Fully Liquid MenACWY-CRM Vaccine: Results from an Integrated Safety Analysis.

INTRODUCTION: The currently licensed quadrivalent MenACWY-CRM conjugate vaccine presentation consists of two vials (lyophilized MenA and liquid MenCWY) to be reconstituted before injection. A new fully liquid, single-vial formulation has been developed to simplify administration and prevent reconstitution errors. We present pooled safety data from two randomized, controlled, observer-blind phase 2b clinical trials, in which the fully liquid presentation was compared with the licensed presentation. METHODS: This is a post hoc analysis of two studies, in which safety data from participants aged 10-40 years who received one dose of either liquid MenACWY-CRM (1337 participants; MenACWY liquid group) or licensed MenACWY-CRM (1332 participants; MenACWY licensed group) were pooled. Frequencies were calculated for solicited adverse events (AEs) during 7 days post-vaccination and unsolicited AEs, including medically attended AEs and serious AEs (SAEs), during the 6-month safety follow-up period. Analysis results are presented by vaccine group, overall and by age category (10-17 and 18-40 years). RESULTS: Overall, AEs solicited for collection during the first 7 days after vaccination were reported by similar percentages of participants (69.2%, MenACWY liquid; 68.2%, MenACWY licensed), and were generally mild/moderate in intensity. Solicited local AEs were reported by 46.0% of the MenACWY liquid group and 43.5% of the MenACWY licensed group and solicited systemic AEs by 55.2 and 54.1%, respectively. During the 6-month post-vaccination period, unsolicited AEs were reported by 32.2 and 31.2% of the MenACWY liquid group and MenACWY licensed group, respectively, and medically attended AEs by 18.6 and 17.3%, respectively. Overall, 14 participants in each group (1.0 and 1.1%, respectively) reported SAEs, none of which was considered vaccine-related by the investigator. The safety profiles of both MenACWY-CRM presentations were similar for each age group and overall. CONCLUSIONS: This pooled analysis shows the safety profile of fully liquid MenACWY-CRM is comparable with that of the currently licensed vaccine presentation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03652610 (August 29, 2018), NCT03433482 (14 February 2018).

Immunological non-inferiority of a new fully liquid presentation of the MenACWY-CRM vaccine to the licensed vaccine: results from a randomized, controlled, observer-blind study in adolescents and young adults.

A fully liquid MenACWY-CRM vaccine presentation has been developed, modifying the meningococcal serogroup A (MenA) component from lyophilized to liquid. The safety and immunogenicity of the liquid presentation at the end of the intended shelf-life (aged for 24 or 30 months) were compared to the licensed lyophilized/liquid presentation. This multicenter, randomized (1:1), observer-blind, phase 2b study (NCT03433482) enrolled adolescents and young adults (age 10-40 years). In part 1, 844 participants received one dose of liquid presentation stored for approximately 24 months or licensed presentation. In part 2, 846 participants received one dose of liquid presentation stored for approximately 30 months or licensed presentation. After storage, the MenA free saccharide (FS) level was approximately 25% and O-acetylation was approximately 45%. The primary objective was to demonstrate non-inferiority of the liquid presentation to licensed presentation, as measured by human serum bactericidal assay (hSBA) geometric mean titers (GMTs) against MenA, 1-month post-vaccination. Immune responses against each vaccine serogroup were similar between groups. Between-group ratios of hSBA GMTs for MenA were 1.21 (part 1) and 1.11 (part 2), with two-sided 95% confidence interval lower limits (0.94 and 0.87, respectively) greater than the prespecified non-inferiority margin (0.5), thus meeting the primary study objective. No safety concerns were identified. Despite reduced O-acetylation of MenA and increased FS content, serogroup-specific immune responses induced by the fully liquid presentation were similar to those induced by the licensed MenACWY-CRM vaccine, with non-inferior anti-MenA responses. The safety profiles of the vaccine presentations were similar.

