Antibody Kinetics and Response to Routine Vaccinations in Infants Born to Women Who Received an Investigational Trivalent Group B Streptococcus Polysaccharide CRM197-Conjugate Vaccine During Pregnancy.

BACKGROUND: Maternal vaccination against group B Streptococcus (GBS) might provide protection against invasive GBS disease in infants. We investigated the kinetics of transplacentally transferred GBS serotype-specific capsular antibodies in the infants and their immune response to diphtheria toxoid and pneumococcal vaccination. METHODS: This phase 1b/2, observer-blind, single-center study (NCT01193920) enrolled infants born to women previously randomized (1:1:1:1) to receive either GBS vaccine at dosages of 0.5, 2.5, or 5.0 µg of each of 3 CRM197-glycoconjugates (serotypes Ia, Ib, and III), or placebo. Infants received routine immunization: combination diphtheria vaccine (diphtheria-tetanus-acellular pertussis-inactivated poliovirus/Haemophilus influenzae type b vaccine; age 6/10/ 14 weeks) and 13-valent pneumococcal CRM197-conjugate vaccine (PCV13; age 6/14 weeks and 9 months). Antibody levels were assessed at birth, day (D) 43, and D91 for GBS serotypes; 1 month postdose 3 (D127) for diphtheria; and 1 month postprimary (D127) and postbooster (D301) doses for pneumococcal serotypes. RESULTS: Of 317 infants enrolled, 295 completed the study. In infants of GBS vaccine recipients, GBS serotype-specific antibody geometric mean concentrations were significantly higher than in the placebo group at all timepoints and predictably decreased to 41%-61% and 26%-76% of birth levels by D43 and D91, respectively. Across all groups, ≥95% of infants were seroprotected against diphtheria at D127 and ≥91% of infants had seroprotective antibody levels against each PCV13 pneumococcal serotype at D301. CONCLUSIONS: Maternal vaccination with an investigational CRM197-glycoconjugate GBS vaccine elicited higher GBS serotype-specific antibody levels in infants until 90 days of age, compared with a placebo group, and did not affect infant immune responses to diphtheria toxoid and pneumococcal vaccination. CLINICAL TRIALS REGISTRATION: NCT01193920.

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial.

BACKGROUND: Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS: In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS: Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION: Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING: Novartis Vaccines.

Persistence of specific bactericidal antibodies at 5 years of age after vaccination against serogroup B meningococcus in infancy and at 40 months.

BACKGROUND: The multicomponent serogroup B meningococcal (4CMenB) vaccine induces antibodies against indicator strains of serogroup B meningococcus under various schedules. We investigated the persistence of antibodies in 5-year-old children 18-20 months after their last dose (at about 3.5 years of age). METHODS: We assessed 5-year-old children who received the 4CMenB vaccine or a recombinant protein vaccine in a previous randomized trial. We also recruited 50 vaccine-naive 5-year-olds and administered 2 doses of 4CMenB to each child. We measured serum bactericidal antibody titres against 4 indicator strains of serogroup B meningococcus matched to each individual vaccine component and against 4 mismatched strains. RESULTS: Of those who received the 4CMenB vaccine at 2, 4, 6, 12 and 40 months (n = 16), the percentage with protective antibody titres (≥ 1:4) at 60 months ranged from 44% to 88% against matched strains and from 13% to 81% against mismatched strains. Loss of protective titres was also observed for those who received the 4CMenB vaccine at 12, 40 and 42 months (n = 5) (80%-100% against matched strains, 60%-100% against mismatched strains) or at 40 and 42 months (n = 29) (31%-100% against matched strains, 41%-81% against mismatched strains). Administering the 4CMenB vaccine to 5-year-old children yielded protective titres against matched strains in 92%-100% and against mismatched strains in 59%-100%. The majority of these children reported injection-site pain (40/50 [80%] after dose 1, 39/46 [85%] after dose 2) and erythema (47/50 [94%] and 40/46 [87%], respectively); rates of fever were low (5/50 [10%] and 2/46 [4%], respectively). INTERPRETATION: Waning of immunity by 5 years of age occurred after receipt of the 4CMenB vaccine in infancy, even with an additional booster at 40 months. The 4CMenB vaccine is immunogenic and was fairly well tolerated by 5-year-old children, although injection-site pain was noteworthy. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01027351.

Immunogenicity and tolerability of a multicomponent meningococcal serogroup B (4CMenB) vaccine in healthy adolescents in Chile: a phase 2b/3 randomised, observer-blind, placebo-controlled study.

