Genetic basis for adverse events after smallpox vaccination.
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ABSTRACT:
SUBMITTER: Reif DM
PROVIDER: S-EPMC2746083 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Complex clinical outcomes, such as adverse reaction to vaccination, arise from the concerted interactions among the myriad components of a biological system. Therefore, comprehensive etiological models can be developed only through the integrated study of multiple types of experimental data. In this study, we apply this paradigm to high-dimensional genetic and proteomic data collected to elucidate the mechanisms underlying the development of adverse events (AEs) in patients after smallpox vaccination. As vaccination was successful in all of the patients under study, the AE outcomes reported likely represent the result of interactions among immune system components that result in excessive or prolonged immune stimulation. In this study, we examined 1442 genetic variables (single nucleotide polymorphisms) and 108 proteomic variables (serum cytokine concentrations) to model AE risk. To accomplish this daunting analytical task, we employed the Random Forests (RF) method to filter the most important attributes, then we used the selected attributes to build a final decision tree model. This strategy is well suited to integrated analysis, as relevant attributes may be selected from categorical or continuous data. Importantly, RF is a natural approach for studying the type of gene-gene, gene-protein and protein-protein interactions we hypothesize to be involved in the development of clinical AEs. RF importance scores for particular attributes take interactions into account, and there may be interactions across data types. Combining information from previous studies on AEs related to smallpox vaccination with the genetic and proteomic attributes identified by RF, we built a comprehensive model of AE development that includes the cytokines intercellular adhesion molecule-1 (ICAM-1 or CD54), interleukin-10 (IL-10), and colony stimulating factor-3 (CSF-3 or G-CSF) and a genetic polymorphism in the cytokine gene interleukin-4 (IL4). The biological factors included in the model support our hypothesized mechanism for the development of AEs involving prolonged stimulation of inflammatory pathways and an imbalance of normal tissue damage repair pathways. This study shows the utility of RF for such analytical tasks, while both enhancing and reinforcing our working model of AE development after smallpox vaccination.
| S-EPMC2692715 | biostudies-literature
Project description:Adverse events upon smallpox vaccination with fully-replicative strains of Vaccinia virus (VACV) comprise an array of clinical manifestations that occur primarily in immunocompromised patients leading to significant host morbidity/mortality. The expansion of immune-suppressed populations and the possible release of Variola virus as a bioterrorist act have given rise to concerns over vaccination complications should more widespread vaccination be reinitiated. Our goal was to evaluate the components of the host immune system that are sufficient to prevent morbidity/mortality in a murine model of tail scarification, which mimics immunological and clinical features of smallpox vaccination in humans. Infection of C57BL/6 wild-type mice led to a strictly localized infection, with complete viral clearance by day 28 p.i. On the other hand, infection of T and B-cell deficient mice (Rag1(-/-)) produced a severe disease, with uncontrolled viral replication at the inoculation site and dissemination to internal organs. Infection of B-cell deficient animals (µMT) produced no mortality. However, viral clearance in µMT animals was delayed compared to WT animals, with detectable viral titers in tail and internal organs late in infection. Treatment of Rag1(-/-) with rabbit hyperimmune anti-vaccinia serum had a subtle effect on the morbidity/mortality of this strain, but it was effective in reduce viral titers in ovaries. Finally, NUDE athymic mice showed a similar outcome of infection as Rag1(-/-), and passive transfer of WT T cells to Rag1(-/-) animals proved fully effective in preventing morbidity/mortality. These results strongly suggest that both T and B cells are important in the immune response to primary VACV infection in mice, and that T-cells are required to control the infection at the inoculation site and providing help for B-cells to produce antibodies, which help to prevent viral dissemination. These insights might prove helpful to better identify individuals with higher risk of complications after infection with poxvirus.
