Vaccination for healthy aging.

As the world's population grows older, vaccination is becoming a key strategy for promoting healthy aging. Despite scientific progress in adult vaccine development, obstacles such as immunosenescence and vaccine hesitancy remain. To unlock the potential of adult vaccines fully, we must enhance immunization programs, dispel misinformation, and invest in research that deepens our understanding of aging and immunity.

Lessons learned from COVID-19, H1N1, and routine vaccine pharmacovigilance in the United States: a path to a more robust vaccine safety program.

INTRODUCTION: Vaccine pharmacovigilance is an essential component of vaccine safety programs. Vaccine pharmacovigilance refers to detecting uncommon adverse events following immunization (AEFI), determining whether they are due to the vaccine or are only a coincidence, and, for those AEFI considered related to vaccination, characterizing them further. When AEFI are due to vaccination, it is important to characterize the attributable risk and ascertain the biological mechanism causing the adverse reaction to inform efforts to prevent or mitigate the risk. A robust post-authorization safety system is necessary for vaccine decision-making, clinical recommendations, vaccine compensation, and vaccine communication and confidence. AREAS COVERED: This paper describes the key characteristics of vaccine pharmacovigilance programs, reviews US vaccine pharmacovigilance for routine vaccination programs, COVID-19, and H1N1, and makes recommendations for improving future vaccine safety systems. EXPERT OPINION: The key characteristics of vaccine pharmacovigilance programs include passive surveillance, active surveillance, clinical investigation and special studies, and causality assessment. Recent examples illustrate the strengths of US pharmacovigilance systems, including systems for passive and active surveillance, as well as areas for improvement, including study of pathogenesis, consistent funding, and leadership. We make recommendations that would, if implemented, further strengthen the vaccine safety system for future routine and pandemic immunizations.

The role of real-world evidence for regulatory and public health decision-making for Accelerated Vaccine Deployment- a meeting report.

The COVID-19 pandemic underscored the need for rapid evidence generation to inform public health decisions beyond the limitations of conventional clinical trials. This report summarises presentations and discussions from a conference on the role of Real-World Evidence (RWE) in expediting vaccine deployment. Attended by regulatory bodies, public health entities, and industry experts, the gathering was a collaborative exchange of experiences and recommendations for leveraging RWE for vaccine deployment. RWE proved instrumental in refining decision-making processes to optimise dosing regimens, enhance guidance on target populations, and steer vaccination strategies against emerging variants. Participants felt that RWE was successfully integrated into lifecycle management, encompassing boosters and safety considerations. However, challenges emerged, prompting a call for improvements in data quality, standardisation, and availability, acknowledging the variability and potential inaccuracies in data across diverse healthcare systems. Regulatory transparency should also be prioritised to foster public trust, and improved collaborations with governments are needed to streamline data collection and navigate data privacy regulations. Moreover, building and sustaining resources, expertise, and infrastructure in LMICs emerged as imperative for RWE-generating capabilities. Continued stakeholder collaboration and securing adequate funding emerged as vital pillars for advancing the use of RWE in shaping responsive and effective public health strategies.

Considerations for unblinding individual study participants during vaccine trials.

Premature unblinding of individual participants is rarely reported in publications, but such unblinding can disrupt vaccine trials by causing worry and drop-out of other participants or "pseudo unblinding," in which participants or investigators over-interpret certain symptoms as being related to receiving an investigational product. This review summarizes appropriate reasons for unblinding in vaccine trials. Regulatory guidance could be improved by distinguishing guidance for vaccine trials from drug trials, with the recognition that unblinding individual participants in vaccine studies is rarely needed for management of adverse events following immunization.

Vaccines for a sustainable planet.

The health of the planet is one objective of the United Nations' Sustainable Development Goals. Vaccines can affect not only human health but also planet health by reducing poverty, preserving microbial diversity, reducing antimicrobial resistance, and preventing an increase in pandemics that is fueled partly by climate change.

The trillion dollar vaccine gap.

New technologies and unprecedented public investment have transformed vaccine development and allowed fast delivery of safe and efficacious COVID-19 vaccines, mitigating the impact of the pandemic on health and the economy. A quantum change in public investment for vaccine development and widespread vaccine distribution are necessary to achieve global pandemic preparedness.

Association between delays to patient admission from the emergency department and all-cause 30-day mortality.

