Subcutaneous nodules following immunization in children; in Victoria,Australia from 2007 to 2016

BackgroundSubcutaneous nodules are a rare adverse event following immunization (AEFI). We aimed to describe nodules at the injection site reported to SAEFVIC (Surveillance of Adverse Events Following Vaccination in the Community) using the Brighton Collaboration Case Definition (BCCD), management and recurrence following subsequent immunizations.MethodWe assessed 58 cases (<18 years of age) of ‘nodule at injection site’ reported to SAEFVIC, Melbourne, Australia, between May 2007 and June 2016. Case details were analyzed from records and phone interview follow-up. The Australian Immunization Registry was reviewed for immunization status.Results71% (41/58 reported cases) were consistent with the BCCD for subcutaneous nodule, 14% (8 cases) were ‘possible subcutaneous nodules’, 10% (6 cases) were nodules associated with BCG immunization and 5% (3 cases) were attributable to an alternative diagnosis. The median age at immunization was 12 months, (range 1 month–12 years); 54% male (22/41 cases). 17% (7 cases) had multiple nodules. Nodules were associated with immunizations containing aluminum (74%, 36/49 nodules), no aluminum (8%, 4 nodules) and unknown (18%, 9 nodules). Most cases developed symptoms within 3 days post-immunization (59%, 24 cases) and in the thigh (59%, 29 nodules). Pruritus was associated in 41% (17 cases). Around 1/3 (34%) of nodules resolved 6 months post immunization, 2/3 (68%) by 12 months, however 1/4 (24%) remained persistent for >24 months. 5 cases had prior nodules and 1 case had recurrence with subsequent immunization. 83% (34 cases) were fully immunized for age at follow-up.ConclusionSubcutaneous nodules at the injection site may occur following a wide range of vaccines, including vaccines without aluminum. All cases require careful review and where possible, specialist management and to support subsequent immunizations.     

Anosmia: Brighton Collaboration case definition and guidelines for data collection,analysis, and presentation of immunization safety data

This is a Brighton Collaboration case definition of anosmia to be used in the evaluation of adverse events following immunization, and for epidemiologic studies for the assessment of background incidence or hypothesis testing. The case definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of SARS-CoV-2 vaccines. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by two expert reviewers prior to submission.     

Risk of intussusception after monovalent rotavirus vaccine (Rotavac) in Indian infants: A self-controlled case series analysis

BackgroundAn association between rotavirus vaccination and intussusception has been documented in post-licensure studies in some countries. We evaluated the risk of intussusception associated with monovalent rotavirus vaccine (Rotavac) administered at 6, 10 and 14 weeks of age in India.MethodsActive prospective surveillance for intussusception was conducted at 22 hospitals across 16 states from April 2016 through September 2017. Data on demography, clinical features and vaccination were documented. Age-adjusted relative incidence for 1–7, 8–21, and 1–21 days after rotavirus vaccination in children aged 28–364 days at intussusception onset was estimated using the self-controlled case-series (SCCS) method. Only Brighton Collaboration level 1 cases were included.ResultsOut of 670 children aged 2–23 months with intussusception, 311 (46.4%) children were aged 28–364 days with confirmed vaccination status. Out of these, 52 intussusception cases with confirmed receipt of RVV were included in the SCCS analysis. No intussusception case was observed within 21 days of dose 1. Only one case occurred during 8–21 days after the dose 2. Post-dose 3, two cases in 1–7 days and 7 cases during 8–21 days period were observed. There was no increased risk of intussusception during 1–7 days after the doses 1 and 2 (zero cases observed) or dose 3 (relative incidence [RI], 1.71 [95% confidence interval {CI} 0.0–5.11]). Similarly, no increased risk during 8–21 days after the dose 1 (zero cases observed), dose 2 (RI, 0.71 [95% CI, 0.0–3.28]) or dose 3 (RI, 2.52 [95% CI, 0.78–5.61]). The results were similar for 1–21 day periods after the doses separately or pooled.ConclusionsThe risk of intussusception during the first 21 days after any dose of rotavirus vaccine (Rotavac) was not higher among the Indian infants than the background risk, based on limited SCCS analysis of 52 children.     

