Current progress towards prevention of Nipah and Hendra disease in humans: A scoping review of vaccine and monoclonal antibody candidates being evaluated in clinical trials.

OBJECTIVES: Nipah and Hendra are deadly zoonotic diseases with pandemic potential. To date, no human vaccine or monoclonal antibody (mAb) has been licensed to prevent disease caused by these pathogens. The aim of this scoping review was to identify and describe all Phase I, II, and III clinical trials of vaccine candidates or mAbs candidates designed to prevent Nipah and Hendra in humans and to compare the characteristics of the vaccine candidates to characteristics outlined in the Target Product Profile drafted by the World Health Organisation as part of the WHO Research & Development Blueprint for Action to Prevent Epidemics. METHODS: We searched 23 clinical trial registries, the Cochrane Central Register of Clinical Trials, and grey literature up to June 2023 to identify vaccine and mAb candidates being evaluated in registered clinical trials. Vaccine candidate and trial characteristics were double-extracted for evaluation and the vaccine candidate characteristics were compared with the preferred and critical criteria of the World Health Organisation's Target Product Profile for Nipah virus vaccine. RESULTS: Three vaccine candidates (Hendra Virus Soluble Glycoprotein Vaccine [HeV-sG-V], PHV02, and mRNA-1215) and one mAb (m102.4) had a registered human clinical trial by June 2023. All trials were phase 1, dose-ranging trials taking place in the United States of America or Australia and enrolling healthy adults. Although all vaccine candidates meet the dose regimen and route of administration criteria of the Target Product Profile, other criteria such as measures of efficacy and reactogenicity will need to be evaluated in the future as evidence becomes available. CONCLUSION: Multiple vaccine candidates and one mAb candidate have reached the stage of human clinical trials and are reviewed here. Monitoring progress during evaluation of these candidates and candidates entering clinical trials in the future can help highlight many of the challenges that remain.

The Effects of Cognitive Ability, Mental Health, and Self-Quarantining on Functional Ability of Older Adults During the COVID-19 Pandemic: Results From the Canadian Longitudinal Study on Aging.

OBJECTIVES: Determine whether levels of anxiety and depression, cognitive ability, and self-quarantining during and prior to the pandemic predict decreases in perceived functional ability. DESIGN AND SETTING: Longitudinal data collected from the Canadian Longitudinal Study on Aging (CLSA) COVID-19 Questionnaire Study (2020) and core CLSA study (Follow-Up 1; 2014-2018). PARTICIPANTS: 17 541 CLSA participants. MEASUREMENTS: Self-quarantining behaviours from questionnaires administered at Baseline (April 2020), Monthly, and Exit (December 2020) time points of the CLSA COVID-19 Questionnaire Study, levels of anxiety and depression at Baseline, perceived change in functional ability at Exit, and performance on neuropsychological tests (Rey Auditory Verbal Learning Task, Mental Alternation Task, Animal Fluency Test) and functional ability (Older Americans Resources and Services [OARS] Multidimensional Assessment Questionnaire) from the core CLSA study. RESULTS: Greater cognitive ability pre-pandemic (B = -.003, P < .01), higher levels of anxiety (B = -.024, P < .01) and depressive symptoms (B = -.110, P < .01) at Baseline, and higher frequency of engaging in self-quarantining throughout the COVID-19 survey period (B = -.098, P < .01) were associated with perceived loss in functional ability at Exit. Self-quarantining behaviour was associated with perceived loss in functional ability only at average and high levels of depressive symptoms (B = -.013, P < .01). CONCLUSIONS: Older adults with higher cognitive and lower functional ability prior to the pandemic were at greater risk of decreased perceived functional ability during the first year of the pandemic, as were those who experienced greater levels of anxiety and depressive symptoms during the pandemic. Strategies/interventions to preserve functional ability in older adults with cognitive independence prior to future pandemics are warranted.

Influenza vaccine coverage and factors associated with non-vaccination among caregiving and care-receiving adults in the Canadian Longitudinal Study on Aging (CLSA).

