Two-dose SARS-CoV-2 vaccine effectiveness with mixed schedules and extended dosing intervals: test-negative design studies from British Columbia and Quebec, Canada

Background The Canadian COVID-19 immunization strategy deferred second doses and allowed mixed schedules. We compared two-dose vaccine effectiveness (VE) by vaccine type (mRNA and/or ChAdOx1), interval between doses, and time since second dose in two of Canada's larger provinces. Methods Two-dose VE against infections and hospitalizations due to SARS-CoV-2, including variants of concern, was assessed between May 30 and October 2, 2021 using test-negative designs separately conducted among community-dwelling adults ≥18-years-old in British Columbia (BC) and Quebec, Canada. Findings In both provinces, two doses of homologous or heterologous SARS-CoV-2 vaccines were associated with ~95% reduction in the risk of hospitalization. VE exceeded 90% against SARS-CoV-2 infection when at least one dose was an mRNA vaccine, but was lower at ~70% when both doses were ChAdOx1. Estimates were similar by age group (including adults ≥70-years-old) and for Delta-variant outcomes. VE was significantly higher against both infection and hospitalization with longer 7-8-week vs. manufacturer-specified 3-4-week interval between doses. Two-dose mRNA VE was maintained against hospitalization for the 5-7-month monitoring period and while showing some decline against infection, remained ≥80%. Interpretation Two doses of mRNA and/or ChAdOx1 vaccines gave excellent protection against hospitalization, with no sign of decline by 5-7 months post-vaccination. A 7-8-week interval between doses improved VE and may be optimal in most circumstances. Findings indicate prolonged two-dose protection and support the use of mixed schedules and longer intervals between doses, with global health, equity and access implications in the context of recent third-dose proposals.

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Single-dose mRNA vaccine effectiveness against SARS-CoV-2, including P.1 and B.1.1.7 variants: a test-negative design in adults 70 years and older in British Columbia, Canada

10.1101/2021.06.07.21258332 ◽

2021 ◽

Author(s):

Danuta M Skowronski ◽

Solmaz Setayeshgar ◽

Macy Zou ◽

Natalie Prystajecky ◽

John R Tyson ◽

...

Keyword(s):

British Columbia ◽

Single Dose ◽

Vaccine Effectiveness ◽

Community Dwelling ◽

Rt Pcr ◽

Vaccine Protection ◽

Post Vaccination ◽

Randomized Controlled ◽

Specimen Collection ◽

Negative Controls

Introduction: Randomized-controlled trials of mRNA vaccine protection against SARS-CoV-2 included relatively few elderly participants. We assess singe-dose mRNA vaccine effectiveness (VE) in adults ≥70-years-old in British Columbia (BC), Canada where the second dose was deferred by up to 16 weeks and where a spring 2021 wave uniquely included co-dominant circulation of B.1.1.7 and P.1 variants of concern (VOC). Methods: Analyses included community-dwelling adults ≥70-years-old with specimen collection between April 4 (epidemiological week 14) and May 1 (week 17). Adjusted VE was estimated by test-negative design through provincial laboratory and immunization data linkage. Cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Vaccine status was defined by receipt of a single-dose ≥21 days before specimen collection, but a range of intervals was assessed. In variant-specific analyses, test-positive cases were restricted to those genetically-characterized as B.1.1.7, P.1 or non-VOC. Results: VE analyses included 16,993 specimens: 1,226 (7.2%) test-positive cases and 15,767 test-negative controls. Of 1,131 (92%) viruses genetically categorized, 509 (45%), 314 (28%) and 276 (24%) were B.1.1.7, P.1 and non-VOC lineages, respectively. VE was negligible at 14% (95% CI 0-26) during the period 0-13 days post-vaccination but increased from 43% (95% CI 30-53) at 14-20 days to 75% (95% CI 63-83) at 35-41 days post-vaccination. VE at ≥21 days was 65% (95% CI 58-71) overall: 72% (95% CI 58-81), 67% (95% CI 57-75) and 61% (95% CI 45-72) for non-VOC, B.1.1.7 and P.1, respectively. Conclusions: A single dose of mRNA vaccine reduced the risk of SARS-CoV-2 in adults ≥70-years-old by about two-thirds, with protection only minimally reduced against B.1.1.7 and P.1 variants. Substantial single-dose protection in older adults reinforces the option to defer the second dose when vaccine supply is scarce and broader first-dose coverage is needed.

