Risk factors for side effects following administration of one of the SARS-CoV-2 vaccines subject to the analysis included being female, young, and suffering from a diagnosed allergy. Our results clearly show that the short-term safety profiles of the eligible COVID-19 vaccines  are acceptable. Nevertheless, the two-dose COVID-19 vaccines available in Poland differ significantly in the frequency of both local and systemic side effects and their intensity. Women, young people, and patients diagnosed with allergies are particularly exposed to the risk of side effects. Further studies are needed to determine the long-term safety profile of COVID-19 vaccines.The aim of the study was to compare the safety profiles  of COVID-19 vaccines  among healthcare workers  administered with a first and a second dose of the vaccines. Another goal of the research was to evaluate potential demographic and clinical risk factors for the frequency and intensity of side effects. A post-marketing, cross-sectional survey-based study was carried out on a sample of 971 respondents , all more than 18 years old, who have taken two doses of the following SARS-CoV-2 vaccines: BNT162b2 (Pfizer–BioNTech) (group 1), mRNA-1273 (Moderna) (group 2), and ChAdOx1 nCoV-19 (Oxford–AstraZeneca) (group 3). A validated, self-administered questionnaire was developed and delivered online to the target population group of healthcare workers. The survey was conducted during the third wave of the COVID-19 (1 February 2021–1 July 2021) pandemic. It was based on the CAWI (computer-assisted web interview) method. Questionnaires were disseminated using selected social media. The BNT162b2 (Pfizer–BioNTech) vaccine was the most commonly administered COVID-19 vaccine among healthcare professionals in Poland (69.61%). Side effects following a SARS-CoV-2 vaccine were reported by 53.11% of respondents in group 1, 72% in group 2, and 67.59% in group 3. The following were the most common side effects regardless of the type of vaccine administered: pain at the injection site, headache, muscle pain, fever, chills, and fatigue. The number and intensity of reported side effects following administration of a BNT162b2 (Pfizer–BioNTech) vaccine were significantly lower than in the other two study groups ( The first patient with coronavirus disease 2019 (COVID-19) was identified in China in December 2019 . If adeqEffective vaccines are one of the most significant preventive measures to contain infectious diseases . COVID-1Current evidence on the safety of COVID-19 vaccines relies mainly on data from phase one–three randomized controlled trials and vaccine safety surveillance systems in several countries . In the In Poland, the national SARS-CoV-2 vaccination program includes the use of four vaccines: BNT162b2 (Pfizer–BioNTech), mRNA-1273 (Moderna), ChAdOx1-S (Oxford–AstraZeneca), and Ad26.COV2.S (Johnson Pharm). The National Vaccination Program in Poland, like other government programs in the European Union (EU), has decided to prioritize healthcare workers in receiving the COVID-19 vaccine in the early stages of the national immunization strategy. Therefore, Polish healthcare decision makers have tried to ensure uninterrupted care and protect the most vulnerable patients. On 27 December 2020, the first cohort of health professionals received the COVID-19 vaccine. The implementation of the program began in Poland as a basic anti-COVID-19 strategy established by the Ministry of Health of the Republic of Poland .The long-term effect of mass vaccination programs and related reports on their safety profile obtained from independent studies is also expected to positively impact many healthcare aspects indirectly affected by the COVID-19 pandemic, such as diagnosis and treatment of various conditions.Accordingly, the presented study aimed to evaluate the short-term side effects  experienced after a Pfizer–BioNTech (BNT162b2), a Moderna (mRNA-1273), or an Oxford–AstraZeneca (ChAdOx1 nCoV-19) vaccine among healthcare professionals . Another goal of the research work was to identify selected clinical factors that have a significant impact on the risk of side effects following a SARS-CoV-2 virus vaccination.This post-marketing trial was designed as a cross-sectional survey-based study. The study group consisted of doctors, pharmacists, and nurses registered in the official database kept by the Supreme Chamber of Doctors and Nurses and Chief Pharmaceutical Inspectorate. Three thousand e-mails were sent to the above healthcare workers with a request to join the study voluntarily. The e-mail contained a link to the research questionnaire and all necessary information about the study’s purpose and rules of participation. Moreover, potential respondents were able to download the link to the study questionnaire from the Poznan University of Medical Sciences website promoting our study project. The recruitment process took place during February and March 2021 and was subsequently extended to July 2021. A total of 1130 respondents  were taken into consideration. However, based on the inclusion criteria of the study and incomplete questionnaires by 159 healthcare workers, 971 respondents were finally included in the study. The response rate, defined as the number of adequately completed online forms, was 86% .The study group consisted of 971 respondents , all more than 18 years old, who had taken two doses of the following SARS-CoV-2 vaccines: BNT162b2 (Pfizer–BioNTech), mRNA-1273 (Moderna), or ChAdOx1 nCoV-19 (Oxford–AstraZeneca), within the priority groups from January–April 2021 . A resean = 676):Group 1 ( Respondents vaccinated with two doses of vaccine BNT162b2 (Pfizer–BioNTech) against SARS-CoV-2 virus;n = 150):Group 2 ( Respondents vaccinated with two doses of vaccine mRNA-1273 (Moderna) against SARS-CoV-2 virus;n = 145):Group 3 ( Respondents vaccinated with two doses of vaccine ChAdOx1 nCoV-19 (Oxford–AstraZeneca) against SARS-CoV-2 virus.Patients were divided into three groups:An anonymous questionnaire on Google Forms was constructed based on the scientific literature. It was validated and then implemented with the use of the CAVI (computer-assisted web interview) method. This method was chosen because of the pandemic and the applicable restrictions, to avoid any potential risks to the survey subjects. The Poznan University of Medical Sciences website and social media  were used to distribute questionnaires. Questionnaires were also distributed electronically (by e-mail) throughout the country. The questionnaire was developed following a standardized protocol that consisted of a literature review , focusedDemographic data .Medical anamneses .COVID-19-related anamneses .Vaccine side effects .The questionnaire comprised 25 questions divided into four categories:The questionnaire inquired about the short-term side effects experienced following both doses of a COVID-19 vaccine. The side effects were classified as local or systemic, and their onset, duration, and intensity were self-assessed and self-reported by the participating subjects.The primary outcome was a safety profile assessment . Identification of selected clinical factors that have a significant impact on the risk of adverse effects following the administration of a SARS-CoV-2 vaccine was a secondary outcome.All respondents who qualified for the study completed a safety profile assessment questionnaire for the selected SARS-CoV-2 vaccines twice. The first time was after the first dose of the vaccine and one day before the scheduled second dose of the vaccine. The second time was at least 28 days after receiving the 2nd dose of the SARS-CoV-2 virus vaccine.p) < 0.05. Analysis was carried out using the TIBCO Software Inc. (2017) statistical package. Statistica , version 13. http://statistica.io (accessed on 5 October 2021). All tests were considered significant at p < 0.05.The quantitative parameters were presented using mean value, median, and standard deviation. Categorical data were presented as counts and percentages. A comparison of more than two groups was performed using the Kruskal–Wallis test with the post hoc Dunn’s test. The chi-square test for independence was used to analyze categorical data. In order to evaluate the potential demographic and medical predictors of side effects of administering COVID-19 vaccines, binary logistic regression for the incidence of local and systemic SRAEs was used. The inferential tests were done with the assumption for a confidence interval (CI) of 95% and a significance level of , all more than 18 years old, who had taken two doses of the following SARS-CoV-2 vaccines: BNT162b2 (Pfizer–BioNTech), mRNA-1273 (Moderna) or ChAdOx1 nCoV-19 (Oxford–AstraZeneca).n = 676, 69.61%), 150 respondents (15.48%) were vaccinated with the mRNA-1273 vaccine, while the ChAdOx1 nCoV-19 vaccine was administered to 145 respondents (14.93%). The analyzed groups of respondents did not differ in terms of gender, structure, age, health status, the frequency of presence of comorbidities, the frequency of stimulants use, or the frequency of infection with the SARS-CoV-2 virus (p > 0.05). There were significantly more subjects diagnosed with spine diseases in the group vaccinated with the ChAdOx1 nCoV-19 vaccine  compared with the other two groups . Arterial hypertension was significantly more common in group 3 , while hypothyroidism was substantially more frequent in group 2  (The characteristics of the study respondents are presented in 0.03243) .As a result of the study, we found that the vast majority of respondents in each study group experienced side effects following the administration of one of the three SARS-CoV-2 vaccines subject to analysis. This percentage was highest in group 2 (72%) and lowest in group 1 (53.11%) .In the conducted study, no cases of anaphylaxis, thrombosis, and thrombocytopenia were observed after administering any of the analyzed COVID-19 vaccines .p < 0.00001). A total of 67.59% of subjects in group 3 reported pain at the injection site.The most common local side effects in each study group was pain at the injection site. The above symptom was reported most frequently in the group following administration of the mRNA-1273 vaccine (72%) and least frequently by the group of respondents who had received the BNT162b2 vaccine (53.11%) (The most common systemic side effects following the BNT162b2 vaccine were fatigue (30.18%), headache (28.89%), muscle pain (25%), chills (19.67%), fever (16.57%), and joint pain (9.20%) .The most common systemic side effects following the mRNA-1273 vaccine were headache (50.00%), muscle pain (43.33%), fever (42.67%), fatigue (39.33%), chills (39.33%), joint pain (14.67%), lymphadenopathy (14.00%), and nausea (10.67%) .The most common systemic side effects following the ChAdOx1 nCoV-19 vaccine were fever (51.72%), muscle pain (46.90%), chills (46.21%), headache (42.76%), fatigue (33.10%), joint pain (24.14%), and nausea (11.72%) .p = 0.06056  was reported only by 2.22% of respondents in group 1 and by 4.00% of respondents in group 2,  0.06056 .p = 0. 