BACKGROUND: Influenza vaccination is recommended for those at increased risk of influenza complications and their household contacts to help reduce influenza exposure. Adults who require care often experience health issues that could increase the risk of severe influenza and have close contact with caregivers. Assessing influenza vaccination prevalence in caregivers and care recipients can provide important information about uptake. OBJECTIVES: We aimed to (1) estimate influenza non-vaccination prevalence and (2) assess factors associated with non-vaccination among caregivers aged ≥ 45 years and among care recipients aged ≥ 65 years. METHODS: We conducted an analysis of cross-sectional data from the Canadian Longitudinal Study on Aging collected 2015-2018. We estimated non-vaccination prevalence and reported adjusted odds ratios with 95% confidence intervals from logistic regression models to identify factors associated with non-vaccination among caregivers and care recipients. RESULTS: Of the 23,500 CLSA participants who reported providing care, 41.4% (95% CI: 40.8%, 42.0%) reported not receiving influenza vaccine in the previous 12 months. Among the 5,559 participants who reported receiving professional or non-professional care, 24.8% (95% CI: 23.7%, 26.0%) reported not receiving influenza vaccine during the same period. For both groups, the odds of non-vaccination were higher for those who had not visited a family doctor in the past year, were daily smokers, and those who identified as non-white. DISCUSSION: Identifying groups at high risk of severe influenza and their close contacts can inform public health efforts to reduce the risk of influenza. Our results suggest sub-optimal influenza vaccination uptake among caregivers and care recipients. Efforts are needed to increase influenza vaccination and highlight the direct and indirect benefits for caregiver-care recipient pairs. CONCLUSION: The proportions of both caregivers and care recipients who had not been vaccinated for influenza was high, despite the benefits of vaccination. Influenza vaccination campaigns could target undervaccinated, high-risk groups to increase coverage.

Obesity and adverse childhood experiences in relation to stress during the COVID-19 pandemic: an analysis of the Canadian Longitudinal Study on Aging.

BACKGROUND: People with obesity are at increased risk of chronic stress, and this may have been exacerbated during the COVID-19 pandemic. Adverse childhood experiences (ACE) are also associated with both obesity and stress, and may modify risk of stress among people with obesity. The objectives of this study were to evaluate the associations between obesity, ACEs, and stress during the pandemic, and to determine if the association between obesity and stress was modified by ACEs. METHODS: A longitudinal study was conducted among adults aged 50-96 years (n = 23,972) from the Canadian Longitudinal Study on Aging (CLSA) COVID-19 Study. Obesity and ACEs were collected pre-pandemic (2015-2018), and stress was measured at COVID-19 Exit Survey (Sept-Dec 2020). We used logistic, Poisson, and negative binomial regression to estimate relative risks (RRs) and 95% confidence intervals (CIs) for the associations between obesity, ACEs, and stress outcomes during the pandemic. Interaction by ACEs was evaluated on the additive and multiplicative scales. RESULTS: People with obesity were more likely to experience an increase in overall stressors (class III obesity vs. healthy weight RR = 1.19; 95% CI: 1.12-1.27) as well as increased health related stressors (class III obesity vs. healthy weight RR: 1.25; 95% CI: 1.12-1.39) but did not perceive the consequences of the pandemic as negative. ACEs were also associated an increase in overall stressors (4-8 ACEs vs. none RR = 1.38; 95% CI: 1.33-1.44) and being more likely to perceive the pandemic as negative (4-8 ACEs vs. none RR = 1.32; 95% CI: 1.19-1.47). The association between obesity and stress was not modified by ACEs. CONCLUSIONS: Increased stress during the first year of the COVID-19 pandemic was observed among people with obesity or ACEs. The long-term outcomes of stress during the pandemic need to be determined.

Lassa fever vaccine candidates: A scoping review of vaccine clinical trials.

OBJECTIVE: Lassa fever (LF) is caused by a viral pathogen with pandemic potential. LF vaccines have the potential to prevent significant disease in individuals at risk of infection, but no such vaccine has been licensed or authorised for use thus far. We conducted a scoping review to identify and compare registered phase 1, 2 or 3 clinical trials of LF vaccine candidates, and appraise the current trajectory of LF vaccine development. METHOD: We systematically searched 24 trial registries, PubMed, relevant conference abstracts and additional grey literature sources up to 27 October 2022. After extracting key details about each vaccine candidate and each eligible trial, we qualitatively synthesised the evidence. RESULTS: We found that four LF vaccine candidates (INO-4500, MV-LASV, rVSV∆G-LASV-GPC, and EBS-LASV) have entered the clinical stage of assessment. Five phase 1 trials (all focused on healthy adults) and one phase 2 trial (involving a broader age group from 18 months to 70 years) evaluating one of these vaccines have been registered to date. Here, we describe the characteristics of each vaccine candidate and trial and compare them to WHO's target product profile for Lassa vaccines. CONCLUSION: Though LF vaccine development is still in early stages, current progress towards a safe and effective vaccine is encouraging.

