Quadrivalent Meningococcal Vaccine Research Articles

2724. Safety and Immunogenicity of a Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) Administered in Healthy Meningococcal Vaccine-Naïve Children (2–9 Years)

BackgroundMenACYW-TT is an investigational quadrivalent meningococcal conjugate vaccine that contains tetanus toxoid as carrier protein. The vaccine is intended for global use in individuals 6 weeks of age and older. We evaluated the safety and immunogenicity of MenACYW-TT compared with a licensed quadrivalent conjugate meningococcal vaccine (MenACWY-CRM [Menveo®]) in US children 2–9 years of age.MethodsIn a modified double-blind Phase III study (NCT03077438), 1000 children were randomized to receive one dose of either MenACYW-TT vaccine or MenACWY-CRM vaccine. Serum bactericidal assays with human (hSBA) and baby rabbit (rSBA) complement were used to measure antibodies against representative meningococcal serogroup strains at baseline and 30 days after vaccination. Safety data were collected up to 6 months post-vaccination.ResultsNon-inferiority of immune responses for all four serogroups, based on percentages of participants achieving hSBA vaccine seroresponse, was demonstrated for MenACYW-TT compared with MenACWY-CRM at Day 30 compared with baseline. The proportions of individuals with hSBA titers ≥ 1:8 following MenACYW-TT administration were higher than those after MenACWY-CRM administration for all four serogroups (A: 86.4% vs 79.3%; C: 97.8% vs 67.1%; W: 94.8% vs 86.3%; Y: 98.5% vs 90.8%). Similar results were observed in two age substrata (2 to 5 years and 6 to 9 years). Percentages of participants with post-vaccination rSBA titers ≥ 1:128 were comparable between both groups. The safety profiles of MenACYW-TT and MenACWY-CRM were comparable. Reactogenicity at the MenACYW-TT injection site was lower than at the MenACWY-CRM injection site. There were no immediate adverse events (AEs), no AEs leading to study discontinuation, and no vaccine-related serious adverse events reported in the study.ConclusionMenACYW-TT vaccine was well tolerated and demonstrated a non-inferior immune response compared with that for the licensed MenACWY-CRM vaccine when administered as a single dose to meningococcal vaccine-naïve children.Disclosures All authors: No reported disclosures.

Concomitant Utilization of Pre-Exposure Prophylaxis (PrEP) and Meningococcal Vaccine (MenACWY) Among Gay, Bisexual, and Other Men Who Have Sex with Men in Los Angeles County, California.

Recent outbreaks of serogroup C meningococcal disease in Southern California have led the California Department of Public Health to recommend the quadrivalent meningococcal vaccine (MenACWY) for gay, bisexual, and other men who have sex with men (GBMSM) in Southern California. High-risk GBMSM have also been advised to utilize pre-exposure prophylaxis (PrEP) for HIV prevention. Data collected from a community-based sample of HIV-negative GBMSM in Los Angeles County (N = 476) were used in a multinomial logit regression analysis to identify patterns in MenACWY and PrEP usage and evaluate factors associated with use of both, one, or neither of these prevention methods. More than half (56%) of participants had neither been vaccinated nor used PrEP. A smaller percentage (34%) had either been vaccinated or were PrEP users, leaving 10% who had concomitant PrEP and MenACWY use. Higher education, more recent sex partners, illicit drug use, and recent receptive condomless anal sex (CAS) were significantly associated with greater odds of using both prevention methods relative to neither. Higher education, prior sexually transmitted infection diagnosis, more recent sex partners, and recent receptive CAS were significantly associated with greater odds of just PrEP use relative to neither. Higher education was the only factor significantly associated with greater odds of just MenACWY immunization relative to neither. Findings highlight important gaps in immunization among PrEP users and opportunities to screen for PrEP eligibility among GBMSM in conjunction with immunization. Public health practitioners should consider the ways in which strategies to increase PrEP and vaccine-preventable illnesses among GBMSM may complement one another.

Immunogenicity of a Quadrivalent Human Papillomavirus Vaccine When Co-Administered with Tetanus-Reduced Diphtheria-Acellular Pertussis and Quadrivalent Meningococcal Conjugate Vaccines in Healthy Adolescents: Results from a Randomized, Observer-Blind, Controlled Trial.