ICD-10 anaphylaxis algorithm and the estimate of vaccine-attributable anaphylaxis incidence in Medicare

BackgroundAnaphylaxis is a rare, serious allergic reaction. Its identification in large healthcare databases can help better characterize this risk.ObjectiveTo create an ICD-10 anaphylaxis algorithm, estimate its positive predictive values (PPVs) in a post-vaccination risk window, and estimate vaccination-attributable anaphylaxis rates in the Medicare Fee For Service (FFS) population.MethodsAn anaphylaxis algorithm with core and extended portions was constructed analyzing ICD-10 anaphylaxis claims data in Medicare FFS from 2015 to 2017. Cases of post-vaccination anaphylaxis among Medicare FFS beneficiaries were then identified from October 1, 2015 to February 28, 2019 utilizing vaccine relevant anaphylaxis ICD-10 codes. Information from medical records was used to determine true anaphylaxis cases based on the Brighton Collaboration’s anaphylaxis case definition. PPVs were estimated for incident anaphylaxis and the subset of vaccine-attributable anaphylaxis within a 2-day post-vaccination risk window. Vaccine-attributable anaphylaxis rates in Medicare FFS were also estimated.ResultsThe study recorded 66,572,128 vaccinations among 21,685,119 unique Medicare FFS beneficiaries. The algorithm identified a total of 190 suspected anaphylaxis cases within the 2-day post-vaccination window; of these 117 (62%) satisfied the core algorithm, and 73 (38%) additional cases satisfied the extended algorithm. The core algorithm’s PPV was 66% (95% CI [56%, 76%]) for identifying incident anaphylaxis and 44% (95% CI [34%, 56%]) for vaccine-attributable anaphylaxis. The vaccine-attributable anaphylaxis incidence rate after any vaccination was 0.88 per million doses (95% CI [0.67, 1.16]).ConclusionThe ICD-10 claims algorithm for anaphylaxis allows the assessment of anaphylaxis risk in real-world data. The algorithm revealed vaccine-attributable anaphylaxis is rare among vaccinated Medicare FFS beneficiaries.     

Thrombosis and thromboembolism: Brighton collaboration case definition and guidelines for data collection,analysis, and presentation of immunization safety data

This is a Brighton Collaboration case definition of thrombosis and thromboembolism to be used in the evaluation of adverse events following immunization, and for epidemiologic studies for the assessment of background incidence or hypothesis testing. The case definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of SARS-CoV-2 vaccines. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected expert reviewers prior to submission.     

Adverse events following immunization with typhoid conjugate vaccine in an outbreak setting in Hyderabad,Pakistan

Pakistan is facing the world's largest outbreak of extensively drug-resistant (XDR) Typhoid. Vaccination campaign for children aged 6 months to 10 years old with Typhoid Conjugate Vaccine (Typbar-TCV®) was conducted in high-risk areas of Hyderabad during 2018. About 207,000 children were vaccinated. Here we report the adverse events following immunization (AEFI) during the campaign. The campaign was carried out using outreach and fixed centre strategy. Community mobilizers visited each household to perform line listing and mobilize parents with age-eligible children. Children were observed for 30 min post-vaccination. Two-pronged strategy was used for ascertainment of AEFI. A 24/7 hotline number was provided to all parents/caretakers (n = 199,861) to report AEFI during 14 days following immunization. An age-stratified (n = 7139 children) were actively followed at days 7 and 14 for the ascertainment of AEFI. All AEFI were examined by three trained medical officers. A structured questionnaire using Brighton collaboration criteria with level 3 diagnostic certainty was used for the recording of AEFI. Data were analysed using Microsoft Excel Office 365. Overall, 499 AEFI (433 in the subset actively followed and 66 self-reported through hotline) were observed. The rate of AEFI was significantly higher among very young children (age group 6 to 12 months) as compared to 2 to 3 years old children (0.54% vs. 0.33% respectively; p-value < 0.001). Fever was the most common AEFI self-reported through the hotline (38/199,861 = 0.02%) and among the subset followed actively for 14 days (206/7139 = 2.89%). Fever was followed by local reactogenicity 10/199,861(0.01%), and 134/7139 (1.88%) through self-reported hotline and active follow-up, respectively. No serious AEFI was observed. Administration of a single dose of Typbar-TCV among children aged 6 months to 10 years old during an outbreak setting of Hyderabad Pakistan was safe.     