Increased prevalence of loneliness and associated risk factors during the COVID-19 pandemic: findings from the Canadian Longitudinal Study on Aging (CLSA).

BACKGROUND: Older adults have been disproportionately impacted by COVID-19 and related preventative measures undertaken during the pandemic. Given clear evidence of the relationship between loneliness and health outcomes, it is imperative to better understand if, and how, loneliness has changed for older adults during the COVID-19 pandemic, and whom it has impacted most. METHOD: We used "pre-pandemic" data collected between 2015-2018 (n = 44,817) and "during pandemic" data collected between Sept 29-Dec 29, 2020 (n = 24,114) from community-living older adults participating in the Canadian Longitudinal Study on Aging. Loneliness was measured using the 3-item UCLA Loneliness Scale. Weighted generalized estimating equations estimated the prevalence of loneliness pre-pandemic and during the pandemic. Lagged logistic regression models examined individual-level factors associated with loneliness during the pandemic. RESULTS: We found the adjusted prevalence of loneliness increased to 50.5% (95% CI: 48.0%-53.1%) during the pandemic compared to 30.75% (95% CI: 28.72%-32.85%) pre-pandemic. Loneliness increased more for women (22.3% vs. 17.0%), those in urban areas (20.8% vs. 14.6%), and less for those 75 years and older (16.1% vs. 19.8% or more in all other age groups). Loneliness during the pandemic was strongly associated with pre-pandemic loneliness (aOR 4.87; 95% CI 4.49-5.28) and individual level sociodemographic factors [age < 55 vs. 75 + (aOR 1.41; CI 1.23-1.63), women (aOR 1.34; CI 1.25-1.43), and no post-secondary education vs. post-secondary education (aOR 0.73; CI 0.61-0.86)], living conditions [living alone (aOR 1.39; CI 1.27-1.52) and urban living (aOR 1.18; CI 1.07-1.30)], health status [depression (aOR 2.08; CI 1.88-2.30) and having two, or ≥ three chronic conditions (aOR 1.16; CI 1.03-1.31 and aOR 1.34; CI 1.20-1.50)], health behaviours [regular drinker vs. non-drinker (aOR 1.15; CI 1.04-1.28)], and pandemic-related factors [essential worker (aOR 0.77; CI 0.69-0.87), and spending less time alone than usual on weekdays (aOR 1.32; CI 1.19-1.46) and weekends (aOR 1.27; CI 1.14-1.41) compared to spending the same amount of time alone]. CONCLUSIONS: As has been noted for various other outcomes, the pandemic did not impact all subgroups of the population in the same way with respect to loneliness. Our results suggest that public health measures aimed at reducing loneliness during a pandemic should incorporate multifactor interventions fostering positive health behaviours and consider targeting those at high risk for loneliness.

Factors Associated With Willingness to Receive a COVID-19 Vaccine Among 23,819 Adults Aged 50 Years or Older: An Analysis of the Canadian Longitudinal Study on Aging.

Identifying persons who are least willing to receive a coronavirus disease 2019 (COVID-19) vaccine is critical for increasing uptake via targeted outreach. We conducted a survey of 23,819 Canadian Longitudinal Study on Aging participants from September 29 to December 29, 2020, to assess factors associated with COVID-19 vaccination willingness and reasons for willingness or lack thereof. Among adults aged 50-96 years, 84.1% (95% confidence interval (CI): 83.7, 84.6) were very or somewhat willing to receive a COVID-19 vaccine; 15.9% (95% CI: 15.4, 16.3) were uncertain or very or somewhat unwilling. Based on logistic regression, those who were younger, female, had lower education and income, were non-White, and lived in a rural area were less willing to receive a COVID-19 vaccine. After controlling for these factors, recent receipt of influenza vaccine (adjusted odds ratio = 14.3, 95% CI: 12.5, 16.2) or planning to receive influenza vaccine (adjusted odds ratio = 10.5, 95% CI: 9.5, 11.6), as compared with no receipt or planning, was most strongly associated with COVID-19 vaccination willingness. Willingness was also associated with believing one had never been infected with severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) and experiencing negative pandemic consequences. Safety concerns were most common among those unwilling. Our comprehensive assessment of COVID-19 vaccination willingness among older adults in Canada, a prioritized group for vaccination due to their risk of severe COVID-19 outcomes, provides a road map for conducting outreach to increase uptake, which is urgently needed.

