{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T10:10:22Z","timestamp":1767175822062,"version":"build-2238731810"},"update-to":[{"DOI":"10.12688\/f1000research.26523.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T00:00:00Z","timestamp":1609891200000}}],"reference-count":52,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T00:00:00Z","timestamp":1609891200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondazione Allineare Sanit\u00e0 e Salute"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>Vaccine surveillance programs are crucial for the analysis of the vaccine\u2019s safety profile and the guidance of health policies. The Epidemiological Observatory of the Italian Apulia Region carried out an active surveillance program of adverse effects following immunization (AEFI) after the first dose of the measles-mumps-rubella-varicella (MMRV) vaccine, finding 462 AEFIs per 1000 doses, with 11% rated serious. Applying the World Health Organization (WHO) causality assessment algorithm, 38 serious AEFIs\/1000 enrolled were classified as \u2018consistent causal associations\u2019 with MMRV immunization. Severe hyperpyrexia, neurological symptoms and gastrointestinal diseases occurred in 38, 20 and 15 cases\/1000 enrolled, respectively. A projection of such AEFIs in an Italian birth cohort would give tens of thousands of serious AEFIs. These incidence data are much greater than the incidence of serious AEFIs reported by the Italian Medicines Agency (AIFA) for years 2017 and 2018, mainly based on passive (or mixed) pharmacovigilance. In a previous epidemiological study in the same Italian Region, during an eight year passive surveillance, the reporting rate of serious AEFI was 0.06\/1000 doses, and no cases of febrile seizures were detected applying the WHO algorithm. Taken together, the data suggest that passive pharmacovigilance is utterly inadequate to document the real incidence of serious AEFIs and that current methods of assessing causality may be questioned. Active surveillance programs are required in representative population samples, with results presented separately from those of spontaneous reporting, and causality assessment should be performed carefully and using a correct technique for AEFIs presenting as complex and multifactorial diseases, like those with serious neurologic disorders.<\/ns3:p>","DOI":"10.12688\/f1000research.26523.2","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T12:21:19Z","timestamp":1609935679000},"page":"1176","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Adverse events following measles-mumps-rubella-varicella vaccine: an independent perspective on Italian pharmacovigilance data"],"prefix":"10.12688","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5086-3504","authenticated-orcid":false,"given":"Paolo","family":"Bellavite","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Donzelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2021,1,6]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"243","DOI":"10.12688\/f1000research.13694.2","article-title":"Revised World Health Organization (WHO)'s causality assessment of adverse events following immunization-a critique.","volume":"7","author":"J Puliyel","year":"2018","journal-title":"F1000Res."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"170","DOI":"10.12688\/f1000research.22600.2","article-title":"Causality assessment of adverse events following immunization: the problem of multifactorial 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Immunother."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/9-1176\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/9-1176\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/9-1176\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T12:21:24Z","timestamp":1609935684000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/9-1176\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,6]]},"references-count":52,"URL":"https:\/\/doi.org\/10.12688\/f1000research.26523.2","relation":{},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,6]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/9-1176\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.29282.r75394, Arthur Brawer, School of Medicine, Drexel University, Philadelphia, USA, 26 Nov 2020, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/9-1176\/v1#referee-response-75394","order":0,"name":"referee-response-75394","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Paolo Bellavite<\/b>; \n<i>Posted: 22 Dec 2020<\/i>; We thank the Reviewer for these notes, confirming and deepening some points of our work. In particular, we agree on the emphasis on informed consent, sometimes underestimated by pediatricians, especially because of the laws that oblige parents to have fully vaccinated children undergo all vccinations, under penalty of exclusion from nursery school or sanctions. Therefore, we have included in the discussion a paragraph about this issue, as follows: \u201cIn this context, it seems useful to extend our attention to the choice among different vaccines and even to the choice of whether to vaccinate or not, a choice that must be made by the patient or by parents of underage children, properly advised by their doctors. Informed consent and\/or the refusal of therapy by patients (or by parents in case of pediatric vaccinations) are debated issues in the medical profession and their importance is underlined by various international statements, such as the Convention on Human Rights and Biomedicine (ETS No 164) signed the 4 April 1997 in Oviedo (Spain). The introduction in the legislation of many countries of an obligation to be vaccinated has significantly altered the patient-doctor and parents-doctor relationships. Regardless of the different vaccines being useful or not, the rare possible single exemptions provided by the law, if there is a legal obligation the doctor\u2019s role risks to switch from an &quot;evidence-based&quot; counsellor to a public officer enforcing the government\u2019s decisions.&nbsp; Such issues were further exacerbated by the introduction of multiple component vaccines, such as the tetravalent with live attenuated viruses or the hexavalent with antigens fixed on aluminum nanoparticles. In these cases the doctor was also denied the possibility of recommending the most appropriate choice based on the epidemiological conditions and on the characteristics of the individual patient's susceptibility. The Italian law issued in July 2017 (law 119\/2017) mandated that the vaccination obligation for MMRV should be revised after three years, but so far nothing has been done and nothing is expected to be done in the near future. Although these issues are still open, it is agreed that patients consulting their doctors for vaccination advice should be offered correct information of the highest qualitative and quantitative standard. This is why the principle of informed consent does not seem satisfied by a generic statement of a &quot;safe profile&quot; or &quot;lack of worrying signals&quot; of a vaccine, that indeed&nbsp; has shown serious adverse effects in a significant percentage of subjects. We hope our contribution may be useful to help the medical professionals and especially the pediatricians to evaluate the information to be shared with the public by utilizing authentic scientific evidence.