ΕΜΒΟΛΙΑ ΧΗΜΕΙΟΠΡΟΦΥΛΑΞΗ. Ορέστης Παναγιώτου

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1 ΕΜΒΟΛΙΑ ΧΗΜΕΙΟΠΡΟΦΥΛΑΞΗ Ορέστης Παναγιώτου

2 ΕΜΒΟΛΙΑ Εμβόλιο: μια βιολογική ουσία που στόχο έχει να δημιουργήσει ή να ενισχύσει την ανοσολογική απάντηση και την ανοσολογική μνήμη προς παθογόνους παράγοντες - πρόληψη της λοίμωξης σε περίπτωση έκθεσης στους παθογόνους παράγοντες - μετρίαση και εξάλειψη των συμπτωμάτων σε περίπτωση έναρξης της λοίμωξης - προστασία άλλων ομάδων του πληθυσμού

3 ΑΝΟΣΙΑ Ενεργητική: - η χορήγηση βιολογικών ουσιών έχει σκοπό την έμμεση δημιουργία ή ενίσχυση της ανοσολογικής απάντησης και μνήμης - επιτυγχάνεται με τον εμβολιασμό - ανοσολογική απάντηση από τον ίδιο τον οργανισμό - συνήθως ισχυρή - όχι απαραίτητα δια βίου - ανοσία και ανοσολογική απάντηση παρόμοια με τις αντίστοιχες μετά από νόσο αλλά χωρίς να νοσήσει ο εμβολιαζόμενος π.χ. MMR, HepB, DTaP

4 ΑΝΟΣΙΑ Παθητική: οι βιολογικές ουσιίες αποτελούν οι ίδιες συστατικά της ανοσολογικής απάντησης π.χ. αντιτετανικός ορός, αντιλυσσικός ορός, IVIG

5 ΕΠΙΔΗΜΙΕΣ Κοινής πηγής Προοδευτικές Μικτές

6 ΠΡΟΟΔΕΥΤΙΚΕΣ ΕΠΙΔΗΜΙΕΣ ΜΟΝΤΕΛΟ SIR Προοδευτικές επιδημίες - προοδευτικός χαρακτήρας στον πληθυσμό - εξάπλωση με τη μετάδοση από άτομο σε άτομο μέσω επαφών Μοντέλο SIR Susceptible Infectives Removals

7 ΜΟΝΤΕΛΟ SIR Συσχετίζει με μαθηματικούς τύπους τους υποπληθυσμούς των επίνοσων (ευάλωτων) ατόμων που δεν έχουν μολυνθεί ακόμα susceptibles [X] των μολυσμένων/μολυσματικών ατόμων infectives [Y] των ατόμων που έχουν πάψει να είναι μολυσματικά και άρα έχουν αποσυρθεί removals [Z]!S!t = "bxy!y!t = bxy " gy!z!t = gy

8 ΜΟΝΤΕΛΟ SIR Η μείωση των επίνοσων ατόμων που γίνεται με μεταφορά τους προς τη δεξαμενή των μουσματικών ατόμων είναι ανάλογη του αριθμού των μολυσματικών ατόμων (Y), του αριθμού των επίνοσων (X) και μιας σταθεράς μολυσματικότητας b που χαρακτηρίζει το νόσημα και τις συνθήκες του πληθυσμού (infection rate)!s!t = "bxy

9 ΜΟΝΤΕΛΟ SIR Η αύξηση της ομάδας των ατόμων που έχουν αποσυρθεί γίνεται με μεταφορά ατόμων από τη δεξαμενή των μολυσματικών ατόμων (Y) και είναι ανάλογη του αριθμού των μολυσματικών ατόμων και μιας σταθεράς απόσυρσης g (removal rate)!z!t = gy

10 ΜΟΝΤΕΛΟ SIR Η εξέλιξη της δεξαμενής των μολυσματικών ατόμων εξαρτάται από τη μεταφορά νέων ατόμων από τη δεξαμεωή των επίνοσων και την απόσυρση άλλων προς τη δεξαμενή των ατόμων που έχουν αποσυρθεί!y!t = bxy " gy

11 ΕΝΑΡΞΗ ΕΠΙΔΗΜΙΑΣ!Y!t > 0 " bxy > gy Αν X 0 ο αρχικός αριθμός των επίνοσων ατόμων, τότε για την έναρξη επιδημίας πρέπει X 0 >g/b Βασικός Αριθμός Αναπαραγωγής (R 0 ) bx 0 /g >1