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Recombinant Zoster Vaccine (Shingrix) real-world effectiveness in the first two years post-licensure

Clinical Infectious Diseases ◽

10.1093/cid/ciab125 ◽

2021 ◽

Author(s):

Hector S Izurieta ◽

Xiyuan Wu ◽

Richard Forshee ◽

Yun Lu ◽

Heng-Ming Sung ◽

...

Keyword(s):

Clinical Trials ◽

Herpes Zoster ◽

Real World ◽

Postherpetic Neuralgia ◽

Vaccine Effectiveness ◽

Community Dwelling ◽

Zoster Vaccine ◽

Post Market ◽

Recombinant Zoster Vaccine ◽

Dose Vaccine

Abstract Background Shingrix™ (recombinant zoster vaccine) was licensed to prevent herpes zoster, dispensed as two doses given 2–6 months apart, among adults ages ≥50 years. Clinical trials yielded efficacy of >90% for confirmed herpes zoster,but post-market vaccine performance has not been evaluated. Efficacy of a single dose, delayed second dose, or among persons with autoimmune or general immunosuppressive conditions have also not been studied. We aimed to assess post-market vaccine effectiveness of Shingrix. Methods We conducted a cohort study among vaccinated and unvaccinated Medicare Part D community dwelling beneficiaries ages >65 years. Herpes zoster was identified using a medical office visit diagnosis with treatment, and postherpetic neuralgia using a validated algorithm. We used inverse probability of treatment weighting to improve cohort balance, and marginal structural models to estimate hazard ratios. Results We found a vaccine effectiveness of 70.1% (95% CI, 68.6–71.5) and 56.9% (95% CI, 55.0–58.8) for two and one doses, respectively. The two-dose vaccine effectiveness was not significantly lower for beneficiaries 80+ years, for second doses received at ≥180 days, or for individuals with autoimmune conditions. The vaccine was also effective among individuals with immunosuppressive conditions. Two-dose vaccine effectiveness against postherpetic neuralgia was 76.0% (95% CI, 68.4-81.8). Conclusions This large real-world observational study of effectiveness of Shingrix demonstrates the benefit of completing the two-dose regimen. Second doses administered beyond the recommended 6 months did not impair vaccine effectiveness.Our effectiveness estimates were lower than the clinical trials estimates, likely due to differences in outcome specificity.

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Comparative single-dose mRNA and ChAdOx1 vaccine effectiveness against SARS-CoV-2, including early variants of concern: a test-negative design, British Columbia, Canada

10.1101/2021.09.20.21263875 ◽

2021 ◽

Author(s):

Danuta M Skowronski ◽

Solmaz Setayeshgar ◽

Macy Zou ◽

Natalie Prystajecky ◽

John R Tyson ◽

...

Keyword(s):

