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.

Optimizing Canadian public immunization programs: a prescription for action.

Recent expansion of public vaccination programs for children and youth offers new health benefits but at substantially increased cost. As with other large public investments, immunization programs ought to be systematically evaluated for safety, effectiveness and economic value. At present, program evaluations are suboptimal in most provinces and territories. Experts in public health and vaccinology who attended a workshop in 2009 reviewed the shortcomings and produced "prescriptions for action" to improve matters. Six key recommendations were made: 1) a formal requirement should exist to evaluate all public vaccination programs appropriately; 2) greater voluntary harmonization of programs will facilitate evaluations; 3) a mechanism is needed to prioritize and coordinate program-specific evaluations; 4) new funding mechanisms are needed for basic jurisdictional studies and joint studies of broad relevance; 5) strong emphasis is needed on capacity development and training; and 6) administrative barriers to accessing health information systems and publishing evaluation studies need to be overcome. The expert group considered the need to improve program evaluations as urgent and compelling, with success achievable with dedicated funding and effective leadership. Demonstrating that Canadian immunization programs are among the world's best and safest is a sound strategy for maintaining public participation in those programs.

The Fifth International Neonatal and Maternal Immunization Symposium (INMIS 2019): Securing Protection for the Next Generation.

Despite significant progress in reaching some milestones of the United Nations Sustainable Development Goals, neonatal and early infant morbidity and mortality remain high, and maternal health remains suboptimal in many countries. Novel and improved preventative strategies with the potential to benefit pregnant women and their infants are needed, with maternal and neonatal immunization representing effective approaches. Experts from immunology, vaccinology, infectious diseases, clinicians, industry, public health, and vaccine-related social sciences convened at the 5th International Neonatal and Maternal Immunization Symposium (INMIS) in Vancouver, Canada, from 15 to 17 September 2019. We critically evaluated the lessons learned from recent clinical studies, presented cutting-edge scientific progress in maternal and neonatal immunology and vaccine development, and discussed maternal and neonatal immunization in the broader context of infectious disease epidemiology and public health. Focusing on practical aspects of research and implementation, we also discussed the safety, awareness, and perception of maternal immunization as an existing strategy to address the need to improve maternal and neonatal health worldwide. The symposium provided a comprehensive scientific and practical primer as well as an update for all those with an interest in maternal and neonatal infection, immunity, and vaccination. The summary presented here provides an update of the current status of progress in maternal and neonatal immunization.

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.

Effectiveness of pneumococcal conjugate vaccine in Greater Vancouver, Canada: 2004-2005.

Active, population-based surveillance for invasive pneumococcal infections in Greater Vancouver (population 473,000 children) demonstrated a rapid, substantial decrease in incidence rates for children 6-23 months old with routine infant vaccination. In the subpopulation with best case ascertainment disease rates for 6-23 month olds decreased 84.6% (92.5% for vaccine serotypes).

Maternal immunisation: collaborating with mother nature.

Maternal immunisation has the potential to substantially reduce morbidity and mortality from infectious diseases after birth. The success of tetanus, influenza, and pertussis immunisation during pregnancy has led to consideration of additional maternal immunisation strategies to prevent group B streptococcus and respiratory syncytial virus infections, among others. However, many gaps in knowledge regarding the immunobiology of maternal immunisation prevent the optimal design and application of this successful public health intervention. Therefore, we did an innovative landscape analysis to identify research priorities. Key topics were delineated through review of the published literature, consultation with vaccine developers and regulatory agencies, and a collaborative workshop that gathered experts across several maternal immunisation initiatives-group B streptococcus, respiratory syncytial virus, pertussis, and influenza. Finally, a global online survey prioritised the identified knowledge gaps on the basis of expert opinion about their importance and relevance. Here we present the results of this worldwide landscape analysis and discuss the identified research gaps.

Oculorespiratory syndrome after influenza immunization in children.