Frailty and the impacts of the COVID-19 pandemic on community-living middle-aged and older adults: an analysis of data from the Canadian Longitudinal Study on Aging (CLSA).

BACKGROUND: frailty imparts a higher risk for hospitalisation, mortality and morbidity due to COVID-19 infection, but the broader impacts of the pandemic and associated public health measures on community-living people with frailty are less known. METHODS: we used cross-sectional data from 23,974 Canadian Longitudinal Study on Aging participants who completed a COVID-19 interview (Sept-Dec 2020). Participants were included regardless of whether they had COVID-19 or not. They were asked about health, resource, relationship and health care access impacts experienced during the pandemic. Unadjusted and adjusted prevalence of impacts was estimated by frailty index quartile. We further examined if the relationship with frailty was modified by sex, age or household income. RESULTS: community-living adults (50-90 years) with greater pre-pandemic frailty reported more negative impacts during the first year of the pandemic. The frailty gradient was not explained by socio-demographic or health behaviour factors. The largest absolute difference in adjusted prevalence between the most and least frail quartiles was 15.1% (challenges accessing healthcare), 13.3% (being ill) and 7.4% (increased verbal/physical conflict). The association between frailty and healthcare access differed by age where the youngest age group tended to experience the most challenges, especially for those categorised as most frail. CONCLUSION: although frailty has been endorsed as a tool to inform estimates of COVID-19 risk, our data suggest it may have a broader role in primary care and public health by identifying people who may benefit from interventions to reduce health and social impacts of COVID-19 and future pandemics.

Does mothers' and caregivers' access to information on their child's vaccination card impact the timing of their child's measles vaccination in Uganda?

INTRODUCTION: On-time measles vaccination is essential for preventing measles infection among children as early in life as possible, especially in areas where measles outbreaks occur frequently. Characterizing the timing of routine measles vaccination (MCV1) among children and identifying risk factors for delayed measles vaccination is important for addressing barriers to recommended childhood vaccination and increasing on-time MCV1 coverage. We aim to assess the timing of children's MCV1 vaccination and to investigate the association between demographic and healthcare factors, mothers'/caregivers' ability to identify information on their child's vaccination card, and achieving on-time (vs. delayed) MCV1 vaccination. METHODS: We conducted a population-based, door-to-door survey in Kampala, Uganda, from June-August of 2019. We surveyed mothers/caregivers of children aged one to five years to determine how familiar they were with their child's vaccination card and to determine their child's MCV1 vaccination status and timing. We assessed the proportion of children vaccinated for MCV1 on-time and delayed, and we evaluated the association between mothers'/caregivers' ability to identify key pieces of information (child's birth date, sex, and MCV1 date) on their child's vaccination card and achieving on-time MCV1 vaccination. RESULTS: Of the 999 mothers/caregivers enrolled, the median age was 27 years (17-50), and median child age was 29 months (12-72). Information on vaccination status was available for 66.0% (n = 659) of children. Of those who had documentation of MCV1 vaccination (n = 475), less than half (46.5%; n = 221) achieved on-time MCV1 vaccination and 53.5% (n = 254) were delayed. We found that only 47.9% (n = 264) of the 551 mothers/caregivers who were asked to identify key pieces of information on their child's vaccination card were able to identify the information, but ability to identify the key pieces of information on the card was not independently associated with achieving on-time MCV1 vaccination. CONCLUSION: Mothers'/caregivers' ability to identify key pieces of information on their child's vaccination card was not associated with achieving on-time MCV1 vaccination. Further research can shed light on interventions that may prompt or remind mothers/caregivers of the time and age when their child is due for measles vaccine to increase the chance of the child receiving it at the recommended time.

Symptoms of depression and anxiety, and unmet healthcare needs in adults during the COVID-19 pandemic: a cross-sectional study from the Canadian Longitudinal Study on Aging.

