Immunogenicity of 2 and 3 Doses of the Quadrivalent Human Papillomavirus Vaccine up to 120 Months Postvaccination: Follow-up of a Randomized Clinical Trial.

BACKGROUND: Several countries have implemented a 2-dose (2D) human papillomavirus (HPV) vaccination schedule for adolescents based on immunobridging studies. We compared immunogenicity of 2D vs 3-dose (3D) schedules of the quadrivalent vaccine (4vHPV) up to 10 years after the first dose. METHODS: Girls aged 9-13 years were randomized to receive 2D or 3D and were compared with women aged 16-26 receiving 3D at day 1 and months 7, 24, and 120 after the first dose. Antibody levels for HPV6/11/16/18 were evaluated using the competitive Luminex immunoassay (cLIA) and total immunoglobulin G assay. Geometric mean titers (GMTs) and seropositivity rates were compared between the different groups at different time points. Noninferiority of GMT ratios was defined as the lower bound of the 2-sided 95% confidence interval (CI) being greater than 0.5. Kinetics of antibody titers over time among study groups were examined. RESULTS: At 120 months, data from 35 2D girls, 38 3D girls, and 30 3D women were used for analyses. cLIA seropositivity rates were above 95% for all HPV vaccine types and all schedules, except HPV18, with the lowest seropositivity observed among 3D women (60.0%; 95% CI, 40.6%-77.3%). GMT ratios (cLIA) for both 2D and 3D girls were noninferior to 3 doses in women for HPV6/11/16/18. Trends were comparable between assays. CONCLUSIONS: GMTs for HPV6/11/16/18 after 2D or 3D of 4vHPV in girls were noninferior to 3D in adult women up to 120 months postvaccination. This study demonstrates long-term immunogenicity of the 2D HPV vaccine schedule.

Randomized Trial of 2 Schedules of Meningococcal B Vaccine in Adolescents and Young Adults, Canada1.

Emergency vaccination programs often are needed to control outbreaks of meningococcal disease caused by Neisseria meningitidis serogroup B (MenB) on college campuses. Such campaigns expend multiple campus and public health resources. We conducted a randomized, controlled, multicenter, observer-blinded trial comparing immunogenicity and tolerability of an accelerated vaccine schedule of 0 and 21 days to a longer interval of 0 and 60 days for 4-component MenB vaccine (MenB-4C) in students 17-25 years of age. At day 21 after the first MenB-4C dose, we observed protective human serum bactericidal titers >4 to MenB strains 5/99, H44/76, and NZ 98/254 in 98%-100% of participants. Geometric mean titers increased >22-fold over baseline. At day 180, >95% of participants sustained protective titers regardless of their vaccine schedule. The most common adverse event was injection site pain. An accelerated MenB-4C immunization schedule could be considered for rapid control of campus outbreaks.

Comparing the Use of a Mobile App and a Web-Based Notification Platform for Surveillance of Adverse Events Following Influenza Immunization: Randomized Controlled Trial.

BACKGROUND: Vaccine safety surveillance is a core component of vaccine pharmacovigilance. In Canada, active, participant-centered vaccine surveillance is available for influenza vaccines and has been used for COVID-19 vaccines. OBJECTIVE: The objective of this study is to evaluate the effectiveness and feasibility of using a mobile app for reporting participant-centered seasonal influenza adverse events following immunization (AEFIs) compared to a web-based notification system. METHODS: Participants were randomized to influenza vaccine safety reporting via a mobile app or a web-based notification platform. All participants were invited to complete a user experience survey. RESULTS: Among the 2408 randomized participants, 1319 (54%) completed their safety survey 1 week after vaccination, with a higher completion rate among the web-based notification platform users (767/1196, 64%) than among mobile app users (552/1212, 45%; P<.001). Ease-of-use ratings were high for the web-based notification platform users (99% strongly agree or agree) and 88.8% of them strongly agreed or agreed that the system made reporting AEFIs easier. Web-based notification platform users supported the statement that a web-based notification-only approach would make it easier for public health professionals to detect vaccine safety signals (91.4%, agreed or strongly agreed). CONCLUSIONS: Participants in this study were significantly more likely to respond to a web-based safety survey rather than within a mobile app. These results suggest that mobile apps present an additional barrier for use compared to the web-based notification-only approach. TRIAL REGISTRATION: ClinicalTrials.gov NCT05794113; https://clinicaltrials.gov/show/NCT05794113.

Strategies for successful rapid trials of influenza vaccine.