| S-EPMC3078145 | biostudies-literature
Project description:The Vaccine Adverse Event Reporting System (VAERS) is a passive reporting system, used for monitoring the safety of all US licensed vaccines. In March 2008, ACAM2000(®) replaced Dryvax(®) as the only licensed smallpox vaccine and is administered to all persons entering military service and certain civilian researchers. In 2011, routine data mining of VAERS identified a vaccine safety concern resulting in acute ischemic cardiac events (ICE) following ACAM2000(®).During March 1, 2008 through June 30, 2013, we reviewed all serious reports received following ACAM2000(®)and classified them by diagnostic category. We identified possible ICE cases by searching the Medical Dictionary for Regulatory Affairs (MedDRA(®)) terms for "myocardial ischaemia," "acute myocardial infarction," "myocardial infarction," and "ischaemia," and applied standardized surveillance case definitions.VAERS received 1149 reports following ACAM2000(®) administration; 169 (14.7%) were serious (resulting in permanent disability, hospitalization or prolongation of hospitalization, life-threatening illness or death), including one death. The two most frequent diagnostic categories for serious reports were cardiovascular and other infectious conditions. The MedDRA(®) search found 31 reports of possible ICE after receipt of ACAM2000(®) vaccine. Of a total 30 possible ICE cases with demographic information, all but one was male; the age range was 20-45 years (median 32) and median interval to onset of symptoms was 12 days. On clinical review there were 16 cases of myocarditis/pericarditis and 15 ICE cases.Our review of the data mining signal did not substantiate the concerns about ICE after ACAM2000(®). Our study also suggests that with current pre-vaccination screening, cardiac morbidity in generally healthy vaccinated populations remains uncommon.
| S-EPMC5946322 | biostudies-other
Project description:We present a stochastic model for the spread of smallpox after a small number of index cases are introduced into a susceptible population. The model describes a branching process for the spread of the infection and the effects of intervention measures. We discuss scenarios in which ring vaccination of direct contacts of infected persons is sufficient to contain an epidemic. Ring vaccination can be successful if infectious cases are rapidly diagnosed. However, because of the inherent stochastic nature of epidemic outbreaks, both the size and duration of contained outbreaks are highly variable. Intervention requirements depend on the basic reproduction number (R0), for which different estimates exist. When faced with the decision of whether to rely on ring vaccination, the public health community should be aware that an epidemic might take time to subside even for an eventually successful intervention strategy.
| S-EPMC3323203 | biostudies-literature
Project description:ImportanceSafety surveillance of vaccines against COVID-19 is critical to ensure safety, maintain trust, and inform policy.ObjectivesTo monitor 23 serious outcomes weekly, using comprehensive health records on a diverse population.Design, setting, and participantsThis study represents an interim analysis of safety surveillance data from Vaccine Safety Datalink. The 10 162 227 vaccine-eligible members of 8 participating US health plans were monitored with administrative data updated weekly and supplemented with medical record review for selected outcomes from December 14, 2020, through June 26, 2021.ExposuresReceipt of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) COVID-19 vaccination, with a risk interval of 21 days for individuals after vaccine dose 1 or 2 compared with an interval of 22 to 42 days for similar individuals after vaccine dose 1 or 2.Main outcomes and measuresIncidence of serious outcomes, including acute myocardial infarction, Bell palsy, cerebral venous sinus thrombosis, Guillain-Barré syndrome, myocarditis/pericarditis, pulmonary embolism, stroke, and thrombosis with thrombocytopenia syndrome. Incidence of events that occurred among vaccine recipients 1 to 21 days after either dose 1 or 2 of a messenger RNA (mRNA) vaccine was compared with that of vaccinated concurrent comparators who, on the same calendar day, had received their most recent dose 22 to 42 days earlier. Rate ratios (RRs) were estimated by Poisson regression, adjusted for age, sex, race and ethnicity, health plan, and calendar day. For a signal, a 1-sided P < .0048 was required to keep type I error below .05 during 2 years of weekly analyses. For 4 additional outcomes, including anaphylaxis, only descriptive analyses were conducted.ResultsA total of 11 845 128 doses of mRNA vaccines (57% BNT162b2; 6 175 813 first doses and 5 669 315 second doses) were administered to 6.2 million individuals (mean age, 49 years; 54% female individuals). The incidence of events per 1 000 000 person-years during the risk vs comparison intervals for ischemic stroke was 1612 vs 1781 (RR, 0.97; 95% CI, 0.87-1.08); for appendicitis, 1179 vs 1345 (RR, 0.82; 95% CI, 0.73-0.93); and for acute myocardial infarction, 935 vs 1030 (RR, 1.02; 95% CI, 0.89-1.18). No vaccine-outcome association met the prespecified requirement for a signal. Incidence of confirmed anaphylaxis was 4.8 (95% CI, 3.2-6.9) per million doses of BNT162b2 and 5.1 (95% CI, 3.3-7.6) per million doses of mRNA-1273.Conclusions and relevanceIn interim analyses of surveillance of mRNA COVID-19 vaccines, incidence of selected serious outcomes was not significantly higher 1 to 21 days postvaccination compared with 22 to 42 days postvaccination. While CIs were wide for many outcomes, surveillance is ongoing.