BACKGROUND: Delays to timely admission from emergency departments (EDs) are known to harm patients. OBJECTIVE: To assess and quantify the increased risk of death resulting from delays to inpatient admission from EDs, using Hospital Episode Statistics and Office of National Statistics data in England. METHODS: A cross-sectional, retrospective observational study was carried out of patients admitted from every type 1 (major) ED in England between April 2016 and March 2018. The primary outcome was death from all causes within 30 days of admission. Observed mortality was compared with expected mortality, as calculated using a logistic regression model to adjust for sex, age, deprivation, comorbidities, hour of day, month, previous ED attendances/emergency admissions and crowding in the department at the time of the attendance. RESULTS: Between April 2016 and March 2018, 26 738 514 people attended an ED, with 7 472 480 patients admitted relating to 5 249 891 individual patients, who constituted the study's dataset. A total of 433 962 deaths occurred within 30 days. The overall crude 30-day mortality rate was 8.71% (95% CI 8.69% to 8.74%). A statistically significant linear increase in mortality was found from 5 hours after time of arrival at the ED up to 12 hours (when accurate data collection ceased) (p<0.001). The greatest change in the 30-day standardised mortality ratio was an 8% increase, occurring in the patient cohort that waited in the ED for more than 6 to 8 hours from the time of arrival. CONCLUSIONS: Delays to hospital inpatient admission for patients in excess of 5 hours from time of arrival at the ED are associated with an increase in all-cause 30-day mortality. Between 5 and 12 hours, delays cause a predictable dose-response effect. For every 82 admitted patients whose time to inpatient bed transfer is delayed beyond 6 to 8 hours from time of arrival at the ED, there is one extra death.

Surveillance and control of meningococcal disease in the COVID-19 era: A Global Meningococcal Initiative review.

This review article incorporates information from the 4th Global Meningococcal Initiative summit meeting. Since the introduction of stringent COVID-19 infection control and lockdown measures globally in 2020, there has been an impact on IMD prevalence, surveillance, and vaccination compliance. Incidence rates and associated mortality fell across various regions during 2020. A reduction in vaccine uptake during 2020 remains a concern globally. In addition, several Neisseria meningitidis clonal complexes, particularly CC4821 and CC11, continue to exhibit resistance to antibiotics, with resistance to ciprofloxacin or beta-lactams mainly linked to modifications of gyrA or penA alleles, respectively. Beta-lactamase acquisition was also reported through horizontal gene transfer (blaROB-1) involving other bacterial species. Despite the challenges over the past year, progress has also been made on meningococcal vaccine development, with several pentavalent (serogroups ABCWY and ACWYX) vaccines currently being studied in late-stage clinical trial programmes.

Applicability of the GAIA Maternal and Neonatal Outcome Case Definitions for the Evaluation of Adverse Events Following Vaccination in Pregnancy in High-income Countries.

BACKGROUND: The Brighton Collaboration Global Alignment of Immunization Safety in Pregnancy (GAIA) project developed case definitions for the assessment of adverse events in mothers and infants following maternal immunization. This study evaluated the applicability of these definitions to data collected in routine clinical care and research trial records across 7 sites in high-resource settings. METHODS: Data collection forms were designed and used to retrospectively abstract the key elements of the GAIA definitions from records for 5 neonatal and 5 maternal outcomes, as well as gestational age. Level of diagnostic certainty was assessed by the data abstractor and an independent clinician, and then verified by Automated Brighton Case logic. The ability to assign a level of diagnostic certainty for each outcome and the positive predictive value (PPV) for their respective ICD-10 codes were evaluated. RESULTS: Data from 1248 case records were abstracted: 624 neonatal and 622 maternal. Neonatal outcomes were most likely to be assessable and assigned by the level of diagnostic certainty. PPV for preterm birth, low birth weight, small for gestational age and respiratory distress were all above 75%. Maternal outcomes for preeclampsia and fetal growth restriction showed PPV over 80%. However, microcephaly (neonatal outcome) and dysfunctional labor (maternal outcome) were often nonassessable, with low PPVs. CONCLUSIONS: The applicability of GAIA case definitions to retrospectively ascertain and classify maternal and neonatal outcomes was variable among sites in high-resource settings. The implementation of the case definitions is largely dependent on the type and quality of documentation in clinical and research records in both high- and low-resource settings. While designed for use in the prospective evaluation of maternal vaccine safety, the GAIA case definitions would likely need to be specifically adapted for observational studies using alternative sources of data, linking various data sources and allowing flexibility in the ascertainment of the elements and levels of certainty of the case definition.

Transforming vaccine development.

The urgency to develop vaccines against Covid-19 is putting pressure on the long and expensive development timelines that are normally required for development of lifesaving vaccines. There is a unique opportunity to take advantage of new technologies, the smart and flexible design of clinical trials, and evolving regulatory science to speed up vaccine development against Covid-19 and transform vaccine development altogether.

Meeting report narcolepsy and pandemic influenza vaccination: What we know and what we need to know before the next pandemic? A report from the 2nd IABS meeting.