British Columbia ◽

Single Dose ◽

Genetic Characterization ◽

Infection Risk ◽

Vaccine Effectiveness ◽

Rt Pcr ◽

Randomized Controlled ◽

Specimen Collection ◽

Dose Vaccine

Introduction: In randomized controlled trials, single-dose efficacy against SARS-CoV-2 illness exceeded 90% for mRNA vaccines (BNT162b2 and mRNA-1273), and 75% for ChAdOx1. In British Columbia (BC), Canada second doses were deferred up to 16 weeks and ChAdOx1 was only initially recommended for adults 55 years of age and older. We compared single-dose vaccine effectiveness (VE) during the spring 2021 wave in BC when Alpha and Gamma variants of concern (VOC) predominated. Methods: VE was estimated against infection and hospitalization by test-negative design: cases were RT-PCR test-positive for SARS-CoV-2 and controls were test-negative. Adults 50-69 years old with specimen collection between April 4 and May 22 (weeks 14-20) were included. Variant-specific VE was estimated between weeks 17-20 when genetic characterization of all case viruses was performed, primarily through whole genome sequencing. Results: VE analyses included 7,116 (10%) cases and 60,958 controls. Three-quarters of vaccinated participants received mRNA vaccine (60% BNT162b2, 15% mRNA-1273) and 25% received ChAdOx1. Half of genetically characterized viruses were Alpha, with 38% Gamma, 4% Delta and 8% non-VOCs. Single-dose VE against any infection was 75% (95%CI: 72-78) for BNT162b2, 82% (95%CI: 76-87) for mRNA-1273 and 61% (95%CI: 54-66) for ChAdOx1. VE against hospitalization was 83% (95%CI: 76-89), 85% (95%CI: 63-94) and 96% (95%CI: 86-99), respectively. VE against Alpha vs. Gamma infections did not differ among mRNA (78%;95%CI: 73-82 and 80%;95%CI: 74-85) or ChAdOx1 (66%;95%CI: 57-74 and 60%;95%CI: 48-69) recipients. Conclusions: A single dose of mRNA vaccine reduced the SARS-CoV-2 infection risk by at least 75%, including infections due to early VOC. Although effectiveness of a single dose of ChAdOx1 was lower at 60% against infection, just one dose of any vaccine reduced the hospitalization risk by more than 80%. In the context of constrained vaccine supplies, these findings have implications for global vaccine deployment to reduce the overall burden of infections and hospitalizations due to SARS-CoV-2.

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Effectiveness of COVID-19 Vaccines: Eight Months Post Single Dose Vaccination

10.1101/2021.09.18.21263262 ◽

2021 ◽

Author(s):

Naif Khalaf Alharbi ◽

Jaffar A. Al-Tawfiq ◽

Suliman Alghnam ◽

Amal Alwehaibe ◽

Abrar Alasmari ◽

...

Keyword(s):

Single Dose ◽

Medical Records ◽

Real World Data ◽

Kingdom Of Saudi Arabia ◽

Post Vaccination ◽

Vaccine Type ◽

National Databases ◽

Site Pain ◽

Saudi Male

Objectives: To describe the real-world data on the effectiveness of Pfizer-BioNtech BNT162b2 and AstraZeneca-Oxford AZD1222 vaccines against COVID-19 in a large cohort in the Kingdom of Saudi Arabia (KSA). Methods: A total of 18,543 subjects received a single-dose of either of the vaccines at one vaccination centre in KSA, and were followed up for three to eight months. Clinical data from medical records, adverse events (AEs) from a self-reporting system, and COVID-19 infection data from the national databases were retrieved and analysed. Results: Subjects median age was 33 years old with an average of 27.3 body mass index and the majority were male (60.1%). 92.17% of the subjects had no COVID-19 infection post-vaccination. Diabetes mellitus (p=0.0325), organ transplantation (p=0.0254), and morbid obesity (p=0.0014) were risk factors for infection post-vaccination. Unlike vaccine type, being Saudi, male, or obese was more likely to get the infection earlier. AE reports from 1084 subjects included injection site pain, fatigue, fever, myalgia, headache. Conclusion: Single-dose COVID-19 vaccines in KSA showed an effectiveness rate of 92.17% up to eight months follow-up. The rate for AZD1222 was higher than what have been previously reported. Side effects and AEs were within what has been reported in clinical trials.

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Early signals of vaccine driven perturbation seen in pneumococcal carriage population genomic data

10.1101/459693 ◽

2018 ◽

Author(s):

Chrispin Chaguza ◽

Ellen Heinsbroek ◽

Rebecca A. Gladstone ◽

Terence Tafatatha ◽

Maaike Alaerts ◽

...

Keyword(s):