BACKGROUND: Effective glycoconjugate vaccines against Neisseria meningitidis serogroups A, C, W-135, and Y have been developed, but serogroup B remains a major cause of severe invasive disease in infants and adolescents worldwide. We assessed immunogenicity and tolerability of a four-component vaccine (4CMenB) in adolescents. METHODS: We did a randomised, observer-blind, placebo-controlled, study at 12 sites in Santiago and Valparaíso, Chile. Adolescents aged 11-17 years received one, two, or three doses of 4CMenB at 1 month, 2 month, or 6 month intervals. Immunogenicity was assessed as serum bactericidal activity using human complement (hSBA) against three reference strains for individual vaccine antigens, and assessed by ELISA against the fourth strain. Local and systemic reactions were recorded 7 days after each vaccination, and adverse events were monitored throughout the study. Participants were initially randomised to five groups (3:3:3:3:1) during the primary phase to receive either one dose, two doses 1 or 2 months apart, or three doses of 4CMenB, or three doses of placebo, with an additional three groups generated for the booster phase. All subjects received at least one dose of 4CMenB. Geometric mean titres, proportions of participants with serum bactericidal antibody titres of 4 or more, and Clopper-Pearson 95% CIs were calculated. The study is registered with ClinicalTrials.gov, number NCT00661713. FINDINGS: Overall, 1631 adolescents (mean age 13·8 [SD 1·9] years) received at least one dose of 4CMenB. After two or three doses, 99-100% of recipients had hSBA titres of 4 or more against test strains, compared with 92-97% after one dose (p<0·0145) and 29-50% after placebo. At 6 months 91-100% of participants still had titres of 4 or more for each strain after two or three doses, but only 73-76% after one dose; seroresponse rates reached 99-100% for each strain after second or third doses at 6 months. Local and systemic reaction rates were similar after each 4CMenB injection and did not increase with subsequent doses, but remained higher than placebo. No vaccine-related serious adverse events were reported and no significant safety signals were identified. INTERPRETATION: On the basis of immunogenicity responses this study provides evidence for an adolescent 4CMenB vaccine schedule of two doses, 1-6 months apart, to provide protection against meningococcal B infection. The extent of this protection against meningococcus B variants circulating worldwide will be determined by national surveys. FUNDING: Novartis Vaccines and Diagnostics.

Persistence of bactericidal antibodies following early infant vaccination with a serogroup B meningococcal vaccine and immunogenicity of a preschool booster dose.

BACKGROUND: The multicomponent serogroup B meningococcal (4CMenB) vaccine was recently licensed for use in Europe. There are currently no data on the persistence of bactericidal antibodies induced by use of this vaccine in infants. Our objective was to evaluate serogroup B-specific bactericidal antibodies in children aged 40-44 months previously vaccinated at 2, 4, 6 and 12 months of age. METHODS: Participants given 4 doses of 4CMenB as infants received a fifth dose of the vaccine at 40-44 months of age. Age-matched participants who were MenB vaccine-naive received 4CMenB and formed the control group. We evaluated human complement serum bactericidal activity (hSBA) titres at baseline and 1 month after each dose of 4CMenB. RESULTS: Before a booster dose at enrolment, 41%-76% of 17 participants previously vaccinated with 4CMenB in infancy had hSBA titres of 4 or greater against 4 reference strains. Before vaccination in the control group (n = 40) these proportions were similar for strains 44/76-SL (63%) and M10713 (68%) but low for strains NZ98/254 (0%) and 5/99 (3%). A booster dose in the 4CMenB-primed participants generated greater increases in hSBA titres than in controls. INTERPRETATION: As has been observed with other meningococcal vaccines, bactericidal antibodies waned after vaccination with 4CMenB administered according to an approved infant vaccination schedule of 2, 4, 6 and 12 months of age, but there was an anamnestic response to a booster dose at 40-44 months of age. If 4CMenB were introduced into routine vaccination schedules, assessment of the need for a booster dose would require data on the impact of these declining titres on vaccine effectiveness. ClinicalTrials.gov, no. NCT01027351.

Phase III comparison of an investigational quadrivalent meningococcal conjugate vaccine with the licensed meningococcal ACWY conjugate vaccine in adolescents.