A group of scientific and public health experts and key stakeholders convened to discuss the state of knowledge on the relationship between adjuvanted monovalent inactivated 2009 influenza A H1N1 vaccines used during the 2009 influenza pandemic and narcolepsy. There was consensus that an increased risk of narcolepsy was consistently observed after Pandemrix (AS03-adjuvanted) vaccine, but similar associations following Arepanrix (AS03-adjuvanted) or Focetria (MF59-adjuvanted) vaccines were not observed. Whether the differences are due to vaccine composition or other factors such as the timing of large-scale vaccination programs relative to H1N1pdm09 wild-type virus circulation in different geographic regions is not clear. The limitations of retrospective observational methodologies could also be contributing to some of the differences across studies. More basic and epidemiologic research is needed to further elucidate the association between adjuvanted influenza vaccine and narcolepsy and its mechanism and to inform planning and preparation for vaccination programs in advance of the next influenza pandemic.

What is the heterogeneity in the impact seen with pneumococcal conjugate vaccines telling us?

Pneumococcal conjugate vaccines have proven highly effective in decreasing invasive disease and pneumonia in young children. However, there is considerable geographic variability in the impact of these vaccines on other disease endpoints and in other age groups. Investigation of the possible causes of this variability would greatly improve our understanding of pneumococcal pathophysiology and stimulate the effort to design more broadly effective vaccines.

Multicriteria decision analysis and core values for enhancing vaccine-related decision-making.

Vaccines have the potential to transform the health of all individuals and to reduce the health inequality between rich and poor countries. However, to achieve these goals, it is no longer sufficient to prioritize vaccine development using cost-effectiveness as the sole indicator. During a symposium entitled "Mission Grand Convergence-The Role of Vaccines," held in Siena, Italy, in July 2015, key stakeholders agreed that the prioritization of vaccine development and deployment must use multicriteria decision-making based on the following core concepts: (i) mortality and severity of the disease, (ii) vaccine safety considerations, and (iii) economic evaluation that captures the full benefits of vaccination.

Pandemic influenza vaccine & narcolepsy: simulations on the potential impact of bias.

Several studies have identified an association between Pandemrix(TM), an AS03 adjuvanted pandemic influenza A(H1N1) vaccine, and narcolepsy, a rare and under-diagnosed sleep disorder with a median onset-to-diagnosis interval of ten years. This paper reviews potential sources of bias in published studies and aims to provide, through simulation, methodological recommendations for assessment of vaccine safety signals. Our simulation study showed that in the absence of an association between the vaccine and the outcome, presence of detection bias and differential exposure misclassification could account for elevated risk estimates. These may play a major role, particularly in alert situations when observation times are limited and the disease has a long latency period. Estimates from the case-control design were less inflated than those from the cohort design when these biases were present. Overall, these simulations provide useful insights for the design and interpretation of future studies.

A prospective study of the incidence of myocarditis/pericarditis and new onset cardiac symptoms following smallpox and influenza vaccination.

BACKGROUND: Although myocarditis/pericarditis (MP) has been identified as an adverse event following smallpox vaccine (SPX), the prospective incidence of this reaction and new onset cardiac symptoms, including possible subclinical injury, has not been prospectively defined. PURPOSE: The study's primary objective was to determine the prospective incidence of new onset cardiac symptoms, clinical and possible subclinical MP in temporal association with immunization. METHODS: New onset cardiac symptoms, clinical MP and cardiac specific troponin T (cTnT) elevations following SPX (above individual baseline values) were measured in a multi-center prospective, active surveillance cohort study of healthy subjects receiving either smallpox vaccine or trivalent influenza vaccine (TIV). RESULTS: New onset chest pain, dyspnea, and/or palpitations occurred in 10.6% of SPX-vaccinees and 2.6% of TIV-vaccinees within 30 days of immunization (relative risk (RR) 4.0, 95% CI: 1.7-9.3). Among the 1081 SPX-vaccinees with complete follow-up, 4 Caucasian males were diagnosed with probable myocarditis and 1 female with suspected pericarditis. This indicates a post-SPX incidence rate more than 200-times higher than the pre-SPX background population surveillance rate of myocarditis/pericarditis (RR 214, 95% CI 65-558). Additionally, 31 SPX-vaccinees without specific cardiac symptoms were found to have over 2-fold increases in cTnT (>99th percentile) from baseline (pre-SPX) during the window of risk for clinical myocarditis/pericarditis and meeting a proposed case definition for possible subclinical myocarditis. This rate is 60-times higher than the incidence rate of overt clinical cases. No clinical or possible subclinical myocarditis cases were identified in the TIV-vaccinated group. CONCLUSIONS: Passive surveillance significantly underestimates the true incidence of myocarditis/pericarditis after smallpox immunization. Evidence of subclinical transient cardiac muscle injury post-vaccinia immunization is a finding that requires further study to include long-term outcomes surveillance. Active safety surveillance is needed to identify adverse events that are not well understood or previously recognized.