BACKGROUND: The COVID-19 pandemic disrupted access to healthcare services in Canada. Research prior to the pandemic has found that depression and anxiety symptoms were associated with increased unmet healthcare needs. The primary objective of this study was to examine if mental health was associated with perceived access to healthcare during the pandemic METHODS: A cross-sectional study was conducted using data from 23,972 participants (aged 50-96) in the Canadian Longitudinal Study on Aging COVID-19 Exit Survey (Sept-Dec 2020). We used logistic regression to estimate how the presence of depression and anxiety symptoms, defined using scores of ≥10 on the Center for Epidemiologic Studies Depression Scale and ≥10 on the Generalized Anxiety Disorder Scale, were associated with the odds of reporting: 1) challenges accessing healthcare, 2) not going to a hospital or seeing a doctor when needed, 3) experiencing barriers to COVID-19 testing. Models were adjusted for sex, age, region, urban/rural residence, racial background, immigrant status, income, marital status, work status, chronic conditions, and pre-pandemic unmet needs. RESULTS: The presence of depressive (aOR=1.96; 95% CI=1.82, 2.11) and anxiety symptoms (aOR=2.33; 95% CI=2.04, 2.66) compared to the absence of these symptoms were independently associated with higher odds of challenges accessing healthcare. A statistically significant interaction with sex suggested stronger associations in females with anxiety. Symptoms of depression (aOR=2.88; 95% CI=2.58, 3.21) and anxiety (aOR=3.05; 95% CI=2.58, 3.60) were also associated with increased odds of not going to a hospital or seeing a doctor when needed. Lastly, depressive (aOR=1.99; 95% CI=1.71, 2.31) and anxiety symptoms (aOR=2.01; 95% CI=1.58, 2.56) were associated with higher odds of reporting barriers to COVID-19 testing. There was no significantly significant interaction with sex for the latter two outcomes. CONCLUSION: The presence of depression and anxiety symptoms were strongly associated with perceived unmet healthcare needs during the COVID-19 pandemic. Interventions to improve healthcare access for adults with depression and anxiety during the pandemic may be necessary.

Probability of Success and Timelines for the Development of Vaccines for Emerging and Reemerged Viral Infectious Diseases.

BACKGROUND: Anticipated success rates and timelines for COVID-19 vaccine development vary. Recent experience with developing and testing viral vaccine candidates can inform expectations regarding the development of safe and effective vaccines. OBJECTIVE: To estimate timelines and probabilities of success for recent vaccine candidates. DESIGN: ClinicalTrials.gov was searched to identify trials testing viral vaccines that had not advanced to phase 2 before 2005, and the progress of each vaccine from phase 1 through to U.S. Food and Drug Administration (FDA) licensure was tracked. Trial characteristics were double-coded. (Registration: Open Science Framework [https://osf.io/dmuzx/]). SETTING: Trials launched between January 2005 and March 2020. PARTICIPANTS: Preventive viral vaccine candidates for 23 emerging or reemerged viral infectious diseases. MEASUREMENTS: The primary end point was the probability of vaccines advancing from launch of phase 2 to FDA licensure within 10 years. RESULTS: In total, 606 clinical trials forming 220 distinct development trajectories (267 343 enrolled participants) were identified. The probability of vaccines progressing from phase 2 to licensure within 10 years was 10.0% (95% CI, 2.6% to 16.9%), with most approvals representing H1N1 or H5N1 vaccines. The average timeline from phase 2 to approval was 4.4 years (range, 6.4 weeks to 13.9 years). The probabilities of advancing from phase 1 to 2, phase 2 to 3, and phase 3 to licensure within the total available follow-up time were 38.2% (CI, 30.7% to 45.0%), 38.3% (CI, 23.1% to 50.5%), and 61.1% (CI, 3.7% to 84.3%), respectively. LIMITATIONS: The study did not account for preclinical development and relied primarily on ClinicalTrials.gov and FDA resources. Success probabilities do not capture the varied reasons why vaccines fail to advance to regulatory approval. CONCLUSION: Success probabilities and timelines varied widely across different vaccine types and diseases. If a SARS-CoV-2 vaccine is licensed within 18 months of the start of the pandemic, it will mark an unprecedented achievement for noninfluenza viral vaccine development. PRIMARY FUNDING SOURCE: McGill Interdisciplinary Initiative in Infection and Immunity (MI4) Emergency COVID-19 Research Funding program.

Challenges related to human papillomavirus (HPV) vaccine uptake in Minnesota: clinician and stakeholder perspectives.

