The complementary roles of Phase 3 trials and post-licensure surveillance in the evaluation of new vaccines

Vaccines have led to significant reductions in morbidity and saved countless lives from many infectious diseases and are one of the most important public health successes of the modern era. Both vaccines’ effectiveness and safety are keys for the success of immunisation programmes. The role of post-licensure surveillance has become increasingly recognised by regulatory authorities in the overall vaccine development process. Safety, purity, and effectiveness of vaccines are carefully assessed before licensure, but some safety and effectiveness aspects need continuing monitoring after licensure; Post-marketing activities are a necessary complement to pre-licensure activities for monitoring vaccine quality and to inform public health programmes. In the recent past, the availability of large databases together with data-mining and cross-linkage techniques have significantly improved the potentialities of post-licensure surveillance. The scope of this review is to present challenges and opportunities offered by vaccine post-licensure surveillance. While pre-licensure activities form the foundation for the development of effective and safe vaccines, post-licensure monitoring and assessment, are necessary to assure that vaccines are effective and safe when translated in real world settings. Strong partnerships and collaboration at an international level between different stakeholders is necessary for finding and optimally allocating resources and establishing robust post-licensure processes.     

Two media-reported vaccine events in China from 2013 to 2016: Impact on confidence and vaccine utilization

BackgroundChina media reported infant deaths following hepatitis B vaccination in late 2013, leading to temporary suspension of hepatitis B vaccine (HepB Event) until the deaths were shown to be coincidental and the vaccine was of standard, good quality. In 2016, a criminal ring in Shandong province that had been purchasing, improperly storing, and reselling Category 2 vaccines (private-sector) to 60 (of 200,000) clinics for 5 years, was exposed, publicized, and prosecuted, and the potential health and epidemiological impacts were investigated to determine whether revaccination was necessary (Shandong Vaccine Event).MethodsWe assessed parental confidence in vaccines through 9 telephone surveys in 6 and 11 provinces before, during, and after the two events. Provider confidence was assessed through in-person interviews following each event. Vaccine utilization was assessed using Immunization Information Management System data from township clinics.ResultsIn the early stages of each event, approximately 30% of parents indicated vaccine hesitancy and 18% said they would refuse routine immunization. Five and nine months after each event, hesitancy and refusal decreased, but not to pre-event levels. During the Shandong Vaccine Event, 49·1% of parents indicated refusal to use Category 2 vaccines; six months later, the rate was 32·8%. Use of HepB decreased by 21% during the first 2 weeks of the HepB Event and by 12·6% during the first 4 weeks of Shandong Vaccine Event, but returned to baseline in less than 3 months. Use of Category 2 vaccine decreased by 49·5% in the first 3 weeks of the Shandong Vaccine Event and by 28·7% 6 months later. After the Shandong Vaccine Event, 64% of clinicians held high confidence in routine immunization, lower than at baseline.ConclusionsThe two events caused mistrust, loss of confidence, and decreases in use of vaccines by parents and providers. In addition to ensuring immunization program integrity, effective communications and ongoing monitoring of vaccine use and confidence should be included to restore confidence and trust in vaccines.     

Differential maternal responses to a newly developed vaccine information pamphlet

We compared the response to a new vaccine information pamphlet with the current CDC Vaccine Information Statements (VIS) among recently delivered mothers who were screened to identify those with concerns about immunization. Eligible mothers (n = 226) were randomly assigned to one of three equal groups; those reviewing only the new pamphlet, those receiving only VIS, or those receiving both. Among those mothers reviewing both, 61% preferred the new pamphlet for its visual appeal (P < 0.0001) and ease of understanding (P = 0.005). Overall, mothers expressed increased confidence and fewer concerns regarding multiple injections after reviewing the pamphlet. However, older, more-highly educated mothers were less likely to report improved vaccine confidence after reviewing either the pamphlet or the VIS. Mothers in all three groups stated a preference for receiving the vaccine information during pregnancy or prior to the actual immunization visit. These data suggest that early provision of tailored immunization material along with the VIS to new mothers may enhance their overall confidence in vaccines and that additional strategies targeted toward certain mothers may be needed.     