00009), swelling at the injection site (p < 0.00001), headache (p < 0.00001), muscle pain (p < 0.00001), chills (p < 0.00001), joint pain (p < 0.00001), fever (p < 0.00001), dizziness (p = 0.04945), nausea (p < 0.00001), lymphadenopathy (p < 0.00001), and diarrhea (p = 0.01620). Prevalence of both local and systemic side effects was significantly lower in group 1 (BNT162b2 vaccine) compared with the other two groups (mRNA-1273—group 2 and ChAdOx1 nCoV-19—group 3). Details of the comparative analysis of the incidence of adverse reactions following receipt of one of the three SARS-CoV-2 vaccines are shown in Pearson chi-square comparative analysis on the incidence of side effects between the three types of SARS-CoV-2 vaccines revealed statistically significant differences in the incidence of the following side effects: pain at the injection site (p < 0.00001). Group 1 respondents (BNT162b2 vaccine) reported the least number of side effects—median: 2.00 (0–5). The number of side effects in the other two groups was comparable: group 2—median: 5.00 (0–7); group 3—median: 5.00 (0–6) (p = 0.808387). The number of reported side effects following administration of a SARS-CoV-2 vaccine in group 1 was significantly lower than in the other two study groups (p < 0.00001).We used the Kruskal–Wallis test, to show that the SARS-CoV-2 vaccines analyzed were significantly different in terms of the number of side effects experienced following their administration (p < 0.0001). Respondents in group 3 were significantly more likely to report side effects after receiving only one dose of the ChAdOx1 nCoV-19 vaccine (96.94%) compared with the other study groups . In contrast, respondents in both group 1 and group 2 were significantly more likely to report side effects after both the first and second dose of a vaccine  compared with group 3 respondents (3.06%)  .p = 0.52475)  .p = 0.6647). The mean duration of side effects to one of the three vaccines analyzed was: 2.53 ± 3.09—group 1, 2.31 ± 1.39—group 2, and 2.40 ± 2.84—group 3 . Compared with the other two study groups , group 1 respondents were significantly more likely to assess the severity of side effects as mild (37.40%). On the other hand, in both groups 2 and 3, respondents were significantly more likely to assess the nature of the course of side effects as moderate  and severe  when compared with group 1   .p = 0.0364—group 1; 8.3 ± 2.5 vs. 5.7 ± 3.4, p = 0.0052—group 2). However, no correlation was observed between the confirmed SARS-CoV-2 infection at baseline and the number and intensity of side effects following the administration of SARS-CoV-2 virus vaccines among all study groups (p > 0.005) (In the case of the respondents vaccinated against COVID-19 based on mRNA technology (groups 1 and 2), a relationship between the duration of side effects and the confirmed SARS-CoV-2 infection at baseline was demonstrated. In both study groups, the duration of side effects after receiving the COVID-19 vaccine was significantly longer in people with confirmed SARS-CoV-2 virus infection at baseline than those who did not have a previously confirmed infection  .p < 0.0001), the presence of an allergy (p = 0.005), and respiratory diseases (0.039) significantly influenced the risk of side effects following administration of the BNT162b2 vaccine. The risk of side effects after receiving the BNT162b2 vaccine was highest for women and those with a diagnosed allergy or respiratory disease  and age (p = 0.007) were the two factors significantly affecting the risk of side effects. The risk of side effects after receiving the mRNA-1273 vaccine was highest for women and younger individuals , and nicotine consumption (p = 0.008) significantly affected the risk of side effects. The risk of side effects after receiving the AZD1222 vaccine was highest for younger subjects and subjects with a diagnosed allergy and who did not consume nicotine , the presence of allergies , mRNA-1273 (Moderna), ChAdOx1-S (Oxford–AstraZeneca), and Ad26.COV2.S (Johnson Pharm). A fifth vaccine will soon be available  for which the European Medicines Agency (EMA) has issued a positive scientific opinion for conditional marketing authorization on 20 December 2021 ,18. As oDuring the COVID-19 pandemic, prompt research and simultaneous lack of follow-up time post-vaccination aroused great public concern about the safety profile of vaccine candidates. While rare and non-serious side effects should not derail mass vaccination, a thorough risk-benefit analysis should be done . EMA’s dAccording to the survey the vast majority of healthcare workers in Poland are vaccinated with Pfizer–BioNTech’s BNT162b2 (69.61%). This is due to the fact that Pfizer–BioNTech’s BNT162b2 vaccine was the first to be licensed in the EU, and the Polish government, as part of its strategy to implement a national COVID-19 vaccination program, classified healthcare workers as group 0, i.e., priority in the vaccination order. Furthermore, out of all vaccines available in the EU, the Polish government purchased the most doses of the Pfizer–BioNTech vaccine (42.9 million) . These dIn this study, the occurrence of side effects following a SARS-CoV-2 vaccine administration was reported by 53.11% of respondents vaccinated with BNT162b2 (Pfizer–BioNTech), 72% of those vaccinated with mRNA-1273 (Moderna), and 67.59% of those vaccinated with ChAdOx1-S (Oxford–AstraZeneca). The most common local or systemic side effects regardless of the type of vaccine received were pain at the injection site , headache , muscle pain , fever , chills  and fatigue . These observations are in line with the results reported in phase three clinical trials and vaccine fact sheets ,27,28,29In clinical trials evaluating the efficacy and safety profile of the BNT162b2 vaccine (Pfizer–BioNTech), local and systemic reactions occurring within 7 days of an injection were reported by 66% and 50% of subjects, respectively. The most common side effects in participants aged 16 years or older were pain at the injection site (>80%), fatigue (>60%), headache (>50%), muscle pain and chills (>30%), joint pain (>20%), and fever and swelling at the injection site (>10%) . More BNIn clinical trials evaluating the efficacy and safety profile of the ChAdOx1 nCoV-19 vaccine (Oxford–AstraZeneca), 60% of subjects reported the occurrence of local and systemic side effects. The most commonly reported side effects were tenderness at the injection site (63.7%), pain at the injection site (54.2%), headache (52.6%), fatigue (53.1%), muscle pain (44.0%), malaise (44.2%), fever (33.6%), chills (31.9%), joint pain (26.4%), and nausea (21.9%) . A totalp = 0.435), whereas viral vector-based vaccines caused mainly mild systemic side effects  after both doses. Research conducted in the U.K. and Saudi Arabia also confirms the obtained results [In addition, the results obtained are consistent with previous observational studies conducted in Poland and worldwide. In a Polish study mentioned above, 78.9% and 60.7% of the individuals reported at least one local and one systemic side effect after the first and second dose of the COVID-19 vaccine, respectively . There w results ,27. Both results  and Menn results ,26,27,30This study found that the majority of local and systemic side effects, regardless of the type of vaccine received, were mild to moderate in severity and were usually resolved within 2–3 days of their onset. The vast majority of side effects, irrespective of the type of vaccine, occurred on the first day after vaccination. For Pfizer and Moderna vaccines, the highest proportion of subjects reported experiencing side effects after both the first and second dose: 42.94% and 46.30%, respectively. For the Oxford–AstraZeneca vaccine, however, side effects after the first dose were reported significantly more frequently than after the second dose (96.94% vs. 0.00%). It was proved, both in clinical trials and in the real-world data, that side effects associated with the COVID-19 vaccine are mild to moderate ,27,28,29The study found that being female, young, and suffering from a diagnosed allergy are all risk factors for side effects following administration of one of the SARS-CoV-2 vaccines subject to analysis. The obtained results are consistent with both clinical and observational studies ,25,26,27Similar to other medications, allergic reactions can occur during vaccination. While most reactions are neither frequent nor serious, anaphylactic reactions are potentially life-threatening allergic reactions that are encountered rarely but can cause serious complications. Reactions are more often caused by inert substances, called excipients, which are added to vaccines to improve stability and absorption, increase solubility, influence palatability, or create a distinctive appearance, and not by the active vaccine itself. The excipients mostly incriminated for allergic reactions are polyethylene glycol, also known as macrogol, found in the currently available Pfizer–BioNTech and Moderna COVID-19 mRNA vaccines, and polysorbate 80, also known as Tween 80, present in Oxford–AstraZeneca and Johnson & Johnson COVID-19 vaccines . TherefoDifferences in the safety profiles of vaccines should always be discussed in the context of their efficacy. Currently, efficacy data confirm that all available vaccines exceed the 50% threshold set by WHO  and can As of 28 December 2021, a total of 8,687,201,202 vaccine doses have been administered . AnaphylThere is some evidence that two COVID-19 mRNA vaccines (BNT162b2 and mRNA-1273) are safe in certain populations such as pregnant women  immunosuFurther studies are needed to determine the long-term safety profile of COVID-19 vaccines. Further studies will