| S-EPMC8511971 | biostudies-literature
Project description:BackgroundVaccination against coronavirus disease 2019 (COVID-19) is underway globally to prevent the infection caused by the severe acute respiratory syndrome coronavirus 2. We aimed to investigate the adverse events following immunization (AEFIs) for COVID-19 among healthcare workers (HCWs).MethodsThis was a retrospective study of the AEFIs associated with the first dose of the ChAdOx1 nCoV-19 vaccine at the Kosin University Gospel Hospital from March 3 to March 22, 2021. We investigated the systemic and local adverse events during the 7 days following the vaccination using the Mobile Vaccine Adverse Events Reporting System (MVAERS) developed by our hospital.ResultsA total of 1,503 HCWs were vaccinated, and the data of 994 HCWs were reported in the MVAERS. The most commonly reported AEFIs were tenderness at the injection site (94.5%), fatigue (92.9%), pain at the injection site (88.0%), and malaise (83.8%). The severity of most AEFIs was mild-to-moderate, and the severity and number of AEFIs were less in the older age group. There were no serious events requiring hospitalization, and most AEFIs improved within a few days.ConclusionThe AEFIs associated with the ChAdOx1 nCoV-19 vaccine were tolerable, and the use of the MVAERS was helpful in monitoring the AEFIs. The use of MVAERS will help in sharing accurate and ample information about vaccination against COVID-19.
| S-EPMC8093606 | biostudies-literature
Project description:The innate immune response shapes the development of adaptive immunity following infections and vaccination. However, it can also induce symptoms such as fever and myalgia, leading to the possibility that the molecular basis of immunogenicity and reactogenicity of vaccination are inseparably linked. To test this possibility, we used the yellow fever live-attenuated vaccine (YFLAV) as a model to study the molecular correlates of reactogenicity or adverse events (AEs). We analyzed the outcome of 68 adults who completed a YFLAV clinical trial, of which 43 (63.2%) reported systemic AEs. Through whole-genome profiling of blood collected before and after YFLAV dosing, we observed that activation of innate immune genes at day 1, but not day 3 after vaccination, was directly correlated with AEs. These findings contrast with the gene expression profile at day 3 that we and others have previously shown to be correlated with immunogenicity. We conclude that although the innate immune response is a double-edged sword, its expression that induces AEs is temporally distinct from that which engenders robust immunity. The use of genomic profiling thus provides molecular insights into the biology of AEs that potentially forms a basis for the development of safer vaccines.
| S-EPMC5841882 | biostudies-literature
Project description:BackgroundLarge quantities of smallpox vaccine have been stockpiled to protect entire nations against a possible reintroduction of smallpox. Planning for an appropriate use of these stockpiled vaccines in response to a smallpox outbreak requires a rational assessment of the risks of vaccination-related adverse events, compared to the risk of contracting an infection. Although considerable effort has been made to understand the dynamics of smallpox transmission in modern societies, little attention has been paid to estimating the frequency of adverse events due to smallpox vaccination. Studies exploring the consequences of smallpox vaccination strategies have commonly used a frequency of approximately one death per million vaccinations, which is based on a study of vaccination with the New York City Board of Health (NYCBH) strain of vaccinia virus. However, a multitude of historical studies of smallpox vaccination with other vaccinia strains suggest that there are strain-related differences in the frequency of adverse events after vaccination. Because many countries have stockpiled vaccine based on the Lister strain of vaccinia virus, a quantitative evaluation of the adverse effects of such vaccines is essential for emergency response planning. We conducted a systematic review and statistical analysis of historical data concerning vaccination against smallpox with different strains of vaccinia virus.Methods and findingsWe analyzed historical vaccination data extracted from the literature. We extracted data on the frequency of postvaccinal encephalitis and death with respect to vaccinia strain and age of vaccinees. Using a hierarchical Bayesian approach for meta-analysis, we estimated the expected frequencies of postvaccinal encephalitis and death with respect to age at vaccination for smallpox vaccines based on the NYCBH and Lister vaccinia strains. We found large heterogeneity between findings from different studies and a time-period effect that showed decreasing incidences of adverse events over several decades. To estimate death rates, we then restricted our analysis to more-recent studies. We estimated that vaccination with the NYCBH strain leads to an average of 1.4 deaths per million vaccinations (95% credible interval, 0-6) and that vaccination with Lister vaccine leads to an average of 8.4 deaths per million vaccinations (95% credible interval, 0-31). We combined age-dependent estimates of the frequency of death after vaccination and revaccination with demographic data to obtain estimates of the expected number of deaths in present societies due to vaccination with the NYCBH and Lister vaccinia strains.ConclusionsPrevious analyses of smallpox vaccination policies, which rely on the commonly assumed value of one death per million vaccinations, may give serious underestimates of the number of deaths resulting from vaccination. Moreover, because there are large, strain-dependent differences in the frequency of adverse events due to smallpox vaccination, it is difficult to extrapolate from predictions for the NYCBH-derived vaccines (stockpiled in countries such as the US) to predictions for the Lister-derived vaccines (stockpiled in countries such as Germany). In planning for an effective response to a possible smallpox outbreak, public-health decision makers should reconsider their strategies of when to opt for ring vaccination and when to opt for mass vaccination.