BACKGROUND: Human papillomavirus (HPV) vaccination rates among adolescents are increasing in Minnesota (MN) but remain below the Healthy People 2020 goal of 80% completion of the series. The goal of this study was to identify messaging and interventions impacting HPV vaccine uptake in MN through interviews with clinicians and key stakeholders. METHODS: We conducted semi-structured key participant interviews with providers and stakeholders involved in HPV vaccination efforts in MN between 2018 and 2019. Provider interview questions focused on messaging around the HPV vaccine and clinic-based strategies to impact HPV vaccine uptake. Stakeholder interview questions focused on barriers and facilitators at the organizational or state level, as well as initiatives and collaborations to increase HPV vaccination. Responses to interviews were recorded and transcribed. Thematic content analysis was used to identify themes from interviews. RESULTS: 14 clinicians and 13 stakeholders were interviewed. Identified themes were grouped into 2 major categories that dealt with messaging around the HPV vaccine, direct patient-clinician interactions and external messaging, and a third thematic category involving healthcare system-related factors and interventions. The messaging strategy identified as most useful was promoting the HPV vaccine for cancer prevention. The need for stakeholders to prioritize HPV vaccination uptake was identified as a key factor to increasing HPV vaccination rates. Multiple providers and stakeholders identified misinformation spread through social media as a barrier to HPV vaccine uptake. CONCLUSION: Emphasizing the HPV vaccine's cancer prevention benefits and prioritizing it among healthcare stakeholders were the most consistently cited strategies for promoting HPV vaccine uptake. Methods to combat the negative influence of misinformation about HPV vaccines in social media are an urgent priority.

Serodiagnostics for Severe Acute Respiratory Syndrome-Related Coronavirus 2 : A Narrative Review.

Accurate serologic tests to detect host antibodies to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) will be critical for the public health response to the coronavirus disease 2019 pandemic. Many use cases are envisaged, including complementing molecular methods for diagnosis of active disease and estimating immunity for individuals. At the population level, carefully designed seroepidemiologic studies will aid in the characterization of transmission dynamics and refinement of disease burden estimates and will provide insight into the kinetics of humoral immunity. Yet, despite an explosion in the number and availability of serologic assays to test for antibodies against SARS-CoV-2, most have undergone minimal external validation to date. This hinders assay selection and implementation, as well as interpretation of study results. In addition, critical knowledge gaps remain regarding serologic correlates of protection from infection or disease, and the degree to which these assays cross-react with antibodies against related coronaviruses. This article discusses key use cases for SARS-CoV-2 antibody detection tests and their application to serologic studies, reviews currently available assays, highlights key areas of ongoing research, and proposes potential strategies for test implementation.

Evaluating the Effectiveness of Vaccines Using a Regression Discontinuity Design.

The regression discontinuity design (RDD), first proposed in the educational psychology literature and popularized in econometrics in the 1960s, has only recently been applied to epidemiologic research. A critical aim of infectious disease epidemiologists and global health researchers is to evaluate disease prevention and control strategies, including the impact of vaccines and vaccination programs. RDDs have very rarely been used in this context. This quasi-experimental approach using observational data is designed to quantify the effect of an intervention when eligibility for the intervention is based on a defined cutoff such as age or grade in school, making it ideally suited to estimating vaccine effects given that many vaccination programs and mass-vaccination campaigns define eligibility in this way. Here, we describe key features of RDDs in general, then specific scenarios, with examples, to illustrate that RDDs are an important tool for advancing our understanding of vaccine effects. We argue that epidemiologic researchers should consider RDDs when evaluating interventions designed to prevent and control diseases. This approach can address a wide range of research questions, especially those for which randomized clinical trials would present major challenges or be infeasible. Finally, we propose specific ways in which RDDs could advance future vaccine research.

Immunogenicity of a Meningococcal B Vaccine during a University Outbreak.