Bactericidal antibodies against hypervirulent Neisseria meningitidis C field strains following MenC-CRM or MenACWY-CRM priming and MenACWY-CRM booster in children.

An increase in invasive meningococcal disease (IMD) incidence was observed in Tuscany in 2015/2016, mainly due to hypervirulent clonal complex (cc) 11 strains. In a post-hoc analysis, we assessed bactericidal activity of antibodies in sera from children primed with MenACWY-CRM or MenC-CRM conjugate vaccines and receiving a MenACWY-CRM booster dose against 5 meningococcal C (MenC) strains isolated from IMD cases. Sera collected from 90 infants/toddlers who participated in a phase III, open-label study (NCT00667602) and its extension (NCT01345721) were tested by serum bactericidal activity assay with human complement (hSBA). Children were primed with either MenACWY-CRM at 6-8 and 12 months of age (group 2_MenACWY; N = 30), MenACWY-CRM (group 1_MenACWY; N = 30), or MenC-CRM at 12 months of age (group 1_MenC; N = 30); all received MenACWY-CRM booster dose at 22-45 months of age. Four tested strains (FI001-FI004) were C:P1.5-1,10-8:F3-6:ST-11 (cc11) and 1 (FI005) was C:P1.7-4,14-6:F3-9:ST-1031 (cc334). Overall, immune responses tended to be higher against Fl002-FI004 than Fl001 and Fl005. Geometric mean titers were high in group 2_MenACWY (range: 94.8 [FI005]-588.1 [FI004]) and very high post-boosting with MenACWY-CRM in all groups (176.9 [FI005]-3911.0 [FI004]). Seroresponse rates tended to be higher in group 1_MenC (33.3% [FI005]-93.3% [FI004]) than in group 1_MenACWY (16.7% [FI005]-73.3% [FI004]). Irrespective of strains tested or the identity/number of priming doses, ≥96.7% of children had hSBA titers ≥1:8 post-MenACWY-CRM booster dose. MenACWY-CRM and MenC-CRM elicited bactericidal antibodies and immunological memory against hypervirulent cc11 and cc334 MenC strains responsible for IMD outbreaks.

MenACWY-CRM conjugate vaccine booster dose given 4-6 years after priming: Results from a phase IIIb, multicenter, open label study in adolescents and adults.

BACKGROUND: Vaccination strategies against bacterial meningitis vary across countries. In the United States, a single dose of quadrivalent meningococcal conjugate vaccine (MenACWY) is recommended at 11-12 years of age, with a booster dose approximately 5 years later. We assessed immune responses to a booster dose of MenACWY-CRM vaccine after priming with MenACWY-CRM or MenACWY-D vaccines in adolescents and adults. METHODS: In this phase IIIb, multicenter, open-label study, healthy 15-55-year-olds, who received MenACWY-CRM (N = 301) or MenACWY-D (N = 300) 4-6 years earlier or were meningococcal vaccine-naïve (N = 100), received one MenACWY-CRM vaccine dose. Immunogenicity was evaluated pre-vaccination, 3 or 5 days post-vaccination (sampling subgroups), and 28 days post-vaccination by serum bactericidal activity assay using human complement (hSBA). After vaccination, participants were monitored for 7 days for reactogenicity, 29 days for unsolicited adverse events (AEs), and 181 days for serious AEs and medically-attended AEs. RESULTS: Sufficiency of the immune response to a MenACWY-CRM booster dose was demonstrated; the lower limit of the 1-sided 97.5% confidence interval for percentages of participants with hSBA seroresponse at 28 days post-vaccination was >75% for each serogroup in those primed with either the MenACWY-CRM or MenACWY-D vaccine. Seroresponse was observed in ≥93.24% of primed participants and ≥35.87% of naïve participants 28 days post-vaccination. At 5 days post-booster, among primed participants, hSBA titers ≥1:8 were achieved in ≥47.14% of participants for MenA and in ≥85.52% of participants for MenC, MenW and MenY, and 3.25- to 8.59-fold increases in hSBA geometric mean titers against each vaccine serogroup were observed. No safety concerns were raised throughout the 6-month follow-up period. CONCLUSIONS: A booster dose of the MenACWY-CRM vaccine induced a robust and rapid anamnestic response in adolescents and adults, irrespectively of either MenACWY-CRM or MenACWY-D vaccine administered 4-6 years earlier, with an acceptable clinical safety profile. ClinicalTrials.gov registration: NCT02986854.

