Efficacy of a monovalent (D614) SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3, multi-country study.

Background: The literature on first generation COVID-19 vaccines show they were less effective against new SARS-CoV-2 variants of concern including Omicron (BA.1, BA.2, BA.4 and BA.5 subvariants). New vaccines developed against variant strains may provide cross-protection against emerging variants when used as boosters and facilitate vaccination across a range of countries, healthcare settings and populations. However, there are no data on such vaccines when used as a primary series. Methods: A global Phase 3, multi-stage efficacy study (NCT04904549) among adults (≥18 years) was conducted in 53 research centres in eight countries (United States, Honduras, Japan, Colombia, Kenya, India, Ghana, Nepal). Participants were randomized 1:1 to receive two intramuscular injections of a monovalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (10 µg of the spike (S) protein from the ancestral D614 strain) or placebo on Day 1 (D01) and Day 22 (D22). The primary efficacy endpoint was prevention of virologically confirmed SARS-CoV-2 infection with symptoms of COVID-19-like illness (CLI) ≥14 days after the second injection (post-dose 2 [PD2]) in participants who were SARS-CoV-2 naïve on D01 + D22. Safety and reactogenicity were also evaluated. Findings: Between May 26 and November 7, 2021, 10,114 participants received ≥1 study injection, and 9441 participants received both injections. 2108 (20.8%) participants were SARS-CoV-2 naïve at D01 and D22. The primary endpoint was analysed in a subset of the full analysis set (the modified full analysis set PD2 [mFAS-PD2], excluding participants who did not complete the vaccination schedule or received vaccination despite meeting one of the contraindication criteria, had onset of symptomatic COVID-19 between the first injection and before 14 days after the second injection, or participants who discontinued before 14 days after the second injection [n = 9377; vaccine, n = 4702; placebo, n = 4675]). Data were available for 2051 SARS-CoV-2 naïve and 7159 non-naïve participants. At the cut-off date (January 28, 2022), symptomatic COVID-19 was reported in 169 naïve participants (vaccine, n = 81; placebo, n = 88) ≥14 days PD2, with a vaccine efficacy (VE) of 15.3% (95% CI, -15.8; 38.2). VE regardless of D01/D22 serostatus was 32.9% (95% CI, 15.3; 47.0) and VE in non-naïve participants was 52.7% (95% CI, 31.2; 67.9). Viral genome sequencing was performed up to the data cut-off point and identified the infecting strain in 99/169 adjudicated cases in the PD2 naïve population (Delta [25], Omicron [72], other variants [3], one participant had infection with both Delta and Omicron variants and has been included in the totals for both Delta and Omicron). The vaccine was well-tolerated with an acceptable safety profile. Interpretation: In the context of changing circulating viral variants, it is challenging to induce protection in naïve individuals with a two-dose priming schedule based on the parental D614 strain. However, while the primary endpoint of this trial was not met, the results show that a monovalent D614 vaccine can still be of value in individuals previously exposed to SARS-CoV-2. Funding: This study was funded in whole or in part by Sanofi and by federal funds from the Biomedical Advanced Research and Development Authority, part of the office of the Administration for Strategic Preparedness and Response at the U.S. Department of Health and Human Services under contract number HHSO100201600005I, and in collaboration with the U.S. Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense under contract number W15QKN-16-9-1002. The views presented here are those of the authors and do not purport to represent those of the Department of the Army, the Department of Health and Human Services, or the U.S. government.

Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 recombinant protein vaccine with AS03 adjuvant in adults: a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial.