BACKROUND: In December 2013, a multicomponent meningococcal serogroup B (4CMenB) vaccine was used before licensure on the basis of special consideration by the Food and Drug Administration to respond to an outbreak of Neisseria meningitidis B at a U.S. university. Data suggested that vaccination would control the outbreak because isolates expressed antigens that were closely related to the vaccine antigens (factor H-binding protein [fHbp] and neisserial heparin-binding antigen). We quantified the immune responses induced by 4CMenB during the outbreak. METHODS: We conducted a seroprevalence survey among students to assess vaccination status and collect serum specimens to quantify titers of serum bactericidal antibodies (SBA) with an assay that included human complement (hSBA). We compared the proportion of vaccinated and unvaccinated participants who were seropositive for the outbreak strain and for one closely related reference strain (44/76-SL, which included fHbp) and one mismatched reference strain (5/99, which included neisserial adhesin A), both of which were used in vaccine development. Seropositivity was defined as an hSBA titer of 4 or higher. RESULTS: Among the 499 participants who received two doses of the 4CMenB vaccine 10 weeks apart, 66.1% (95% confidence interval [CI], 61.8 to 70.3) were seropositive for the outbreak strain, although the geometric mean titer was low at 7.6 (95% CI, 6.7 to 8.5). Among a random subgroup of 61 vaccinees who also received two doses but did not have a detectable protective response to the outbreak strain, 86.9% (95% CI, 75.8 to 94.2) were seropositive for the 44/76-SL strain, for which there was a geometric mean titer of 17.4 (95% CI, 13.0 to 23.2), whereas 100% of these vaccinees (95% CI, 94.1 to 100) were seropositive for the 5/99 strain and had a higher geometric mean titer (256.3; 95% CI, 187.3 to 350.7). The response to the outbreak strain was moderately correlated with the response to the 44/76-SL strain (Pearson's correlation,0.64; P<0.001) but not with the response to the 5/99 strain (Pearson's correlation,-0.06; P=0.43). CONCLUSIONS: Eight weeks after the second dose of the 4CMenB vaccine was administered, there was no evidence of an hSBA response against the outbreak strain in 33.9% of vaccinees, although no cases of meningococcal disease caused by N. meningitidis B were reported among vaccinated students. (Funded by Princeton University and others.).

National Trends in Parental Human Papillomavirus Vaccination Intentions and Reasons for Hesitancy, 2010-2015.

Background: Human papillomavirus (HPV) vaccination uptake remains lower than other recommended adolescent vaccines in the United States. Parental attitudes are important predictors of vaccine uptake, yet little is known about how they have changed over time. Methods: Participants included US residents aged 13-17 years with documented vaccination status who had received <3 doses of HPV vaccine whose parents responded to the National Immunization Survey-Teen, 2010-2015. Results: Of the 76971 participants, 63.0% were male, 58.8% were non-Hispanic white, and 14.4 years was the median age. The percentage of unvaccinated teens decreased from 2010 to 2015, yet, annually, parents of unvaccinated teens of both sexes most often reported that they were "not likely at all" to vaccinate their teen. The percentage decreased significantly from 41.5% to 31.2% (P < .001) for parents of unvaccinated females from 2010 to 2015 but did not change among parents of males from 2012 to 2015. Conversely, parents of undervaccinated teens of both sexes reported higher and increasing vaccination intent over time. In 2015, nearly one-third of parents of unvaccinated teens reported that the vaccine was "not needed/necessary." Concerns about vaccine safety and side effects declined among parents of unvaccinated females but increased among parents of males (7.3% to 14.8%; P < .001). Conclusions: Although parental vaccination intent and knowledge improved over time, intent remains low and many parents still have significant concerns about HPV vaccination, even after series initiation. Multiple strategies are needed to improve series initiation and completion in the United States.

Pertussis and the Minnesota State Fair: Demonstrating a Novel Setting for Efficiently Conducting Seroepidemiologic Studies.

Seroepidemiologic studies, which measure serum antibody levels produced in response to infection and/or vaccination, can be valuable tools for gaining insight into population level dynamics of infectious diseases. However, because seroepidemiologic studies are expensive and logistically challenging, they are not routinely conducted for surveillance purposes. We have identified a novel venue, state fairgrounds, in which annual sera samples from a population may be rapidly collected with minimal recruitment expenses. We conducted a pilot pertussis seroepidemiologic study over the course of 3 days at the 2016 Minnesota State Fair to determine if this setting, which hosts nearly 2 million visitors over 12 days each year, is viable for facilitating larger seroepidemiologic studies. A total of 104 adults and children were enrolled to provide a finger stick blood sample for serologic testing and to take a written survey regarding recent cough illness and pertussis vaccination. The survey was used to distinguish between antibodies induced by vaccination and pertussis infection. Elevated antibodies suggestive of recent infection were found among two adults. The prevalence of undetectable antibodies, suggestive of susceptibility, was 72.3% (95% CI 59.6, 85.1%) among 7-17 year olds, 53.8% (95% CI 26.7, 80.9%) among 1-6 year olds, and 23.3% (95% CI 8.2, 38.5%) among adults. Our ability to rapidly enroll participants and collect satisfactory specimens suggests that seroepidemiologic studies with 1000-2000 participants could efficiently be completed over the 12-day course of the Minnesota State Fair. This setting raises the possibility of efficiently conducting annual population-based seroepidemiologic studies to supplement traditional public health surveillance in estimating disease prevalence, monitoring vaccine impact, and identifying at-risk groups.