Population Structure ◽

Mobile Genetic Elements ◽

Post Vaccination ◽

Accessory Genome ◽

Genetic Elements ◽

Genomic Level ◽

Accessory Genes ◽

Serotype Replacement ◽

Vaccine Type ◽

Genome Level

AbstractPneumococcal conjugate vaccines (PCV) have reduced pneumococcal diseases globally. Despite this, much remains to be learned about their effect on pathogen population structure. Here we undertook whole genome sequencing of 660 pneumococcal strains from asymptomatic carriers to investigate population restructuring in pneumococcal strains sampled before and after PCV13 introduction in a previously vaccine-naïve setting. We show substantial decreasing frequency of vaccine-type (VT) strains and their strain diversity post-vaccination in the vaccinated but not unvaccinated age groups indicative of direct but limited or delayed indirect effect of vaccination. Clearance of identical VT serotypes associated with multiple lineages occurred regardless of their genetic background. Interestingly, despite the increasing frequency of non-vaccine type (NVT) strains through serotype replacement, the serotype diversity was not fully restored to the levels observed prior to vaccination implying limited serotype replacement. The frequency of antibiotic resistant strains was low and remained largely unchanged post-vaccination but intermediate-penicillin-resistant lineages were reduced in the post vaccine population. Significant perturbations marked by changing frequency of accessory genes associated with diverse functions especially mobile genetic elements and bacteriocin activity were detected. This phylogenomic analysis demonstrates early vaccine-induced pneumococcal population restructuring not only at serotype but also accessory genome level.Author summaryDifferent formulations of PCVs have been effective in reducing the invasive pneumococcal disease burden globally. Clinical trials have started to indicate high impact and effectiveness of PCV13 in Sub Saharan Africa (SSA) but there is limited understanding of how the introduction of PCVs alters the population structure of pneumococcal strains at serotype and genomic level. Here we investigated this using pneumococcal strains sampled pre‐ and post-PCV13 introduction from a previously vaccine naïve setting in Northern Malawi. Our findings reveal decrease in frequency of VT serotypes and their associated lineages in the largely vaccinated under-five population but not older individuals indicating a direct but limited or delayed indirect protection. The diversity of serotypes also decreased post-vaccination in VT strains in the under-fives but there was no change in NVT strains suggesting incomplete serotype replacement. At the genomic level, logistic regression revealed changing frequency of accessory genes largely associated with mobile genetic elements but such changes did not include any antibiotic resistance genes. These findings show significant perturbations at serotype and accessory genome level in carried pneumococcal population after two years from PCV13 introduction but the pneumococcal population was still perturbed and had not returned to a new equilibrium state.

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Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: test negative design study

BMJ ◽

10.1136/bmj.n1943 ◽

2021 ◽

pp. n1943 ◽

Cited By ~ 1

Author(s):

Hannah Chung ◽

Siyi He ◽

Sharifa Nasreen ◽

Maria E Sundaram ◽

Sarah A Buchan ◽

...

Keyword(s):

Hospital Admission ◽

Clinical Characteristics ◽

Hospital Admissions ◽

Vaccine Effectiveness ◽

Community Dwelling ◽

Rt Pcr ◽

Chain Reaction ◽

Design Study ◽

Symptomatic Infection ◽

Polymerase Chain

AbstractObjectiveTo estimate the effectiveness of mRNA covid-19 vaccines against symptomatic infection and severe outcomes (hospital admission or death).DesignTest negative design study.SettingOntario, Canada between 14 December 2020 and 19 April 2021.Participants324 033 community dwelling people aged ≥16 years who had symptoms of covid-19 and were tested for SARS-CoV-2.InterventionsBNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine.Main outcome measuresLaboratory confirmed SARS-CoV-2 by reverse transcription polymerase chain reaction (RT-PCR) and hospital admissions and deaths associated with SARS-CoV-2 infection. Multivariable logistic regression was adjusted for personal and clinical characteristics associated with SARS-CoV-2 and vaccine receipt to estimate vaccine effectiveness against symptomatic infection and severe outcomes.ResultsOf 324 033 people with symptoms, 53 270 (16.4%) were positive for SARS-CoV-2 and 21 272 (6.6%) received at least one dose of vaccine. Among participants who tested positive, 2479 (4.7%) were admitted to hospital or died. Vaccine effectiveness against symptomatic infection observed ≥14 days after one dose was 60% (95% confidence interval 57% to 64%), increasing from 48% (41% to 54%) at 14-20 days after one dose to 71% (63% to 78%) at 35-41 days. Vaccine effectiveness observed ≥7 days after two doses was 91% (89% to 93%). Vaccine effectiveness against hospital admission or death observed ≥14 days after one dose was 70% (60% to 77%), increasing from 62% (44% to 75%) at 14-20 days to 91% (73% to 97%) at ≥35 days, whereas vaccine effectiveness observed ≥7 days after two doses was 98% (88% to 100%). For adults aged ≥70 years, vaccine effectiveness estimates were observed to be lower for intervals shortly after one dose but were comparable to those for younger people for all intervals after 28 days. After two doses, high vaccine effectiveness was observed against variants with the E484K mutation.ConclusionsTwo doses of mRNA covid-19 vaccines were observed to be highly effective against symptomatic infection and severe outcomes. Vaccine effectiveness of one dose was observed to be lower, particularly for older adults shortly after the first dose.