Consensus summary report for CEPI/BC March 12–13, 2020 meeting: Assessment of risk of disease enhancement with COVID-19 vaccines

A novel coronavirus (CoV), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 in Wuhan, China and has since spread as a global pandemic. Safe and effective vaccines are thus urgently needed to reduce the significant morbidity and mortality of Coronavirus Disease 2019 (COVID-19) disease and ease the major economic impact. There has been an unprecedented rapid response by vaccine developers with now over one hundred vaccine candidates in development and at least six having reached clinical trials. However, a major challenge during rapid development is to avoid safety issues both by thoughtful vaccine design and by thorough evaluation in a timely manner. A syndrome of “disease enhancement” has been reported in the past for a few viral vaccines where those immunized suffered increased severity or death when they later encountered the virus or were found to have an increased frequency of infection. Animal models allowed scientists to determine the underlying mechanism for the former in the case of Respiratory syncytial virus (RSV) vaccine and have been utilized to design and screen new RSV vaccine candidates. Because some Middle East respiratory syndrome (MERS) and SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a particular concern for SARS-CoV-2 vaccines. To address this challenge, the Coalition for Epidemic Preparedness Innovations (CEPI) and the Brighton Collaboration (BC) Safety Platform for Emergency vACcines (SPEAC) convened a scientific working meeting on March 12 and 13, 2020 of experts in the field of vaccine immunology and coronaviruses to consider what vaccine designs could reduce safety concerns and how animal models and immunological assessments in early clinical trials can help to assess the risk. This report summarizes the evidence presented and provides considerations for safety assessment of COVID-19 vaccine candidates in accelerated vaccine development.     

Vaccine-associated enhanced disease: Case definition and guidelines for data collection,analysis, and presentation of immunization safety data

This is a Brighton Collaboration Case Definition of the term “Vaccine Associated Enhanced Disease” to be utilized in the evaluation of adverse events following immunization. The Case Definition was developed by a group of experts convened by the Coalition for Epidemic Preparedness Innovations (CEPI) in the context of active development of vaccines for SARS-CoV-2 vaccines and other emerging pathogens. The case definition format of the Brighton Collaboration was followed to develop a consensus definition and defined levels of certainty, after an exhaustive review of the literature and expert consultation. The document underwent peer review by the Brighton Collaboration Network and by selected Expert Reviewers prior to submission.     

Effect of a vaccine information statement (VIS) on immunization status and parental knowledge,attitudes, and beliefs regarding infant immunization in Japan

BackgroundBecause of the overabundance of vaccination information on the internet, in the media, and on social media, providing clear and correct information on immunization is critical for parental decision-making. In 2018, the Japan Pediatric Society created and distributed a Vaccine Information Statement (VIS) to provide appropriate immunization information to caregivers. The objectives of the present study were to evaluate the effect of the VIS on immunization rates, adherence to schedule, and parental understanding of immunization in Japan.MethodsThis cross-sectional study was conducted at 18 centers in 2 prefectures in Japan. Caregivers were assigned to an intervention group, which received the VIS and a questionnaire when their child reached the age of 1 month, and a control group, which received only the questionnaire. Using the self-reported questionnaires, we evaluated vaccination rates and schedule adherence at age 2 months, and parental knowledge, attitudes, and beliefs regarding immunization. Three months later, the questionnaires were returned, and the findings were compared between the 2 groups.ResultsWe contacted 422 and 428 persons in the intervention and control groups, respectively, and 111/422 (26.3%) and 119/428 (27.8%) returned the surveys. Vaccination rates and adherence rates for the first dose of 4 recommended vaccines did not differ significantly (P > 0.25); however, there were some positive effects on items related to vaccine knowledge (P = 0.03), perceived benefits (P = 0.02), perceived barriers (P < 0.001), and perceived behavioral control (P = 0.01).ConclusionThe VIS improved parent comprehension of infant immunization. Future studies should examine if the effects of such an intervention persist and affect vaccine uptake throughout childhood.     