Vaccination coverage levels among children enrolled in the Vaccine Safety Datalink

Introduction

The Vaccine Safety Datalink (VSD) is a collaborative project whose infrastructure provides comprehensive medical and immunization histories for more than 9 million adults and children annually, a predominantly insured population. This study provides the coverage rates of recommended vaccines among children 19–35 months in the VSD from 2005 through 2010. We examine the consistency in vaccine coverage levels, detect possible trends, and evaluate any effect of vaccine shortages on coverage in the VSD.

Methods

We included data from all 10 VSD sites, and examined each year independently. Coverage rates were defined as the percentage of children in the VSD aged 19, 24, or 35 months in a given study year who had received the specified Advisory Committee on Immunization Practices (ACIP) recommended vaccine(s).

Results

We assessed coverage on 658,154 children. The overall coverage rate for children receiving all of the specified ACIP recommended vaccines was 73%, 80%, and 78% at ages 19, 24, and 35 months respectively. The range of coverage across all ages and years was 95–97% for polio vaccine, 91–97%, for MMR vaccine, 94–97% for HepB vaccine, 81–95% for DTaP vaccine, 90–95% for varicella vaccine, 66–91% for PCV, and 93–98% for Hib vaccine. Coverage rates of 4 or more doses of PCV were relatively low in 2005 possibly due to a vaccine shortage, and increased sharply in 2007. Hib vaccine coverage was relatively stable among all ages until 2009 when rates declined among children aged 19 and 24 months also during a vaccine shortage.

Conclusions

Vaccine coverage in the VSD is high, but there is a decline from 2005 to 2010. The results of this study provide benchmark data for future studies, and describe how vaccine supply shortages and resulting changes in ACIP recommendations may have affected vaccine coverage rates in the VSD.     

Changes in childhood immunization decisions in the United States: Results from 2012 & 2014 National Parental Surveys

ObjectiveUnderstanding the current status of parents’ vaccine decision making is crucial to inform public policy. We sought to assess changes in vaccine decisions among parents of young children.MethodsWe conducted a web-based national poll of parents of children <7 years in 2012 and 2014. Participants reported vaccine decisions for their youngest child. We calculated survey-weighted population estimates of overall immunizations decisions, and delay/refusal rates for specific vaccines.ResultsIn 2012, 89.2% (95% CI, 87.3–90.8%) reported accepting or planning to accept all recommended non-influenza childhood vaccines, 5.5% (4.5–6.6%) reported intentionally delaying one or more, and 5.4% (4.1–6.9%) reported refusing one or more vaccines. In 2014, the acceptance, delay, and refusal rates were 90.8% (89.3–92.1%), 5.6% (4.6–6.9%), and 3.6% (2.8–4.5%), respectively. Between 2012 and 2014, intentional vaccine refusal decreased slightly among parents of older children (2–6 years) but not younger children (0–1 years). The proportion of parents working to catch up on all vaccines increased while those refusing some but not all vaccines decreased. The South experienced a significant increase in estimated acceptance (90.1–94.1%) and a significant decrease in intentional ongoing refusal (5.0–2.1%). Vaccine delay increased in the Northeast (3.2–8.8%).ConclusionsNationally, acceptance and ongoing intentional delay of recommended non-influenza childhood vaccines were stable. These findings suggest that more effort is warranted to counter persistent vaccine hesitancy, particularly at the local level. Longitudinal monitoring of immunization attitudes is also warranted to evaluate temporal shifts over time and geographically.     