also facilitate improved vaccine recommendations, vaccine safety surveillance systems, monitoring of early COVID-19 vaccine recipients, standardized reporting, and pharmacovigilance mechanisms. Safety issues noted for mass vaccination may have a deleterious impact on the global vaccine supply and the already fragile confidence in vaccines. Government agencies and scientists working on the development of COVID-19 vaccines should widely present any safety issues noted in mass vaccinations in order to reduce public vaccine hesitancy. Mass COVID-19 vaccination seems to be one of the most important ways to allow a worldwide return to normal life.Despite it being pioneering research in Poland to discuss the side effects related to COVID-19 vaccines, there are some limitations. The primary weakness of this study is related to self-reported data and information about COVID-19 vaccine side effects, instead of objective information reported by healthcare workers following formalized, unbiased assessments. The authors expected that healthcare workers were more likely to be cautious about health issues, as compared with the general population, as this group, by default, has adequate levels of health literacy, as well as scientific interest. Another limitation was the predominance of respondents vaccinated by a BNT162b2 (Pfizer–BioNTech) COVID-19 vaccine, which resulted from phase one administration of this vaccine among healthcare professionals in the first weeks of 2021. Such a procedure was ordered by decision makers and public health officials. We decided to conduct this research project as a web-based study to ensure maximum safety for all study participants during the COVID-19 pandemic. Therefore, data were collected online in the form of a self-assessment survey. This might have compromised the inclusion of healthcare workers with limited internet access. However, the presented study is a good source of information on the occurrence of short-term adverse events of the most frequently administered COVID-19 vaccines. Therefore, the presented study meets the information needs of healthcare policymakers and the whole medical community.Our results clearly show that the short-term safety profiles of the eligible COVID-19 vaccines  are acceptable. The incidence, duration, and nature of the severity of side effects reported by the recruited subjects are similar to those reported in clinical trials, indicating all three vaccines have safe profiles. Nevertheless, the two-dose COVID-19 vaccines available in Poland differ significantly in the frequency of both local and somatic side effects and their intensity. Women, young people, and patients diagnosed with allergies are particularly exposed to the risk of side effects. Further studies are needed to determine the long-term safety profile of COVID-19 vaccines.


Similarly, headache is correlated with fever (r = 0.801) and pain at the site of injection (r = 0.868). Overall, it was observed that recipients of the Sinopharm vaccine reported the mildest side effects among all four vaccines. The crucial finding of this study is that the first and second dosage post-vaccination side effects were modest and predictable with no occurrences of hospitalization; this information can assist in lessening vaccine apprehension.Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) created a global pandemic (COVID-19) that has resulted in massive health and economic losses. The current unavailability of treatments leaves vaccination as the only way to control this disease. There are four vaccines  available in Bahrain. This project aimed to study the most common side effects resulting from the first and second doses of these four vaccines. Data were collected through an online questionnaire answered by 311 individuals who received both doses of one of these four vaccines. The results of this study revealed that regardless of the vaccine identity, participants experienced more side effects from the second dose. Among the different side effects, pain at the site of injection was primarily observed after the first dose of the Pfizer vaccine (43%), which was followed by the AstraZeneca vaccine (31%). Moreover, fever was observed in participants after the first dose of the Sputnik vaccine (37%), while headache was mainly observed after the first dose of the Pfizer vaccine (32%). It is important to note that fatigue was observed after the first dose of all four vaccines but was reported by the highest proportion of respondents in the Pfizer group (28%). Interestingly, there are some side effects, such as pain at the site of injection, that are correlated with fever ( The coronavirus disease 2019 (COVID-19) first reported in December in Wuhan, China, as an epidemic ,4,5,6. SIt has been reported that 11,503 clinical studies and 2388 randomized controlled trials (RCTs) were registered for COVID-19 . There were 308 vaccine candidates in different stages of development as of March 2021, with 73 in clinical trials, including 24 in Phase I trials, 33 in Phase I–II trials, and 16 in Phase III development . SeveralThe development of these vaccines generated hope for an end to the COVID-19 pandemic. However, many were afraid of taking these vaccines due to myths, misconceptions, and side effects. Many studies have reported the unique side effects of individual vaccines ,15,16,17Common side effects of the above-mentioned vaccines are pain at the site of infection, fever, headache, fatigue, joint pains, cough, myalgia, and nausea ,17. FollThere is little published data to corroborate adverse responses to the COVID-19 vaccination. Only a few studies discuss the side effects of the Sinopharm vaccines ,23,24,25The Kingdom of Bahrain has approved only four vaccines: the Pfizer-BioNTech vaccine, Sputnik V, the AstraZeneca vaccine, and the Sinopharm vaccine. However, vaccine hesitancy remains high due to concerns regarding vaccine safety, side effects, and effectiveness against the COVID-19 virus. Therefore, this study was designed to determine the side effects of the COVID-19 vaccines provided by the Ministry of Health in the Kingdom of Bahrain. A randomized, cross-sectional study was conducted from 10 April to 15 May 2021, on Bahraini people who were vaccinated against COVID-19. Citizenship, ethnicity, occupation, and location of residence were not considered. Adults (18 years and older) were invited to participate in a self-administered online survey (Google Form) that was distributed through social media platforms . Potential participants were first informed about the study through distribution of a detailed description of the study’s purpose. Then, those who wished to participate were asked to sign a mandatory electronic informed consent form that included statements regarding voluntary participation and anonymity. The participants who took only one shot of vaccine were not included in this study. Three hundred and eleven participants were included in this study, while 24 participants were excluded, as they took only 1 dose of any vaccine. This study was approved by the ethics committee of the Department of Biology. A questionnaire was prepared following a thorough review of the literature on databases including but not limited to Google Scholar and PubMed. The participants were informed in the questionnaire about some medical terms, for example, anosmia (loss of smell), dysgeusia (loss of taste), myalgia (muscle pain), and dyspnea (shortness of breath). This extensive literature review revealed a wide range of potential post-vaccination side effects that were subsequently considered in the design of the survey. Several questions requested demographic information, participants’ general health status vaccination, and pre-and post-vaccination imprints of COVID-19 vaccinations. The survey was developed in English and modified following review by a panel of experts. The poll was translated into Arabic before being testing and distribution.A pilot study was conducted with 40 participants to test the clarity and comprehensibility of survey material. These pilot study participants were not included in the formal evaluation. Survey reliability was determined using the Cronbach’s alpha test of internal consistency. In this study, the test indicated that the survey instrument was generally reliable, with a Cronbach’s alpha of 0.79.The data were categorized based on the type of vaccine and side effects following vaccination, such as headache, fatigue, myalgia, fever, nausea, and injection site pain. The data were stored in Google forms until final responses were downloaded and used for data analysis. Univariate models were applied to estimate the percentage of symptoms reported after receipt. Pearson’s correlation was applied to understand the association between each pair of symptoms. The null hypothesis for the Shapiro–Wilk test confirmed that the data were normally distributed in this sample population. The number of participants was standardized for each vaccine to study the side effects of each vaccine using ANOVA. Another critical side effect that was observed after both doses was headache. The highest proportion of individuals reported headaches after the first dose of Pfizer (32.35%), which was followed by Sputnik (16.67%), whereas only 6% of participants felt headaches after the first dose of AstraZeneca and 8% after Sinopharm. Similar to the previously mentioned side effects, respondents reported less severe symptoms compared to the first dose. It was noticed that the second dose of Sputnik caused a headache in more participants (6.06%) than the other three vaccines . The difFew participants complained of myalgia after either the first or second doses of any of the four vaccines. A small number of participants reported myalgia after the first dose of AstraZeneca (10.3%) and Sputnik vaccinations (7.5%) .It is interesting to note that nausea was observed in participants who received the first doses of AstraZeneca (3.45%) and Pfizer (0.8%), but in the Pfizer group, nausea was observed only after the second dose (1.96%) . The difFatigue was one of the most common symptoms reported after COVID-19 vaccination. Following the first dose, fatigue was reported primarily by those who received Pfizer (28%), followed by Sputnik (20%), then Sinopharm (13%). Notably, very few individuals reported fatigue as a side effect after receiving the second dose of any