vaccine and is concluding the preclinical stage of a nasal meningococcal vaccine. In conclusion, AFPL1 and AFCo1 induced signal 1, 2 and 3 polarizing to a Th1 (including CTL) response when they acted directly as vaccines or were used as adjuvants with incorporated or co-administered antigens by parenteral or mucosal routes. Both are very promising adjuvants.

Empiric first-line antibiotic treatment of acute otitis in the era of the heptavalent pneumococcal conjugate vaccine.

OBJECTIVES: Our goal was to estimate the local prevalence of Streptococcus pneumoniae nonsusceptible to penicillin and amoxicillin after widespread use of the heptavalent pneumococcal vaccine and to revise community-specific recommendations for first-line antibiotic treatment of acute otitis media. METHODS: We conducted serial prevalence surveys between 2000 and 2004 in the offices of community pediatricians in St Louis, Missouri. Study participants were children <7 years of age with acute upper respiratory infections. Children treated with an antibiotic in the past 4 weeks were excluded. S pneumoniae was isolated from nasopharyngeal swabs using standard techniques. Isolates with a penicillin minimum inhibitory concentration >2 microg/mL were considered to be S pneumoniae nonsusceptible to amoxicillin. RESULTS: There were 327 patients enrolled in the study. Between 2000 and 2004, vaccine coverage with > or =3 doses of heptavalent pneumococcal vaccine increased from 0% to 54%, but nasopharyngeal carriage of S pneumoniae was stable at 39%. The prevalence of S pneumoniae nonsusceptible to penicillin fell from 25% to 12% among patients, did not vary if <2 years of age, was reduced in children with > or =3 doses of heptavalent pneumococcal vaccine, and increased in child care attendees but reduced in attendees who had > or =3 doses of heptavalent pneumococcal vaccine. The prevalence of S pneumoniae nonsusceptible to amoxicillin in patients remained <5%. CONCLUSIONS: In our community, widespread use of heptavalent pneumococcal vaccine has reduced the prevalence of S pneumoniae nonsusceptible to penicillin, and the prevalence of S pneumoniae nonsusceptible to amoxicillin remains low (<5%). If antibiotic treatment is elected for children with uncomplicated acute otitis media, we recommend treatment with standard-dose amoxicillin (40-45 mg/kg per day) for children with > or =3 doses of heptavalent pneumococcal vaccine, regardless of age and child care status. High-dose amoxicillin should be used for children with <3 doses of heptavalent pneumococcal vaccine and those treated recently with an antibiotic.

[Perspectives for development of polyvalent meningococcal vaccine].

Experimental whole-culture oral polyvalent meningococcal vaccines against serogroups A, B and C consisting of three monovalent components in different proportions have been developed and evaluated. Kinetics of IgG response to meningococcal antigens (outer membrane proteins, polysaccharide, lypooligosaccharide of these serogroups) in sera of rabbits immunized orally with these preparations was measured. Sharp rise of IgG levels (on 2 - 3 orders) compared to baseline has been detected as well as persistence of high titers during the observation period (322 days).

[Antigenic activity of oral whole-culture meningococcal serogroup B vaccine]. / Antigennaia aktivnost' peroral'nogo tsel'nokul'tural'nogo preparata meningokokkov serogruppy B.

The whole-culture vaccine preparation of Neisseria meningitidis, serogroup B, obtained by cultivation in a computer-controlled bioreactor, was studied. The preparation was shown to contain antigenically active polysaccharide, outer membrane proteins, as well as lipooligosaccharide, faintly pyrogenic and with low toxicity. After oral immunization of rabbits a multiple increase in the levels of IgG antibodies to these antigens in their blood serum was noted during the period of observation (303 days).

Postlicensure surveillance for pneumococcal invasive disease after use of heptavalent pneumococcal conjugate vaccine in Northern California Kaiser Permanente.

OBJECTIVE: To assess the direct and indirect effects of the introduction of routine use of pneumococcal conjugate vaccine in infants and toddlers at risk for invasive disease caused by vaccine serotypes and nonvaccine serotypes in vaccinated children and unvaccinated children of the same age. Secondary objectives included determination of the risk of pneumococcal infections in unvaccinated older children and adults in the same population and the impact of vaccine introduction on patterns of antimicrobial resistance. METHODS: Northern California Kaiser Permanente provides integrated comprehensive care to 3.1 million people and has an annual birth cohort of 38,000 infants. Microbiology services use a regional laboratory. Automated laboratory results, immunization records as well as diagnoses for inpatient and outpatient utilization are available from clinical data bases. Beginning in April 2000, the heptavalent pneumococcal conjugate (PNCV7) vaccine was introduced into routine use in the Northern California Kaiser Permanente population. Cases of invasive pneumococcal disease were identified from the automated hospital diagnosis as well as laboratory databases for all individuals, vaccinees and nonvaccinees, inpatient and outpatient. For the purpose of these analyses, pneumococcal invasive disease was defined as a positive culture from a normally sterile site. RESULTS: As of March 2003, 157,471 children had received 1 dose or more of PNCV7, but only 24% of those <2 years of age received all 4 doses as a result of shortages of vaccine. During the last year of observation, no cases of vaccine serotype disease were seen in children <1 year of age compared with an incidence ranging between 51.5 and 98.2 cases per 100,000 person-years (16-34 cases per year) in the years before vaccine introduction. Similar reductions were seen in children <5 years of age. There was no evidence of any concomitant increase in pneumococcal disease caused by nonvaccine serotypes. High level resistance of pneumococci to penicillin fell from a peak of 15% in 2000 to 5% in the first half of 2003. Similar trends were seen for other antibiotics. CONCLUSION: The PNCV7 vaccine is highly effective in reducing the burden of pneumococcal disease in children <5 years of age, and there is evidence of a herd effect as well as a decrease in the antibiotic resistant in strains causing disease. For invasive disease, there is no current evidence of serotype replacement.

Protective activity of monoclonal antibodies to genome-derived neisserial antigen 1870, a Neisseria meningitidis candidate vaccine.

Genome-derived neisserial Ag (GNA) 1870 is a meningococcal vaccine candidate that can be subdivided into three variants based on amino acid sequence variability. Variant group 1 accounts for approximately 60% of disease-producing group B isolates. The Ag went unrecognized until its discovery by genome mining because it is expressed in low copy number by most strains. To investigate the relationship between Ab binding to GNA1870 and complement-mediated protective functions, we prepared a panel of four murine IgG mAbs against rGNA1870 (variant 1) and evaluated their activity against nine genetically diverse encapsulated Neisseria meningitidis strains expressing subvariants of variant 1 GNA1870. Based on flow cytometry with live encapsulated bacteria, surface accessibility of the epitopes recognized by the mAbs appeared to be low in most strains. Yet mAb concentrations <1 to 5 micro g/ml were sufficient to elicit bactericidal activity with human complement and/or activate C3b deposition on the bacterial surface. Certain combinations of mAbs were highly bactericidal against strains that were resistant to bactericidal activity of the respective individual mAbs. The mAbs conferred passive protection against bacteremia in infant rats challenged by strains resistant to bacteriolysis, and the protective activity paralleled the ability of the mAb to activate C3b deposition. Thus, despite low GNA1870 surface exposure, anti-GNA1870 variant 1 Abs are bactericidal and/or elicit C3b deposition and confer protection against bacteremia caused by encapsulated N. meningitidis strains expressing GNA1870 subvariant 1 proteins. The data support GNA1870 as a promising vaccine candidate for prevention of meningococcal group B disease caused by GNA1870 variant 1 strains.