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COVID19 vaccine type and humoral immune response in patients receiving dialysis

10.1101/2021.08.02.21261516 ◽

2021 ◽

Author(s):

Pablo Garcia ◽

Shuchi Anand ◽

Jialin Han ◽

Maria Montez-Rath ◽

Sumi Sun ◽

...

Keyword(s):

Immune Response ◽

Antibody Index ◽

Igg Antibody ◽

Post Vaccination ◽

Humoral Immune ◽

Vaccination Response ◽

Vaccine Type ◽

Igg Index ◽

Impaired Immune Response ◽

Index Value

Background Patients on dialysis vaccinated with the attenuated adenovirus SARS-CoV-2 vaccine might mount an impaired response to vaccination. Methods We evaluated the humoral vaccination response among 2,099 fully vaccinated patients receiving dialysis. We used commercially available assays (Siemens) to assess prevalence of no response or diminished response to COVID-19 vaccination by vaccine type. We defined no seroconversion as lack of change from negative to positive in total RBD Ig antibody, no detectable response on semiquantitative RBD IgG antibody (index value <1) as no RBD IgG response, and a semiquantitative RBD IgG index value <10 as diminished RBD IgG response Results Of the 2,099 fully vaccinated patients on dialysis, the proportion receiving the mRNA1273, BNT162b2, and Ad26.COV2.S were 62% (n=1316), 20% (n=416) and 18% (n=367), respectively. A third (33.3%) of patients receiving the attenuated adenovirus Ad26.COV2.S vaccine failed to seroconvert and an additional 36% had no detectable or diminished IgG response even 28-60 days post vaccination. Conclusions One in three fully vaccinated patients receiving dialysis had evidence of an impaired immune response to the attenuated adenovirus Ad26.COV2.S vaccine.

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Serotypes and antibiotic susceptibility profile of Streptococcus pneumoniae isolated from nasopharynges of children infected with HIV in Jakarta, Indonesia, pre- and post-pneumococcal vaccination

Access Microbiology ◽

10.1099/acmi.0.000215 ◽

2021 ◽

Author(s):

Dina Muktiarti ◽

Miftahuddin Majid Khoeri ◽

Wisnu Tafroji ◽

Lia Waslia ◽

Dodi Safari

Keyword(s):

Antibiotic Susceptibility ◽

Type Species ◽

Pneumococcal Vaccination ◽

Nasopharyngeal Swab ◽

Post Vaccination ◽

Content Type ◽

Link Type ◽

Vaccine Type ◽

Before And After ◽

Type Strains

The aim of this prospective study was to investigate the serotypes and antibiotic susceptibility of S. pneumoniae carried by children infected with HIV before and after vaccination with the seven-valent pneumococcal conjugate vaccine in Jakarta, Indonesia in 2013. We collected nasopharyngeal swab specimens from 52 children pre-vaccination and 6 months post-vaccination. Serotyping was performed by conventional multiplex polymerase chain reaction and Quellung reaction. The antibiotic susceptibility profile was obtained by disc diffusion. We determined that 27 (52%) and 24 (46%) of the 52 children carried S. pneumoniae during pre- and post-vaccination periods, respectively with the majority of the isolates being non-vaccine type strains (85% pre-vaccination and 75% post-vaccination). Serotypes 34, 6C, and 16F (two strains each) were the most commonly identified serotypes at pre-vaccination. Serotypes 23A (three strains) and 19F (two strains) were the most commonly identified serotypes post-vaccination. In general, isolates were most commonly susceptible to chloramphenicol (88%) and clindamycin (88%), followed by erythromycin (84%), trimethoprim-sulphamethoxazole (69%), tetracycline (61%), and penicillin (59%). In conclusion, serotypes of S. pneumoniae isolated from the nasopharynges of children infected with HIV varied and were more likely to be non-vaccine type strains both before and after vaccination.