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.

INTRODUCTION: Vaccines 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. METHODS: Healthy 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. RESULTS: Post-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. CONCLUSION: Overall, these data support the concomitant administration of HPV4, Tdap and MenACWY-CRM in adolescents. FUNDING: Novartis Vaccines and Diagnostics Inc., now part of the GSK group of companies. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01424644.

Equivalence testing for similarity in bioassays using bioequivalence criteria on the relative bioactivity.

Similarity in bioassays means that the test preparation behaves as a dilution of the standard preparation with respect to their biological effect. Thus, similarity must be investigated to confirm this biological property. Historically, this was typically conducted with traditional hypothesis testing, but this has received substantial criticism. Failing to reject similarity does not imply that the 2 preparations are similar. Also, rejecting similarity when bioassay variability is small might simply demonstrate a nonrelevant deviation in similarity. To remedy these concerns, equivalence testing has been proposed as an alternative to traditional hypothesis testing, and it has found its way in the official guidelines. However, similarity has been discussed mainly in terms of the parameters in the dose-response curves of the standard and test preparations, but the consequences of nonsimilarity on the relative bioactivity have never been investigated. This article provides a general equivalence approach to evaluate similarity that is directly related to bioequivalence on the relative bioactivity of the standard and test preparations. Bioequivalence on the relative bioactivity can only be guaranteed for positive (only nonblanks) and finite dose intervals. The approach is demonstrated on 4 case studies in which we also show how to calculate a sample size and how to investigate the power of equivalence on similarity.

A comparison of statistical methods for combining relative bioactivities from parallel line bioassays.

This paper compares the ordinary unweighted average, weighted average, and maximum likelihood methods for estimating a common bioactivity from multiple parallel line bioassays. Some of these or similar methods are also used in meta-analysis. Based on a simulation study, these methods are assessed by comparing coverage probabilities of the true relative bioactivity and the length of the confidence intervals computed for these methods. The ordinary unweighted average method outperforms all statistical methods by consistently giving the best coverage probability but with somewhat wider confidence intervals. The weighted average methods give good coverage and smaller confidence intervals when combining homogeneous bioactivities. For heterogeneous bioactivities, these methods work well when a liberal significance level for testing homogeneity of bioactivities is used. The maximum likelihood methods gave good coverage when homogeneous bioactivities were considered. Overall, the preferred methods are the ordinary unweighted average and two weighted average methods that were specifically developed for bioassays.

Determinants of age at sexual debut and associated risks among South African youths.

The research uses data from a representative national survey to explore the determinants of age at sexual debut among South African youths in the age group 15-24 years. A random sample of 5 708 youths were interviewed and 92% responded to questions on whether or not they had ever had sex and their age at first sex for those who had. The research used survival analyses techniques to combine 'current status data' and 'recall data' for respondents who reported ever having had sex. The females were more likely than the males to report ever having had sex (p≤0.001). The median age at sexual debut was 18 years for both males and females. The hazard ratio pertaining to early sexual debut was 0.81-times less for those in the age group 15-19 as compared to those in the age group 20-24 (p≤0.001). Age, race, geographical location, and level of education were found to be important determinants of age at sexual debut. The 'hazards of sexual debut' (θ=0.112; p≤0.001) varied significantly between geographical areas (rural or urban). Youths with an earlier age of sexual debut were less likely to have used condoms, a behaviour which increases their risk of HIV infection. HIV prevalence was consistently higher among the females than among the males. We recommend that HIV-prevention interventions target community sets rather than only individuals at higher risk of exposure to HIV.

