Valérie Delbos

From tailor-made to ready-to-wear meningococcal B vaccines: longitudinal study of a clonal meningococcal B outbreak

BACKGROUNDnOuter-membrane-vesicle vaccines for meningococcal B outbreaks are complex and time consuming to develop. We studied the use of already available vaccine to control an outbreak caused by a genetically close strain.nnnMETHODSnFrom 2006 to 2009, all individuals younger than 20 years living in the region of Normandy, France, in which an outbreak caused by a B:14:P1.7,16 strain occurred, were eligible to receive MenBvac, a Norwegian vaccine designed 20 years earlier against a strain sharing the same serosubtype (B:15:P1.7,16). The immunogenicity (in a randomly selected cohort of 400 children aged 1-5 years), safety, and epidemiological effect of the vaccination were assessed.nnnFINDINGSn26,014 individuals were eligible to receive the vaccine. Shortage of vaccine production prompted start of the campaign in the highest incidence groups (1-5 years). 16,709 (64%) received a complete vaccination schedule of whom 13,589 (81%) received a 2+1 dose schedule (week 0, week 6, and month 8). At 6 weeks after the third dose, of 235 vaccinees for whom samples were available, 206 (88%) had a seroresponse, and 108 (56 %) of 193 had a seroresponse at 15 months. These results were similar to those described for tailor-made vaccines and their homologous strain. Only previously described adverse effects occurred. The incidence of B:14:P1.7,16 cases decreased significantly in the vaccine targeted population after the primary vaccination period (from 31·6 per 100,000 to 5·9 per 100,000; p=0·001).nnnINTERPRETATIONnThe ready-to-wear approach is reliable if epidemic and vaccine strains are genetically close. Other meningococcal B clonal outbreaks might benefit from this strategy; and previously described outer-membrane-vesicle vaccines can be effective against various strains.nnnFUNDINGnFrench Ministry of Health.

Impact of MenBvac, an outer membrane vesicle (OMV) vaccine, on the meningococcal carriage.

The aim of the study was to analyze the impact of MenBvac, an outer membrane vesicle (OMV) vaccine against P1.7,16 strains, on meningococcal carriage. During a B:14:P1.7,16/ST-32 outbreak in Normandy (France), children aged 1-7 years were randomly selected to participate in the study. Among the 1082 volunteers, there were 17 Neisseria meningitidis carriers (carriage rate of 1.57%). MenBvac vaccination appeared associated with lower carriage rate, i.e., 0.31% among the vaccinated children versus 2.10% among the non-vaccinated (p=0.03). The beneficial effect on carriage was observed regardless of the strain serogroup. OMV-vaccinated mice also showed reduction of bacterial acquisition of OMV-homolog and hererolog strains in respiratory pathways after intranasal challenge. These results suggest that meningococcal OMV-based vaccines reduce meningococcal carriage and may hence confer herd immunity.

Evolution of immune response against Neisseria meningitidis B:14:P1.7,16 before and after the outer membrane vesicle vaccine MenBvac

A meningococcal B:14:P1.7,16 outbreak in Normandy (France) was recently controlled using MenBvac, an outer membrane vesicle vaccine previously designed against the B:15:P1.7,16 strain. The further emergence of a new B:14:P1.7,16 outbreak in another district in Normandy led us to explore immunity against B:14:P1.7,16 before and after the MenBvac campaign using a 2+1 (day 0, week 6, month 8) schedule. Children (1-5 years) were sampled before, during and up to one year after vaccination. Serum bactericidal activity against B:14:P1.7,16 was titrated using human complement (hSBA) and immune response was defined by hSBA titer ≥4 as a surrogate for protection. The percentage of hSBA titer ≥4 was 10.8% before vaccination, raised to 84.1% 6 weeks after the completion of the schedule, but declined to 39.7% one year later. This level is lower than the targeted 60% level and suggests only short-term persistence of response against B:14:P1.7,16 using this schedule.