The role of National Immunization Technical Advisory Groups (NITAG) in strengthening health system governance: Lessons from three middle-income countries—Argentina,Jordan, and South Africa (2017–2018)

IntroductionToward the Global Vaccine Action Plan 2020 goal, almost 90% of countries have established a National Immunization Technical Advisory Group (NITAG). However, little is known about NITAG's contributions to governance.MethodsIn 2017–2018, a two-step, qualitative retrospective study was conducted. Jordan (JO), Argentina (AR), and South Africa (SA) were selected owing to government-financed NITAGs from middle-income countries (MICs), geographic diversity, and a vaccine introduction with NITAG support. Country case studies were developed, collecting data through desk review and face-to-face key informant interviews (KIIs) from Ministry of Health (MoH) and NITAG. Case studies were analyzed together, to assess governance applying the European Observatory on Health Systems and Policies framework focusing on transparency, accountability, participation, integrity, and policy capacity (TAPIC).ResultsDocument review and 53 KII (22 AR, 20 SA, 11 JO) showed NITAGs played a pivotal role as advisors promoting a culture of evidence-informed policies. NITAGs strengthened governance, although practices varied among countries. Meetings were conducted behind-closed-doors, participation restricted to members, only in one country agendas, and recommendations were public (AR). To increase participation, policy capacity, and transparency, countries considered adding experts in communications, advocacy, and economics. AR and SA contemplated including community members. NITAGs functioned autonomously from the government, with no established internal or external monitoring or supervision. NITAG meeting minutes allowed the review of integrity, adherence to terms of reference, standard operating procedures, and conflict of interest (CoI). For the most part, NITAGs abided by their mandates. Significant issues were related to the level of MoH support and oversight of CoI declaration and documentation.ConclusionsSystematically implementing governance approaches could improve processes, better tailor policies, and implementation. The long-term survival and resilience of NITAGs in these countries showed they play a significant role in strengthening governance. Lessons learned could be useful to those promoting country-driven evidence-informed decision-making.     

Assessing the feasibility of passive surveillance for maternal immunization safety utilizing archival medical records in Kinshasa,Democratic Republic of the Congo

IntroductionSince the establishment of the Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) case definitions in 2015, there has been an urgent need for field validation of pharmacovigilance feasibility in low- and middle-income countries. In this study, we assess the availability and quality of archival medical records at ten randomly selected high-traffic maternity wards in Kinshasa province, Democratic Republic of Congo (DRC).MethodsA retrospective cohort of mother-child pairs was established from all recorded births taking place at study sites between July 1, 2019 to February 28, 2020 through digitization of medical records. Adverse birth outcomes and maternal vaccination status, where available and linkable, were defined according to GAIA. Basic demographic information on mothers and newborns was also tabulated; birth outcomes were assessed for both intra-site prevalence and a pooled prevalence.ResultsA total of 7,697 mother-newborn pair records were extracted, with 37% of infants screening positive as cases of adverse outcomes. Maternal vaccination information was linkable to 67% of those cases. In total, 51% of stillbirths, 98% of preterm births, 100% of low birthweight infants, 90% of small for gestational age infants, 100% of microcephalic infants, and 0% of neonatal bloodstream infections were classifiable according to GAIA standards following initial screening. Forty percent of case mothers had some indication of tetanus vaccination prior to delivery in their medical records, but only 26% of case mothers met some level of GAIA definition for maternal vaccination during the pregnancy of interest.ConclusionsArchival birth records from delivery centers can be feasibly utilized to screen for stillbirth and maternal tetanus vaccination, and to accurately classify preterm birth, low birthweight, small for gestational age, and congenital microcephaly. Assessment of other neonatal outcomes were limited by inconsistent postpartum infant follow-up and records keeping.     