IntroductionVaccines against human papillomavirus (HPV), tetanus, diphtheria, pertussis (Tdap) and Neisseria meningitidis are widely recommended in adolescents. A phase-4 observer-blind study was performed to investigate the impact of concomitant administration of a quadrivalent HPV (HPV4) and Tdap vaccine with a quadrivalent meningococcal CRM197-conjugate vaccine (MenACWY-CRM) in terms of immunogenicity against the different vaccine antigens and overall safety profile. Previous results showed that concomitant administration of the three vaccines did not impact the immunogenicity of Tdap and MenACWY, or safety. This article presents recently released HPV immunogenicity results.MethodsHealthy adolescents aged 11–18 years (801) were randomized to receive either HPV4 + Tdap + MenACWY or HPV4 + Tdap + Placebo and two additional doses of HPV4 at 2 and 6 months after the first dose. Antibody responses to HPV types (HPV-6, -11, -16 and -18) were assessed at baseline and at 1 month post-full vaccination.ResultsPost-third HPV4 dose, non-inferiority of immune responses to HPV4 + Tdap + MenACWY vs. HPV4 + Tdap + Placebo was demonstrated; the lower limits of two-sided 95% CIs of the between-group differences in seroconversion rates were > − 5% (non-inferiority margin) against each HPV type tested. Seroconversion rates ranged between 98.0% (HPV-6) and 99.7% (HPV-11 and HPV-18) in group HPV4 + Tdap + MenACWY and from 99.0% (HPV-11 and HPV-16) to 99.7% (HPV-6 and HPV-18) in group HPV4 + Tdap + Placebo.ConclusionOverall, these data support the concomitant administration of HPV4, Tdap and MenACWY-CRM in adolescents.FundingNovartis Vaccines and Diagnostics Inc., now part of the GSK group of companies.Trial RegistrationClinicalTrials.gov identifier, NCT01424644.

The Hajj 2019 Vaccine Requirements and Possible New Challenges

Each year millions of pilgrims perform the annual Hajj from more than 180 countries around the world. This is one of the largest mass gathering events and may result in the occurrence and spread of infectious diseases. As such, there are mandatory vaccinations for the pilgrims such as meningococcal vaccines. The 2019 annual Hajj will take place during August 8–13, 2019. Thus, we review the recommended and mandated vaccinations for the 2019 Hajj and Umrah. The mandatory vaccines required to secure the visa include the quadrivalent meningococcal vaccine for all pilgrims, while yellow fever, and poliomyelitis vaccines are required for pilgrims coming from countries endemic or with disease activity. The recommended vaccines are influenza, pneumococcal, in addition to full compliance with basic vaccines for all pilgrims against diphtheria, tetanus, pertussis, polio, measles, and mumps. It is imperative to continue surveillance for the spread of antimicrobial resistance and occurrence of all infectious diseases causing outbreaks across the globe in the last year, like Zika virus, MDR-Typhoid, Nipah, Ebola, cholera, chikungunya and Middle East Respiratory Syndrome Coronavirus.

Effect on meningococcal serogroup W immunogenicity when Tdap was administered prior, concurrent or subsequent to the quadrivalent (ACWY) meningococcal CRM197-conjugate vaccine in adult Hajj pilgrims: A randomised controlled trial

Immune responses to the capsular polysaccharide administered in the polysaccharide-protein conjugate vaccines can be either improved or suppressed by the pre-existence of immunity to the carrier protein. Receiving multiple vaccinations is essential for travellers such as Hajj pilgrims, and the use of conjugated vaccines is recommended.We studied the immune response to meningococcal serogroup W upon prior, concurrent and sequential administration of a quadrivalent meningococcal conjugate vaccine (MCV4) conjugated to CRM197 (coadministered with 13 valent pneumococcal vaccine conjugate CRM197 [PCV13]), and tetanus-diphtheria-acellular pertussis (Tdap) vaccine in Australian adults before attending the Hajj pilgrimage in 2014.Participants were randomly assigned, by computer-generated numbers, to three study arms by 1:1:1 ratio. Group A received Tdap followed by MCV4-CRM197 (+PCV13) 3–4 weeks later. Group B received all three vaccines in a single visit. Group C received MCV4-CRM197 (+PCV13) followed by Tdap 3–4 weeks later. Blood samples obtained prior to and 3–4 weeks after immunisation with MCV4-CRM197 were tested for meningococcal serogroup W-specific serum bactericidal antibody responses using baby rabbit complement (rSBA).One hundred and seven participants aged between 18 and 64 (median 40) years completed the study. No significant difference in meningococcal serogroup W rSBA geometric mean titre (GMT) was observed between the study arms post vaccination with MCV-CRM197 but Group A tended to have a slightly lower GMT (A = 404, B = 984 and C = 1235, p = 0.15). No statistical difference was noticed between the groups in proportions of subjects achieving a ≥4-fold rise in rSBA titres or achieving rSBA titre ≥8 post vaccination.In conclusion, receipt of MCV4-CRM197 vaccine prior, concurrent or subsequent to Tdap has similar immunologic response, and hence concurrent administration is both immunogenic and practical. However, further investigation into whether carrier induced suppression is a public health issue is suggested.Clinical trial registration: ANZCTR no. ACTRN12613000536763.