Parental experiences with vaccine information statements: Implications for timing,delivery, and parent-provider immunization communication

ObjectiveWe examined Vaccine Information Statements (VIS) dissemination practices and parental use and perceptions.MethodsWe conducted a national online panel survey of 2603 US parents of children aged <7. Primary outcomes included reported VIS receipt, delivery timing, reading experiences, and perceived utility.ResultsMost parents received a VIS (77.2%; [95% CI: 74.5–79.7%]), 59.7% [56.6–62.7%] before vaccination but 14.5% [12.5–16.8%] reported receiving it after their child’s immunization; 15.1% [13.0–17.6%] were unsure of receipt status or timing; another 10.7% [9.0–12.6%] reported non-receipt of a VIS. Less than half who received a VIS before vaccination completed it before vaccination (46.2% [42.4, 50.0%]), but most who read at least some found the information useful (95.7% [93.8–97.0%]). Parents who delayed or refused at least one recommended non-influenza vaccine reported fewer opportunities to ask providers VIS questions.ConclusionsMost parents report receiving VIS before vaccination as per federal guidelines. Continued effort is needed to enhance VIS distribution practice and parent-provider VIS content communication.     

A framework for research on vaccine effectiveness

The need for a systematic approach to research on vaccine effectiveness (VE) is increasing with growing numbers of vaccines and complexity of immunization programs. The diverse scientific fields that investigate how vaccines work and why they fail continue to evolve, yet definitions related to such advances have not kept pace. Researchers in disciplines ranging from basic science through immunopathology, clinical and epidemiological research, and mathematical modelling need more precise definitions to promote communication and interdisciplinary VE research to ensure that studies are designed to appropriately address relevant questions. To meet these aims, we suggest standardized definitions, consider models of vaccine failure, and offer general approaches for incorporation into study design. We further propose a framework for conducting VE research that builds on the traditional epidemiological triad of host, pathogen and environment, and also includes additional elements such as characteristics of both the vaccine and vaccinee, the effect of time on likelihood of exposure and protection, and the impact of environment and pathogen, as well as how outcomes of interest and study design may impact observed vaccine effectiveness. The framework is relevant to researchers in all disciplines who investigate the effectiveness of vaccines and vaccination programs and why they may fail. Stronger research in this field will help policy makers optimise decision-making on vaccination programs, ensuring we maximize the health benefits of vaccines. It is also important for clinicians communicating the benefits of vaccines to the public.     

Effects of vaccination status in the United States on willingness to undergo surgery during a pandemic: A prospective survey study

Purpose of the ResearchModifiable and non-modifiable patient and hospital characteristics may affect willingness to undergo surgery during a pandemic. We hypothesized that vaccination of hospital staff and patients, type of surgery, and length of stay, would affect willingness to undergo a surgical procedure. 2006 adult participants in the United States were recruited electronically using Amazon’s ® Mechanical Turk ® and answered a 26-item survey in English about hypothetical surgery, manipulating requirements for: staff vaccination, patient vaccination, surgical urgency, and time in hospital. They also answered questions about their opinions about vaccination, personal vaccination status, and demographics.Principle ResultsParticipants are more willing to undergo surgery if they have been vaccinated, if staff vaccinations are required, and if surgery is lifesaving and outpatient.Major ConclusionsWillingness to undergo surgery varies with hospital staff and patient vaccination. This may inform policies for vaccination, boosters, and resource allocation.     

Ebola epidemic in war-torn Democratic Republic of Congo, 2018: Acceptability and patient satisfaction of the recombinant Vesicular Stomatitis Virus – Zaire Ebolavirus Vaccine

Background

The current Ebola outbreak in Eastern Democratic Republic of the Congo (DRC) is the second largest in history and the first in which the recombinant Vesicular Stomatitis Virus – Zaire Ebolavirus (rVSV-ZEBOV) vaccine has been used at scale. We assessed side-effects, satisfaction, and attitudes toward the new vaccine.