Novel colloidal associations of soyasaponins and lipid components (DPPC,cholesterol) as potential adjuvants for vaccines

Soyasaponins from soybean (Glycine max) represent promising new potent adjuvants for vaccine research because of their immunostimulating properties and weak hemolytic activity. In the present study, saponin microstructures of soyasaponins (soyasaponin Bb, soyasaponin Ab) with lipid components (cholesterol, DPPC (dipalmitoylphosphatidylcholine)) were designed by the lipid film method. In interaction studies between soyasaponins (soyasaponin Ab/Bb) and Langmuir monolayers (model membranes), composed of cholesterol and DPPC, marked interactions between soyasaponins and a pure cholesterol monolayer were observed. No interaction was detected for soyasaponins with a pure DPPC monolayer. The intercalation of soyasaponins in a mixed DPPC/cholesterol (3:1, w/w) monolayer was only observed for the monodesmosidic soyasaponin Bb whereas the second sugar chain of the bidesmosidic soyasaponin Ab impaired the access to the monolayer. Transmission electron microscopy was used for visualizing particle formation of soyasaponins and lipid components. Pseudo-binary systems (soyasaponin Ab/Bb, cholesterol) formed colloidal associations built up from ring-like subunits in the nanometer size range. In pseudo-ternary systems (soyasaponin, cholesterol, DPPC) soyasaponin Bb attacked the liposomal membrane by forming colloidal associations. Colloidal associations in pseudo-ternary systems with soyasaponin Ab, cholesterol and a phospholipid were only observed in the presence of PE (phosphatidylethanolamine) instead of DPPC. In an MTT assay with a HaCaT cell line (keratinocyte cell line) the cell viability was neither affected by the soyasaponins nor by the corresponding formulations. Both the pure soyasaponin solution and the saponin formulations may be promising adjuvant systems for the intradermal vaccine application. Furthermore, interaction studies between the model antigen ovalbumin and colloidal associations of saponins and cholesterol using MST (Microscale Thermophoresis) gave first indications of an antigen binding to colloidal associations. Ex vivo T-cell proliferation in the presence of soyasaponin Ab was confirmed.     

WHO preferred product characteristics for monoclonal antibodies for passive immunization against respiratory syncytial virus (RSV) disease in infants – Key considerations for global use

World Health Organization (WHO) preferred product characteristics describe preferences for product attributes that would help optimize value and use to address global public health needs, with a particular focus on low- and middle-income countries. Having previously published preferred product characteristics for both maternal and paediatric respiratory syncytial virus (RSV) vaccines, WHO recently published preferred product characteristics for monoclonal antibodies to prevent severe RSV disease in infants. This article summarizes the key attributes from the preferred product characteristics and discusses key considerations for future access and use of preventive RSV monoclonal antibodies.     

Adverse events following immunization with the live-attenuated recombinant Japanese encephalitis vaccine (IMOJEV®) in Taiwan, 2017–18

BackgroundJapanese encephalitis (JE) is a significant public health concern in the Asia-Pacific region, with a case-fatality rate of around 20% for those who develop encephalitis. Mouse-brain derived vaccines against JE have been used in the publicly funded national immunization program (NIP) in Taiwan since 1968. They were replaced with a live-attenuated recombinant vaccine (JE-CV, IMOJEV®) in May 2017. We assessed reports of adverse events (AE) following the introduction of JE-CV into the Taiwan NIP to characterize its post-licensure safety profile.MethodsAEs reported between 1 May 2017 and 31 December 2018 post vaccination with JE-CV were extracted from the National Adverse Drug Reactions (ADR) Reporting System, a passive surveillance system run by the Taiwan Food and Drug Administration. The report rates were calculated based on the number of doses distributed by the manufacturer during the assessment period.ResultsThere were 51 AEs reported among 30 subjects (12 girls and 18 boys; mean age 25 months), with a reporting rate of 4.7 AEs per 100,000 doses distributed. The AEs occurred after a median of.1-day post vaccination. Eight subjects had received concomitant vaccination with another vaccines. There were four serious AEs reported: febrile seizure, acute renal failure, viral respiratory tract infection, and injection site cellulitis. None of these serious AEs were classified as being causally related to JE-CV vaccination.ConclusionThese post-licensure AE surveillance data confirm the favorable safety profile of JE-CV.     