2462. Immunogenicity and Safety of a Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) Administered in Individuals 56 Years of Age and Older

BackgroundThe MenACYW-TT conjugate vaccine is a quadrivalent meningococcal vaccine candidate intended for global use in all age groups. This Phase III study evaluated the safety and immunogenicity of the vaccine when compared with a licensed quadrivalent meningococcal polysaccharide vaccine (MPSV4) in adults ≥56 years of age.MethodsA randomized, modified double-blind, multicenter study (NCT02842866) was conducted in 907 healthy adults in the United States. Participants were randomized to receive a single dose of either MenACYW-TT conjugate vaccine or MPSV4, stratified according to age into 2 subsets: 56 to 64 and ≥65 years. Descriptive analyses were also planned for age subsets 65–74 years and ≥75 years. Serum bactericidal assay with human (hSBA) and baby rabbit (rSBA) complement was used to measure antibodies against serogroups A, C, Y, and W test strains at baseline and 30 days after vaccination. Safety data were collected up to six months post-vaccination.ResultsNon-inferiority of immune responses was demonstrated between MenACYW-TT conjugate vaccine and MPSV4 based on percentages of subjects achieving hSBA vaccine seroresponse for serogroups A, C, Y, and W at Day 30 compared with baseline. The proportions of individuals with hSBA ≥ 1:8 obtained after MenACYW-TT conjugate vaccine were higher than those after MPSV4 for all four serogroups (A: 89.4% vs. 84.2%; C: 90.1% vs. 70.9%; W: 77.4% vs. 63.0%; Y: 91.7% vs. 67.7%). Overall, the results were similar in the three age substrata. Percentages of participants with post vaccination rSBA ≥ 1:128 were numerically higher for all serogroups in subjects vaccinated with MenACYW-TT conjugate vaccine. A difference in the local reactogenicity profiles was observed between the two vaccine groups, possibly influenced by the different routes of administration. Most unsolicited adverse events were of Grade 1 or Grade 2 intensity. No vaccine related serious adverse events were reported.ConclusionMenACYW conjugate vaccine was immunogenic and well tolerated when administered to individuals ≥56 years of age. Such a vaccine will offer an alternative for the prevention of invasive meningococcal disease in areas of the world where only polysaccharide vaccines are currently available for immunization of older adults.Disclosures A. Esteves-Jaramillo, Sanofi Pasteur: Employee, Educational support and Salary. D. Neveu, Sanofi Pasteur: Employee, Salary. M. S. Dhingra, Sanofi Pasteur: Employee, Educational support and Salary.

1967. Study of the Immunogenicity and Safety of an Investigational Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) When Co-administered with Other Vaccines in Healthy Adolescents

BackgroundThe MenACYW-TT conjugate vaccine is a quadrivalent meningococcal vaccine candidate intended for global use in all age groups. This pivotal phase II study evaluated the safety and immunogenicity of the vaccine when compared with a licensed quadrivalent conjugated meningococcal vaccine (MCV4-CRM) when co-administered with tetanus, diphtheria, acellular pertussis (Tdap), and human papilloma virus (HPV4) vaccines in meningococcal vaccine naïve adolescents (10–17 years of age).MethodsA randomized, open-label, multicenter study (NCT02199691) was conducted in 1,715 healthy subjects in the United States, who were randomly assigned to receive MenACYW-TT conjugate vaccine, MCV4-CRM, MenACYW-TT conjugate vaccine (co-administered with Tdap and HPV4), or Tdap and HPV4 vaccines. Serum bactericidal assay with human (hSBA) and baby rabbit (rSBA) complement was used to measure antibodies against serogroups A, C, W, and Y test strains at baseline and 30 days after vaccination. Safety data were collected up to 6 months post-vaccination.ResultsNoninferiority of immune response was demonstrated between MenACYW-TT conjugate vaccine and MCV4-CRM, and MenACYW-TT conjugate vaccine when co-administered with Tdap and HPV4 vaccines vs. when administered alone, based on percentages of study participants achieving hSBA vaccine seroresponse at Day 30 fromD0 baseline. The proportions of individuals with hSBA ≥ 1:8 after MenACYW-TT conjugate vaccine administration were higher than those after MCV4-CRM administration for all four serogroups (A: 93.5% vs. 82.8%; C: 98.5% vs. 76.0%; W: 99.1% vs. 90.7%; Y: 97.2% vs. 83.2%). Co-administration of MenACYW conjugate, Tdap and HPV4 vaccines did not generate any results suggestive of immune interference. Reactogenicity profiles were comparable across study groups. Most unsolicited adverse events were of Grade 1 or Grade 2 intensity. No vaccine related serious adverse events were reported.ConclusionMenACYW-TT conjugate vaccine was immunogenic and well tolerated when administered as a single dose to meningococcal vaccine naïve adolescents along with Tdap and HPV4 vaccines. Such a vaccine will offer an alternative for the prevention of invasive meningococcal disease in susceptible populations across the world.Disclosures All authors: No reported disclosures.