Assessing misclassification of vaccination status: Implications for studies of the safety of the childhood immunization schedule

BackgroundTo address public concern about the safety of the childhood immunization schedule, the Institute of Medicine recommended observational studies comparing adverse health outcomes of fully vaccinated children to children under-vaccinated due to parental choice. Misclassification of vaccination status could bias such studies.ObjectiveTo assess risk of misclassification of vaccination status within the Vaccine Safety Datalink (VSD).Design/methodsA retrospective cohort study was conducted in three phases. In phase 1, electronic health record (EHR) data were used to identify patterns of under-vaccination during the first 24 months of life potentially due to parental choice. In phase 2, a random sample of records of under-vaccinated children was manually reviewed. In phase 3, a separate sample of parents were surveyed to assess whether EHR data accurately reflected their child’s vaccination status. Phases 1 and 2 were conducted at 6 VSD sites, phase 3 at 1 site.ResultsThe study cohort included 361,901 children born 2004 through 2012. By 24 months of age, 198,249 (54.8%) were fully vaccinated with no delays, 84,698 (23.4%) experienced delays but were fully vaccinated by 24 months of age, 4865 (1.3%) received no vaccines, 3789 (1.0%) delayed starting vaccination until ≥4 months of age, 4781 (1.3%) had consistent vaccine-limiting (≤2 vaccines per visit), and the remaining 65,519 (18.1%) were missing vaccine series or doses. When a diagnosis code for vaccine refusal was present in EHR data, encounter notes confirmed vaccine refusal as the reason for under-vaccination for nearly 100% of sampled records. Parent surveys confirmed these findings. Parents of under-vaccinated children were more likely to report visiting an alternative medical provider than parents of fully vaccinated children.ConclusionsSpecific groups of children, under-vaccinated due to parental choice, can be identified with relatively low likelihood of misclassification of vaccination status using EHR-based vaccine data and diagnosis codes.     

Vaccine sentiments and under-vaccination: Attitudes and behaviour around Measles,Mumps, and Rubella vaccine (MMR) in an Australian cohort

ObjectiveThe study aimed to examine the consistency in factors associated with attitudes towards vaccination and MMR vaccination status.MethodsUsing the nationally representative Longitudinal Study of Australian Children matched with the Australian Childhood Immunisation Register, 4,779 children were included from 2004–2005 to 2010–11. Different MMR vaccine dosages and general attitude towards vaccination were modelled individually with multinomial logit regressions, controlling for demographic, socioeconomic, and health related factors of the children and their primary carers.ResultsThe group with non-vaccination and negative attitudes was characterised by more siblings and older parents; the group with under-vaccination but positive attitudes was characterised by younger parental age; and the group with under-vaccination and neutral attitudes was characterised by less socioeconomically advantaged areas. The presence of parental medical condition(s), being private or public renters, and higher parental education were associated with under-vaccination but not with attitudes towards vaccination, whilst parental religion was associated with attitudes towards vaccination but not reflected in the vaccine uptake.ConclusionsVaccine attitudes were largely consistent with MRR vaccine outcomes. However, there was variation in the associations of factors with vaccine attitudes and uptake. The results have implications for different policy designs that target subgroups with consistent or inconsistent vaccination attitudes and behaviour. Parents with intentional and unintentional under-vaccination are of policy concern and require different policy solutions.     

Vaccine bidding,procurement and distribution management practices in mainland China: A nationwide study

ObjectiveTo conduct a nationwide evaluation of vaccine bidding, procurement and distribution management for understanding and improving the current situation well in mainland China.MethodsAn institution survey was carried out to collect information on tendering, procurement, distribution and related issues to vaccines by structured questionnaires administered to 31 provinces in mainland China from April to July 2019.ResultsIn 13 (41.9%) of 31 provinces, centralized bidding of National Immunization Program (NIP) vaccines was accomplished, and others conducted independent tendering and purchasing in 2018. For non-NIP vaccines, all provinces implemented unified bidding at the provincial level and over half (18, 58.1%) of them chose provincial public resource trading platforms, but their modes varied over provinces. Then procurement was undertaken by the district-level centers for disease control and prevention (CDC) while they were unable to choose the best option of too many vaccines targeted by the province-level CDC for local populations. The distribution modes of NIP and non-National Immunization Program (non-NIP) vaccines were similar overall in a province but very different over provinces. Main mode was that CDCs at different levels delivered about two thirds (64.5%) of NIP vaccines distribution and more than one third (35.5%) of non-NIP vaccines. Another distribution mode was occupied as fully buying the service from third parties in 3 municipalities. Some provinces mixed both modes, too. The total distribution volume of vaccines was 430.7 million doses in 2018. The top five non-NIP vaccines delivered in 2018 were human rabies vaccine, varicella vaccine, EV71 hand foot mouth disease vaccine, hepatitis B vaccine and influenza vaccine.ConclusionThe vaccine biding, procurement and distribution management varied over provinces in mainland China in 2018, especially for non-NIP vaccines. Specific policies and measures should be developed for different regions to improve the immunization management better.     