12 ΒΑΣΙΚΟΣ ΑΡΙΘΜΟΣ ΑΝΑΠΑΡΑΓΩΓΗΣ Αριθμός των νέων κρουσμάτων που προκαλεί ένα μολυσμένο άτομο πριν αποσυρθεί - πεθάνει - θεραπευτεί - πάψει να είναι μολυσματικό Ανάλογος - του αριθμού των επαφών μεταξύ επίνοσων και μολυσματικών ατόμων στη μονάδα του χρόνου (c) - της πιθανότητας μετάδοσης κατά τη διάρκεια μιας επαφής (p) - της διάρκειας της μολυσματικότητας (d=1/g) R 0 = c p d

13 ΑΠΟΤΕΛΕΣΜΑΤΙΚΟΣ ΑΡΙΘΜΟΣ ΑΝΑΠΑΡΑΓΩΓΗΣ Αν ο πληθυσμός δεν αποτελείται μόνο από επίνοσα άτομα αλλά και από ένα ποσοστό άνοσων ατόμων (ξ) τα οποία δεν μπορούν να προσβληθούν, τότε ο αποτελεσματικός αριθμός αναπαραγωγής είναι R=R 0 (1-ξ) Για να μην διατηρηθεί μία επιδημία και να σβήσει από μόνη της, πρέπει R 1 Συνεπώς, το ποσοστό των ατόμων που πρέπει να εμβολιαστούν είναι (προυπόθεση: αποτελεσματικότητα 100%)!!1" 1 Ro

14 ΠΑΡΑΔΕΙΓΜΑ Αν ο βασικός αριθμός αναπαραγωγής είναι 5, τότε για να μην διαδοθεί η επιδημία πρεπει να εμβολιαστούν... α) 10%? β) 5%? γ) 80%?

15 ΑΠΟΤΕΛΕΣΜΑΤΙΚΟΤΗΤΑ Ποσοστό ατόμων που καθίστανται τελείως άνοσα όταν κάνουν το εμβόλιο (φ) Τότε, 1- φ δεν καθίστανται άνοσα. Θα πρέπει να εμβολιαστούν: κ=ξ/φ Οσο πιο μεγάλος είναι ο βασικός αριθμός αναπαραγωγής, τόσο πιο μικρό είναι το ανεκτό ποσοστό αποτυχίας.

16 ΜΕΙΩΣΗ ΠΕΡΙΟΔΟΥ ΜΟΛΥΣΜΑΤΙΚΟΤΗΤΑΣ Το εμβόλιο μπορεί να μην προσδίδει τέλεια ανοσία αλλά απλά να μειώνει τη διάρκεια της περιόδου μολυσματικότητας. - η νέα περίοδος μολυσματικότητας είναι ένα κλάσμα ρ της περιόδου μολυσματικότητας χωρίς το εμβόλιο Το εμβόλιο μπορεί να μειώνει την πιθανότητα μετάδοσης κατά τη διάρκεια μιας επαφής - είτε μειώνοντας το πόσο ευάλωτο είναι ένα εμβολιασμένο άτομο σε σχέση με ένα μη εμβολιασμένο (σχετική πιθανότητα θ) - είτε μειώνοντας τη μεταδοτικότητα από ένα μολυσμένο εμβολιασμένο άτομο σε σχέση με ένα μη εμβολιασμένο μολυσμένο άτομο (σχετική πιθανότητα ζ)

17 ΤΟΤΕ... R = θ ζ ρ R 0 Για να μην προκύψει επιδημία πρέπει θ ζ ρ < 1/ R 0 Ανοσολογικά Παρθένο Ισοδύναμο

18 Αν το ανοσολογικά παρθένο ισοδύναμο είναι μικρό, η πρόληψη της επιδημίας επιτυγχάνεται και εμβολιάζοντας μικρό ποσοστό του πληθυσμού. Αποτελεσματικότητα Ε= 1 - θζρ

19 ΕΜΒΟΛΙΑ Ζώντα εξασθενημένα π.χ. MMR, Var, BCG Αδρανοποιημένα - ολόκληρα - τμηματικά π.χ. HepA/B, Hib, DTaP, MCC etc.