BACKGROUND: Neisseria meningitidis is an important cause of invasive bacterial infection in the United States, and disease rates are higher for adolescents than for the general population. Quadrivalent meningococcal conjugate vaccine is recommended for routine vaccination of adolescents and high-risk groups. This study compares the safety and immunogenicity of the Novartis Vaccines investigational quadrivalent meningococcal CRM(197) conjugate vaccine, MenACWY-CRM, with the licensed meningococcal conjugate vaccine, Menactra. METHODS: In this multicenter phase III study, 2180 adolescents 11-18 years of age were randomly assigned to 4 groups (1:1:1:1) to receive a single dose of 1 of 3 lots of MenACWY-CRM or a single dose of Menactra. Serum samples obtained before vaccination and 1 month after vaccination were tested for serogroup-specific serum bactericidal activity using human complement (hSBA). The hSBA titers after vaccination with MenACWY-CRM or Menactra were compared in noninferiority and superiority analyses. RESULTS: The hSBA geometric mean titers after MenACWY-CRM vaccination were higher than the hSBA geometric mean titers after Menactra vaccination, and criteria for superiority were met for this end point for all 4 serogroups. Also, the criteria for superiority of MenACWY-CRM, compared with Menactra, were met for the end points of proportion of subjects with postvaccination hSBA titers 1:8 and proportion of seroresponders for serogroups A, W-135, and Y. MenACWY-CRM was noninferior to Menactra for serogroup C for these end points. Reactogenicity was similar, with 64% of the MenACWY-CRM recipients and 70% of the Menactra recipients reporting mild and/or moderate solicited reactions. Neither vaccine was associated with a serious adverse event. CONCLUSIONS: MenACWY-CRM vaccine is well tolerated in adolescents and generates a stronger immune response than Menactra for all 4 serogroups. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT00450437 .

A randomized trial to determine the tolerability and immunogenicity of a quadrivalent meningococcal glycoconjugate vaccine in healthy adolescents.

BACKGROUND: Because of the well-documented increased risk of meningococcal disease among adolescents, vaccination is recommended for this population in many countries, including the United States. This study compared the tolerability and immunogenicity in adolescents of a candidate quadrivalent meningococcal CRM197 glycoconjugate vaccine against serogroups A, C, W-135, and Y (MenACWY-CRM) with that of the licensed unconjugated quadrivalent polysaccharide vaccine (MPSV4). METHODS: This phase II study was conducted in the United States among 524 adolescents aged 11-17 years in 2 stages, with different randomization schemes. The first 334 participants, enrolled in Stage 1, were randomized (1:1) to receive either MenACWY-CRM(+) (with adjuvant) or MPSV4. The next 190 participants, enrolled in Stage 2, were randomized (4:1) to receive either MenACWY-CRM(-) (without adjuvant) or MPSV4. Safety data were collected using diary cards and active surveillance. Human complement serum bactericidal activity (hSBA) titers were measured 1 and 12 months postvaccination. RESULTS: MenACWY-CRM and MPSV4 vaccines were well tolerated (local reactions, 63%-71% vs. 60%-62%; systemic reactions, 44%-56% vs. 46%-59%, respectively). One month postvaccination, similar hSBA titers were observed with the adjuvanted and nonadjuvanted MenACWY-CRM. The immunogenicity of MenACWY-CRM(-), measured by geometric mean titer, was significantly (P < 0.05) greater than that of MPSV4 for all 4 vaccine serogroups at 1 month. The percentage of subjects with hSBA titers > or =1:4 was also significantly greater (P < 0.01) for MenACWY-CRM(-) recipients for serogroups A, C, and Y and noninferior for W-135. The proportions of MenACWY-CRM(-) recipients with hSBA titers > or =1:4 to the vaccine serogroups at 1 month were 84% to 96% and geometric mean titers were 34 to 100. The percentage of subjects with hSBA titers > or =1:4 was significantly (P < 0.01) greater than MPSV4 for serogroups C, W-135, and Y 12 months postvaccination. CONCLUSIONS: MenACWY-CRM was well tolerated and immunogenic, with evidence of persistence of bactericidal antibodies for at least 12 months postvaccination.

Immunogenicity and immune memory of a nonadjuvanted quadrivalent meningococcal glycoconjugate vaccine in infants.

BACKGROUND: The highest rate of invasive meningococcal disease is among children under 2 years of age. There is currently no licensed quadrivalent (serogroups A, C, W-135, and Y) meningococcal glycoconjugate vaccine approved for infants. We evaluated the immunogenicity and reactogenicity of a novel quadrivalent nonadjuvanted meningococcal glycoconjugate vaccine (MenACWY-CRM) in healthy infants. METHODS: One hundred eighty infants (90 in Canada and 90 in the United Kingdom) received 2 doses of MenACWY-CRM at 2 and 4 months of age administered concomitantly with routine infant vaccines. At 12 months of age, the Canadian infants received either MenACWY-CRM or a reduced dose of a licensed meningococcal polysaccharide vaccine. In the United Kingdom, all infants received a further dose of MenACWY-CRM. The serological marker of protection was a titer of > or =1:4 using a serum bactericidal assay with human complement (hSBA). RESULTS: Two doses of MenACWY-CRM induced hSBA titers > or =1:4 in 57% (95% confidence interval [CI]: 45-67) and 50% (95% CI: 38-62) of infants against serogroup A in Canada and the United Kingdom, respectively, 93% (95% CI: 85-97) and 86% (95% CI: 46-93) against serogroup C, 95% (95% CI: 87-99) and 82% (95% CI: 71-90) against serogroup W-135, and 91% (95% CI: 82-96) and 74% (95% CI: 63-83) against serogroup Y. After a booster dose of MenACWY-CRM at 12 months, at least 94% of participants achieved hSBA titers > or =1:4 against each of the serogroups C, W-135, and Y and more than 79% against serogroup A. The vaccine was well tolerated. CONCLUSIONS: The nonadjuvanted MenACWY-CRM is immunogenic and well tolerated in infancy and could provide broad protection against meningococcal disease in this vulnerable age group.