Skin immunization with third-generation hepatitis B surface antigen using microneedles

L-HBsAg is a third-generation hepatitis vaccine capable of inducing antibodies in non-responders and thus providing potentially therapeutic treatment. In this study, L-HBsAg was administered using microneedles (MN) without an adjuvant to induce intradermal (ID) immunization, and the efficacy of ID immunization was compared with that of intramuscular (IM) immunization that uses a conventional formulation with an adjuvant of aluminum hydroxide (L-HBsAg-AL-IM).The L-HBsAg was dip-coated onto 800-μm-long microneedles made of polylactic acid (PLA). Delivery efficiency and administration time were determined through in vitro experiments using porcine skin. The denaturation of the formulation against sterilization by gamma rays was observed. A storage test and a freeze-thaw cycle test of the microneedles with trehalose as a stabilizer (L-HBsAg-MN-Tre) were observed. An antibody titer of L-HBsAg-MN-Tre was compared with that of the conventional IM immunization of the L-HBsAg solution with aluminum hydroxide (L-HBsAg-AL-IM).The formulation containing L-HBsAg was located on the upper third of the microneedle tips. The formulation on the MN was dissolved and delivered within 30 min of insertion into porcine skin in vitro. Trehalose was selected as a stabilizer, and the stabilizing effect increased with the increase of trehalose content in the solidified formulation. L-HBsAg-MN with 15% of trehalose was stable for 7 days at 40 °C and showed increased stability compared to the conventional liquid formulations. L-HBsAg-MN-Tre showed improved stability during the freeze-thaw cycle. The antibody titer of L-HBsAg-MN-Tre at 28 days was higher than that of L-HBsAg-AL-IM.ID administration of L-HBsAg-MN-Tre showed better efficacy and improved thermal and freeze thaw stability compared to L-HBsAg-AL-IM. Therefore, L-HBsAg-MN-Tre administration showed the possibility of ID delivery of L-HBsAg without the use of an adjuvant for the efficacy, convenience, and safety of pediatric vaccination.     

Optimization of frequency and targeting of measles supplemental immunization activities in Nigeria: A cost-effectiveness analysis

BackgroundMeasles causes significant childhood morbidity in Nigeria. Routine immunization (RI) coverage is around 40% country-wide, with very high levels of spatial heterogeneity (3–86%), with supplemental immunization activities (SIAs) at 2-year or 3-year intervals. We investigated cost savings and burden reduction that could be achieved by adjusting the inter-campaign interval by region.MethodsWe modeled 81 scenarios; permuting SIA calendars of every one, two, or three years in each of four regions of Nigeria (North-west, North-central, North-east, and South). We used an agent-based disease transmission model to estimate the number of measles cases and ingredients-based cost models to estimate RI and SIA costs for each scenario over a 10 year period.ResultsDecreasing SIAs to every three years in the North-central and South (regions of above national-average RI coverage) while increasing to every year in either the North-east or North-west (regions of below national-average RI coverage) would avert measles cases (0.4 or 1.4 million, respectively), and save vaccination costs (save $19.4 or $5.4 million, respectively), compared to a base-case of national SIAs every two years. Decreasing SIA frequency to every three years in the South while increasing to every year in the just the North-west, or in all Northern regions would prevent more cases (2.1 or 5.0 million, respectively), but would increase vaccination costs (add $3.5 million or $34.6 million, respectively), for $1.65 or $6.99 per case averted, respectively.ConclusionsOur modeling shows how increasing SIA frequency in Northern regions, where RI is low and birth rates are high, while decreasing frequency in the South of Nigeria would reduce the number of measles cases with relatively little or no increase in vaccination costs. A national vaccination strategy that incorporates regional SIA targeting in contexts with a high level of sub-national variation would lead to improved health outcomes and/or lower costs.