Meningococcal carriage during a clonal meningococcal B outbreak in France

The aim of this study performed in Normandy, France, was to analyze the pharyngeal meningococcal carriage at the peak of a clonal meningococcal B outbreak, which was subsequently controlled using an outer membrane vesicle vaccination. This cross-sectional study included randomly selected subjects aged 1–25xa0years. Carriers and non carriers were compared using unconditional logistic regression. Among the 3,522 volunteers, there were 196 (standardized rate: 6.46xa0%) Neisseria meningitidis carriers, of which there were only five with the outbreak strain (B:14:P1.7,16/ST-32; standardized rate: 0.18xa0%). From the multivariate analysis, older age, smoking, higher degree of socialization, and social deprivation appear to favor the carriage of all the strains included. Prior antibiotic treatment up to 12 months before swabbing, even with β-lactam, was protective against carriage. Our data indicate a low overall meningococcal carriage rate with a surprising protective effect of prior antibiotic exposure. The observed low carriage rate of the epidemic strain (B:14:P1.7,16/ST-32) contrasts with the high incidence of invasive meningococcal diseases (IMD) due to this strain. Hence, our data underline the high virulence of the strain and suggest a low level of natural immunity of the population against this strain. Although highly resource-consuming, carriage studies are helpful in guiding the implementation of control measures of IMD, such as mass vaccination or chemoprophylaxis.

Genetic diversity and levels of expression of factor H binding protein among carriage isolates of Neisseria meningitidis.

The prevention of meningococcal disease may be improved by recombinant vaccines such as 4CMenB and rLP2086 that target the factor H binding protein (fHbp), an immunogenic surface component of Neisseria meningitidis present as one of three variants. Whether such vaccines decrease carriage of invasive isolates and thus induce herd immunity is unknown. We analyzed the genetic diversity and levels of expression of fHbp among 268 carriage strains and compare them to those of 467 invasive strains. fhbp gene sequencing showed higher proportions of variants 2 and 3 among carriage isolates (p<0.0001). Carriage isolates expressed lower levels of fHbp (p<0.01) but that remain high enough to predict targeting by antibodies against fHbp particularly in group B isolates belonging to the frequent hypervirulent clonal complexes in Europe and North America (cc32, cc41/44, cc269). This suggests that fHbp targeting meningococcal vaccines might reduce, at least in part, the acquisition of some hyperinvasive isolates.

Durability of immunogenicity and strain coverage of MenBvac, a meningococcal vaccine based on outer membrane vesicles: Lessons of the Normandy campaign

OBJECTIVESnMenBvac® is an outer membrane vesicle (OMV)-based meningococcal vaccine. From 2006 to 2012, it was used to control a clonal B outbreak in Normandy (France). We aimed to analyse the durability of the response against the epidemic strain and coverage beyond the vaccine strain. These data should help to optimize the use of OMV-containing vaccines, such as the new 4CMenB/Bexsero® recombinant vaccine.nnnMETHODSnSerum bactericidal activity (SBA) was measured in two cohorts of children who received their first dose of MenBvac® at 1-5years of age and accepted to provide a blood sample either one or four years after a 2+1+1 schedule. All sera were tested against the outbreak strain. Sera from responder subjects were also tested against 12 additional B or C strains which were chosen to entirely, partially, or not at all match the two variable regions (VR1 and VR2) of the PorA vaccine strain.nnnRESULTSnOnly 47.9% and 31.3% of subjects showed an SBA titre consistent with protection one and four years, respectively, after the last boost. Protective SBA titres were observed in all sera against B or C strains that entirely matched P1.7,16, and was high (75-100%) for all but one strain that partially matched VR1 or VR2. Extrapolating our data to the OMV component of 4CMenB/Bexsero® suggests that 14.5% of the current B strains would be covered based on PorA matching to the OMV component of 4CMenB/Bexsero® (regardless of the coverage of the three other vaccine components).nnnCONCLUSIONSnOur data confirm that OMV-based vaccines elicit short-lasting SBA titres and may require repeated booster injections. However, strain coverage may be greater than expected.