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.

Immunogenicity and Safety of a 3- and 4-dose Vaccination Series of a Meningococcal ACWY Conjugate Vaccine in Infants: Results of a Phase 3b, Randomized, Open-label Trial.

BACKGROUND: The quadrivalent meningococcal glycoconjugate vaccine MenACWY-CRM is licensed for children from 2 months of age as a 4-dose series. This study assessed the immunogenicity of a 3-dose MenACWY-CRM vaccination series in infants, compared with the 4-dose series, and evaluated the impact of MenACWY-CRM concomitant administration on immune responses to the 13-valent pneumococcal conjugate vaccine (PCV13). METHODS: Overall, 751 healthy infants (age: 55-89 days) were randomized to receive 3 or 4 doses of MenACWY-CRM (2/4/12 or 2/4/6/12 months of age, respectively) with PCV13 + routine vaccinations (ACWY3 and ACWY4 groups, respectively) or PCV13 + routine vaccinations only (routine group). Immunological noninferiority of the 3-dose versus 4-dose MenACWY-CRM vaccination series was evaluated at 13 months of age for serogroups CWY; noninferiority of immune responses to PCV13 serotypes for concomitant administration of MenACWY-CRM and PCV13 was evaluated at 7 and 13 months of age. RESULTS: At 13 months, 88%-100% of subjects in groups ACWY3 and ACWY4 achieved seroprotective bactericidal antibody titers against serogroups ACWY; noninferiority criteria for the 3-dose versus 4-dose MenACWY-CRM vaccination series were met. At 7 months, noninferiority criteria were met for all PCV13 serotypes except for serotypes 3 and 5 (group ACWY3) and 19A (group ACWY4). At 13 months, noninferiority criteria were met for all PCV13 serotypes for both ACWY groups. CONCLUSIONS: After completion of either MenACWY-CRM vaccination series, most subjects achieved seroprotective titers against serogroups ACWY, with the 3-dose series being noninferior to the 4-dose series for serogroups CWY, and no interference with immune responses against PCV13 serotypes was observed (NCT01214837).

Maternal Immunization With an Investigational Trivalent Group B Streptococcal Vaccine: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the safety and immunogenicity of an investigational trivalent group B streptococcal vaccine in pregnant women and antibody transfer to their newborns. METHODS: The primary outcome of this observer-blind, randomized study was to estimate placental antibody transfer rates at birth. Secondary outcomes included measurement of serotype-specific antibodies at screening, 30 days postvaccination, at delivery, and 91 days postpartum, infant antibody levels at 3 months of age, the potential effect on routine infant diphtheria vaccination at 1 month after the third infant series dose, and safety in mother and infant participants through at least 5 months postpartum. Sample size was based on 60 participants in the vaccine group giving a probability of observing at least one adverse event of 90% if the actual rate of the event was 3.8%. RESULTS: From September 2011 to October 2013, 86 pregnant women were allocated in a 3:2 ratio to receive an investigational group B streptococcal vaccine containing glycoconjugates of serotypes Ia, Ib, and III or placebo. Demographics were similar across groups. Transfer ratios were 66-79% and maternal geometric mean concentrations increased 16-, 23-, and 20-fold by delivery against serotypes Ia, Ib, and III, respectively, Women with no detectable antibodies at inclusion had lower responses than those with detectable antibodies. Three months after birth, infant antibody concentrations were 22-25% of birth levels. Antidiphtheria geometric mean concentrations were similar across groups. In the vaccine and placebo groups, 32 of 51 women (63%) and 26 of 35 women (74%) reported adverse effects, respectively. CONCLUSION: The investigational vaccine was well-tolerated without safety signals in recipients and their infants or interference with routine infant diphtheria vaccination, although further studies on safety and effectiveness are needed. The investigational vaccine was immunogenic for all serotypes, particularly among women with detectable antibody levels at baseline. Antibody transfer to neonates was at similar levels to other maternally administered polysaccharide vaccines. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01446289.

