Heterologous prime boost COVID 19 vaccination.

Heterologous prime boost vaccination is a primary vaccination with different vaccines, most often from different vaccine platforms. It combines the immunological properties of the different vaccines and thereby induces humoral, cellular and, in some cases, mucosal response. For Covid prevention, it has been used in primary vaccination, due to safety issues and in boosters. We have evaluated some articles reporting on the results of this type of vaccine, and demonstrating its usefulness.

Characteristics of human metapneumovirus infection in adults hospitalized for community-acquired influenza-like illness in France, 2012-2018: a retrospective observational study.

OBJECTIVES: To describe the prevalence, clinical features and complications of human metapneumovirus (hMPV) infections in a population of adults hospitalized with influenza-like illness (ILI). METHODS: This was a retrospective, observational, multicenter cohort study using prospectively collected data from adult patients hospitalized during influenza virus circulation, for at least 24 h, for community-acquired ILI (with symptom onset <7 days). Data were collected from five French teaching hospitals over six consecutive winters (2012-2018). Respiratory viruses were identified by multiplex reverse transcription polymerase chain reaction (RT-PCR) on nasopharyngeal specimens. hMPV + patients were compared with hMPV- patients, influenza+ and respiratory syncytial virus (RSV)+ patients using multivariate logistic regressions. Primary outcome was the prevalence of hMPV in patients hospitalized for ILI. RESULTS: Among the 3148 patients included (1449 (46%) women, 1988 (63%) aged 65 and over; 2508 (80%) with chronic disease), at least one respiratory virus was detected in 1604 (51%, 95% confidence interval (CI) 49-53), including 100 cases of hMPV (100/3148, 3% 95% CI 3-4), of which 10 (10%) were viral co-infection. In the hMPV + patients, mean length of stay was 7 days, 62% (56/90) developed a complication, 21% (14/68) were admitted to intensive care unit and 4% (4/90) died during hospitalization. In comparison with influenza + patients, hMPV + patients were more frequently >65 years old (adjusted odds ratio (aOR) = 3.3, 95% CI 1.9-6.3) and presented more acute heart failure during hospitalization (aOR = 1.8, 95% CI 1.0-2.9). Compared with RSV + patients, hMPV + patients had less cancer (aOR = 0.4, 95% CI 0.2-0.9) and were less likely to smoke (aOR = 0.5, 95% CI 0.2-0.9) but had similar outcomes, especially high rates of respiratory and cardiovascular complications. CONCLUSIONS: Adult hMPV infections mainly affect the elderly and patients with chronic conditions and are responsible for frequent cardiac and pulmonary complications similar to those of RSV infections. At-risk populations would benefit from the development of antivirals and vaccines targeting hMPV.

Barriers and motivations for participation in preventive vaccine clinical trials: Experience of 5 clinical research sites.

Recruitment in preventive vaccine trials (PVT) is challenging due to common barriers to clinical research and lack of vaccine confidence. Identifying determinants of participation can help to improve recruitment. A prospective survey was conducted in 5 French clinical investigational sites. People asked to participate in a PVT were given a questionnaire whether they decided to participate or not in the trial. A total of 341 people answered the survey: 210 accepting and 131 declining to participate in a PVT. Acceptors were significantly younger (38.5 vs 54.9 years old), more likely to be involved in early phase trials, had a higher level of education (p < 0.005) and a significantly better general opinion concerning vaccines (92.3% versus 72.3%, p < 0.005) compared with those who declined. Factors associated with acceptance or refusal were evaluated in 224 people in the 4 sites where both groups were included. In a multivariate analysis, three factors: older age, having heard about PVT through multiple sources and financial incentives were significantly associated with refusal to participate in the PVT. A generally favourable opinion of vaccines was associated with acceptance. The main motivation for participation was altruism (93.2%) whereas fear of side effects was at the forefront of the barriers (36.6%). Information given by the physician was a key point for decision-making in 70.2% of those who accepted. In brief, vaccine hesitancy may decrease recruitment in PVTs; reinforcing altruism and quality of information given are key points in acceptance of participation in PVT.

[History and principles of vaccination]. / Histoire et principes de la vaccination.