20 ΠΡΟΓΡΑΜΜΑΤΑ ΕΜΒΟΛΙΑΣΜΩΝ

21 ! ΠΡΟΓΡΑΜΜΑΤΑ ΕΜΒΟΛΙΑΣΜΩΝ

22 ! ΜΟΝΟ ΣΕ ΠΑΙΔΙΑ;

23 ΑΠΟΤΕΛΕΣΜΑΤΙΚΟΤΗΤΑ Disease Pre-vaccine Era* 2006** % decrease Diphtheria 175, Measles 503, Mumps 152, , Pertussis 147,271 15, Polio (paralytic) 16, Rubella 47, Congenital Rubella Syn Tetanus 1, H. influenzae type b 20, and unknown (<5 yrs) Total 1,064,854 22, Vaccine Adverse Events N/A 15, * Baseline 20 th century annual morbidity + Estimated because no national reporting existed in the pre-vaccine era

24 TETANUS USA !"#$%&'()%*#"+ )%*#"+,#$#"'3 -./ Cas ses

25 ΑΣΦΑΛΕΙΑ Μελέτες σε ανθρώπους πριν την κυκλοφορία Σε μεγάλους πληθυσμούς Μελέτες φάσης I, II και III Ανίχνευση συχνών αντδράσεων

26 Publication Delay of Randomized Trials on 2009 Influenza A (H1N1) Vaccination John P. A. Ioannidis 1, Lamberto Manzoli 2 *, Corrado De Vito 3, Maddalena D Addario 3, Paolo Villari 3 1 Stanford Prevention Research Center, Department of Medicine and Department of Health Research Policy, Stanford University School of Medicine, Stanford, Publication California, United States of America, 2 Section Delay of Hygiene, Epidemiology, of Randomized Pharmacology Legal Medicine, University Trials G. d Annunzio of on Chieti, Chieti, 2009 Italy, 3 Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy Influenza A (H1N1) Vaccination Abstract Publication Delay of Trials on H1N1 Vaccine John P. A. Ioannidis 1, Lamberto Manzoli 2 *, Corrado De Vito 3, Maddalena D Addario 3, Paolo Villari 3 Background: Randomized evidence for vaccine immunogenicity and safety is urgently needed in the setting of pandemics 1 Stanford with new Prevention emerging Research infectious Center, agents. Department We carried of out Medicine an observational and Department surveyof tohealth evaluate Research how many and randomized Policy, Stanford controlled University School of Medicine, Stanford, California, trialsunited testingstates 2009 H1N1 of America, vaccines 2 Section were published of Hygiene, among Epidemiology, those registered, Pharmacology and what and waslegal the time Medicine, lag from University their start G. to d Annunzio of Chieti, Chieti, Italy, publication and from their completion to publication. 3 Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy Methods: PubMed, EMBASE and 9 clinical trial registries were searched for eligible randomized controlled trials. The units of the analysis were single randomized trials on any individual receiving influenza vaccines in any setting. Abstract Results: 73 eligible trials were identified that had been registered in By June 30, 2011 only 21 (29%) of these trials had been published, representing 38% of the randomized sample size (19905 of 52765). Trials starting later were published less rapidly (hazard ratio 0.42 per month; 95% Confidence Interval: 0.27 to 0.64; p,0.001). Similarly, trials completed later were published less rapidly (hazard ratio 0.43 per month; 95% CI: 0.27 to 0.67; p,0.001). Randomized controlled trials were completed promptly (median, 5 months from start to completion), but only a minority were subsequently published. Background: Randomized evidence for vaccine immunogenicity and safety is urgently needed in the setting of pandemics with new emerging infectious agents. We carried out an observational survey to evaluate how many randomized controlled trials testing 2009 H1N1 vaccines were published among those registered, and what was the time lag from their start to publication and from their completion to publication. Conclusions: Most registered randomized trials on vaccines for the H1N1 pandemic are not published in the peer-reviewed literature. Methods: PubMed, EMBASE and 9 clinical trial registries were searched for eligible randomized controlled trials. The units of the analysis were single randomized trials on any individual receiving influenza vaccines in any setting. Citation: Ioannidis JPA, Manzoli L, De Vito C, D Addario M, Villari P (2011) Publication Delay of Randomized Trials on 2009 Influenza A (H1N1) Vaccination. PLoS ONE 6(12): e doi: /journal.pone Results: 73 eligible trials were identified that had been registered in By June 30, 2011 only 21 (29%) of these trials had been published, representing 38% of the randomized sample size (19905 of 52765). Trials starting later were published less rapidly (hazard ratio 0.42 per month; 95% Confidence Interval: 0.27 to 0.64; p,0.001). Similarly, trials completed later were published less rapidly (hazard ratio 0.43 per month; 95% CI: 0.27 to 0.67; p,0.001). Randomized controlled trials were completed promptly (median, 5 months from start to completion), but only a minority were subsequently published. Editor: Neil R. Smalheiser, University of Illinois-Chicago, United States of America Received October 10, 2011; Accepted November 7, 2011; Published December 2, 2011 Copyright: ß 2011 Ioannidis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist. Conclusions: Most registered randomized trials on vaccines for the H1N1 pandemic are not published in the peer-reviewed literature. * lmanzoli@post.harvard.edu Introduction Figure 2. Cumulative sample size in launched and published trial registries trials inof andh1n and vaccines evaluated over whether time. these trials doi: /journal.pone g002 Citation: Ioannidis JPA, Manzoli L, De Vito C, D Addario M, Villari P (2011) have published Publicationany Delay dataof inrandomized the peer-reviewed Trials on literature 2009 Influenza by the end A (H1N1) Vaccination. PLoS Randomized controlled trials are pivotal in providing reliable ONE 6(12): e doi: /journal.pone of June 2011 and also how long it took from the time they started informationthis about is the noteffectiveness surprising given and safety the relatively of vaccines. simple In thedesignuntil of these they published particular their results. phase III trials, can vary substantially on the time they