Quadrivalent Meningococcal Vaccine Uptake Among Men Who Have Sex With Men During a Meningococcal Outbreak in Los Angeles County, California, 2016-2017.

The objective of our study was to assess meningococcal ACWY (MenACWY) vaccine uptake among men who have sex with men (MSM) during an ongoing, invasive meningococcal disease outbreak in Southern California. This research was important to inform future vaccination uptake interventions for this high-priority population. We conducted venue-based sampling to recruit and enroll MSM living in Los Angeles County, California, from December 2016 through February 2017. We conducted bivariate and multivariable analyses to evaluate associations between MenACWY vaccine uptake and other predetermined factors. Of 368 participants, 138 (37.5%) reported receiving the MenACWY vaccine. In multivariable analyses, older age (adjusted odds ratio [aOR] = 2.57; 95% confidence interval [CI], 1.31-5.03), previous diagnosis of a sexually transmitted infection (aOR = 2.22; 95% CI, 1.14-4.30), belief that MenACWY vaccine is important (aOR = 3.49; 95% CI, 1.79-6.82), confidence in the MenACWY vaccine (aOR = 5.53; 95% CI, 3.11-9.83), and knowing someone who had been vaccinated (aOR = 5.82; 95% CI, 3.05-11.12) were significantly associated with MenACWY vaccine uptake. Our findings reflect low uptake of the recommended MenACWY vaccine among MSM after a local outbreak, despite public health efforts. In addition to ongoing, widespread campaigns to inform MSM about local outbreaks and vaccination recommendations, MSM may be responsive to direct outreach from peers who have been vaccinated.

Dupilumab does not affect correlates of vaccine-induced immunity: A randomized, placebo-controlled trial in adults with moderate-to-severe atopic dermatitis

The impact of dupilumab, an anti-interleukin (IL) 4 receptor α antibody that inhibits IL-4 and IL-13 signaling, on vaccine responses of patients with atopic dermatitis (AD) is unknown. To assess T-cell-dependent and T-cell-independent humoral immune responses to tetanus and meningococcal vaccines, IgE seroconversion to tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccination, and dupilumab efficacy and safety. In a randomized, double-blinded, placebo-controlled study (NCT02210780), adults with moderate-to-severe AD received dupilumab (300mg) or placebo weekly for 16weeks, and single doses of Tdap and quadrivalent meningococcal polysaccharide vaccines at week 12. Primary endpoint was proportion of patients achieving satisfactory IgG response to tetanus toxoid at week 16. In total, 178 patients completed the study. Similar positive immune responses (≥4-fold increase in antibody titer, or an antibody titer of ≥8) were achieved in the dupilumab and placebo groups to tetanus (83.3% and 83.7%, respectively) and meningococcal polysaccharide (86.7% and 87.0%, respectively). Dupilumab significantly decreased total serum IgE; most dupilumab-treated patients were Tdap-IgE seronegative at week 32 (62.2% dupilumab and 34.8% placebo). Dupilumab improved key AD efficacy endpoints (P<.001). Injection-site reactions and conjunctivitis were more common with dupilumab; AD exacerbations more frequent with placebo. Patients' prior vaccination status was not available before enrollment. Dupilumab did not affect responses to the vaccines studied, significantly decreased IgE, and improved measures of AD severity versus placebo, with an acceptable safety profile.

Meningococcal B Vaccine Efficacy in Children at High Risk for Meningococcal Disease

A quadrivalent conjugate meningococcal vaccine that covers serotypes A, C, W, and Y is recommended for children with high-risk conditions such as

Failure of first meningococcal vaccination in patients with atypical haemolytic uraemic syndrome treated with eculizumab

The C5 complement inhibitor eculizumab is a first-line treatment in atypical haemolytic uraemic syndrome (aHUS). Therapy with eculizumab is associated with a highly increased risk for meningococcal infection. Therefore, vaccination is highly recommended before beginning treatment. Efficacy of quadrivalent meningococcal vaccines (MenACWY) in patients treated with the C5 complement inhibitor eculizumab in aHUS has not yet been determined. Patients with aHUS received one dose of a MenACWY conjugate vaccine before eculizumab treatment commenced. Bactericidal titres against meningococcal serogroups A, C, W and Y were determined using baby rabbit complement in 25 patients. Full immune response to meningococcal vaccination was detected in five patients (20%), while seven patients (28%) showed no immune response in any of the tested serogroups. The remaining 13 patients showed incomplete immune response with proof of protective antibody titres for one to three serogroups without perceptible preference for any serogroup. Bactericidal titres after re-vaccination were available for 17 patients. Nine patients with incomplete immune response after first vaccinations showed protective antibody titres for all serogroups after re-vaccination. Kidney function had improved in >50% of patients at the time of re-vaccination compared with the time of first vaccination and immunosuppressive therapy was only applied to re-vaccinated patients following kidney transplantation. Immunogenicity of first quadrivalent meninongococcal vaccination is insufficient in patients with aHUS. Booster response is promising, but incomplete. Therefore, establishing antibiotic prophylaxes seems pivotal.