of the four vaccines . The difr = 0.909). Headache is also correlated with fever (r = 0.801) and pain at the site of injection (r = 0.868). Some symptoms, primarily myalgia and cough, seem to be independent of any other side effect. Pearson’s heatmap was applied to determine the correlation of reported side effects of four COVID-19 vaccines that have been used in the Kingdom of Bahrain. As shown in r = 0.909), headache and fever (r = 0.801), and headache and pain at the site of injection (r = 0.868) In contrast nausea, myalgia, and cough are not associated with other side effects. This study analyzed the side effects of first and second doses of four vaccines that have been used in the Kingdom of Bahrain. The results of this study revealed that the first dose of all four vaccines had more side effects than the second dose of these vaccines. Among different side effects, pain at the site of injection primarily observed after the first dose of the Pfizer vaccine (43.14%) followed by the AstraZeneca vaccine (31.03%). Fever was observed in the highest proportion of respondents who following the first dose of the Sputnik vaccine, while headache was mainly observed after the first dose of the Pfizer vaccine (37%). It is important to note that fatigue was observed after the first dose of all vaccines, most predominantly in individuals who received the Pfizer vaccine (28%). Surprisingly a few side effects are correlated to each other: pain at the site of injection and fever (The topic of this study is crucial due to the prevalence of vaccine hesitancy. It is a time to provide the public with data on the side effects of these vaccines. A few studies have reported on the side effects of a particular vaccine. Minimal reports are available where scientists have compared data on the side effects of four vaccines. The comparative nature of this study will play a key role in alleviating fears about the side effects of COVID-19 vaccines. A comparison of few important studies has been discussed in the Recently reports have highlighted the side effects of the Sinopharm vaccine . These sSeveral studies have reported the side effects of the Pfizer vaccine ,28,29,30AstraZeneca is the third Bahrain-approved vaccine developed to combat COVID-19. Interestingly, a study reported the short-term side effects of Pfizer and AstraZeneca in Saudi Arabia . SimilarThe primarily non-life-threatening short-term side effects reported in this study could help to dispel conspiracy theories and reassure vaccine-apprehensive members of the public of the safety of this vaccine. Nevertheless, there are few limitations of such self-reported online surveys. The reliance of our results on this method could have resulted in information bias due to misclassification of side effects. Furthermore, the sample diversity may differ from the wider public cohort due to the sole inclusion of people with internet access. The sample was not evenly distributed across gender or career, necessitating caution in generalizing the findings. However, these data are instrumental for the vaccine campaign, which is the only solution in the fight against the COVID-19 pandemic. In conclusion, all four vaccines available in Bahrain have short-term side effects that are modest in frequency, mild in intensity, and short-lived. These findings may help to boost public trust in the safety of COVID-19 vaccinations, hastening the immunization process in Bahrain by dispelling misconceptions and conspiracy theories concerning post-vaccination side effects.


Background: Pfizer-BioNTech and Oxford-AstraZeneca are recently introduced vaccines to combat COVID-19 pandemic. During clinical trials, mild to moderate side effects have been associated with these vaccines. Thus, we aimed to evaluate short-term post-vaccination side effects. Methods: Cross-sectional, retrospective study using an online questionnaire was conducted among COVID-19 vaccines recipients in Saudi Arabia. General and demographic data were collected, and vaccine-associated side effects after receiving at least one dose of each vaccine were evaluated. Results: Our final sample consisted of 515 participants with a median age of 26 years. Most of the study participants were female (57%). Nearly 13% of the study subjects have reported previous infections with SARS-CoV-2. Oxford-AstraZeneca and Pfizer-BioNTech vaccines have been received by 75% and 25% of the study participants, respectively. Side effects associated with COVID-19 vaccines have been reported by 60% of the study subjects, and most of them reported fatigue (90%), pain at the site of the injections (85%). Conclusion: Side effects that are reported post Oxford-AstraZeneca and Pfizer-BioNTech vaccines among our study participants are not different from those that were reported in the clinical trials, indicating safe profiles for both vaccines. Further studies are needed to evaluate the effectiveness of the current vaccines in protection against SARS-CoV-2 reinfections. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a newly identified member of the human coronaviruses family that was discovered during the outbreak of the highly transmissible respiratory disease in Wuhan, China in 2019. SARS-CoV-2 causes the Coronavirus disease 19 (COVID-19) and is now continuing to spread worldwide causing a global pandemic ,4. By thIn our study, we evaluated the short-term side effects after receiving either Pfizer-BioNTech mRNA (BNT162b2) or Oxford-AstraZeneca (ChAdOx1 nCoV-19) vaccines in a sample of 18 years and older citizens and residents of Saudi Arabia.t-test and chi-square test were done for statistical analysis. The data were statistically analyzed using SPSS v.23  with a significance level of p ≤ 0.05. Multivariate logistic regression models were also applied to all symptoms that might be related to the side effects from which we obtained adjusted odds ratio (aOR), 95% confidence intervals (CI).This is a retrospective, cross-sectional, online survey that was conducted over a period of 3 weeks, between 7 April and 28 April 2021, in Saudi Arabia. The vaccination of the general population against COVID-19 in Saudi Arabia was initiated in early 2021 for both Pfizer-BioNTech and Oxford-AstraZeneca vaccines. A dual language (Arabic and English) online questionnaire was designed using Google Forms which was delivered to participants via social media. Additionally, an electronic email was also established and used to facilitate communication between study investigators and participants. Investigators kept careful and frequent verification for the participants’ responses. The study questionnaire was divided into two main sections. The first section was designed to collect general information about the participants such as gender, age, chronic diseases, and infection status with SARS-CoV-2. The second section focused on the COVID-19 vaccine-related data such as type and date of COVID-19 vaccine, the first or second doses, side effects that are commonly associated with the COVID-19 vaccine, timing, and duration of the side effects. In our side effects subsection, we have included the most common side effects which were reported in other studies , includin = 294). Thirteen percent (66) of the study participants have been previously diagnosed with COVID-19. About 86% of the participants denied having a history of any chronic diseases. Most of the participants received Oxford-AstraZeneca (75%), followed by Pfizer-BioNTech (25%). Only 39 (8%) of the participants have received two doses from the same vaccine [Five hundred thirty-three individuals have participated in this study, and 18 of them did not meet our inclusion criteria. Our final sample consists of 515 participants with a median age of 26 years (SD:9) ranging from 18 to 70 years, of whom 57% were female (Three hundred seven of our study participants (60%) experienced side effects due to the COVID-19 vaccines . Nearly p 0.012). It has been reported, either from the trial results or the real-world data, that the side effects associated with the COVID-19 vaccine are mild to moderate [Since the beginning of the COVID-19 pandemic in January 2020, most countries have taken precautionary measures to control SARS-CoV-2 transmission with the hope of rapid production of safe and effective vaccines . Saudi Amoderate ,17,18. IDespite it being one of the few studies in Saudi Arabia that has discussed the side effects related to COVID-19 vaccines, our study has many limitations. The data have been collected by a self-administered online questionnaire and this could result in a reporting bias. Because COVID-19 pandemic and the recommendation to continue the social distancing and the preventive measures in Saudi Arabia, we preferred to conduct this study as a web-based study to ensure the safety of all study participants. Moreover, community-based surveys would be difficult to be done during this pandemic. Therefore, data collection was online as a self-reported survey, and the distribution of this survey depending on the authors’ networks. As such, most of the participants were young. It would be insightful if we included more participants who benefited from the Pfizer-BioNTech vaccine, but the distribution process at the time of the study for the Pfizer-BioNTech vaccine was limited. Furthermore, it was not possible to assess the long-term side effects of the COVID-19 vaccine due to the inaccessibility of the online questionnaire to the participants. However, it would be helpful to assess the thromboembolic profiles and symptoms for the participants to evaluate its association with the current vaccines.In this study, we assessed the short-term side effects associated with COVID-19 vaccines approved for use in Saudi Arabia, Oxford-AstraZeneca, and Pfizer-BioNTech vaccines. We found that most of the participants reported fatigue, pain at the site of the injection, fever, and headache, and they are more common in those after the second dose of the vaccines. Moreover, only a few patients needed to see a doctor or to be admitted to the hospital due to vaccines’ side effects. Fatigue and fever were significantly associated with Oxford-AstraZeneca, compared to the Pfizer-BioNTech vaccine. A follow-up study on a larger population is warranted to evaluate the effectiveness of the vaccines on the control and prevention of SARS-CoV-2 infection as well as the long-term side effects.