27 ΑΣΦΑΛΕΙΑ Παρακολούθηση μετά την κυκλοφορία μελέτες τύπου IV (~10,000) ανίχνευση σπάνιων αντιδράσεων στενότερη παρακολούθηση των ήδη γνωστών αντιδράσεων ανίχνευση παραγόντων κινδύνου για αντιδράσεις καταγραφή ασυνήθιστων σε συχνότητα συμβαμάτων

28 (C-score p-values = 0.03 and 0.06 for single dose and two doses dose formulations tended to show significantly lower immunogenicity than higher doses, with relative risks increasing on average networks). Meta-Analysis of the Immunogenicity about and1.05- Tolerability and 1.10-fold, respectively ofwith each dose step Immunogenicity increase when all age groups were considered. The improvement PandemicOverall, Influenza the 18 RCTs included A 2009 in primary(h1n1) analyses reportedvaccines with higher doses tended to be higher in children and in the immunogenicity data on a total of 18,444 subjects, of whom elderly. Conversely, after two doses, there was hardly any doseresponse that could be detected (relative risks on average were 16,725 received at least one dose of vaccine. Lamberto Manzoli 1 *, Corrado De Vito 2, Georgia Salanti 3, Maddalena D Addario 2, Paolo Villari 2, John P.A. When single arm results were examined (Tables S2 and S3), and 1.05-fold per each dose step increase, respectively for Ioannidis 3,4 the immunogenicity tended to be higher in almost all trials among adjuvanted and non-adjuvanted formulations). 1 Section of Hygiene, Epidemiology, adults andpharmacology adolescentsand than Legal elderly Medicine, anduniversity children. G. d Annunzio After two doses of Chieti, Chieti, We Italy, also 2 Department tried tof Public quantify Healththe and Infectious increase in immunogenicity Diseases, Publication Sapienza University of split/subunit of Rome, Rome, Italy, inactivated Delay 3 Department vaccine, of Hygiene of seroconversion andrandomized Epidemiology, rates University were of Ioannina provided School by Trials of Medicine, a secondioannina, doseon Greece, of vaccine 4 Stanford 2009 computing the absolute Prevention Research Center,. = Department 75% in of allmedicine arms evaluating and Department adults of Health (n = Research 25) and andadolescents Policy, Stanford University percentages School of Medicine, subjects Stanford, who achieved California, seroconversion United only after the Influenza A (H1N1) Vaccination States of America John Abstract P. A. Ioannidis 1, Lamberto Manzoli 2 *, Corrado De Vito 3, Maddalena D Addario 3, Paolo Villari 3 1Background: Stanford Prevention Although Research the 2009 Center, (H1N1) Department influenza pandemic of Medicine officially and Department ended in August of Health 2010, Research the virus andwill Policy, probably Stanford circulate University School of Medicine, Stanford, California, in future years. UnitedSeveral States of types America, of H1N1 2 Section vaccines of Hygiene, have been Epidemiology, tested including Pharmacology various dosages and Legaland Medicine, adjuvants, University and meta- Department is needed of Public to identify Health and theinfectious best formulation. Diseases, Sapienza University of Rome, Rome, G. d Annunzio of Chieti, Chieti, Italy, 3analysis Italy Methods: We searched MEDLINE, EMBASE, and nine clinical trial registries to April 2011, in any language for randomized clinical trials (RCTs) on healthy children, adolescents, adults and the elderly. Primary outcome was the seroconversion rate according Abstract to hemagglutinination-inhibition (HI); secondary outcomes were adverse events. For the primary outcome, we used head-to-head meta-analysis and multiple-treatments meta-analysis. Background: Randomized