Group B streptococcus vaccination in pregnant women with or without HIV in Africa: a non-randomised phase 2, open-label, multicentre trial.

BACKGROUND: Neonates born to women infected with HIV are at increased risk for invasive group B streptococcus (GBS) disease. We aimed to compare safety and immunogenicity of trivalent glycoconjugate GBS vaccine in pregnant women with and without HIV in Malawi and South Africa. METHODS: In our non-randomised phase 2, open-label, multicentre study, we recruited pregnant women attending two antenatal clinics, one in Blantyre, Malawi, and one in Soweto, Johannesburg, South Africa. Participants were divided into three groups on the basis of their HIV infection status (no infection, infection and high CD4 cell count [>350 cells per µL], and infection and low CD4 cell count [>50 to ≤350 cells per µL]) and received a 5 µg dose of glycoconjugate GBS vaccine (serotypes Ia, Ib, and III, with CRM197 [Novartis Vaccines, Siena, Italy]) intramuscularly at 24-35 weeks' gestation. GBS serotype-specific antibody concentrations were measured before vaccination (day 1), day 15, day 31, and at delivery, and in infants at birth and day 42 of life. The primary outcomes were safety in mothers and infants and the amount of placental transfer of GBS serotype-specific antibodies from mothers to their infants. All immunogenicity and safety analyses were done on the full analysis set, including participants who, or whose mother, correctly received the vaccine and who provided at least one valid assessable serum sample. This study is registered with ClinicalTrials.gov, number NCT01412801. FINDINGS: 270 women and 266 infants were enrolled between Sept 26, 2011, and Dec 4, 2012 (90 women and 87 infants without HIV, 89 and 88 with HIV and high CD4 cell counts, and 91 and 91 with HIV and low CD4 cell counts, respectively). Seven women were lost to follow-up, six withdrew consent, one died, and two relocated. Eight infants died or were stillborn and two were lost to follow-up. Across serotypes, fold change in antibody concentrations were higher for the HIV-uninfected group than the HIV-infected groups. Transfer ratios were similar across all three groups (0·49-0·72; transfer ratio is infant geometric mean antibody concentration in blood collected within 72 h of birth divided by maternal geometric mean antibody concentration in blood collected at delivery); however, at birth, maternally derived serotype-specific antibody concentrations were lower for infants born to women infected with HIV (0·52-1·62 µg/mL) than for those born to women not infected with HIV (2·67-3·91 µg/mL). 151 (57%) of 265 women reported at least one solicited adverse reaction: 39 (45%) of 87 women with HIV and low CD4 cell counts, 52 (59%) of 88 women with HIV and high CD4 cell counts, and 60 (67%) of 90 women in the HIV-uninfected group. 49 (18%) of 269 women had at least one adverse event deemed possibly related to the vaccine (six [7%] in the HIV and low CD4 cell count group, 12 [13%] in the HIV and high CD4 cell count group, and 21 [23%] in the HIV-uninfected group), as did three (1%) of 266 neonates (zero, two [1%], and one [1%]); none of these events was regarded as serious. INTERPRETATION: The vaccine was less immunogenic in women infected with HIV than it was in those not infected, irrespective of CD4 cell count, resulting in lower levels of serotype-specific maternal antibody transferred to infants, which could reduce vaccine protection against invasive GBS disease. A validated assay and correlate of protection is needed to understand the potential protective value of this vaccine. FUNDING: Novartis Vaccines and Diagnostics division (now part of the GlaxoSmithKline group of companies), Wellcome Trust UK, Medical Research Council: Respiratory and Meningeal Pathogens Research Unit.

Persistence of Bactericidal Antibodies After Infant Serogroup B Meningococcal Immunization and Booster Dose Response at 12, 18 or 24 Months of Age.