Antiretroviral Therapy as Prevention of … Pneumococcal Infections?

Background. Despite antiretroviral therapy, it is generally believed that the risk for pneumococcal infections (PnIs) is high among patients infected with human immunodeficiency virus (HIV). However, most studies in this field have been conducted before 2010, and the proportion of virologically suppressed patients has drastically increased in these latter years thanks to larger indications and more effective antiretroviral regimens. This study aimed to re-evaluate the current risk of PnI among adult patients infected with HIV. Methods. The incidence of PnI was evaluated between 1996 and 2014 in 2 French regional hospitals. The 80 most recent cases of PnI (2000–2014) were retrospectively compared with 160 controls (HIV patients without PnI) to analyze the residual risk factors of PnI. Results. Among a mean annual follow-up cohort of 1616 patients, 116 PnIs were observed over 18 years. The risk factors of PnI among patients infected with HIV were an uncontrolled HIV infection or “classic” risk factors of PnI shared by the general population such as addiction, renal or respiratory insufficiency, or hepatitis B or C coinfection. Pneumococcal vaccination coverage was low and poorly targeted, because only 5% of the cases had been previously vaccinated. The incidence of invasive PnIs among HIV patients with a nonvirologically suppressed infection or comorbidities was 12 times higher than that reported in the general population at the country level (107 vs 9/100000 patients), whereas the incidence among virologically suppressed HIV patients without comorbidities was lower (7.6/100000 patients). Conclusions. Human immunodeficiency virus infection no longer per se seems to be a significant risk factor for PnI, suggesting a step-down from a systematic to an “at-risk patient” targeted pneumococcal vaccination strategy.

HIV rapid screening tests and self-tests: Be aware of differences in performance and cautious of vendors

Background Rapid tests for HIV testing are essential tools to achieve the 90-90-90 target of the World Health Organization. Many tests are available, some directly from websites. Evaluation of the performance of rapid tests, under close to real-life usage, is therefore needed to ensure accurate diagnosis in the context of the recommendation for their more widespread use. Method Nine third- (3G) or fourth-generation (4G) rapid screening tests or self-tests (two bought on websites), were evaluated on an extensive panel of 200 HIV-negative and 312 HIV-positive samples, representative of a wide variety of clinical situations and HIV genetic diversity. A whole blood reconstitution protocol was designed to simulate real-life usage of these tests in community-based and private settings. Findings The specificity was high (98.5–100%) and sensitivity excellent (100%) for samples from patients chronically infected with the pandemic strains. The performance for infrequent situations with a major epidemiological and clinical impact, such as infection with divergent viruses or primary infection, was highly variable, depending on the test. One of the two 4G tests allowed detection of additional positive samples from early stages of infection, whereas the second (sold as a 4G test on a website) corresponded in reality to a 3G test. Interpretation Our study showed that not all tests are equal for the detection of major HIV variants or early stages of HIV infection; adding the detection of specific p24Ag improved the latter point. This study also showed, for the first time, that buying through web-based vendors can be risky, due to the varying performance of the tests and questionable sales practices. Our results are of particular importance in the context of the increasing use of rapid tests in an “outside laboratory” settings. Fund Santé Publique France, COREVIH – Normandie, and Rouen University Hospital.