Simulations for designing and interpreting intervention trials in infectious diseases.

BACKGROUND: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods. DISCUSSION: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects. CONCLUSION: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials.

Population-Level Persistence of Immunity 2 Years After the PsA-TT Mass-Vaccination Campaign in Mali.

BACKGROUND: In 2010, Africa's first preventive meningococcal mass vaccination campaign was launched using a newly developed Neisseria meningitidis group A (NmA) polysaccharide-tetanus toxoid conjugate vaccine, PsA-TT (MenAfriVac), designed specifically for the meningitis belt. Given PsA-TT's recent introduction, the duration of protection against meningococcal group A is unknown. METHODS: We conducted a household-based, age-stratified seroprevalence survey in Bamako, Mali, in 2012, 2 years after the vaccination campaign targeted all 1- to 29-year-olds. Randomly selected participants who had been eligible for PsA-TT provided a blood sample and responded to a questionnaire. Sera were analyzed to assess NmA-specific serum bactericidal antibody titers using rabbit complement (rSBA) and NmA-specific immunoglobulin G (IgG) by enzyme-linked immunosorbent assay. The proportion of participants putatively protected and the age group- and sex-specific rSBA geometric mean titers (GMTs) and IgG geometric mean concentrations (GMCs) were determined. RESULTS: Two years postvaccination, nearly all of the 800 participants (99.0%; 95% confidence interval [CI], 98.3%-99.7%) maintained NmA-specific rSBA titers ≥8, the accepted threshold for protection; 98.6% (95% CI, 97.8%-99.4%) had titers ≥128, and 89.5% (95% CI, 87.4%-91.6%) had titers ≥1024. The rSBA GMTs were significantly higher in females than in males aged <18 years at vaccination (P < .0001). NmA-specific IgG levels ≥2 µg/mL were found in 88.5% (95% CI, 86.3%-90.7%) of participants. CONCLUSIONS: Two years after PsA-TT introduction, a very high proportion of the population targeted for vaccination maintains high antibody titers against NmA. Assessing the duration of protection provided by PsA-TT is a priority for implementing evidence-based vaccination strategies. Representative, population-based seroprevalence studies complement clinical trials and provide this key evidence.

Higher Tetanus Toxoid Immunity 2 Years After PsA-TT Introduction in Mali.

BACKGROUND: In 2010, mass vaccination with a then-new meningococcal A polysaccharide-tetanus toxoid protein conjugate vaccine (PsA-TT, or MenAfriVac) was undertaken in 1- to 29-year-olds in Bamako, Mali. Whether vaccination with PsA-TT effectively boosts tetanus immunity in a population with heterogeneous baseline tetanus immunity is not known. We assessed the impact of PsA-TT on tetanus toxoid (TT) immunity by quantifying age- and sex-specific immunity prior to and 2 years after introduction. METHODS: Using a household-based, age-stratified design, we randomly selected participants for a prevaccination serological survey in 2010 and a postvaccination survey in 2012. TT immunoglobulin G (IgG) antibodies were quantified and geometric mean concentrations (GMCs) pre- and postvaccination among all age groups targeted for vaccination were compared. The probability of TT IgG levels ≥0.1 IU/mL (indicating short-term protection) and ≥1.0 IU/mL (indicating long-term protection) by age and sex was determined using logistic regression models. RESULTS: Analysis of 793 prevaccination and 800 postvaccination sera indicated that while GMCs were low pre-PsA-TT, significantly higher GMCs in all age-sex strata were observed 2 years after PsA-TT introduction. The percentage with short-term immunity increased from 57.1% to 88.4% (31.3-point increase; 95% confidence interval [CI], 26.6-36.0;, P < .0001) and with long-term immunity increased from 20.0% to 58.5% (38.5-point increase; 95% CI, 33.7-43.3; P < .0001) pre- and postvaccination. CONCLUSIONS: Significantly higher TT immunity was observed among vaccine-targeted age groups up to 2 years after Mali's PsA-TT mass vaccination campaign. Our results, combined with evidence from clinical trials, strongly suggest that conjugate vaccines containing TT such as PsA-TT should be considered bivalent vaccines because of their ability to boost tetanus immunity.