INTRODUCTION: Vaccination constitutes a major advance in the prevention of infectious diseases. The principle of vaccination is to induce protection against a pathogen by mimicking its natural interaction with the human immune system. The vaccine reduces the risk of complications and mortality following subsequent exposure to an infectious agent. STATE OF THE ART: In this review we recall the history of vaccination as well as the basic immunological principles underlying the composition of vaccines and the response to vaccination. In this way, vaccines induce the immune system to produce an immunological memory based on T and B lymphocytes in order to produce a rapid and effective response to exposure to the targeted pathogen. OUTLOOK: The improvement of existing vaccines and the discovery of new vaccines requires an understanding of the immunological principles of vaccination. Great challenges remain, particularly in terms of target pathogens for future vaccine candidates and also the acceptance of vaccination. CONCLUSION: Understanding the principles of vaccination allows development of vaccines and the control of infectious diseases.

Bacillus Calmette-Guerin infection following intravesical instillation: Does the strain matter?

PURPOSE: Intravesical BCG is the standard treatment of non-muscle invasive bladder cancer. No difference has yet been reported in the safety profiles of the various BCG strains. METHODS: A nationwide multidisciplinary retrospective survey was conducted between January 2013 and December 2016 to identify cases of BCG infection and differentiate them based on the type of BCG strain used. RESULTS: Forty patients were identified (BCG RIVM 28; other strains 8; unknown 4). Patients treated with BCG RIVM were less severely ill, with fewer occurrences of septic shock (3.6% vs. 50%, P=0.003) and ICU admission (7.1% vs. 62.5%, P=0.003). A higher frequency of pulmonary miliaries (71.4% vs. 12.5%, P=0.005) but lower transaminase levels (mean AST 65 vs. 264 U/L, P=0.001) were observed in these patients. No difference in terms of recovery was reported. CONCLUSION: The type of BCG strain could correlate with the frequency and severity of subsequent BCG infections.

Cost-effectiveness of vaccination against cytomegalovirus (CMV) in adolescent girls to prevent infections in pregnant women living in France.

BACKGROUND: CMV infections are the most frequent congenital infections worldwide. AIM: Assess the cost-effectiveness of vaccination strategies of adolescent girls vs. current practice (hygiene counseling) to prevent CMV seroconversions during pregnancy in France. METHOD: A Markov decision-tree model simulated overtime the trajectory of a single fictive cohort of 390,000 adolescent women aged 14 years old, living in France. Impact of vaccination was explored until the end of their reproductive live 40 years later. STRATEGIES COMPARED: "S1: No vaccination" (current practice); "S2: Routine vaccination"; "S3: Screening and vaccination of the seronegative". MODEL PARAMETERS: Seroconversion rate without vaccination (0.035%/pregnant woman-week); fetal transmission risk (41%). Vaccine vs. no vaccination: a 50% decrease in maternal seroconversions. OUTCOMES: Quality-Adjusted Life-Years (QALYs) of the cohort-born babies; discounted costs; Incremental Cost-Effectiveness Ratio (ICER). RESULTS: S2 was the most effective strategy (with 35,000 QALYs gained) and the most expensive (€211,533,000); S1 was the least effective and least costly (€75,423,000). ICERs of strategy S3 vs. S1, and S2 vs. S3 were 6,000€/QALY gained (95% uncertainty range [2700-13,300]) and 16,000€/QALY [negative ICER (S3 dominated by S2) - 94,000] gained, respectively; highly cost-effective because ICER < 1∗France's GPD/capita = €30,000. SENSITIVITY ANALYSIS: If the seroprevalence was >62% (vs. 20% in the base case), S3 would become the most efficient strategy. CONCLUSION: In France, systematic vaccination of adolescent girls was the most efficient strategy to prevent maternal seroconversions. If the population was less than 62% immune, systematic screening and vaccination of susceptibles would become the most cost-effective approach.

Safety and immunogenicity of a recombinant Plasmodium falciparum AMA1-DiCo malaria vaccine adjuvanted with GLA-SE or Alhydrogel® in European and African adults: A phase 1a/1b, randomized, double-blind multi-centre trial.