evidence for vaccine immunogenicity and safety is urgently needed in the setting of pandemics Results: witheighteen new emerging RCTs couldinfectious be includedagents. all primary We carried analyses, out foran a total observational of 76 arms (16,725 surveysubjects). to evaluate Afterhow 2 doses, many all randomized controlled 2009 H1N1 split/subunit inactivated were highly immunogenic and overcome CPMP seroconversion criteria. After 1 trials testing 2009 H1N1 vaccines were published among those registered, and what was the time lag from their start to dose only, all split/subunit vaccines induced a satisfactory immunogenicity (. = 70%) in adults and adolescents, while only somepublication formulationsand showed fromacceptable their completion results for to children publication. and elderly (non-adjuvanted at high-doses and oil-in-water adjuvanted vaccines). Vaccines with oil-in-water adjuvants were more immunogenic than both nonadjuvanted and aluminum-adjuvanted Methods: PubMed, vaccines EMBASE at equal and doses 9 clinical and their trial immunogenicity registries were at doses searched, = 6 mg for(even eligible withrandomized as little as controlled mg trials. The units of of hemagglutinin the analysisantigen) were single was not randomized significantly lower trials than on any thatindividual achieved after receiving higher doses. influenza Finally, vaccines the ratein of any serious setting. vaccine-related adverse events was low for all 2009 H1N1 vaccines (3 cases, resolved in 10 days, out of vaccinated subjects). Results: However, 73 eligible mild to moderate trials were adverse identified reactions that werehad more been (and very) registered frequent infor oil-in-water adjuvanted By June 30, vaccines only 21 (29%) of these Conclusions: trials had Several been one-dose published, formulations representing might be38% validof forthe future randomized vaccines, butsample 2 doses size may be (19905 needed offor 52765). children, Trials starting later were especially published if a low-dose less rapidly non-adjuvanted (hazardvaccine ratio is 0.42 used. per Given month; that 1595% RCTsConfidence were sponsored Interval: by vaccine 0.27manufacturers, to 0.64; p,0.001). Similarly, trials futurecompleted trials sponsored laterbywere non-industry published agencies less and rapidly comparing (hazard vaccines ratiousing 0.43different per month; types of 95% adjuvants CI: 0.27 areto needed. 0.67; p,0.001). Randomized controlled trials were completed promptly (median, 5 months from start to completion), but only a minority were subsequently published. Citation: Manzoli L, De Vito C, Salanti G, D Addario M, Villari P, et al. (2011) Meta-Analysis of the Immunogenicity and Tolerability of Pandemic Influenza A 2009 (H1N1) Vaccines. PLoS ONE 6(9): e doi: /journal.pone Conclusions: Most registered randomized trials on vaccines for the H1N1 pandemic are not published in the peer-reviewed literature. Editor: Leo L. M. Poon, University of Hong Kong, Hong Kong Received June 16, 2011; Accepted August 5, 2011; Published September 6, 2011 Copyright: ß 2011 Manzoli et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Citation: Ioannidis JPA, Manzoli L, De Vito C, D Addario M, Villari P (2011) Publication Delay of Randomized Trials on 2009 Influenza A (H1N1) Vaccination. PLoS Funding: Georgia Salanti received a European Research Council (ERC) starting grant (IMMA ). Lamberto Manzoli received a grant from his university, the ONE 6(12): e Figuredoi: /journal.pone The network for multiple-treatments meta-analysis (MTM) includes all the randomized controlled trials that evaluate