Immunogenicity and safety of the quadrivalent meningococcal vaccine MenACWY-TT co-administered with a combined diphtheria-tetanus-acellular pertussis vaccine versus their separate administration in adolescents and young adults: A phase III, randomized study

BackgroundThis study evaluated the immunogenicity and safety of quadrivalent meningococcal conjugate vaccine using tetanus (T) toxoid as carrier protein (MenACWY-TT) co-administered with combined diphtheria-tetanus-acellular pertussis vaccine (Tdap) versus their separate administration in adolescents and young adults. MethodsIn this phase III, randomized, partially-blind study (NCT01767376), healthy 11–25-year-olds (N = 660) were randomized (1:1:1) to receive MenACWY-TT and Tdap at Month 0 (Co-ad group), MenACWY-TT at Month 0 and Tdap at Month 1 (ACWY_Tdap group) or Tdap at Month 0 and MenACWY-TT at Month 1 (Tdap_ACWY group). Immune responses to MenACWY-TT were measured by serum bactericidal assay using rabbit complement (rSBA). Anti-diphtheria (D), anti-tetanus (T), anti-pertussis toxin (PT), anti-filamentous hemagglutinin (FHA) and anti-pertactin (PRN) antibody concentrations were assessed using enzyme-linked immunosorbent assays. Non-inferiority of immunogenicity was assessed using pre-defined clinical criteria. Safety was also evaluated. ResultsNon-inferiority of immunogenicity of MenACWY-TT and Tdap when co-administered versus their separate administration was demonstrated in terms of rSBA geometric mean titers (GMTs) for 4 meningococcal serogroups and of the percentage of participants with antibody concentrations >1 IU/ml for D and T. Among the pertussis antigens, non-inferiority criteria for geometric mean concentrations (GMCs) were reached for PT, but not met for FHA and PRN. Across all groups, ≥93.2% of participants had vaccine responses to each meningococcal serogroup, ≥99.1% were seroprotected against T and D, and ≥85.5% had booster responses to each pertussis antigen. Robust increases in antibody GMTs/GMCs were observed for all antigens between pre-and post-vaccination. Both vaccines had clinically acceptable safety profiles. ConclusionImmune responses to MenACWY-TT and to the T and D antigens from Tdap were not impacted by their co-administration. The lower antibody concentrations observed against the pertussis components may be of limited clinical relevance since robust anti-pertussis booster responses were observed. This study supports concurrent administration of the 2 vaccines in adolescents.

Safety and immunogenicity of conjugate quadrivalent meningococcal vaccination after hematopoietic cell transplantation

AbstractImmunization with the conjugated quadrivalent (serogroups A, C, Y, and W-135) meningococcal vaccine (MCV4) after hematopoietic cell transplantation (HCT) is recommended. However, immune responses to MCV4 have not been prospectively studied after HCT. We conducted a vaccine response study among 67 adults who received 1 MCV4 dose a year after autologous or allogeneic HCT from January to September 2014. Pre- and postvaccination serogroup serum bactericidal antibody (SBA) titers were measured a median of 57 days after vaccination. Serogroup-specific responses were defined as a fourfold increase in SBA titer with postvaccination titers ≥1:8. Prior to vaccination, 44 (65.7%) patients had no protective titers (<1:8) to any meningococcal serogroup, and 3 (4.5%) patients had protective titers to all 4 serogroups. The median serogroup-specific postvaccination SBA titers were 1:2048 for A, 1:64 for C, 1:128 for W-135, and 1:128 for Y (P < .001 for all pre- and postvaccination pairwise comparisons; similar among serogroups, Spearman ρ 0.5-0.6, P < .0001). Among serogroup-specific nonimmune patients prior to vaccination, serogroup-specific response rates were 76.9%, 65.5%, 51.7%, and 65% to serogroups A, C, W-135, and Y, respectively. One dose of MCV4 elicited protective titers in the majority of patients. These data suggest that a second vaccine dose may be beneficial.