Age at sexual debut: a determinant of multiple partnership among South African youth.

Age at sexual debut is an important determinant of HIV infection. The paper investigates the effects of age at sexual debut on sexual behaviour among South African youth. Among 2 875 respondents who ever had sexual intercourse, 39% had early sexual debut (sexual debut at age 16 years and below). Males (44.6%) were significantly more likely than females (35.1%) to report early sexual debut (odds ratio (OR) = 1.45, p-value < 0.001). Multiple sexual partners are significantly more common among those that had early sexual debut (10.4% vs. 4.8%) than those who had late sexual debut, (OR = 2.29, p-value < 0.001). Those aged 15 to 19 years were 1.4 times more likely to report multiple partners compared to those aged 20 to 24 years. Delaying sexual debut is a strategy many national programmes are promoting. The results of this study provide additional arguments to support such initiatives and show the need to strengthen intervention targeting youth.

Age at sexual debut: a determinant of multiple partnership among south african youth

Age at sexual debut is an important determinant of HIV infection. The paper investigates the effects of age at sexual debut on sexual behaviour among South African youth. Among 2 875 respondents who ever had sexual intercourse, 39% had early sexual debut (sexual debut at age 16 years and below). Males (44.6%) were significantly more likely than females (35.1%) to report early sexual debut (odds ratio (OR)=1.45, p-value <0.001). Multiple sexual partners are significantly more common among those that had early sexual debut (10.4% vs. 4.8%) than those who had late sexual debut, (OR=2.29, p-value<0.001). Those aged 15 to 19 years were 1.4 times more likely to report multiple partners compared to those aged 20 to 24 years. Delaying sexual debut is a strategy many national programmes are promoting. The results of this study provide additional arguments to support such initiatives and show the need to strengthen intervention targeting youth (Afr. J. Reprod. Health 2010; 14[2]:47-54)

Determinants of knowledge of HIV status in South Africa: results from a population-based HIV survey.

BACKGROUND: Over 30% of women and men in the South African national HIV household of 2005 indicated that they had previously been tested for HIV (of which 91% were aware of their test results). This paper seeks to describe the associations between socio-demographic, behavioural and social characteristics and knowledge of HIV status among a nationally representative population in South Africa. METHODS: A multistage probability sample involving 16395 male and female respondents, aged 15 years or older was selected. The sample was representative of the South African population by age, race, province and type of living area, e.g. urban formal, urban informal, etc. Respondents were interviewed on HIV knowledge, perceptions and behaviour and provided blood for research HIV testing. Bivariate and multivariate logistic regression was used to identify socio-demographic, social and behavioural factors associated with knowledge of HIV status. RESULTS: From the total sample 27.6% ever and 7.8% knew their HIV status in the past 12 months. In multivariate analyses being female, the age group 25 to 34 years old, other than African Black population group (White, Coloured, Asian), higher educational level, being employed, urban residence, awareness of a place nearby where one could be tested for HIV, impact of HIV on the household and having had two of more sexual partners in the past year were associated with knowledge of HIV status. Among HIV positive persons awareness of a place nearby where one could be tested for HIV and impact of HIV on the household were associated knowledge of HIV status, and among HIV negative persons HIV risk behaviour (multiple partners, no condom use), awareness of a place nearby where one could be tested for HIV, higher knowledge score on HIV and knowledge of serodiscordance were associated knowledge of HIV status. CONCLUSION: Education about HIV/AIDS and access to HIV counselling and testing (HCT) in rural areas, in particular among the Black African population group needs to be improved, in order to enhance the uptake of HIV counselling and testing services, an essential step for the initiation of treatment.