BACKGROUND: Plasmodium falciparum Apical Membrane Antigen 1 Diversity Covering (PfAMA1-DiCo) candidate vaccine is a formulation of three recombinant variants of AMA1 designed to provide broader protection against parasites with varying AMA1 sequences. METHODS: In this staggered phase Ia/Ib randomized, double blind trial, healthy French adults received AMA1-DiCo with either Alhydrogel® (n=15) or GLA-SE (n=15). Following a safety assessment in French volunteers, GLA-SE was chosen for the phase Ib trial where healthy Burkinabe adults received either AMA1-DiCo/GLA-SE (n=18) or placebo (n=18). AMA1-DiCo (50µg) was administered intramuscularly at baseline, Week 4 and 26. RESULTS: AMAI-DiCo was safe, well tolerated either with Alhydrogel® or GLA-SE. In European volunteers, the ratios of IgG increase from baseline were about 100 fold in Alhydrogel® group and 200-300 fold in GLA-SE group for the three antigens. In African volunteers, immunization resulted in IgG levels exceeding those observed for the European volunteers with a 4-fold increase. DiCo-specific IgG remained higher 26weeks after the third immunization than at baseline in both European and African volunteers. Induced antibodies were reactive against whole parasite derived from different strains. CONCLUSION: AMA1-DiCo vaccine was safe and immunogenic whatever the adjuvant although GLA-SE appeared more potent than Alhydrogel® at inducing IgG responses. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT02014727; PACTR201402000719423.

[Adult immunisation: General points, hot topics and perspectives]. / Vaccination de l'adulte : données générales, actualités et perspectives.

Vaccination in immunocompetent adult mainly concerns booster vaccination against diphtheria, tetanus, polio and pertussis. Some chronic diseases may also require the achievement of pneumococcal and influenza vaccines. In addition, from the age of 65, annual influenza vaccination as well as one dose of a live attenuated shingles vaccine between 64 and 75 years are recommended. Immunocompromised adults, due to the increased risk of serious infections responsible of significant morbidity and mortality, are particularly concerned by vaccination. Main issues in this population are the decreased immunogenicity and efficacy of vaccination and the risk of infection with live attenuated vaccines and. Depending on the type of immunosuppression, the recommended vaccines and vaccination schemes differ. Vaccination of healthy persons caring or residing with immunocompromised patients is an important point in the vaccine strategy. The current perspectives in vaccinology concern the development of vaccines against healthcare associated infections (Clostridium difficile and Staphylococcus aureus in particular), the strategy of vaccination during pregnancy to protect new-borns (respiratory syncytial virus, group B streptococcus) and the development of new adjuvants and new routes of immunization. With the overall decline in immunization coverage and increasing distrust of vaccination, the problem of vaccine hesitancy is also a hot topic. The reasons for doubt in the vaccine usefulness and the solutions to be applied are also crucial issues.

Clinical characteristics and outcome of respiratory syncytial virus infection among adults hospitalized with influenza-like illness in France.

OBJECTIVES: The aim of this study was to analyse characteristics and outcome of respiratory syncytial virus (RSV) infection in adults hospitalized with influenza-like illness (ILI). METHODS: Patients hospitalized with ILI were included in this prospective, multicentre study carried out in six French hospitals during three consecutive influenza seasons (2012-2015). RSV and other respiratory viruses were detected by multiplex PCR in nasopharyngeal swabs. Risk factors for RSV infection were identified by backward stepwise logistic regression analysis. RESULTS: A total of 1452 patients hospitalized with ILI were included, of whom 59% (861/1452) were >65 years and 83% (1211/1452) had underlying chronic illnesses. RSV was detected in 4% (59/1452), and influenza virus in 39% (566/1452). Risk factors for RSV infection were cancer (adjusted OR 2.1, 95% CI 1.1-4.1, p 0.04), and immunosuppressive treatment (adjusted OR 2.0, 95% CI 1.1-3.8, p 0.03). Patients with RSV had a median length of stay of 9 days (6-25), and 57% of them (30/53) had complications, including pneumonia (23/53, 44%) and respiratory failure (15/53, 28%). Fifteen per cent (8/53) were admitted to an intensive care unit, and the in-hospital mortality rate was 8% (4/53). Pneumonia was more likely to occur in patients with RSV than in patients with RSV-negative ILI (44% (23/53) versus 26% (362/1393), p 0.006) or with influenza virus infection (44% versus 28% (157/560), p 0.02). CONCLUSION: RSV is an infrequent cause of ILI during periods of influenza virus circulation but can cause severe complications in hospitalized adults. Risk factors for RSV detection in adults hospitalized with ILI include cancer and immunosuppressive treatment. Specific immunization and antiviral therapy might benefit patients at risk.