Persistent drop in confidence following US recommended pause of Ad26.COV2.S vaccine administration

The Janssen COVID-19 vaccine came to market in February 2021 as the first non-mRNA and first single-dose formula approved for use in the US. In April 2021, a temporary pause was recommended for the vaccine after the discovery of rare but serious post-vaccination side-effects. We fielded a large-scale nationally representative survey (n = 401,398) on individual confidence in each of the COVID-19 vaccine formulas available in the US before, during, and after this pause. We find widespread loss of confidence in the Janssen vaccine across gender, age, and other demographics, which persisted over time and after lifting of the halt. Despite this drop, overall reasons for remaining unvaccinated were stable and there was a concurrent minor bump in confidence towards other vaccine formulas. This contrast between the persistent reduction in confidence in the Janssen vaccine and the apparent maintenance of the broader campaign’s integrity, highlights the complex dynamics and downstream effects of the pause.     

Impact of the introduction of rotavirus vaccine on the timeliness of other scheduled vaccines: The Australian experience

Strict age limits for receipt of rotavirus vaccines and simultaneous use of vaccines requiring two (Rotarix^®) and three (RotaTeq^®) doses in Australia may impact on coverage and timeliness of other vaccines in the infant schedule. Using data from the Australian Childhood Immunisation Register (ACIR), coverage and timeliness of rotavirus vaccines and changes in timeliness of other infant vaccines following rotavirus vaccine introduction was examined, with particular emphasis on Indigenous infants in whom coverage is less optimal. Final dose rotavirus coverage reached 83% within 21 months of program commencement but remained 7% lower than other vaccines due in infancy. Coverage was 11–17% lower in Indigenous infants. Adherence to the first dose upper age limits for rotavirus vaccine was high with >97% of children vaccinated by the recommended age, but for subsequent rotavirus doses, receipt beyond the upper age limits was more common, especially in Indigenous children. Following rotavirus vaccine introduction, there were improvements in timeliness of receipt of all doses of DTPa-containing and 7-valent pneumococcal conjugate vaccines. High population coverage can be attained with rotavirus vaccines, even with adherence to strict upper age restrictions for vaccine dose administration. Rotavirus vaccine introduction appears to have impacted upon the timeliness of other concomitantly scheduled vaccines. These factors should be considered when rotavirus programs are introduced.     

MomsTalkShots: An individually tailored educational application for maternal and infant vaccines

IntroductionThe development and initial assessment in a clinical setting of a theory-driven, individually tailored educational application (app), MomsTalkShots, focused on increasing uptake of maternal and infant vaccines is described.MethodsMomsTalkShots algorithmically tailored videos based on parent needs to deliver an intervention that was specifically responsive to individual vaccine attitudes, beliefs and intentions, demographics, and source credibility. MomsTalkShots was evaluated among 1103 pregnant women recruited from 23 geographically and socio-demographically diverse obstetrician-gynecologist offices in Georgia and Colorado in 2017. Self-reported information needs were assessed pre-and post-videos and participants self-reported factors related to usability and analyzed in 2018.ResultsThe vast majority of women reported MomsTalkShots was helpful (95%), trustworthy (94%), interesting (97%) and clear to understand (99%), none of which varied by demographics or parity. Reported usability was slightly lower among vaccine hesitant women, yet the majority reported MomsTalkShots was helpful (91%), trustworthy (85%), interesting (97%) and clear (99%). The majority of women (72%) who did not have enough vaccine information pre-videos reported enough information post-videos.ConclusionsMomsTalkShots was designed to provide individually tailored vaccine information to pregnant women from a population with varied vaccine intentions, confidence and vaccine concerns. MomsTalkShots was extremely well-received among pregnant women, even among women who were initially vaccine hesitant and did not intend to vaccinate themselves and their infants according to the recommended immunization schedule. Next steps include evaluation to assess impact on vaccine uptake and expansion to adolescent and adult vaccines.     