29 Publication Delay of Randomized Trials on 2009 Influenza A (H1N1) Vaccination John P. A. Ioannidis 1, Lamberto Manzoli 2 *, Corrado DePublication Vito 3 Delay, Maddalena of Trials on H1N1D Addario Vaccine 3, Paolo Villari 3 1 Stanford Prevention Research Center, Department of Medicine and Department of Health Research Policy, Stanford University School of Medicine, Stanford, Publication California, United States of America, 2 Section Delay of Hygiene, Epidemiology, of Randomized Pharmacology Legal Medicine, University Trials G. d Annunzio of on Chieti, Chieti, 2009 Italy, 3 Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy Influenza A (H1N1) Vaccination Abstract John P. A. Ioannidis 1, Lamberto Manzoli 2 *, Corrado De Vito 3, Maddalena D Addario 3, Paolo Villari 3 Background: Randomized evidence for vaccine immunogenicity and safety is urgently needed in the setting of pandemics 1 Stanford with new Prevention emerging Research infectious Center, agents. Department We carried of out Medicine an observational and Department surveyof tohealth evaluate Research how many and randomized Policy, Stanford controlled University School of Medicine, Stanford, California, trialsunited testingstates 2009 H1N1 of America, vaccines 2 Section were published of Hygiene, among Epidemiology, those registered, Pharmacology and what and waslegal the time Medicine, lag from University their start G. to d Annunzio of Chieti, Chieti, Italy, publication and from their completion to publication. 3 Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy Methods: PubMed, EMBASE and 9 clinical trial registries were searched for eligible randomized controlled trials. The units of the analysis were single randomized trials on any individual receiving influenza vaccines in any setting. Abstract Publication Dela Results: 73 eligible trials were identified that had been registered in By June 30, 2011 only 21 (29%) of these trials had been published, representing 38% of the randomized sample size (19905 of 52765). Trials starting later were published Background: less rapidly Randomized (hazard ratio evidence 0.42 per formonth; vaccine 95% immunogenicity Confidence Interval: and0.27 safety to 0.64; is urgently p,0.001). needed Similarly, intrials the setting of pandemics with completed new emerging later were published infectious lessagents. rapidly (hazard We carried ratio 0.43 outper an observational month; 95% CI: 0.27 survey to 0.67; to evaluate p,0.001). how Randomized many randomized controlled trials controlled testing trials2009 wereh1n1 completed vaccines promptly were (median, published 5 months among fromthose start toregistered, completion), and butwhat only awas minority the time were lag from their start to subsequently published. publication and from their completion to publication. Figure 1. Time from start to publication for 2009 H1N1 vaccine trials overall (A) andfigure according 3. Time tofrom sponsor start (B). to completion (A) and from completion to publication (B) for 20 doi: /journal.pone g001 Conclusions: Most registered randomized trials on vaccines for the H1N1 pandemic doi: /journal.pone g003 are not published in the peer-reviewed literature. Methods: PubMed, EMBASE and 9 clinical trial registries were searched for eligible randomized controlled trials. The units of the analysis were single randomized trials on any individual receiving within the first influenza year fromvaccines their publication. in any However, setting. this was just majority of the eviden 20.69, p,0.001). Eight of the 9 trials published in 2009 appeared evidence on the potential vaccines has been published. The global the tip of the iceberg of in New England Citation: Journal Ioannidisof JPA, Medicine, Manzoli L, De Lancet, Vito C, D Addario or JAMA. M, Only Villari P 2(2011) of Publication response Delay to of the Randomized pandemic Trialswas on 2009 ultrafast Influenza 1 the randomized evidence on this topic. appraising the overall and A (H1N1) thisvaccination. includedplos the Interest in the other trials diminished and faded over time, in vaccines [19]. Moreov the 10 trials ONE Results: published 6(12): e indoi: /journal.pone eligible 2010 appeared trials were journals identified with impact that had early been launch registered of numerous particular in after randomized the fall of trials By June Later for testing published 30, 2011 many trials only appeared 21 (29%) in developed of these from at least factor above Editor: trials 6Neil and had R. Smalheiser, even been these published, University did not of Illinois-Chicago, appear representing United any of States 38% theof America ofdifferent the randomized vaccine formulations. journals sample of far However, lesser size citation (19905 very limited impact. of 52765). randomized By 2011Trials two trials starting were later to extrapolate were inferenc aforementioned Received3 published October top-impact less 10, 2011; rapidly Accepted journals. (hazard November The only 7, ratio 2011; two Published trials 0.42 per December evidence month; 2, 2011 was published 95% Confidence published in the as peer-reviewed a single Interval: paper0.27 inliterature a lowtoimpact-factor by the time 0.64; p,0.001). journal, while Similarly, Fragmentation trials and lack published to-date during 2011 were published together as a single major decisions were trialsmade of similar in the magnitude fall of 2009 could have about been thepublished use of in a major on a topic of major pub Copyright: completed ß 2011later Ioannidis were et al. This published an open-access less article rapidly distributed (hazard under the ratio terms0.43 of theper Creative month; Commons95% Attribution CI: License, 0.27 which to 0.67; permits paper (2 p,0.001). Randomized unrestricted in 1) in a use, journal distribution, with impact and reproduction factor less in any than medium, 2.5. provided thethese original vaccines author and[3]. source journal Peer-reviewed are in credited data appeared in the highestimpact journals 5 months over Eventually, from 15,000start less participants thanto30% completion), of bythe thetrials endregistered of but 2009, inonly a minority know the were results of the u Some limitations sho controlled trials were completed promptly (median, Funding: The authors have no support or funding to report. Discussion subsequently published. but relatively limited were evidence published was bypublished mid inthis 2010 lackorof2011 published and data for the seem not even complete Competing Interests: The authors have declared that no competing interests none exist. of the trials launched after October 2009 have been Two years * lmanzoli@post.harvard.edu Conclusions: after the emergence Most registered of the influenza randomized 2009 H1N1 trials on published vaccines as ofor June the2011, H1N1 well pandemic after the are not published influenza in the peer-reviewed pandemic literature. and well after the end of both the and 2010 season has finished. Trials were generally completed promptly, 2011 seasons only a minority of the registered randomized with a median time of 5 months from starting until completion. Introduction trial registries in 2009 and 2010 and evaluated whether these trials Citation: Ioannidis JPA, Manzoli L, De Vito C, D Addario M, Villari P (2011) have published Publicationany Delay dataof inrandomized the peer-reviewed Trials on literature 2009 Influenza by the end A (H1N1) Vaccination. PLoS PLoS Randomized ONE controlled trials are pivotal in providing reliable 3 ONE 6(12): e doi: /journal.pone of June 2011 and December also how 2011 long Volume it took from 6 Issue the time 12 they e28346 started information about the effectiveness and safety of vaccines. In the until they published their results. PLoS ONE 5 Decem