Effect of Tdap upon antibody response to meningococcal polysaccharide when administered before, with or after the quadrivalent meningococcal TT-conjugate vaccine (coadministered with the 13-valent pneumococcal CRM197-conjugate vaccine) in adult Hajj pilgrims: A randomised controlled trial

Hajj pilgrims are susceptible to several serious infections and are required to receive multiple vaccinations. Polysaccharide-protein conjugate vaccines contain carrier proteins such as tetanus toxoid (TT), diphtheria toxoid or a mutant of diphtheria toxoid (CRM197). These carrier proteins may interact with other conjugate or combination vaccines containing tetanus or diphtheria on concurrent or sequential administration. We examined the immune interaction of separate and concomitant administration of a tetanus/diphtheria/acellular pertussis (Tdap) vaccine with a TT-conjugated quadrivalent meningococcal vaccine (MCV4) (coadministered with 13-valent pneumococcal CRM197-conjugate vaccine [PCV13]) in adult Australian pilgrims before attending Hajj in 2015.We randomly assigned each participant to one of three vaccination schedules. Group 1 received Tdap 3–4 weeks before receiving MCV4 coadministered with PCV13. Group 2 received all three vaccines concomitantly. Group 3 received MCV4 and PCV13 3–4 weeks before Tdap. Blood samples were collected at baseline, at each vaccination visit and 3–4 weeks after vaccination and tested for response to meningococcal serogroups C, W and Y using a serum bactericidal antibody (rSBA) assay with baby rabbit complement, and to diphtheria and tetanus toxoid, measuring IgG antibodies by ELISA. Participants completed symptom diaries after each vaccination. A total of 166 participants aged 18–64 (median 42) years were recruited, of whom 160 completed the study. Compared to the other groups, Group 1 (given Tdap first) had significantly lower proportion of subjects achieving a ≥4-fold rise in rSBA for serogroup W. No difference was detected across the three groups in achieving protection threshold (rSBA ≥8 post vaccination) or SBA geometric mean titre (GMT) post vaccination.Group 3, which was given MCV4/PCV13 first, had high levels of antibody against diphtheria and tetanus than the other groups, when tested prior to receipt of Tdap; Only the anti-tetanus responses remained significantly higher after Tdap administration. No serious adverse events were reported.In conclusion, when multiple vaccination is required for Hajj pilgrims, administering Tdap concurrently with MCV4/PCV13 produces adequate immune responses, and avoids meningococcal immune interference, in the convenience of a single consultation. However, giving Tdap 3–4 weeks after MCV4/PCV13 has the advantage of an enhanced tetanus toxoid response.The trial is Trials Registry (ANZCTR): ACTRN12613000536763.

Use of weighted multivariate estimates in trials of multi-serotype vaccines to simplify interpretation of treatment differences

BackgroundMany vaccines contain multiple components. Licensed pneumococcal conjugate vaccines (PCV) contain polysaccharides from 7, 10, or 13 different serotypes of Streptococcus pneumoniae. The main outcomes in randomised trials of pneumococcal vaccines are serotype-specific antibody measures. Comparisons are made between groups for each serotype, resulting in multiple separate comparisons of treatment effects which can be complicated to interpret. We investigated methods for computing the overall difference between vaccine groups across all serotypes.MethodsPneumococcal antibody concentrations were obtained from a randomised controlled trial of ten-valent pneumococcal vaccine, conducted in Kathmandu, Nepal. Infants received either 2 priming doses of vaccine at 6 and 14 weeks of age followed by a booster (2+1), or 3 priming doses at 6, 10, and 14 weeks of age with no booster (3+0). The overall difference between vaccine schedules across all serotypes was computed at each visit using a multivariate linear model with equal weights for each serotype. Alternative weights were derived from invasive pneumococcal disease cases in Nepal, Bangladesh and Pakistan, and from estimates of the relative invasiveness of each serotype and used in sensitivity analyses.ResultsWhen 10 separate estimates of treatment differences were computed the ratio of antibody responses for each serotype in the 2+1 group compared with the 3+0 group at 10 months of age varied greatly, with serotype-specific GMRs ranging from 2.80 for serotype 14, to 9.14 for serotype 18C. Using equal weights for each serotype, the overall geometric mean ratio (GMR) was 5.02 (95% CI 4.06−6.22) at 10 months of age, and 1.46 (95% CI 1.14−1.88) at 3 years of age. Using weights based on disease incidence gave GMRs ranging from 5.15 to 6.63 at 10 months of age, and 1.47 to 1.78 at 3 years of age. Using weights based on relative invasiveness gave estimates of 6.81 and 1.59, at 10 months and 3 years respectively.ConclusionPCV clinical trial data have a multivariate structure with correlated outcomes for different serotypes. When analysing each serotype separately, the multiple estimates of the treatment effect can complicate the interpretation of trial results. Reporting a single overall estimate which accounts for the correlation between outcomes can simplify such interpretation. Treatment effects can be weighted equally or alternative weights derived from independent data can be used.Many modern vaccines have multiple components, such as quadrivalent meningococcal group ACWY vaccine or four-component group B meningococcal vaccine, thus these methods are widely applicable.