BACKGROUND: COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. This study aimed to describe the clinical efficacy and safety of a bivalent SARS-CoV-2 recombinant protein vaccine as a two-injection primary series during a period of circulation of the omicron (B.1.1.529) variant. METHODS: We conducted a phase 3, parallel, randomised, modified double-blind, placebo-controlled trial in adults aged 18 years or older at 54 clinical research centres in eight countries (Colombia, Ghana, India, Kenya, Mexico, Nepal, Uganda, and Ukraine). Participants were recruited from the community and randomly assigned (1:1) by use of an interactive response technology system to receive two intramuscular 0·5 mL injections, 21 days apart, of the bivalent vaccine (5 µg of ancestral [D614] and 5 µg of beta [B.1.351] variant spike protein, with AS03 adjuvant) or placebo (0·9% normal saline). All participants, outcome assessors, and laboratory staff performing assays were masked to group assignments; those involved in the preparation and administration of the vaccines were unmasked. Participants were stratified by age (18-59 years and ≥60 years) and baseline SARS-CoV-2 rapid serodiagnostic test positivity. Symptomatic COVID-19 was defined as laboratory-confirmed (via nucleic acid amplification test or PCR test) COVID-19 with COVID-19-like illness symptoms. The primary efficacy endpoint was the clinical efficacy of the bivalent vaccine for prevention of symptomatic COVID-19 at least 14 days after the second injection (dose 2). Safety was assessed in all participants receiving at least one injection of the study vaccine or placebo. This trial is registered with ClinicalTrials.gov (NCT04904549) and is closed to recruitment. FINDINGS: Between Oct 19, 2021, and Feb 15, 2022, 13 002 participants were enrolled and randomly assigned to receive the first dose of the study vaccine (n=6512) or placebo (n=6490). 12 924 participants (6472 in the vaccine group and 6452 in the placebo group) received at least one study injection, of whom 7542 (58·4%) were male and 9693 (75·0%) were SARS-CoV-2 non-naive. Of these 12 924 participants, 11 543 (89·3%) received both study injections (5788 in the vaccine group and 5755 in the placebo group). The efficacy-evaluable population after dose 2 comprised 11 416 participants (5736 in the vaccine group and 5680 in the placebo group). The median duration of follow-up was 85 days (IQR 50-95) after dose 1 and 58 days (29-70) after dose 2. 121 symptomatic COVID-19 cases were reported at least 14 days after dose 2 (32 in the vaccine group and 89 in the placebo group), with an overall vaccine efficacy of 64·7% (95% CI 46·6 to 77·2). Vaccine efficacy against symptomatic COVID-19 was 75·1% (95% CI 56·3 to 86·6) in SARS-CoV-2 non-naive participants and 30·9% (-39·3 to 66·7) in SARS-CoV-2-naive participants. Viral genome sequencing identified the infecting strain in 68 (56·2%) of 121 cases (omicron [BA.1 and BA.2] in 63; delta in four; and both omicron and delta in one). Immediate unsolicited adverse events were reported by four (<0·1%) participants in the vaccine group and seven (0·1%) participants in the placebo group. Immediate unsolicited adverse reactions within 30 min after any injection were reported by four (<0·1%) participants in the vaccine group and six (<0·1%) participants in the placebo group. In the reactogenicity subset with available data, solicited reactions (solicited injection-site reactions and solicited systemic reactions) within 7 days after any injection occurred in 1398 (57·8%) of 2420 vaccine recipients and 983 (40·9%) of 2403 placebo recipients. Grade 3 solicited reactions were reported by 196 (8·1%; 95% CI 7·0 to 9·3) of 2420 vaccine recipients and 118 (4·9%; 4·1 to 5·9) of 2403 placebo recipients within 7 days after any injection, with comparable frequencies after dose 1 and dose 2 in the vaccine group. At least one serious adverse event occurred in 30 (0·5%) participants in the vaccine group and 26 (0·4%) in the placebo group. The proportion of adverse events of special interest and deaths was less than 0·1% in both study groups. No adverse event of special interest, serious adverse event, or death was deemed to be treatment related. There were no reported cases of thrombosis with thrombocytopenia syndrome, myocarditis, pericarditis, Bell's Palsy, or Guillain-Barré syndrome, or other immune-mediated diseases. INTERPRETATION: The bivalent variant vaccine conferred heterologous protection against symptomatic SARS-CoV-2 infection in the epidemiological context of the circulating contemporary omicron variant. These findings suggest that vaccines developed with an antigen from a non-predominant strain could confer cross-protection against newly emergent SARS-CoV-2 variants, although further investigation is warranted. FUNDING: Sanofi, US Biomedical Advanced Research and Development Authority, and the US National Institute of Allergy and Infectious Diseases.

Efficacy of a bivalent (D614 + B.1.351) SARS-CoV-2 Protein Vaccine.

Background: COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. Methods: We conducted a global Phase 3, multi-stage efficacy study (NCT04904549) among adults aged ≥18 years. Participants were randomized 1:1 to receive two intramuscular injections 21 days apart of a bivalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (5 µg of ancestral (D614) and 5 µg of B.1.351 [beta] variant spike protein) or placebo. Symptomatic COVID-19 was defined as laboratory-confirmed COVID-19 with COVID-19-like illness (CLI) symptoms. The primary efficacy endpoint was the prevention of symptomatic COVID-19 ≥14 days after the second injection (post-dose 2 [PD2]). Results: Between 19 Oct 2021 and 15 Feb 2022, 12,924 participants received ≥1 study injection. 75% of participants were SARS-CoV-2 non-naïve. 11,416 participants received both study injections (efficacy-evaluable population [vaccine, n=5,736; placebo, n=5,680]). Up to 15 March 2022, 121 symptomatic COVID-19 cases were reported (32 in the vaccine group and 89 in the placebo group) ≥14 days PD2 with a vaccine efficacy (VE) of 64.7% (95% confidence interval [CI] 46.6; 77.2%). VE was 75.1% (95% CI 56.3; 86.6%) in non-naïve and 30.9% (95% CI -39.3; 66.7%) in naïve participants. Viral genome sequencing identified the infecting strain in 68 cases (Omicron [BA.1 and BA.2 subvariants]: 63; Delta: 4; Omicron and Delta: 1). The vaccine was well-tolerated and had an acceptable safety profile. Conclusions: A bivalent vaccine conferred heterologous protection against symptomatic infection with newly emergent Omicron (BA.1 and BA.2) in non-naïve adults 18-59 years of age.

Accuracy and efficacy of pre-dengue vaccination screening for previous dengue infection with a new dengue rapid diagnostic test: a retrospective analysis of phase 3 efficacy trials.