BACKGROUND: A serogroup B meningococcal vaccine (4CMenB) is licensed for infant use in countries including Canada, Australia and those of the European Union. Data on serum bactericidal antibody (hSBA) waning and the ideal timing of a "toddler" booster dose are essential to optimize vaccine utilization. METHODS: An open-labeled, multicenter phase-2b follow-on European study conducted from 2009 to 2012. Participants previously receiving 4CMenB with routine vaccines at 2, 4 and 6 or 2, 3 and 4 months (246Con and 234Con) or at 2, 4 and 6 months intercalated with routine vaccines (246Int) received a booster dose at 12, 18 or 24 months. 4CMenB-naïve "Control" participants aged 12, 18 or 24 months received 2 doses of 4CMenB 2 months apart. RESULTS: One thousand five hundred eighty-eight participants were recruited. At 12 months, before any booster doses, the proportions with hSBA titers ≥1:5 for strain 44/76-SL (testing vaccine component fHBP) were 73% (120/165) for the "246Con" group, 85% (125/147) for "246Int," 57% (51/90) for "234Con" and 13% (26/199) for Controls. For strain 5/99 (NadA) proportions were ≥96% (all 4CMenB-recipients) and 1% (Controls). For strain NZ98/254 (PorA), these were 18-35% (4CMenB-recipients) and 1% (Controls). By 24 months, 4CMenB-recipient proportions were 13-22% (44/76-SL), 82-94% (5/99) and 7-13% (NZ98/254) and in controls ≤4%. After a 12-month booster-dose, ≥95% of previously immunized participants had titers ≥1:5 (all strains). CONCLUSIONS: A 4CMenB booster-dose can overcome waning hSBA titers after early-infant immunization. Administration at 12 months could help to maintain immunity during an age of high risk, and the persistence of this response requires further study.

Safety and immunogenicity of an investigational maternal trivalent group B streptococcus vaccine in healthy women and their infants: a randomised phase 1b/2 trial.

BACKGROUND: Maternal group B streptococcus (GBS) serotype-specific capsular antibody concentrations are correlated with susceptibility to neonatal GBS invasive disease. Maternal immunisation against GBS during pregnancy might protect infants across the period of susceptibility to invasive disease, but no licensed vaccine exists. This study assessed the safety and immunogenicity of a CRM197-conjugated trivalent GBS vaccine in non-pregnant and pregnant women, and antibody transfer to their infants. METHODS: We did a phase 1b/2, randomised, observer-blind single-centre study of an investigational trivalent GBS vaccine in healthy non-pregnant women (cohort 1), and a dose-ranging study in healthy pregnant women (cohort 2). The study was done at the Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Participants were healthy non-pregnant or pregnant (28-35 weeks' gestation) women aged 18-40 years. In cohort 1, non-pregnant women were randomly assigned (2:1) to receive the investigational vaccine (two injections, 1 month apart, of a 20 µg dose [of each serotype] of aluminium hydroxide-adjuvanted investigational vaccine) or placebo. In cohort 2, pregnant women were randomly assigned (1:1:1:1) to receive one injection at 28-35 weeks' gestation of 0·5 µg, 2·5 µg, or 5·0 µg of the non-adjuvanted investigational vaccine (for each serotype), or placebo. All study participants and study staff not involved with vaccine preparation were masked to the randomisation group. The vaccine contained an equal dose (0·5 µg, 2·5 µg, 5·0 µg, or 20 µg) of each of three glycoconjugates (serotypes Ia, Ib and III). Reactogenicity was monitored to day 7 and unsolicited adverse events (adverse events) and infant safety were recorded throughout the study. The primary outcomes were tolerability and GBS-specific antibody response (measured as geometric mean concentrations [GMCs] in µg/mL) following the two injections for cohort 1, and selection of one vaccine dose based on analysis of serotype-specific antibody responses at delivery (+72 h) for use in subsequent studies. These outcomes were assessed in participants or infants of participants who correctly received the study vaccine with no major protocol deviations, and provided evaluable serum samples at day 1 and the scheduled timepoints throughout the study. This study is registered with ClinicalTrials.gov, NCT01193920. FINDINGS: Between Oct 5, 2010, and Sept 21, 2011, we screened 75 non-pregnant and 417 pregnant healthy South African women. Of these, 60 non-pregnant women were enrolled in cohort 1 (40 randomly assigned to the GBS 20 µg group and 40 randomly assigned to the placebo group) and 320 pregnant women were enrolled in cohort 2 (80 in each of the four groups). Among the randomised groups of pregnant women, 33-40% experienced at least one local and 54-71% one systemic solicited adverse event, less than 4% of which were severe, and the rate did not differ by study group. Also, 2% of the pregnancies resulted in stillbirth and 3·5% of the liveborn babies died by 12 months age, none of these deaths were attributed to vaccination. There was one death in a GBS-vaccine recipient, which too was unrelated to vaccination. For cohort 1, serotype-specific antibody concentrations were significantly higher, as evident by no overlap of the 95% CIs of GMCs against all three serotypes in the vaccinated group than the placebo group. For cohort 2, pregnant women in all vaccine groups had significantly higher GMCs than did those in the placebo group at delivery (eg, GMCs against serotype Ia were 11 µg/mL [95% CI 7·0-18] for the GBS vaccine 0·5 µg group, 18 µg/mL [11-29] for the GBS vaccine 2·5 µg group, 22 µg/mL [13-35] for the GBS vaccine 5·0 µg group, and 0·64 µg/mL [0·42-0·98] for the placebo group) and at all measured timepoints. GMCs did not differ significantly between the vaccine doses at any of the measured timepoints (p>0·05). INTERPRETATION: The vaccine was well tolerated and induced capsular-specific antibody responses, in non-pregnant and pregnant women. Maternal vaccination led to higher GBS serotype-specific antibody concentrations in infants than did placebo, with both interventions resulting in similar safety profiles. FUNDING: Novartis Vaccines and Diagnostics division, now part of the GlaxoSmithKline group of companies.