A Review of Meningococcal Disease and Vaccination Recommendations for Travelers.

International travel has been steadily increasing since the middle of the twentieth century, including travel to regions with high levels of endemic meningococcal disease and areas with sporadic or sustained meningococcal outbreaks. Although invasive meningococcal disease (IMD) is relatively rare in travelers since the advent of quadrivalent meningococcal vaccines, it remains a serious concern because of its rapid progression, poor prognosis and outcomes, associated treatment delays, and the potential to precipitate outbreaks. Moreover, fatality occurs in up to 22% of those infected. This review will focus on IMD in travelers, with an emphasis on IMD epidemiology and the geographic regions of potential concern for international travelers. As vaccination is the best approach for preventing IMD among travelers, currently available meningococcal vaccines and corresponding country-specific national meningococcal vaccination recommendations, where available, will be summarized by age and type of vaccine recommended. The use of the quadrivalent meningococcal vaccines, specifically the tetanus toxoid conjugate vaccine (including MenACWY-TT; Nimenrix®), as a protective measure against IMD in travelers will be emphasized.FundingPfizer Inc.

Immunogenicity and safety of one or two doses of the quadrivalent meningococcal vaccine MenACWY-TT given alone or with the 13-valent pneumococcal conjugate vaccine in toddlers: A phase III, open-label, randomised study

BackgroundWe evaluated the immunogenicity and safety of 1 and 2 doses of quadrivalent meningococcal serogroup A, C, W and Y tetanus toxoid-conjugate vaccine (MenACWY-TT) given alone or co-administered with 13-valent pneumococcal conjugate vaccine (PCV13) in toddlers. MethodsIn this phase III, open-label, controlled, multicentre study (NCT01939158), healthy toddlers aged 12–14 months were randomised into 4 groups to receive 1 dose of MenACWY-TT at month (M) 0 (ACWY_1), 2 doses of MenACWY-TT at M0 and M2 (ACWY_2), MenACWY-TT and PCV13 at M0 (Co-ad), or PCV13 at M0 and MenACWY-TT at M2 (PCV13/ACWY). Immune responses were assessed 1 month post-each vaccination. Solicited and unsolicited symptoms were recorded for 4 and 31 days post-each vaccination, respectively; serious adverse events (SAEs) and new onset of chronic illnesses (NOCIs) up to M9 from first vaccination. Results802 toddlers were vaccinated. Post-dose 1 of MenACWY-TT, ≥92.8% of toddlers had rSBA titres ≥1:8, and ≥62.5% had hSBA titres ≥1:4 for each meningococcal serogroup. Post-dose 2 of MenACWY-TT, rSBA titres ≥1:8 were observed in ≥98.0% and hSBA titres ≥1:4 in ≥95.3% of toddlers. Percentages of toddlers with hSBA titres ≥1:4 were higher after 2 doses versus 1 dose of MenACWY-TT for MenW (97.1% versus 62.5–68.9%) and MenY (95.3% versus 64.3–67.6%). Non-inferiority of immune responses to co-administered MenACWY-TT and PCV13 over their separate administration was demonstrated. AEs incidence was comparable among groups. SAEs were reported for 4.9%, 5.1%, 5.5% and 7.5%, and NOCIs for 2.0%, 3.0%, 0.5% and 3.5% of toddlers in the ACWY_1, ACWY_2, Co-ad and PCV13/ACWY groups, respectively; 4 SAEs reported in 3 toddlers were vaccine-related. Two fatal vaccine-unrelated SAEs were reported. ConclusionMenACWY-TT was immunogenic when administered as a single dose at 12–14 months of age. A second dose in toddlers increased hSBA responses against MenW and MenY. MenACWY-TT and PCV13 can be co-administered without impairing the immunogenicity or safety profile of either vaccine.

A Phase 2a Randomized Study to Evaluate the Safety and Immunogenicity of the 1790GAHB Generalized Modules for Membrane Antigen Vaccine against Shigella sonnei Administered Intramuscularly to Adults from a Shigellosis-Endemic Country.