These findings were consistent with the results indicated by the clinical trial of ChAdOx1nCoV-19. Logistic regression analysis further revealed that compared to people aged 70 years or above, the incidence of reported side effects was significantly higher in people aged 18–30 years (odds ratio (OR) = 8.56), 31–40 years, (OR = 5.05), 41–50 years (OR = 4.08), 51–60 years (OR = 3.77) and 61–70 years (OR = 3.67). In addition, a significantly higher percentage of female participants suffered from post-vaccination side effects compared to males (OR = 1.51). It was concluded that the Covishield vaccine was well-tolerated among people of different age groups. Nevertheless, further long-term follow-up study with a larger sample size is warranted to establish the long-term safety of the COVID-19 vaccine.In response to the raging COVID-19 pandemic, Bangladesh started its vaccine administration in early 2021; however, due to the rapid development and launch of the vaccines in the market, many people had concerns regarding the safety of these vaccines. The purpose of this study was to evaluate the side effects that were experienced by the Bangladeshi residents after receiving the first dose of the Oxford-AstraZeneca’s Covishield vaccine (ChAdOx1nCoV-19). The study was conducted using both online and printed questionnaires and the data were analysed using SPSS. The results included the responses of 474 vaccine recipients from March–April 2021. Pain at the site of injection, fever, myalgia, fatigue and headache were the most commonly reported symptoms, and the overall side effects were found to be significantly more prevalent in the younger population ( The world has been going through a global crisis since early 2020 due to the COVID-19 pandemic, which is caused by the newly discovered coronavirus, namely, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . FollowiAlthough the treatment of COVID patients with broad-spectrum antibiotics and antivirals has led to the recovery of patients to some extent, many of them have faced severe adverse effects. Therefore, many pharmaceutical companies and research centers have been racing to develop safe and effective vaccinations to tackle the pandemic . AccordiAfter the arrival of the first shipment of Oxford-AstraZeneca’s Covishield vaccine (ChAdOx1nCoV-19) in Bangladesh on 25 January 2021, a countrywide COVID-19 vaccination campaign was initiated on 7 February 2021, with the target of inoculating 3.5 million people in the first month . MoreoveIn the UK, Brazil and the United States, phase 3 trials with ChAdOx1 nCoV-19 are being conducted to examine the vaccine’s effectiveness and safety and the interim analysis of these ongoing trials indicates that it has 70.4% efficacy against symptomatic COVID-19 after completion of a two-dose vaccination ,12. HoweTherefore, it is important to assess any major side effects or undesirable consequences that may occur as a result of the vaccination programs. If no serious side effects of Covishield can be established, then people with low confidence about the COVID-19 vaccine would be more willing to participate in this immunisation program, making it easier to reduce the pandemic by preventing the vulnerable population from infection and disease and stop further transmission of this disease ,15. WithThe purpose of this study was to assess the short-term side effects that were experienced by the recipients of the first dose of Oxford-AstraZeneca’s Covishield vaccine in Bangladesh.A cross-sectional study was conducted among Bangladeshi residents who were aged more than 18 years and who had received the first dose of the Covishield vaccine. To carry out this study, a questionnaire, both in English and Bengali, was developed and was made available on the Google platform. Printed copies were also used to collect data. The questionnaire was pre-tested for validity by conducting a pilot study. The respondents voluntarily participated in the study without any incentives. Each participant was allowed to provide a response only once. In some cases, multiple responses were allowed to gather data from elderly people with technical difficulties. All responses were reviewed carefully to eliminate any discrepancies. Data were collected for 1 month from 6 March to 8 April 2021.The survey consisted of three categories of questions. The first category included the socio-demographic data of the respondents. The second category focused on the perception of the participants towards COVID-19 vaccination. The last segment comprised the vaccination-related data. The side effects were selected according to the side effects observed in the clinical trial of the ChAdOx1nCoV-19 vaccine .Residents of Bangladesh who had received the first dose of the Covishield vaccine were included in the study. People who were not vaccinated against COVID-19 were excluded from the study. By using the Raosoft sample size calculator, the minimum required sample size for conducting the study was found to be 385, considering a 5% margin of error and 95% confidence interval. In the present study, in total, 474 participants who satisfied both the inclusion and exclusion criteria were purposively selected and their responses were subjected to statistical analysis.2) test. Additionally, a logistic regression analysis model was carried out via the “Enter” method to determine the influence of the different demographic characteristics on the presence of individual side effects.After the data collection, it was cleaned and coded using MS Excel and statistically analysed using SPSS v. 25. All data obtained from the 474 participants were subjected to descriptive statistical analysis. Associations of the number of side effects with different demographic groups were analysed using the chi-squared  and the rest were female . Regarding the age groups, the highest number of respondents was from the 41–50-year-old group (33.3%) and the lowest number was from the 70+-year-old group (3.6%). Almost 71.3% of participants achieved university or post-university education levels. The study population comprised 34.4% that were either a teacher or a student, 20.7% were service holders, 19.6% were housewives, 12.4% were business holders, 5.1% were healthcare workers, 5.3% were unemployed and the rest included a small percentage of other occupations. Most participants received their vaccines from vaccination centres located in Dhaka (50.6%), 23.4% from Khulna and 10.8% from Rangpur . Among the others, the majority of the respondents reported hypertension (33.3%), diabetes (24.5%), heart disease (8.4%) and lung disease (8%). About 45.1% had a history of allergic reactions to various allergens, such as the cold (19%), dust (31%), food (14.3%), insects (2.1%) and drugs (0.8%), which were associated with common symptoms, such as sneezing, coughing, itching, swelling, runny nose and shortness of breath.n = 29) had a history of confirmed COVID-19 infection, while 6.8% (n = 32) suffered from COVID-19 like symptoms prior to vaccination , swelling , itching , irritation at the site of injection  and a burning sensation . The solicited systemic side effects included fever or feeling feverish , myalgia , fatigue , a headache , drowsiness , dizziness , joint pain , nausea or vomiting , diarrhea  and a rash . A considerable percentage of vaccine recipients did not complain about any sort of side effects   .After receiving the vaccine, allergic reactions were experienced by 7% of recipients, which were mainly comprised of a cold (5.5%), coughing (3.6%), fever (5.5%), itching (6.5%), swelling (2.3%) and shortness of breath (2.1%). About 37.6% of vaccine recipients had to take some sort of medication for alleviating the adverse effects. Paracetamol was the most used (36.7%), followed by antiallergic drugs (1.7%), and only 1.9% of recipients required hospitalisation .p = 0.016), where female vaccine recipients had a 1.5 times higher chance of showing side effects compared to males (p = 0.067) (A chi-squared test was performed to assess the association between the number of post-vaccination side effects and the different demographic characteristics of the participants . A signi= 0.067) .p = 0.02) between the number of side effects reported by the different age groups of participants (p ≤ 0.05)  . This mep > 0.05).No significant association was found with participants’ educational qualification, occupation type, body mass index (BMI), presence of comorbid conditions or previous history of COVID-19 infections (p = 0.008). Female participants (21.8%) experienced significantly more fatigue compared to male participants (14.6%) (p = 0.044).A chi-squared test was also performed to find out the association of individual side effects with gender and age . Fever wp ≤ 0.05). In the age group of 18–30 years, headache and drowsiness were experienced more than the other groups (p ≤ 0.01)  . No signThe unprecedented pace at which COVID-19 vaccines were developed had heightened the already existing vaccine hesitancy among general population, and further aggravated by the unregulated circulation of conspiracy theories and misinformation in the social media. Hence, research publications and information regarding the safety and efficacy of these vaccines are highly called for to prevent vaccine-related misconception and promote uptake of available vaccines . After ap = 0.016). This pattern was not particularly reported in the clinical trials of Oxford/AstraZeneca. However, this is similar to the trend displayed by adverse vaccine event monitoring studies of Pfizer-BioNTech vaccine in Saudi Arabia and other vaccines in general [The study revealed that a significantly greater number of female participants suffered from post-COVID-19 vaccination side effects compared to males . This finding is in congruence with the results of Oxford AstraZeneca’s clinical trial [In this study, the majority of the participants were aged 40 years and above (73%). The 166.3 million Bangladeshi population comprises 68% of people between the ages of 15 and 64 years and about 5% of people above the age of 65 years . Initialal trial . Similaral trial , and wital trial ,28. Thisal trial , which eAbout two-thirds of vaccine recipients (69%) mentioned that they were confident regarding the vaccine’s efficacy, which is similar to the finding by another recent study in Bangladesh, where 67% of respondents believed that the vaccine would work against COVID-19 infection  Figure b. The maThis study focused on the short-term side effects following the first dose of the COVID-19 vaccine because very few people had received the second dose at the time of the study. Moreover, this study only described self-reported side effects from the respondents and, because of purposive sampling, the generalisability of the study’s outcome might be affected. A further study with a large and representative sample is therefore recommended.Overall, the short-term side effects following the administration of the first dose of the Covishield vaccine were common but not life-threatening and the findings were consistent with the clinical trial results. Despite the higher level of side effects reported by adult women and younger populations, the vaccine had generally been well-tolerated among the different age groups of people. At the time of this study, only Covishield was being administered in Bangladesh; hence, further studies comparing both the short- and long-term side effects of the different types of COVID-19 vaccines are recommended. This might help to curtail the vaccine misconceptions and fears among the general population, encouraging more people to participate in the mass vaccination program in the coming days.