Moderate influenza vaccine effectiveness against hospitalisation with A(H3N2) and A(H1N1) influenza in 2013-14: Results from the InNHOVE network.

We conducted a multicentre test negative case control study to estimate the 2013-14 influenza vaccine effectiveness (IVE) against hospitalised laboratory confirmed influenza in 12 hospitals in France, Italy and Spain. We included all ≥18 years hospitalised patients targeted by local influenza vaccination campaign reporting an influenza-like illness within 7 days before admission. We defined as cases patients RT-PCR positive for influenza and as controls those negative for all influenza virus. We used a logistic regression to calculate IVE adjusted for country, month of onset, chronic diseases and age. We included 104 A(H1N1)pdm09, 157 A(H3N2) cases and 585 controls. The adjusted IVE was 42.8% (95%CI: 6.3;65;0) against A(H1N1)pdm09. It was respectively 61.4% (95%CI: -1.9;85.4), 39.4% (95%CI: -32.2;72.2) and 19.7% (95%CI:-148.1;74.0) among patients aged 18-64, 65-79 and ≥80 years. The adjusted IVE against A(H3N2) was 38.1% (95%CI: 8.3;58.2) overall. It was respectively 7.8% (95%CI: -145.3;65.4), 25.6% (95%CI: -36.0;59.2) and 55.2% (95%CI: 15.4;76.3) among patients aged 18-64, 65-79 and ≥80 years. These results suggest a moderate and age varying effectiveness of the 2013-14 influenza vaccine to prevent hospitalised laboratory-confirmed influenza. While vaccination remains the most effective prevention measure, developing more immunogenic influenza vaccines is needed to prevent severe outcomes among target groups.

Characteristics of patients and physicians correlated with regular influenza vaccination in patients treated for type 2 diabetes: a follow-up study from 2008 to 2011 in southeastern France.

We studied a cohort of 110 823 patients treated with oral hypoglycaemic agents for type 2 diabetes in southeastern France from 1 January 2008 to 31 December 2011, to identify influenza vaccination coverage trends and the patient and physician correlates of influenza vaccine (IFV) uptake. We used French national health insurance fund (NHIF) databases to identify these patients and collect data on their IFV reimbursement claims (IFVC) and patient and physician characteristics. We used multilevel multivariate polytomous logistic regressions to test the correlates of IFVC. Between 2008 and 2011 the annual IFVC rate varied from 33.7% to 32.3% in the 18-64 age group and from 69.5% to 61.1% in the 65 + age group, among whom we saw a clear trend towards reduced vaccination after 2008. In the younger group, the probability of regular vaccination each year from 2008 to 2011 increased with diabetes severity and duration, comorbidities, and the number of general practitioner and nurse visits; it was higher among patients seeing endocrinologists and lower among low-income patients than in other patients. In the older group, there was no association with either diabetes severity or physician specialty. These results suggest different patterns of correlates of influenza vaccination according to age. Endocrinologists might help to improve IFV uptake in the younger group of patients with type 2 diabetes. Communication strategies regarding influenza vaccination should be adapted to age, and collaboration between healthcare professionals should be reinforced to achieve vaccination objectives for these patients.

Impaired sperm motility in HIV-infected men: an unexpected adverse effect of efavirenz?