Shigellosis is a mild-to-severe diarrheal infection, caused by the genus Shigella, and is responsible for significant morbidity and mortality worldwide. We evaluated the safety and immunogenicity of an investigational Shigella sonnei vaccine (1790GAHB) based on generalized modules for membrane antigens (GMMA) in Kenya, a Shigella-endemic country. This phase 2a, observer-blind, controlled randomized study (NCT02676895) enrolled 74 healthy adults aged 18–45 years, of whom 72 were vaccinated. Participants received, in a 1:1:1 ratio, two vaccinations with the 1790GAHB vaccine at doses of either 1.5/25 μg of O antigen (OAg)/protein (group 1.5/25 μg) or 5.9/100 μg (group 5.9/100 μg) at day (D) 1 and D29, or vaccination with a quadrivalent meningococcal vaccine at D1 and tetanus, diphtheria, and acellular pertussis vaccine at D29 (control group). Solicited and unsolicited adverse events (AEs), serious AEs (SAEs), and AEs of special interest (neutropenia and reactive arthritis) were collected. Anti-S. sonnei lipopolysaccharide (LPS) serum immunoglobulin G (IgG) geometric mean concentrations (GMC) were evaluated at D1, D29, and D57 and compared to anti-S. sonnei LPS antibody levels in convalescent patients naturally exposed to S. sonnei. The percentages of participants with seroresponse were also calculated. The most frequently reported solicited local and systemic AEs across all groups were pain and headache, respectively. Only one case of severe systemic reaction was reported (severe headache after first vaccination in group 5.9/100 μg). Seven and three episodes of neutropenia, assessed as probably or possibly related to vaccination respectively, were reported in the investigational and control groups, respectively. No other SAEs were reported. Despite very high baseline anti-S. sonnei LPS serum IgG levels, the 1790GAHB vaccine induced robust antibody responses. At D29, GMC increased 2.10- and 4.43-fold from baseline in groups 1.5/25 and 5.9/100 μg, respectively, whereas no increase was observed in the control group. Antibody titers at D57 were not statistically different from those at D29. Seroresponse was 68% at D29 and 90% at D57 in group 1.5/25 μg, and 96% after each vaccination in group 5.9/100 μg. The 1790GAHB vaccine was well tolerated and highly immunogenic in a population of African adults, regardless of the GMMA OAg/protein content used.

Recommendations for the use of meningococcal vaccines in South Africa

Background: Although meningococcal disease (MD) incidence in South Africa is low, Neisseria meningitidis (NM) causes severe disease that is often life-threatening and can cause long-term disabilities. A quadrivalent protein-conjugated meningococcal vaccine (MCV4) is available, and provides protection against 75% of disease causing serogroups in South Africa. Recommendations: We advise vaccination of persons at high risk of meningococcal disease including those with complement deficiency and asplenia; laboratory personnel from reference laboratories who work with NM; and travellers to Saudi Arabia. The need for routine vaccine against meningococcal disease in South Africa is controversial given the current burden of disease. However, due to the high morbidity/mortality of MD we recommend that clinicians consider vaccination of healthy infants and children; HIV-infected persons with a CD4 count 25%; students attending college /university /military academies; and miners.Conclusion: Protein-conjugated meningococcal vaccine is preferable to the polysaccharide vaccine given the ability of the protein-conjugated meningococcal vaccine to induce immune memory, allow for booster responses and eliminate carriage of the organism in the person vaccinated.

Peri-splenectomy vaccination at tertiary-care facilities in Hamilton, Ontario

Objective: The Canadian Immunization Guide recommends vaccinations against Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b (Hib) either at least 2 weeks before elective splenectomy or within 2 weeks following emergent splenectomy. This study aimed to assess compliance with these national recommendations. Recommended peri-splenectomy vaccines at the time of the study included the 23-valent pneumococcal polysaccharide vaccine (PPSV23), a quadrivalent meningococcal vaccine, and a Hib vaccine. Methods: Data for all adult elective and emergent splenectomy patients between March 2009 and November 2012 at an academic institution in Hamilton, Canada, were retrospectively reviewed. Data collection included indication for and date of splenectomy, vaccine formulation ordered and administered, and date of vaccine administration. Results: The vaccination rates of 125 patients were 55.2% for pneumococcus, 58.4% for meningococcus, and 59.2% for Hib; 66 patients (52.8%) received vaccinations against all three pathogens. Emergent splenectomy patients were significantly more likely than elective splenectomy patients to have documented vaccination against all three pathogens (62.9% versus 42.9%; p=0.003). Only 6 of 73 patients (8.2%) received a recommended quadrivalent meningococcal vaccine, while 49 of 69 pneumococcal-vaccinated patients (62.3%) received the recommended PPSV23. Conclusions: Peri-splenectomy vaccination patterns did not consistently meet national recommendations. Vaccines against S. pneumoniae, N. meningitidis, and Hib were administered in &lt;60% of patients, which highlights a need for strategies to improve peri-operative vaccination rates in this population. Administration of vaccine formulations inconsistent with national guidelines demonstrates a need to improve awareness of the current vaccination recommendations for asplenic patients.