Due to the theragnostic potential of mesoporous silica nanoparticles (MSNs), these were extensively investigated as a novel approach to improve clinical outcomes. Boasting an impressive array of formulations and modifications, MSNs demonstrate significant in vivo efficacy when used to identify or treat myriad malignant diseases in preclinical models. As MSNs continue transitioning into clinical trials, a thorough understanding of the characteristics of effective MSNs is necessary. This review highlights recent discoveries and advances in MSN understanding and technology. Specific focus is given to cancer theragnostic approaches using MSNs. Characteristics of MSNs such as size, shape, and surface properties are discussed in relation to effective nanomedicine practice and projected clinical efficacy. Additionally, tumor-targeting options used with MSNs are presented with extensive discussion on active-targeting molecules. Methods for decreasing MSN toxicity, improving site-specific delivery, and controlling release of loaded molecules are further explained. Challenges facing the field and translation to clinical environments are presented alongside potential avenues for continuing investigations. Small molecule approaches to diagnostic and therapeutic procedures suffer from multiple shortcomings, such as off-target toxicity and rapid clearance from the body. Boasting the ability to simultaneously diagnose and treat patients, theragnostic (a.k.a. theranostic) nanoparticles (NPs) emerged as a rapidly developing technology for overcoming these obstacles and enhancing clinical outcomes. In particular, mesoporous silica nanoparticles (MSNs) demonstrate a significant potential  to becomPairing with appropriate gatekeeper molecules can trap encapsulated molecules within the MSN pores, allowing for efficacious cargo release. In addition, the gatekeeper provides surface functionalization to prevent toxicity. These gatekeeper mechanisms protect the nontarget tissues—in the host environment—from loaded molecules, while simultaneously protecting the loaded molecules from the environment. This two-way shielding provided by MSNs allows for in vivo delivery of small molecules that, alone, would be clinically ineffective as a result of their high hydrophobicity or toxicity .The multifunctional nature of MSNs largely stems from the numerous surface modifications they can undergo. As mentioned, many different gatekeeper molecules can be employed to the encapsulated molecules loaded into MSN pores. These gatekeeper molecules can be chosen or designed to respond to disease-specific stimuli, thus, controlling the release of loaded molecules and limiting off-target delivery . The orgCompared to the number of preclinical studies, very few silica-based nanomedicine approaches were FDA approved for clinical trials ,6. ContiWhile many reaction pathways might be used ,8, MSNs Strategically tailoring MSN surface-oriented functional groups provides avenues to better control interfacial interactions, while offering additional functionality like drug loading and insertion of targeting domains. Both chemical treatment and polymer grafting strategies are widely used approaches for chemically or morphologically modifying MSN surfaces ,21. SelfBeyond the impact of polymeric, gatekeeper, or active targeting molecules, innate properties of the core MSN serve as key predictors of physiological fate. Prior to administration, complete characterization of MSNs is critical to approximating MSN behavior and correlating the theragnostic effect. Some of the common methods for verifying MSN properties by analyzing synthesized particles are dynamic light scattering (DLS)  and tranSeveral organ systems within the body possess structural or functional filtration abilities. For example, the glomerular layers of the kidney are responsible for filtering foreign and waste products that are smaller than approximately 5 nm ,26. SimuWhile control of the MSN size is primarily accomplished prior to treatment, it is critical to consider the fact that significant changes in the nanovehicle size might occur from physiological reactions in vivo. Following intravenous administration, MSNs are exposed to numerous proteins in the blood. Under certain conditions, these proteins can irreversibly bind the MSN surface through a process termed as opsonization ,40. The The final shape of the MSN core plays a similarly critical role in physiological fate and in vivo MSN behavior. MSNs are most commonly shaped as spheres or rods. The final shape primarily depends on the identity and volume ratio relative to water, in the cosolvent used during the sol–gel reaction . The aspMSN porosity is characterized by the shape, diameter, and number of pores. Pore shape is primarily determined by the cosolvents used during synthesis. The standard honeycomb pore shape is produced when strong bases such as NaOH are used for the cosolvent ,62. WormThe major function of MSNs is the specific delivery of encapsulated cargo to a target location in vivo. To incorporate specificity, often a stimuli-sensitive gatekeeper is added to the surface of the MSNs. In addition to providing stimuli-responsivity for cargo release, the gatekeeper has the capability to circumvent toxicity. As the major benefit of the mesoporous nature of the MSNs allows for release of a cargo in conjunction with a particular disease, the MSN should have a gatekeeper on the surface of the MSN to allow promotion of site-specific drug/dye release. While non-coated MSNs reportedly induced proinflammatory and toxic responses, notably through accumulation in the liver and kidney ,68, non-2 form, or as a series of siloxanes . Additionally, hydrogen bonds can form between silanols, based on group density, forming vicinal silanol groups [The primary functional group present on unmodified MSNs is silanol, which has the general form ≡Si-OH . The sill groups ,71. At pl groups . NPs witl groups ,74. Thisl groups ,75,76. Tl groups ,78. The l groups . UnsurprFunctional group modification is assessed as a method for altering MSN cellular interactions. For example, silanol groups can be replaced with the amine functional groups for the net positive surface charge . MSNs poMaintaining non-toxicity of MSNs is crucial in the pursuit of clinical adaptation. Thus far, MSN coatings focus on alternative uses for the biocompatible materials used in applications such as wound healing  or topicOften, polymer synthesis strategies rely on controlled radical polymerization (CRP) techniques, which allow for the controlled design of polymer architecture, chain length, branching, functionality, tacticity, stereochemistry, and composition, among other features. CRP strategies also retain functional end groups with high fidelity ,101,102,Besides altering the MSN surface chemistry, conjugation of organic molecules (such as polymers) to the surface of MSNs is a common strategy for limiting unfavorable MSN–host interactions. Conjugated molecules impart addition functions to MSN nanovehicles, including gatekeeping and active targeting. Some modifications are performed to protect the NP from the host, or vice versa. The most common example of such a molecule is PEG, whose biocompatibility was demonstrated in numerous NP formulations . While PPolymers, polysaccharides, and other organic-based molecules added to the surface of MSNs can substantially alter interactions between the host milieu and the NP, resulting in reduced toxicity. These surface coatings or gatekeeper molecules must exhibit significant biocompatibility and negligible toxicity. Specific assessment of toxicity for gatekeepers was performed for select molecules, including chitosan ,116, polGiven the porous nature of MSNs and the potential toxic effects associated with the exposed functional groups, additional chemical and structural mechanisms are needed to both encapsulate molecules loaded into MSN pores and to limit unfavorable interactions between the MSN surface and the host. These “gatekeeper” systems, commonly comprised of organic polymer networks, facilitate release of loaded molecules, once the MSNs reach the target location or cell. Additionally, they serve as a surface onto which other molecules, such as active targeting ligands, could be conjugated. A selection of polymeric gatekeeper molecules that demonstrated stimuli-specific response in preclinical studies are provided in Controlled release of encapsulated molecules is triggered by cell- or site-specific stimuli that changes the gatekeeper system, exposing the pores of the MSN. Any loaded molecules would then diffuse out of the MSN into the target environment. Appropriate selection of gatekeeper molecule requires knowledge of any internal stimuli produced in the target cell or environment that the gatekeeper would respond to. While common stimuli are found internally, external stimuli provided by clinicians might also be used after sufficient accumulation of MSNs at the target site. Given the