Meningococcal serogroup B vaccine (4CMenB): Booster dose in previously vaccinated infants and primary vaccination in toddlers and two-year-old children.

OBJECTIVE: The multicomponent, recombinant serogroup B vaccine, 4CMenB, is approved in Europe, Canada and Australia from two months of age. We investigated persistence to booster doses at 12 months of age following infant vaccination, and immune response to catch-up vaccination of toddlers and children up to two years of age. METHODS: We assessed persistence of immune responses after one year in participants vaccinated as infants, and responses to two doses at 12-15 or 24-26 months of age in vaccine-naïve children, as serum bactericidal activity with human complement (hSBA) against indicator strains for four vaccine antigens. Adverse events were recorded after each vaccination. RESULTS: High antibody titers were induced against all four 4CMenB components following booster vaccination in infant-primed toddlers and after two doses in previously unvaccinated toddlers or two-year-olds. Antibodies waned over 12 months, particularly those against NZ OMV. Systemic reactogenicity in toddlers was lower than in infants, and lower again in vaccine-naïve two-year-olds. Local reactogenicity was common in all groups. CONCLUSIONS: Four infant or two toddler 4CMenB vaccinations elicit immune responses believed to be protective for the first two years of life, which can be boosted. Reactogenicity is lower in toddlers than in infants.

Antibody persistence 5 years after vaccination at 2 to 10 years of age with Quadrivalent MenACWY-CRM conjugate vaccine, and responses to a booster vaccination.

BACKGROUND: In a multi-center extension study, children 2-10 years of age, initially vaccinated with one or two doses (2-5 year-olds) or one dose (6-10 year-olds) of quadrivalent meningococcal CRM197-conjugate vaccine (MenACWY-CRM), were assessed five years later for antibody persistence and booster response using serum bactericidal assay with human complement (hSBA). METHODS: Children 7-10 and 11-15 years of age, who received MenACWY-CRM in the original study, and age-matched vaccine-naïve children, were enrolled in this extension study. After an initial blood draw, children received one dose of MenACWY-CRM as booster or primary dose, with a second blood draw 28 days later. RESULTS: hSBA titers decreased five years after primary vaccination, but were higher than in non-vaccinated controls against serogroups C, W and Y, with substantial proportions having titers ≥8: 7-22% for A, 32-57% for C, 74-83% for W, and 48-54% for Y. Previously-vaccinated children demonstrated booster responses to revaccination against all four serogroups. Responses to primary vaccination in vaccine-naïve controls were lower and similar to primary responses observed in the original study. All vaccinations were generally well tolerated, with no safety concern raised. CONCLUSIONS: Approximately half the children vaccinated as 2-10 year-olds maintained protective antibodies against serogroups C, W and Y five years later, but fewer did against serogroup A. Declining titers five years after vaccination and robust booster responses suggest that five years may be an appropriate interval to revaccinate children, subject to epidemiology and delivery considerations.

Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents.

This phase 2 study assessed the immunogenicity, safety, and reactogenicity of investigational formulations of meningococcal ABCWY vaccines, consisting of recombinant proteins (rMenB) and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine, combined with components of a licensed quadrivalent meningococcal glycoconjugate vaccine (MenACWY-CRM). A total of 495 healthy adolescents were randomized to 6 groups to receive 2 doses (Months 0, 2) of one of 4 formulations of rMenB antigens, with or without OMV, combined with MenACWY-CRM, or 2 doses of rMenB alone or one dose of MenACWY-CRM then a placebo. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroups ACWY and serogroup B test strains; solicited reactions and any adverse events (AEs) were assessed. Two MenABCWY vaccinations elicited robust ACWY immune responses, with higher seroresponse rates than one dose of MenACWY-CRM. Bactericidal antibody responses against the rMenB antigens and OMV components were highest in subjects who received 2 doses of OMV-containing MenABCWY formulations, with ≥68% of subjects achieving hSBA titers ≥5 against each of the serogroup B test strains. After the first dose, solicited local reaction rates were higher in the MenABCWY or rMenB groups than the MenACWY-CRM group, but similar across groups after the second dose, consisting mainly of transient injection site pain. Fever (≥38.0°C) was rare and there were no vaccine-related serious AEs. In conclusion, investigational MenABCWY formulations containing OMV components elicited highly immunogenic responses against meningococcal serogroups ACWY, as well as serogroup B test strains, with an acceptable safety profile. [NCT01210885].