\u201d","URL":"https:\/\/f1000research.com\/articles\/9-1176\/v2#referee-comment-6230","order":1,"name":"referee-comment-6230","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.29282.r75611, James Lyons-Weiler, The Institute for Pure and Applied Knowledge, Pittsburgh, PA, USA, 03 Dec 2020, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/9-1176\/v1#referee-response-75611","order":2,"name":"referee-response-75611","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Paolo Bellavite<\/b>; \n<i>Posted: 22 Dec 2020<\/i>; We thank the reviewer for these positive notes and suggestions, covering two aspects that we have implemented in the secnd version. The reviewer points out that in order to correctly assess the relationship between benefits and risks of a vaccination it would be important to be able to compare the baseline health status of vaccinated versus unvaccinated children. Unfortunately, these data are lacking because systematic and adequate studies are not carried out on pediatric populations. These studies which would be feasible without too much difficulty if we had require efficient registry functions, capable of documenting the vaccination and health status informing about vaccinations and the state of health of the population. However, there are some observational studies that certainly deserve to be cited, because they can give general indications, even with in the presence of inevitable biases related to the study design. Therefore, we have briefly cited some research, such as that of Hooker-Miller and of the Aaby's group. We also mentioned Weiler's study, although he did not correctly ask for it, because it is a very relevant contribution in this context: \u201cA contribution to evaluate the benefits and risks of vaccines, including long-term ones, could come from comparative studies between vaccinated and unvaccinated groups of children. This type of study cannot be realized in randomized groups for ethical reasons, but preliminary data can be collected anyway from accurate observational studies comparing normally vaccinated children with those who refused one or more vaccines. Unfortunately, few studies of this type are known. Here we mention those of Aaby's group\n<u><sup>47-49<\/sup><\/u>, who reported very different results according to the types of vaccines and regions of the world where the studies were conducted, and those of Hooker's \n<u><sup>50<\/sup><\/u> and Lyons-Weiler \n<u><sup>51<\/sup><\/u>. In the first study \n<u><sup>50<\/sup><\/u> the children were vaccinated before 1 year of age and then evaluated when they reached a minimum age of 3 years. The vaccination was associated with significant higher odds of developmental delays (OR = 2.18), asthma (OR = 4.49) and ear infections (OR = 2.13). However, the study only allowed the computation of unadjusted observational associations. Higher odds ratios for such diseases were observed in quartiles where more vaccine doses were received than in quartile 1. In the second study \n<u><sup>51<\/sup><\/u>\n<sup> <\/sup>it was performed a multicenter retrospective analysis covering ten years of pediatric practice and the incidence of office visits, noting the various pathologies motivating them. The ORs indicated a notable increase in outpatient visits in vaccinated compared with unvaccinated children, because of anemia (OR = 6.3), asthma (OR = 3.5), allergic rhinitis (OR = 6.5) and sinusitis (OR = 3.5). Despite the limitations of this type of investigation and the impossibility of causal inferences, the overall results suggest that vaccinated pediatric patients are no healthier than unvaccinated ones. Further studies are needed to follow vaccinated and non-vaccinated cohorts prospectively, to understand the full spectrum of health effects associated with childhood vaccination.\u201d As a new contribution to this important issue, we have added a final paragraph with a suggestion for possible comparative studies between vaccinated and unvaccinated, taking advantage of the known and frequent phenomenon of &quot;vaccine hesitancy&quot;: \u201cFinally, we want to relaunch a proposal \n<u><sup>52<\/sup><\/u> to investigate the possible \u201cnon-specific effects\u201d of vaccines. The current pharmacovigilance systems are not apt to identify such effects, the observational studies cannot establish causality, and the few randomized clinical trials (RCTs) do not have sufficient size and follow up to identify and prove causality of rare or uncommon non-specific effects, even more so if they have a sizeable background rate. A solution might take advantage on the vaccine hesitancy, that remains in some individuals even after receiving an extensive and balanced information, based on the state of knowledge \n<u><sup>52<\/sup><\/u>. These persistently hesitant individuals (for themselves or for their children) could be tens of thousands in a country: they could be considered as a valuable asset to society, offering them the opportunity to participate in properly designed and long-lasting RCTs. The current ethical barriers to such RCTs (the exclusion of the randomized control groups from the vaccine benefits) could be overcome because these subjects are typically evenly dispersed in a country (posing negligible risk for immunocompromised individuals \n<sup>23<\/sup>), are really and persistently hesitant and may be willing to give their informed consent to participate in such RCTs. So this experimental approach could contribute to an advance in the scientific.\u201d Finally, the reviewer also noted that our sentence &quot;This approach seems more suitable for judging complex cases, in which multiple interacting causes (genetic, infectious, toxic) determine the pathology that occurs after vaccination.&quot; it is itself correct, but incomplete. We agree with this opinion and therefore we have modified it by expressing better the concept, as he suggested, in the &quot;Perspectives&quot; section: \u201cThis approach seems more suitable for judging complex cases, in which multiple interacting causes (genetic, infectious, toxic) determine the pathology that occurs after vaccination. Moreover, the same level of evidence for assessing causality should be applied to the alternatively proposed causal factors. The mere mention of a possible alternative causal factor is not evidence strong enough for ruling out vaccines.\u201d","URL":"https:\/\/f1000research.com\/articles\/9-1176\/v2#referee-comment-6231","order":3,"name":"referee-comment-6231","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The author declared that no grants were involved in supporting this work. Article processing charges were supported by Fondazione Allineare Sanit\u00e0 e Salute a not-for-profit cultural foundation based in Milan, Italy. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}