BACKGROUND: During the 2000-2001 season, an oculorespiratory syndrome (ORS) was identified in association with 1 manufacturer's influenza vaccine in Canada. ORS included bilateral red eyes, facial edema or respiratory symptoms beginning within 24 hours of influenza immunization. Few reports involved children. We assessed the rate of ORS in a pediatric cohort. METHODS: In February 2001, invitation to participate in an influenza vaccine safety survey was sent to the parents of children who attend a diabetes clinic. A questionnaire elicited influenza immunization history and adverse event experience beginning within 1 day of vaccination for the child with diabetes and up to 3 siblings. Follow-up telephone interviews collected information from those who failed to return a questionnaire by mail. RESULTS: Of the 959 households sent a questionnaire, 780 participated (81%). Among 780 children with diabetes, 418 (54%) received influenza vaccine in 2000. Adverse event experience was collected from an additional 242 immunized siblings. Among immunized children, 13% (95% confidence interval, 10-16%) experienced ORS, consisting primarily of respiratory symptoms. The majority (72%) resolved within 2 days. There was association between ORS and first time receipt of influenza vaccine (OR 2.7; 95% confidence interval, 1.6-4.4). Fewer parents of ORS-affected compared with unaffected children indicated that they were likely or very likely to have their child revaccinated (87 versus 97%; P < 0.001). CONCLUSIONS: In 2000-2001, children experienced ORS in Canada at a rate comparable with that of adults. ORS should be incorporated into influenza vaccine safety monitoring and discussed with parents, especially those contemplating influenza vaccine for their child for the first time.

Population-based epidemiology of invasive pneumococcal infection in children in nine urban centers in Canada, 1994 through 1998.

PURPOSE: To describe the epidemiology of invasive pneumococcal infections in Canadian children 0 to 12 years old. METHODS: At each of nine urban centers, active surveillance was conducted to identify all cases of invasive pneumococcal infection in children during 1994 to 1998. Postal codes were used to distinguish cases resident in defined urban areas from referral cases. Census data were obtained for each defined area to calculate age-specific incidence rates. Features of population-based cases were described. RESULTS: From an average defined population of approximately 1 million children, 937 eligible cases arose. Those 6 to 17 months old had the highest average incidence rate of 98.6/100 000/year. The average cumulative risk of infection was 1 in 460 between birth and 59 months, by which age 92% of cases had occurred. Among cases younger than 2 years of age, simple bacteremia accounted for 66%, pneumonia with bacteremia accounted for 14.7% and meningitis accounted for 11% (average incidence rate, 9.0/100 000/year). An underlying illness was present in 16% of all cases. The mortality rate was 1.8%. CONCLUSIONS: Invasive pneumococcal infections are relatively common in early childhood, based on 5 years of data from nearly 20% of the Canadian population ages 0 to 12 years. These data will be valuable for calculating the economic case for universal infant vaccination with newly available vaccines.

Approved but non-funded vaccines: accessing individual protection.

Funded immunization programs are best able to achieve high participation rates, optimal protection of the target population, and indirect protection of others. However, in many countries public funding of approved vaccines can be substantially delayed, limited to a portion of the at-risk population or denied altogether. In these situations, unfunded vaccines are often inaccessible to individuals at risk, allowing potentially avoidable morbidity and mortality to continue to occur. We contend that private access to approved but unfunded vaccines should be reconsidered and encouraged, with recognition that individuals have a prerogative to take advantage of a vaccine of potential benefit to them whether it is publicly funded or not. Moreover, numbers of "approved but unfunded" vaccines are likely to grow because governments will not be able to fund all future vaccines of potential benefit to some citizens. New strategies are needed to better use unfunded vaccines even though the net benefits will fall short of those of funded programs. Canada, after recent delays funding several new vaccine programs, has developed means to encourage private vaccine use. Physicians are required to inform relevant patients about risks and benefits of all recommended vaccines, publicly funded or not. Likewise, some provincial public health departments now recommend and promote both funded and unfunded vaccines. Pharmacists are key players in making unfunded vaccines locally available. Professional organizations are contributing to public and provider education about unfunded vaccines (e.g. herpes zoster, not funded in any province). Vaccine companies are gaining expertise with direct-to-consumer advertising. However, major challenges remain, such as making unfunded vaccines more available to low-income families and overcoming public expectations that all vaccines will be provided cost-free, when many other recommended personal preventive measures are user-pay. The greatest need is to change the widespread perception that approved vaccines should be publicly funded or ignored.

Canadian Association for Immunization Research and Evaluation (CAIRE) guidelines for industry-sponsored clinical trial and epidemiology contract research.

In response to concerns about interactions of academic and public health investigators with industry, the Canadian Association for Immunization Research and Evaluation (CAIRE), in collaboration with six major vaccine manufacturers, developed guidelines for participation in industry-sponsored clinical trial and epidemiology contract research within Canada. Topics addressed include definition of investigators, data ownership, protocol development, data management, data analysis, producing a study report and publication of the results of the study.