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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

For certain types of medicine the biological strength or bioactivity of a drug is the main characteristic for release of products to the market. A pharmaceutical company may decide to use their own in-house reference standard to test the drug instead of using the expensive international reference standard. The company is then legally obliged to verify that the in-house reference standard remains stable over time with respect to the international one. This is a special problem within statistical process control (SPC) since the monitoring period is relatively short and bioassays are typically heterogenous. The objective of this article is to apply methods from SPC and dose-finding studies to different study designs and assess how well these methods perform in detecting a decline in bioactivity. The included methods are the exponentially weighted moving average (EWMA), Shewhart chart, and analysis of variance (ANOVA)-type contrasts (linear, Helmert, and reverse-Helmert). An optimal α-spending function was selected first to avoid inflating the familywise error rate. The normal α-spending function seemed to perform generally the best. Then from the results, the linear, reverse-Helmert, and the EWMA (λ ⩽ 0.6) resulted in high power when a change occurred at earlier time points, while Helmert and the EWMA (λ > 0.6) performed better in later declines. Linear contrasts and the Shewhart chart performed better irrespective of the decline profile. Having more bioassay runs at the beginning of the stability study increased the probability of detecting a decline. If there is no prior information on the expected deterioration profile, linear contrasts or Shewhart chart should be preferred. Otherwise, reverse-Helmert or Helmert contrasts should be chosen for either early or late deterioration, respectively. [ABSTRACT FROM PUBLISHER]

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. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM PUBLISHER]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• A booster MenACWY-CRM dose was given 4–6 years post-MenACWY-CRM or -MenACWY-D priming. • The immune response to the booster was sufficient after priming with either vaccine. • A least 93.2% of primed participants had seroresponse for each vaccine serogroup at 28 days after the booster dose. • An anamnestic response was seen within 5 days after the booster dose. • The booster MenACWY-CRM dose had a clinically acceptable safety profile. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]