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Effects of Prior Influenza Exposure on Immunogenicity of Influenza Vaccine

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa181 ◽

2020 ◽

Author(s):

Jia-Qian Cao ◽

Peng-Fei Jin ◽

Zhao-Zhun Zeng ◽

Li Zhang ◽

Fan-Yue Meng ◽

...

Keyword(s):

Clinical Trials ◽

Influenza Virus ◽

Immune Responses ◽

Influenza Vaccine ◽

Hemagglutination Inhibition ◽

Cross Reactivity ◽

Vaccine Effectiveness ◽

Prior Exposure ◽

Post Vaccination ◽

Blood Samples

Abstract Background To investigate effects of prior influenza exposure on vaccine-elicited humor immune responses to circulating influenza variants. Method We randomly selected 360 participants in previous clinical trials stratified by age. Blood samples before and 28 days after vaccination were collected and tested by hemagglutination-inhibition tests against both vaccine strains and circulating variants during the 2015–2016 influenza seasons in China. The antigenic map was plotted and antigenic distance was calculated. Results Subjects with H1-priming had higher cross-reactive antibodies titers against A/JiangsuTinghu/11019/2015(H3N2) compared with subjects with B-priming did (Padjusted=0.038). Subjects with H1-priming also had higher cross-reactive antibodies titers against A/Jiangsu Qinhuai/11059/2015(H3N2) than subjects with both H1 and B priming did (Padjusted=0.036). Nevertheless, subjects with no H1 and B-priming had higher cross-reactive antibodies titers against A/Jiangsu Qinhuai/11059/2015(H3N2) than subjects with both H1 and B priming did (Padjusted=0.012). Antigenic distance was well-matched with serological results. Besides, age-specific differences in human post-vaccination responses against the identical circulating strain was noted. And children had most cross-reactive response to both H3N2 and B-yamagata subtypes. Conclusion Our results suggest that prior exposure to H1 or B influenza virus may influence cross-reactivity of H3-specific post-vaccination responses and consequently could influence the vaccine effectiveness. Our findings also support that there are age-specific differences in human post-vaccination responses.

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Hospitalization Rates of Nursing Home Residents and Community-Dwelling Seniors in British Columbia

Canadian Journal on Aging / La Revue canadienne du vieillissement ◽

10.3138/cja.27.1.109 ◽

2008 ◽

Vol 27 (1) ◽

pp. 109-115 ◽

Cited By ~ 32

Author(s):

Lisa A. Ronald ◽

Margaret J. McGregor ◽

Kimberlyn M. McGrail ◽

Robert B. Tate ◽

Anne-Marie Broemling

Keyword(s):

British Columbia ◽

Nursing Home ◽

Nous Avons ◽

Nursing Home Residents ◽

Community Dwelling ◽

Personnes Âgées ◽

Fracture Du Fémur ◽

Hospitalization Rates ◽

Données Administratives ◽

Fracture Du Femur

RÉSUMÉl'utilisation de l'ensemble des services de soins actifs par les pensionnaires des CHSLD (centres d'hébergement et de soins de longue durée) au Canada n'a pas été bien documentée. Nous visions à déterminer les principales causes de l'hospitalisation des pensionnaires des CHSLD et à en comparer le taux avec celui des personnes âgées résidant dans la communauté. Nous avons analysé une cohorte rétrospective à l'aide de données administratives sur la santé au niveau de la population, y compris toutes les personnes de 65 ans et plus résidant dans un CHSLD en Colombie-Britannique entre avril 1996 et mars 1999. Les taux d'hospitalisation des pensionnaires des CHSLD ont été comparés aux taux estimatifs des personnes âgées résidant dans la communauté, à l'aide de ratios standardisés d'incidence en fonction du sexe (RSI): RSI = 2,81 (95% CI: 2,71, 2,91) pour les fractures du fémur ; 1,96 (1,88, 2,04) pour la pneumonie ; 0,73 (0,70, 0,76) pour d'autres maladies du coeur; et 1,01 (0,99, 1,02) toutes causes confondues. Les pensionnaires des CHSLD sont plus susceptibles de présenter un écart plus considérable du taux d'hospitalisation pour une fracture du fémur ou une pneumonie, les pensionnaires des CHSLD représentant environ le quart des aînés de la Colombie-Britannique hospitalisés pour une fracture du fémur.

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