A comparative evaluation of two investigational meningococcal ABCWY vaccine formulations: Results of a phase 2 randomized, controlled trial.

BACKGROUND: A meningococcal vaccine protective against all major disease-associated serogroups (A, B, C, W and Y) is an unmet public health need. In this phase 2 observer-blinded, randomized, controlled study, two investigational meningococcal ABCWY vaccine formulations were evaluated to assess their immunological noninferiority to a licensed quadrivalent meningococcal ACWY glycoconjugate vaccine (MenACWY-CRM) for serogroups ACWY and immunogenicity against serogroup B test strains, as well as for formulation selection based on a desirability index (DI). Each investigational MenABCWY formulation contained recombinant protein and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine (4CMenB) combined with components of MenACWY-CRM. METHODS: A total of 484 healthy 10-25 year-old participants were randomized to receive two doses, two months apart, of an investigational MenABCWY formulation that contained either a full or one-quarter dose of OMV, 4CMenB alone, or a Placebo followed by MenACWY-CRM. Immunogenicity against each of serogroups ACWY and four serogroup B test strains was assessed by serum bactericidal assay with human complement (hSBA). MenABCWY formulations were compared by a DI based on key immunogenicity and reactogenicity parameters. RESULTS: Seroresponse rates for serogroups ACWY were significantly higher after two doses of either MenABCWY formulation than after one dose of MenACWY-CRM: respectively, A: 90-92% vs. 73%; C: 93-95% vs. 63%; W: 80-84% vs. 65%; and Y: 90-92% vs. 75%. Prespecified noninferiority criteria were met. Both MenABCWY formulations induced substantial immune responses against serogroup B test strains, although 4CMenB responses were higher. Overall DIs for both MenABCWY formulations were similar. Reactogenicity profiles of the MenABCWY formulations were similar to each other and to that of 4CMenB. No vaccine-related serious adverse events were reported. CONCLUSIONS: Both investigational MenABCWY formulations elicited robust immune responses against serogroups ACWY and serogroup B test strains, and had acceptable reactogenicity profiles, with no safety concerns identified.

Clinical features that discriminate inhalational anthrax from other acute respiratory illnesses.

Inhalational anthrax (IA) is a rapidly progressive disease that frequently results in sepsis and death, and prompt recognition is critical. To distinguish IA from other causes of acute respiratory illness, patients who had IA were compared with patients in an ambulatory clinic who had influenza-like illness (ILI) and with hospitalized patients who had community-acquired pneumonia (CAP) at the initial health care visit. Compared with patients who had ILI, patients who had IA were more likely to have tachycardia, high hematocrit, and low albumin and sodium levels and were less likely to have myalgias, headache, and nasal symptoms. Scoring systems were devised to compare IA with ILI or CAP on the basis of strength of association. For ILI, a score of > or =4 captured all 11 patients with IA and excluded 664 (96.1%) of 691 patients with ILI. Compared with patients who had CAP, patients with IA were more likely to have nausea or vomiting, tachycardia, high transaminase levels, low sodium levels, and normal white blood cell counts. For CAP, a score of > or =3 captured 9 (81.8%) of 11 patients with IA and excluded 528 (81.2%) of 650 patients with CAP. In conclusion, selected clinical features of patients with IA differ from those of patients with ILI and are more similar to those of patients with CAP.

The etiology of febrile illness in adults presenting to Patan hospital in Kathmandu, Nepal.

In Nepal, many infections remain poorly characterized, partly due to limited diagnostic facilities. We studied consecutive febrile adults presenting to a general hospital in Kathmandu, Nepal. Of the 876 patients enrolled, enteric fever and pneumonia were the most common clinical diagnoses. Putative pathogens were identified in 323 (37%) patients, the most common being Salmonella enterica serotype Typhi and S. enterica serotype Paratyphi A (117), Rickettsia typhi (97), Streptococcus pneumoniae (53), Leptospira spp. (36), and Orientia tsutsugamushi (28). Approximately half of the Salmonella isolates were resistant to nalidixic acid. No clinical predictors were identified to reliably distinguish between the different infections. These findings confirm the heavy burden of enteric fever and pneumonia in Kathmandu, and highlight the importance of murine typhus, scrub typhus, and leptospirosis. Given the lack of reliable clinical predictors, the development of cheap and accurate diagnostic tests are likely to be of great clinical utility in this setting.