extensive and ever-growing number of possible gatekeeper molecules, it is more valuable to consider the methods of triggering gatekeeper stimuli-specific response. Upon identifying the stimuli that matches the target disease, an appropriate gatekeeper can be used in formulating the MSN nanovehicle.The altered metabolic behavior of malignant cells results in the synthesis of acidic byproducts that are transported to the extracellular environment . This ph2+ and CO32− ions in acidic pH [Chitosan is successfully used as a pH-sensitive gatekeeper in several MSN preclinical model studies ,120,121.cidic pH .While pH-response can preferentially increase delivery to preferred tissues, it is fundamentally a non-specific targeting strategy that can be neutralized by changes in pH. Any change in the pH of the suspending solution would induce release of the loaded molecules. Gatekeeper motifs can be constructed to break down in the presence of more specific stimuli, such as enzymes. Malignant cells often overexpress enzymes that promote proliferative or metastatic behavior . These eAs with pH-sensitive gatekeepers, many molecular networks stimulated by enzymes comprise polymers. Hyaluronic acid (HA) is a common example used in MSN formulations. HA is advantageous as it serves as both an active targeting molecule that binds to overexpressed CD44 and as a gatekeeper molecule whose dissociation is catalyzed by the lysosomal enzyme hyaluronidase . CD44 isInteractions between gatekeeper molecules and small molecules within the tumor cell or microenvironment can also stimulate controlled release of encapsulated molecules. Glutathione (GSH) is one such small molecule, residing in many tumor cell types at high concentrations, relative to healthy cells . GSH worWhile internal stimuli are abundant in vivo and provide overall ease of clinical application, external stimuli were studied as a means of controlling release from MSNs. These stimuli must be provided by clinicians following administration of MSNs. Further, pharmacokinetic considerations are necessary to apply external stimuli at times when MSN accumulation in target tissue is high. Multiple gatekeeper formulations requiring external stimuli were paired with MSNs. Primarily, these gatekeepers are thermosensitive in nature, requiring an increase of site-specific in vivo temperature . InductiPoly(N-isopropylacrylamide) (PNIPAM), the most studied temperature-sensitive polymer evaluated for biomedical and drug delivery applications, displays a lower critical solution temperature (LCST) at 37 °C ,143,144.For any NP to be clinically effective, it must reach the target site being sequestered in off-target tissue or otherwise cleared from the body. To accomplish this goal, multiple disease-site targeting strategies were implemented in preclinical nanomedicine studies. The primary options could be divided into three categories—passive targeting methods, which take advantage of innate behaviors and characteristics of diseased tissue ; active Diseased tissues are frequently characterized by the gaps between endothelial cells. These gaps increase endothelial permittivity to large particles, such as NPs, while having no effect on the extravasation of small molecules . SubsequN-succinimidyl  cyclohexanecarboxylate contains a reactive amine group that forms maleimide bonds with thiol groups, such as those found on the amino acid cysteine [Malignant cells possess different characteristics than healthy tissue. Examples of such traits include altered metabolism, under- or overexpression of proteins and signaling molecules, or changes in gene expression. Conjugating molecules that selectively respond to these specific markers onto NP surfaces allows for active targeting of diseased cells. Attaching the MSNs to the targeting ligands can occur by multiple strategies. For example, reagents containing functional groups can be attached to MSN surfaces. These selected reagents should possess reactive functional groups that promote bond formation with the specific targeting ligand of interest ligands. For example, cysteine . Functiocysteine . Non-checysteine .Employing active targeting strategies significantly enhances NP accumulation near and engulfment by target cells. Several molecules were used to actively target MSNs to specific cells. While most such options utilize specific ligand–receptor interactions, a few unique cases warrant special attention. A discussion of different active targeting molecules with apparent advantages and disadvantages is provided. For additional reference, The most prevalently used proteins for active targeting in nanomedicine, as well as for NP-free cancer therapies, are monoclonal antibodies (mAbs). Separate from NP applications, mAbs are well researched and clinically used against a myriad of diseases, for decades ,223,224.To overcome the size obstacle experienced with mAbs while still taking advantage of antibody targeting capabilities, antibody antigen-binding fragments (Fabs) can be used ,232. Fabvβ3 integrins [Similar to proteins, peptides possess the ability to selectively interact with diseased tissue cells. The primary advantage peptides have over whole proteins is their much smaller size. The smaller size promotes a more favorable ligand:NP ratio, and subsequently, a more favorable ratio of targeting ligand to target. Smaller size does impart some disadvantages, including high hydrophobicity and a lack of secondary structures, which result in less overall stability as compared to whole proteins ,235. Manntegrins ,240, arentegrins . The abintegrins ,244,245.Ligand–receptor targeting is not the only method through which diseased cells might be distinguished from healthy cells. Often, diseased cells will alter the microenvironment in which they reside. For example, tumor cells increase the acidity of their extracellular environment from pH 7.4  to between pH 6.0–6.8 ,246. LarAnother technique for targeting diseased cells uses cell-penetrating peptides . Commonly derived from natural sources such as viruses, CPPs can act on cells in many ways. CPP action is typically independent of receptor-specific interactions. Their mechanisms does depend on the target cell type or molecules the CPPs might be carrying, among other factors ,257. CPPMSNs might also be functionalized with aptamers, short strands of DNA or RNA that can recognize and interact with malignant cell markers ,260,261 The examples presented thus far demonstrate the targeting effectiveness of large biomolecules. While these larger molecules comprise a significant majority of applied active targeting strategies, small molecule approaches can also be used in targeting diseased cells . The choBeyond physiological or molecular targeting options, magnetic manipulation of metallic agents can be used to induce NP accumulation at target sites. By applying magnetic fields around the desired site, NPs are attracted to the area, remaining in the tissue long enough for their action (such as delivery of loaded molecules) to occur. SPIONs are the primary component for magnetic targeting. While many approaches use such NPs alone or modified , MSNs caFor all the advantages that MSNs possess, several challenges need to be overcome prior to clinical translation. First, more human trials are needed to test the toxicity and clinical efficacy of agents that were shown to have more therapeutic potential than the lone molecules in preclinical animal models. The nature of passive targeting by the EPR effect in humans must be better understood to ensure a greater clinical effect of NP treatments . This isMSNs serve as a multifunctional platform for theragnostic nanomedicine. Innately, MSNs possess high loading capacities, stable porous structures, and high surface-to-volume ratios. Together, these characteristics provide a strong foundation for MSN encapsulation of drug or dye molecules, or even other smaller NPs. By tailoring the MSN properties during and after synthesis, in vivo behavior and clinical efficacy might be optimized. Surface modification of functional groups or application of gatekeeper molecules might prevent toxic interactions between the MSN core and the host environment. Simultaneously, the gatekeeper controls the encapsulation and release of loaded molecules in a stimuli-specific manner. The ability to functionalize MSNs with various targeting options is also highly favorable for enhancing clinical outcomes. Many active targeting strategies demonstrated significant preclinical potential with MSNs, with limited off-target accumulation. Based on the current body of evidence, MSNs that are within the 20–80 nm diameter range paired with stimuli-responsive gatekeepers and active targeting moieties, might operate as the most clinically beneficial formulation. As research continues to address the apparent presented obstacles, MSN formulations will see growing prominence in clinical nanomedicine, which might correlate to enhanced clinical outcomes and patient care.