STUDY QUESTION: Are antiretroviral therapies associated with semen alterations in HIV-infected men? SUMMARY ANSWER: Antiretroviral regimens that included the non-nucleosidic reverse transcriptase inhibitor efavirenz were associated with a significant impairment of sperm motility, whereas regimens without efavirenz were not associated with significant semen changes. WHAT IS KNOWN ALREADY: Semen alterations including decreased ejaculate volume and sperm motility have been reported in HIV-infected men. The hypothesis ascribing reduced sperm motility to damages induced in sperm mitochondria by nucleosidic (or nucleotidic) reverse transcriptase inhibitors (NRTIs) has not been confirmed in HIV-infected patients and the effects of antiretroviral treatments on semen parameters remain unclear. STUDY DESIGN, SIZE, DURATION: This case-control study compared semen characteristics across 378 HIV-1 infected patients receiving different antiretroviral regimens or never treated by antiretroviral drugs, in whom an initial semen analysis was done between 2001 and 2007. PARTICIPANTS/MATERIALS, SETTING, METHODS: The patients were partners from serodiscordant couples requesting medical assistance to procreate safely. Their status with regard to antiretroviral therapy at the time of semen analysis was categorized as follows: 1/ never treated patients (n = 66); 2/ patients receiving NRTIs only (n = 49); 3/ patients receiving a NRTIs + protease inhibitor (PI) regimen (n = 144); 4/ patients receiving a NRTIs + non-nucleosidic reverse transcriptase inhibitor (NNRTI) regimen (n = 119). Semen parameters were assessed through standard semen analysis. Additional analyses included measurement of sperm motion parameters using computer-assisted semen analysis, seminal bacteriological analysis, seminal biochemical markers and testosterone plasmatic levels. All analyses were performed in the Cochin academic hospital. The data were analyzed through multivariate analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Sperm motility was the only semen parameter which significantly varied according to treatment status. The median percentage of rapid spermatozoa was 5% in the group of patients receiving a regimen including efavirenz versus 20% in the other groups (P < 0.0001). Accordingly, sperm velocity was reduced by about 30% in this group (P < 0.0001). The role of chance was minimized by the strict definition and the size of the study population, which included a large enough group of never treated patients, the controlled conditions of semen collection and analysis, the multivariate analysis, the specificity and the high significance level of the observed differences. LIMITATIONS, REASONS FOR CAUTION: The design of the study did not allow demonstrating a causal link between exposure to efavirenz and sperm motility. WIDER IMPLICATIONS OF THE FINDINGS: As efavirenz is widely used in current antiretroviral therapy, these findings may concern many HIV-infected men wishing to have children. This justifies further assessment of the consequences on fertility of the exposure to efavirenz. Moreover, the possibility of common cellular impacts underlying adverse effects of efavirenz in sperm cells and neurons deserved investigation. STUDY FUNDING/COMPETING INTERESTS: No external funding was used for this study. None of the authors has any conflict of interest to declare.

Vaccine coverage in CF children: A French multicenter study.

BACKGROUNDS: Recent reports have pointed the low vaccine coverage in patients with chronic diseases. Data are lacking in patients with cystic fibrosis (CF). Gaining more information on coverage both for mandatory vaccines and those more specifically recommended would help to optimize care of these patients. METHODS: Data were extracted from the "MucoFlu" study, which was a prospective study performed in 2009 in the 5 cystic fibrosis centers of the Paris metropolitan area. Data on mandatory and recommended vaccines in CF were collected in the health booklet and compared to the coverage of the general population. RESULTS: A total of 134 CF children were included. Vaccination coverage for mandatory vaccines was insufficient (DTPCaHi, conjugate pneumococcal, BCG, MMR and hepatitis B) at 1year of age with no catching-up with age in contrast to the general population. Approximately 66% of the children had immunization for seasonal influenza and 91% for 2009 pandemic flu. Coverage for vaccines specifically recommended in CF was low for hepatitis A, non conjugate pneumococcal and varicella. CONCLUSION: This study shows a defect in vaccine coverage for both routine immunization and vaccines more specifically recommended in CF.

Low immunogenicity of quadrivalent meningococcal vaccines in solid organ transplant recipients.

Immunization against meningococcal disease is recommended for solid organ transplant (SOT) recipients at high risk for meningococcal disease or travelling to an endemic country. However, the immunogenicity of meningococcal vaccines has not been studied in this population. We analyzed the immune response of quadrivalent (against Neisseria meningitidis serogroups A, C, Y, and W) polysaccharidic non-conjugate and conjugate meningococcal vaccines in kidney- and liver-transplant patients using bactericidal assays against the targeted serogroups. Upon vaccination with a non-conjugate (n = 5) or a conjugate vaccine (n = 10), respectively, 40% and 50% of patients were able to mount an immune response, achieving at least the threshold correlated with protection defined as human serum bactericidal antibody titers of ≥4. Responders showed only partial and low responses (titers ≤64), thus predicting a rapid decline in bactericidal response. Only 1 patient developed a booster response to preexisting immunity. Our data argue for the need of additional measures for SOT recipients, when they are at risk of meningococcal disease.