30 ΧΗΜΕΙΟΠΡΟΦΥΛΑΞΗ Λήψη βιολογικών ουσιών με σκοπό την πρόληψη της εκδήλωσης νόσων ή των επιπλοκών τους π.χ. - αμοξικιλλίνη πριν από οδοντηατρικές επεμβάσεις για πρόληψη βακτηριακής ενδοκαρδίτιδας σε ασθενείς με προσθετικές βαλβίδες - heparin πριν από μεγάλες χειρουργικές επεμβάσεις - anti-tb αγωγή σε άτομα που έρχονται σε στενή επαφή με ΤΒ+ - ταμοξιφαίνη σε γυναίκες υψηλού κινδύνου για BrCa

31 ΧΗΜΕΙΟΠΡΟΦΥΛΑΞΗ Αναζήτηση πληυθσμού υψηλού κινδύνου για τον οποίο ενδείκνυται η χημεμειοπροφύλαξη. Πολλές φορές οι ασθενείς αυτοί είναι τελείως ασυμπτωματικοί. - δύσκολη συμμόρφωση γιατί το όφελος συχνά δεν είναι άμεσα αισθητό ειδικά σε μακροχρόνιες παρεμβάσεις για σχετικά λιγότερο συχνές εκβάσεις Αντίθετα, σε περιπτώσεις με άμεσο όφελος (π.χ. πρόληψη ενδοκαρδίτιδας), η συμμόρφωση είναι καλύτερη.