We investigated risk factors associated with COVID-19 by conducting a retrospective, frequency-matched case-control study, with three sampling periods (August–October 2020). We compared cases completing routine contact tracing to asymptomatic population controls. Multivariable analyses estimated adjusted odds ratios (aORs) for non-household community settings. Meta-analyses using random effects provided pooled odds ratios (pORs). Working in healthcare , social care  or hospitality  were associated with increased odds of being a COVID-19 case. Additionally, working in bars, pubs and restaurants, warehouse settings, construction, educational settings were significantly associated. While definitively determining where transmission occurs is impossible, we provide evidence that in certain sectors, the impact of mitigation measures may only be partial and reinforcement of measures should be considered in these settings. Non-pharmaceutical interventions (NPIs) play a critical role in the COVID-19 response, and are likely to remain important interventions for infection control despite high effectiveness of vaccines , 3. SomeThe risk of transmission of SARS-CoV-2 is highest in household settings, particularly in multioccupancy households mainly due to the high number of close contacts . CertainWe conducted three a case-control study in England with three sampling periods between August 2020 and October 2020 with the aim of developing improved understanding of settings and activities potentially associated with transmission of COVID-19 in England. The studies focused on non-household activities.We conducted a retrospective case-control study, frequency-matched for age group  and geographical region  to ensure a representative sample of controls and to account for regional variations in restrictions to activities. The study had three sampling periods: August, September and October 2020. The study population consisted of adults (aged 18 years or over) resident in England. Cases were individuals who had tested positive for SARS-CoV-2 and completed the NHS Test and Trace (NHS T&T) contact tracing questionnaire, and who were not reported to NHS T&T as household contacts of a confirmed case. Cases were randomly sampled based on these criteria from the NHS T&T database. Controls were members of the public, registered as volunteers for a market research panel. Controls were excluded if they had tested positive for SARS-CoV-2 or reported COVID-19 symptoms in the 7 days prior to completing the survey. A power calculation was performed for the initial sampling period and used for further samples without further refinement. With a false-positive error probability of 0.05, a total sample size of 4000 subjects, a 1:1 ratio of controls to cases and a minimum important odds ratio of 2, each sampling period had a power of ≥0.9 for exposure proportions of ≥0.02 in the control group.We introduced pragmatic plausibility thresholds for numbers of different activities reported, and excluded individuals who reported high numbers of different types of workplace exposures that appeared unrealistic, likely representing reporting errors .A different sample of controls was obtained for each study period. The sampling periods were late August 2020, late September 2020 and late October 2020, for sampling periods 1, 2 and 3, respectively. Case data were collected as part of routine contact tracing, where cases provide the information either through a digital route (self-completed) or through telephone interview with a contact tracer. The contact tracing programme completion rate for cases during the three study periods was 82.7%, 76.8% and 85.0%, respectively .Information on individuals' activities (exposures) was collected in a structured manner with any activity categorised by three nested levels providing increasing level of detail on activities. The highest level (Level 1) categorises the exposures to work and education activity, or leisure activities. The further information includes sectors, for example, educational, or hospitality setting. The most granular level (Level 3) of categorisation describes the workplace or the setting in more detail, for example, a pub or bar, or a secondary school. An example of this three-level structure for an exposure event associated with working in a warehouse is: Level 1 (least granular): ‘work or education’; Level 2: ‘warehouse or distribution’; Level 3 (most granular): ‘warehouse’.Controls completed an online survey with the same exposure questions structured identically to the case questionnaire. We used the postcode of residence of the cases and controls to adjust for socio-economic deprivation using the Index for Multiple Deprivation (IMD) .P values  were calculated.Cases and controls were described according to their demographic characteristics . Single variable (logistic regression) analyses were undertaken to estimate unadjusted odds ratios (uORs) as crude measures of association between exposures (non-household activities) and outcome (confirmed COVID-19). Confidence intervals (CI) and Sampling periods had a number of settings in which the number of individuals reporting ‘exposure’ was small, leading to the phenomenon of separation. We used the Firth correction  to obtaiInitially a random-effects meta-analysis was used to combine the estimated odds ratios from the multivariable analyses using sector-level exposures. Further meta-analyses explored the associations of the granular level workplace activities. The sector level exposures were broken down to their most granular level (Level 3) if the sectors showed evidence of a risk association  in all three study periods, or a trend of a substantial increase in the observed odds over the three periods. Other exposures were included as sector-level exposures.Across the three study periods, a total of 12 338 individuals were included, of which 6000 were cases. Overall, 3214 (54%) of cases self-completed contact tracing using the digital route, with limited variation between study periods (period 1: 1129 (56%); period 2: 964 (48%); period 3: 1121 (56%)). Females were overrepresented: 6926 (56%) individuals, of which 3268 (47%) were cases. Across the study periods, cases reported fewer activities  than controls . There was a greater proportion of individuals in the control group that were of white ethnicity (83%) compared to the cases (65%), although ethnicity was not recorded in 9% of case respondents. A greater proportion of cases lived in areas of low deprivation (17%) than controls (12%), although deprivation score was unknown for a large proportion of control respondents (11%). Case and control distribution was largely similar for all other demographic variables .Table 1There was statistical evidence that working in social or domiciliary care, health care or hospitality was associated with being a COVID-19 case in all three study periods . AdditioWe did not observe any substantial differences in uOR for point estimates obtained for level 2 workplace exposure groups using only cases completing contact tracing by the two different routes; across all three study periods: median difference = 0.29 (interquartile range 0.12–0.67) (full results not shown). Although some changes in statistical significance were seen when comparing these uOR, there was no change in the direction of the association (i.e. odds ratios both <1 or >1).All multivariable analyses were adjusted for age, sex, ethnicity, socio-economic deprivation (IMD), geographical region and leisure activities. All three study periods showed an association between working in healthcare, social care or hospitality, and becoming a COVID-19 case . WorkingI2 = 78%, P < 0.01). A similar pattern was also observed in construction , and in educational settings   2.87; aORs 2.81, 2.72, 3.08, for studies 1–3 respectively), social care  or hospitality  were associated with increased odds of being a COVID-19 case. There was also evidence that working in a warehouse setting was associated with increased odds . The aORs for the association between warehouses and the odds of infection showed a substantial increase over the three study periods, also indicated by the evidence of heterogeneity between the observed aORs (ctively) .Fig. 2.I2 = 69.4%, P = 0.04) (We explored the association between work-related exposures and infection using more granular level information on work activities . There w = 0.04) .Fig. 3.We observed important associations between certain occupations and SARS-CoV-2 infection. The associations between being a COVID-19 case and working in health and social care, hospitality, education or warehouse settings persisted over the three study periods. The findings highlight that infection control measures may have only a partial effect on reducing transmission in some workplace settings.The findings on hospitality, primarily working in bars, pubs or restaurants, are supported by the accumulating evidence on the risk of COVID-19 associated with these settings from other countries , 20, 21.The associations between certain settings and the odds of infection can only occur when there is an opportunity for the activities to take place. These opportunities are largely affected by NPIs, which in England have varied by geographical region and over time. It is therefore not surprising that, for example, the association between educational settings and increased odds of becoming a COVID-19 case was not observed in the first study period when most educational settings were closed. Educational settings have been associated with outbreaks , 15, andOur findings on the associations between infection and working in manufacturing, construction and warehouse settings are consistent with the most commonly reported outbreak settings in European countries , Canada The findings regarding the association observed between working in healthcare  and social care settings (primarily driven by exposure in care homes) and being a COVID-19 case were expected. These settings were closely associated with transmission in the first wave of the epidemic and, despite the appropriate use of personal protective equipment, healthcare workers experience high COVID-19 infection rates –9. Our sPublic health guidance and advice to reduce the risk of transmission in workplace settings have been published in England  and mitiOur study has a number of limitations. Across all three study periods, cases reported fewer exposures than controls. Cases are often first identified as contacts of other cases and it is possible that people modify their behaviour as a result. It is also possible that multiple biases affect the responses provided. One plausible explanation for this is that the cases going through the NHS T&T questionnaire may be experiencing high levels of questionnaire fatigue due to the length of the questionnaire. While the structure of the control survey (for exposures) was designed to be as identical to the case questionnaire as was practical, cases were required, as part of routine contact tracing, to provide considerable additional non-exposure information . It is also possible that cases may feel inclined to adhere to socially desirable reporting, and not report activities they perceive would not be socially acceptable in the context of the pandemic. This differential misclassification of exposure most likely biased the effect measures towards the null, hence the results described are more likely to be underestimates rather than overestimates. There is also a potential for selection bias. As of the end of the study period three, altogether 630 309 cases were reached by contact tracing, with 82% of cases transferred to NHS T&T being reached by contact tracing . This vaThis study took place in the context of COVID-19 pandemic response when there was an urgent need to provide timely evidence on the risks associated with community exposures. The findings from these sampling periods provided evidence which together with the wider pool of evidence was used to inform risk assessments, policies and targeted public health action in the operational context of the pandemic response. The study allowed rapid, concurrent data collection from both cases and controls, providing epidemiological insights with consistent estimates of associations reported over three study periods. To the best of our knowledge, this is the only case-control study on community risk factors for COVID-19 in England. As such, this study provides valuable insights into the risks associated with community settings and activities, and the findings are likely to be transferrable to other similar settings.We conclude that several workplaces were associated with increased odds of being a COVID-19 case, primarily those in health and social care, hospitality, warehouse and educational settings. The results are aligned with the existing literature. While it was not possible to determine whether transmission occurs at workplaces or outside the workplace, for example, during commuting, our findings provide further evidence that certain sectors have been more affected, highlighting that the mitigation measures in these settings may only be partial. While the study has limitations, these are likely to result in underestimation, rather than overestimations of the associations. Therefore, our recommendation is that further mitigation measures are considered in these sectors to improve the control of COVID-19 in these settings.