| S-EPMC1551910 | biostudies-literature
Project description:ObjectivesBNT-162b2, mRNA-1273, and Ad26.COV2.S vaccines data regarding adverse events (AEs) are scarce. In this report, we aimed to describe fatal and non-fatal possible AEs after COVID-19 vaccine administration.MethodsAn observational multicenter study investigating the causes of emergency department visits and hospital admissions within 10 days of COVID-19 vaccination. Patients who received first or second doses of COVID-19 vaccines and presented to the emergency department (ED), as well as those admitted to the hospitals or intensive care units (ICUs) were included. Causes of ED, hospital, and ICU admissions and discharges were collected based on the International Classification of Diseases, Tenth Revision (ICD-10) coding system.ResultsBetween December 2020 and March 2021, 1842 patients visited the ED within 10 days of COVID-19 vaccine administration. The mean age was 70.3 years. Overall, 1221 patients presented after the first dose of the vaccine and 653 after the second dose. Trauma (14.9%), hypertensive emergency/urgency (7.8%), generalized pain and arthralgia (5.7%), and chest pain (4.4%) were the most common causes of presentation to the ED. Of all ED presentations, mortality rate was at 2.2% (41 patients) with a median follow-up time of 68.0 days, versus 2.6% in unvaccinated ED patients. Postvaccination acute hypoxemic respiratory failure (46.3%), septic shock (24.4%), and cardiogenic shock (12.2%) were the most common causes of death.ConclusionAlthough reported AEs are not necessarily caused by the vaccination, this study provides further information about possible AEs after COVID-19 immunization, especially those requiring hospital admission. This study also supports prior data that serious AEs post vaccination are much lower than primary COVID-19 infections. Further studies are needed to investigate causalities between vaccines and reported AEs across all age groups.
| S-EPMC8514147 | biostudies-literature
Project description:BackgroundOral adverse events (AEs) following COVID-19 vaccination have been sporadically reported during the previous months, warranting further investigation for their prevalence and suspected relationship with vaccine-elicited immune response.MethodsA retrospective analysis using the Vaccine Adverse Event Reporting System (VAERS) data was conducted to evaluate AEs within the oral cavity (mucosa, tongue, lips, palate, dentition, salivary glands) and AEs involving taste and other sensations. Oral AEs reported after receiving COVID-19 vaccination (test group) and seasonal influenza vaccination (control group) were extracted and cross-tabulated to assess their relative prevalence.ResultsAmong the 128 solicited (suspected) oral AEs, oral paresthesia (0.872%) was most reported after receiving COVID-19 vaccines, followed by the swelling of lips (0.844%), ageusia (0.722%), oral hypoesthesia (0.648%), swollen tongue (0.628%), and dysgeusia (0.617%). The reported prevalence of oral AEs was higher in the COVID-19 vaccine group than in the seasonal influenza group. The distribution pattern of the most reported oral AEs was similar for both COVID-19 and seasonal influenza vaccines. Female sex, older age (>39 years old), primer doses, and mRNA-based COVID-19 vaccines exhibited a higher reported prevalence of oral AEs.ConclusionWithin the limitations of this study, COVID-19 vaccines were found to be associated with rare oral AEs that are predominantly similar to those emerging following seasonal influenza vaccines. The most commonly reported oral AEs were oral paraesthesia (mouth-tingling), lip swelling, and ageusia, representing various pathophysiologic pathways that remain unclear. Taste-related AEs should be acknowledged in the context of the COVID-19 pandemic and the public should be adequately informed about a potential taste dysfunction after receiving the COVID-19 vaccination. Dentists and dental teams need to be aware of the prevalence, severity, and prognosis of oral AEs to inform their patients and increase public confidence in vaccines.
| S-EPMC9309565 | biostudies-literature