流行性腮腺炎疫苗两剂次接种保护效果系统评价

目的综合评估腮腺炎二剂次接种和一剂次接种疫苗保护效力的差异,为制定更有效地控制流行性腮腺炎的免疫策略提供依据。方法以＂流行性腮腺炎＂、＂mumps＂,＂Vaccine effectiveness＂等为主题词检索中国生物医学文献光盘数据库、Pubmed、EMbase、Web of Science等数据库,并对所获文献进行质量评价、筛选和提取相关研究资料,并以SD值及95%可信区间为效应指标,利用Stata 10.0软件进行Meta分析。结果两次疫苗接种组的免疫保护效力显著高于单次接种组的免疫保护效力,标准化差值为[SMD=0.24,95%CI（0.03,0.44）,P=0.023]。同时,采用敏感性分析对结果的可靠性和稳定性进行评价,检验的结果为各研究组之间无显著的异质性（χ2=9.21,P=0.162）,说明结果具有一定的可靠性和稳定性。结论二剂次接种具有更好的疫苗保护效果,我国属于腮腺炎高发地区,二剂次接种策略适合在全国范围内推广应用。     

Vaccine hesitancy in pregnant Women: A narrative review

Pregnant women are often at higher risk for morbidity and mortality due to contracting vaccine-preventable diseases that result in adverse pregnancy outcomes such as spontaneous abortion, preterm births, and congenital fetal defects. For example, health care provider recommendation is correlated with maternal acceptance of influenza vaccination, however, up to 33 % of pregnant women remain unvaccinated irrespective of provider recommendation. Vaccine hesitancy is a multifactorial problem that both the medical and public health systems need to address synergistically. Vaccine education should incorporate balanced perspectives to deliver vaccine education. This narrative review addresses four questions: 1) what are the primary concerns of pregnant women that lead them to be hesitant about receiving vaccinations; 2) to what extent does the source (e.g. provider, friend, family) of vaccine advice and information influence a pregnant person’s decision to accept a vaccine; 3) how does the delivery method of vaccine education influence their decision; 4) how can categorizing patients into four distinct groups based on their opinions and behavior regarding vaccines be used to improve provider-patient communication and increase vaccine acceptance. Results from the literature show that the three most common reasons for vaccine hesitancy include: i.) fear of side effects or adverse events; ii.) lack of confidence in vaccine safety; iii.) low perception of being at high risk of infection during pregnancy and/or not having previously received the vaccination when not pregnant. We conclude that vaccine hesitancy is dynamic therefore people do not always hold a static level of vaccine hesitancy. People may move between a continuum of vaccine hesitancy for a multifactorial reasons. A framework, characterized by levels of vaccine hesitancy before and during pregnancy, was constructed to help providers find balance between promoting individual health and public health while providing vaccine education.     

Vaccine hesitancy and anti-vaccination in the time of COVID-19: A Google Trends analysis

The COVID-19 pandemic has produced many calls for a vaccine. There is growing concern that vaccine hesitancy and anti-vaccination presence will dampen the uptake of a coronavirus vaccine. There are many cited reasons for vaccine hesitancy. Mercury content, autism association, and vaccine danger have been commonly found in anti-vaccination messages. It is also mused that the reduced disease burden from infectious diseases has paradoxically reduced the perceived requirement for vaccine uptake. Our analysis using Google Trends has shown that throughout the pandemic the search interest in a coronavirus vaccine has increased and remained high throughout. Peaks are found when public declarations are made, the case number increases significantly, or when vaccine breakthroughs are announced. Anti-vaccine searches, in the context of COVID-19, have had a continued and growing presence during the pandemic. Contrary to what some may believe, the burden of coronavirus has not been enough to dissuade anti-vaccine searches entirely.