BACKGROUND: In contrast to the gradual pace of conventional vaccine trials, evaluation of influenza vaccines often must be accelerated for use in a pandemic or for annual re-licensure. Descriptions of how best to design studies for rapid completion are few. PURPOSE: In August, 2010, we conducted a rapid trial with a seasonal influenza vaccine for 2010-2011 given to persons vaccinated with an adjuvanted H1N1 vaccine in 2009, to determine whether re-exposure to the H1N1(2009) component of the seasonal vaccine would cause increased reactions. We describe the strategies that we believe were responsible for success in meeting the desired timeline. METHODS: The key means for expediting the study were: use of a few experienced, well-staffed centers; efficient completion of administrative approvals; advance recruitment of volunteers; synchronized start among centers with rapid completion (≤1 week) of first visits; rapid data assembly via the Internet; and a well-prepared data analysis plan. We chose to use a randomized, blinded, cross-over design to allow estimation of vaccine-attributable adverse event rates, with sufficient power (320 participants) to detect events occurring at true rates ≥1% with ≥90% probability. RESULTS: Planned enrollment numbers, center synchronization, and timelines, including review by a safety board prior to the cross-over step (second doses), were achieved. A detailed safety report was delivered to federal health officials just 32 days after study initiation and was used to fine-tune public messaging prior to the mass vaccination programs across Canada. LIMITATIONS: This aggressive timeline could not have been met without opportunities for careful planning and the prior existence of a network of experienced, collaborating trial centers. CONCLUSIONS: The means used to accelerate this study timeline were successful and could be used in other urgent situations but the mechanics of collaborative trials must be well rehearsed as a precondition.

Systems Biology Methods Applied to Blood and Tissue for a Comprehensive Analysis of Immune Response to Hepatitis B Vaccine in Adults.

Conventional vaccine design has been based on trial-and-error approaches, which have been generally successful. However, there have been some major failures in vaccine development and we still do not have highly effective licensed vaccines for tuberculosis, HIV, respiratory syncytial virus, and other major infections of global significance. Approaches at rational vaccine design have been limited by our understanding of the immune response to vaccination at the molecular level. Tools now exist to undertake in-depth analysis using systems biology approaches, but to be fully realized, studies are required in humans with intensive blood and tissue sampling. Methods that support this intensive sampling need to be developed and validated as feasible. To this end, we describe here a detailed approach that was applied in a study of 15 healthy adults, who were immunized with hepatitis B vaccine. Sampling included ~350 mL of blood, 12 microbiome samples, and lymph node fine needle aspirates obtained over a ~7-month period, enabling comprehensive analysis of the immune response at the molecular level, including single cell and tissue sample analysis. Samples were collected for analysis of immune phenotyping, whole blood and single cell gene expression, proteomics, lipidomics, epigenetics, whole blood response to key immune stimuli, cytokine responses, in vitro T cell responses, antibody repertoire analysis and the microbiome. Data integration was undertaken using different approaches-NetworkAnalyst and DIABLO. Our results demonstrate that such intensive sampling studies are feasible in healthy adults, and data integration tools exist to analyze the vast amount of data generated from a multi-omics systems biology approach. This will provide the basis for a better understanding of vaccine-induced immunity and accelerate future rational vaccine design.

An evaluation of the feasibility and usability of a proof of concept mobile app for adverse event reporting post influenza vaccination.

The Canadian National Vaccine Safety network (CANVAS) gathers and analyzes safety data on individuals receiving the influenza vaccine during the early stages of annual influenza vaccination campaigns with data collected via participant surveys through the Internet. We sought to examine whether it was feasible to use a mobile application (app) to facilitate AEFI reporting for the CANVAS network. To explore this, we developed a novel smartphone app, recruited participants from a hospital influenza immunization clinic and by word of mouth and instructed them to download and utilize the app. The app reminded participants to complete the CANVAS AEFI surveillance surveys ("AEFI surveys") on day 8 and 30, a survey capturing app usability metrics at day 30 ("usability survey") and provided a mechanism to report AEFI events spontaneously throughout the whole study period. All survey results and spontaneous reports were recorded on a privacy compliant, cloud server. A software plug-in, Lookback, was used to record the on-screen experience of the app sessions. Of the 76 participants who consented to participate, 48(63%) successfully downloaded the app and created a profile. In total, 38 unique participants completed all of the required surveillance surveys; transmitting 1104 data points (survey question responses and spontaneous reports) from 83 completed surveys, including 21 usability surveys and one spontaneous report. In total, we received information on new or worsening health conditions after receiving the influenza vaccine from 11(28%) participants. Of the usability survey responses, 86% agreed or strongly agreed that they would prefer to use a mobile app based reporting system instead of a web-based system. The single spontaneous report received was from a participant who had also reported using the Day 8 survey. Of Lookback observable sessions, an accurate transmission proportion of 100% (n=290) was reported for data points. We demonstrated that a mobile app can be used for AEFI reporting, although download and survey completion proportions suggest potential barriers to adoption. Future studies should examine implementation of mobile reporting in a broader audience and impact on the quality of reporting of adverse events following immunization.