N-13: Immunogénicité à long terme du vaccin MenBvac en Seine-Maritime

Introduction – objectifs MenBvac, vaccin OMV (outer membrane vesicle), a ete utilise pour le controle d’une epidemie regionale a meningocoque B (clone B : 14 : P1.7,16). Le schema a ete successivement adapte selon les doses disponibles et les taux protecteurs mesures dans deux cohortes. La durabilite de l’effet de tels vaccins etant variable, le but fut de l’evaluer 1 a 4 ans apres le dernier rappel. Materiels et methodes Volontaires âges de 4-12 ans, ayant recu MenBvac selon un schema 2+1+1 (J0-S6-M8-M22 a 24). Prelevements 1 an apres la 4 e dose a Neufchâtel-en-Bray, et 4 ans apres la 4 e dose a Dieppe (epicentre de l’hyperendemie et 1 re zone traitee d’ou davantage de recul). Mesure de l’activite bactericide du serum en complement humain (hSBA) vis-a-vis de B : 14 : P1.7,16. Cible selon la litterature : 60 % de sujets a titre hSBA ≥ 4 un an apres rappel. Resultats 1 an apres la 4 e dose (i.e., a Neufchâtel-en-B) : sur 96 sujets, moyenne geometrique des titres (GMT) hSBA : 4,4 et 47 % (IC 95 % : 37 %-57 %) de sujets a titre ≥ 4 (versus 21 % juste avant et 87 % 6 semaines apres la dose) ; 4 ans apres la 4 e dose (i.e., a Dieppe) : sur 117 sujets GMT hSBA : 3,3 et 31 % (IC 95 % : 23 %-40 %) de sujets a titre ≥4 (versus 37 % juste avant). Conclusion Ces resultats confirment le declin rapide de la reponse bactericide a un vaccin OMV (declin moindre dans l’epicentre par circulation accrue de la souche et contribution de l’immunite naturelle ?). Pour controler les hyperendemies/epidemies, il est crucial d’avoir rapidement une large couverture vaccinale, ce qui n’avait pas ete ici possible du fait de la penurie en MenBvac, d’ou la necessite ensuite de rappels iteratifs. Desormais, la disponibilite du vaccin recombinant 4CMenB (Bexsero) devrait permettre l’application efficace d’une vaccination ciblee en cas d’alerte, selon les recommandations du HCSP. Remerciements aux volontaires.

A-11 Évaluation de la réponse immunitaire contre la souche de Neisseria meningitidis B : 14 : P1.7,16 chez les enfants dieppois vaccinés par MenBVac®

Une vaccination par MenBVac ® etait engagee en Seine-Maritime en reponse a l’hyperendemie d’infections a meningocoque B : 14 : P1.7,16. MenBVac ® est un vaccin specifique de clone B jadis developpe en Norvege face a une epidemie a B : 15 : P1.7,16 ; une etude preliminaire a montre une activite bactericide equivalente contre B : 15 : P1.7,16 et B : 14 : P1.7,16 de serums de Norvegiens vaccines par MenBVac ® . La vaccination a debute mi 2006 (J0-S6) chez les enfants de 1 a 5 ans de Dieppe. Cependant, la 3 e dose (prevue a S12) a ete differee (retard de livraison) et une inspection a releve des ecarts (processus modifie ; produit sub-potent ex vivo ). La DGS a recommande la poursuite de la vaccination, mais avec une etude evaluant la reponse immunitaire. L’etude a eu lieu juste avant et 6 semaines apres la 3 e dose (realisee a M8). Sur les 2 835 enfants ayant recus J0-S6, 400 ont ete tires au sort, 262 (66 %) ont accepte de participer, et 235 avaient 2 serums analysables. Le critere principal de jugement etait le pourcentage de sujets ayant un titre d’activite bactericide du serum analyse en serum humain (hSBA) ≥ 4. Il etait de 37 % (IC 95 % : 31 %-43 %) avant la 3 e dose et augmentait ( p e dose, une valeur superieure au taux seuil attendu de 75 %. Pour 32 enfants le titre hSBA a ete determine vis-a-vis d’une souche heterologue B : 2a : P1.5 ; il etait faible (2,1 en moyenne apres la 3 e dose contre 40,6 vs B : 14 : P1.7,16), confirmant l’activite specifique de clone du MenBVac ® . MenBVac ® induit chez les enfants dieppois une reponse immunitaire vis-a-vis de B : 14 : P1.7,16 comparable a celle jadis observee en Norvege vis-a-vis de B : 15 : P1.7,16 ; cette protection croisee est attribuable a l’epitope commun P1.7,16.