BACKGROUND: A dengue pre-vaccination test that is convenient, highly specific, and highly sensitive is still needed. The OnSite Dengue IgG rapid diagnostic test (RDT) is a new rapid diagnostic test specifically designed for pre-vaccination screening. We aimed to retrospectively assess the efficacy of a tetravalent dengue vaccine (CYD-TDV) in participants determined to be dengue seropositive by the OnSite IgG RDT and to evaluate assay performances. METHODS: This was a complementary study using pre-vaccination samples from two CYD-TDV efficacy trials done in five countries in the Asia-Pacific region (NCT01373281) and five countries in Latin America (NCT01374516). Baseline dengue serostatus was determined by the OnSite IgG RDT on samples from the immunogenicity subsets of the two trials. In participants who were test positive, we calculated CYD-TDV vaccine efficacy against symptomatic virologically confirmed dengue (VCD) over 25 months, and against hospitalisation with VCD over 72 months of follow-up after the first vaccination. We used a reference algorithm to determine the reference dengue serostatus for each sample, and sensitivity and specificity of the OnSite IgG RDT were calculated. Analyses were done on the whole population (aged 2-16 years), and on those aged 6 years or older and those aged 9 years or older. FINDINGS: Of 3983 participants in the immunogenicity subsets of the efficacy trials CYD14 and CYD15, 3962 had complete dengue reference test results enabling baseline serostatus classification and 3833 had sufficient serum samples remaining for evaluation with the OnSite IgG RDT. Of the samples tested, 2486 (64·9%) of 3833 were OnSite IgG RDT-positive. In participants aged 2-16 years who were OnSite IgG RDT-positive, vaccine efficacy was 84·1% (95% CI 71·6-91·1) against symptomatic VCD, and 69·2% (38·8-84·5) against hospitalisation with VCD, with similar findings in those aged 6 years or older and those aged 9 years or older. The OnSite IgG RDT showed very high sensitivity (91·1%, 89·9-92·1) and high specificity (92·8%, 91·2-94·2) in participants aged 2-16 years, with significantly higher specificity in those aged 9 years or older (96·6%, 94·9-97·8). INTERPRETATION: The OnSite IgG RDT should provide a valuable tool for screening for previous dengue infection at the point of vaccination. In individuals who were OnSite IgG RDT-positive, the vaccine efficacy of CYD-TDV was high across all three age groups. FUNDING: Sanofi Pasteur.

Analysis of Hospitalized and Severe Dengue Cases Over the 6 years of Follow-up of the Tetravalent Dengue Vaccine (CYD-TDV) Efficacy Trials in Asia and Latin America.

BACKGROUND: CYD-TDV, a live, attenuated, tetravalent dengue vaccine, has been approved for the prevention of symptomatic dengue in previously dengue exposed individuals. This post hoc analysis assessed hospitalized and severe virologically confirmed dengue (VCD) over the complete 6-year follow-up of 3 CYD-TDV efficacy studies (CYD14, CYD15, and CYD23/CYD57). METHODS: The main outcomes were hazard ratios (HRs) for hospitalized or severe VCD by baseline dengue serostatus, focusing on those who were seropositive, and by age at immunization (<9 years/≥9 years). Baseline dengue serostatus was measured or inferred using several methods. Hospitalized VCD cases were characterized in terms of clinical signs and symptoms and wild-type viremia level. Antibody persistence was assessed up to 5 years after the last injection. RESULTS: In those aged ≥9 years and baseline seropositive, CYD-TDV protected against hospitalized and severe VCD over 6 years compared to placebo (HR [95% confidence interval] multiple imputation from month 0 method, .19 [.12-.30] and .15 [.06-.39]; other methods were consistent). Vaccine protection was observed over the different study periods, being highest during the first 2 years. Evidence for a decreased risk of hospitalized and severe VCD was also observed in seropositive participants aged 6-8 years. Clinical signs and symptoms, and quantified dengue viremia from participants with hospitalized VCD were comparable between groups. CONCLUSIONS: CYD-TDV demonstrated robust protection against hospitalized and severe VCD over the entire 6-year follow-up in participants who were seropositive and ≥9 years old. Protection was also observed in seropositive 6-8 year-olds. Clinical Trials Registration: NCT00842530, NCT01983553, NCT01373281, NCT01374516.

Accuracy and efficacy of pre-dengue vaccination screening for previous dengue infection with five commercially available immunoassays: a retrospective analysis of phase 3 efficacy trials.

BACKGROUND: The tetravalent dengue vaccine (CYD-TDV) has been shown to provide protection against dengue disease over 5-year follow-up in participants with previous dengue infection, but increased the risk of dengue hospitalisation and severe dengue during long-term follow-up in those without previous dengue infection. WHO recommended pre-vaccination screening to identify those with previous dengue infection (ie, dengue seropositive) who would benefit from vaccination. We re-evaluated CYD-TDV efficacy in those identified as dengue seropositive using five commercially available immunoassays, and assessed immunoassay performance. METHODS: We included participants in the immunogenicity subsets of the phase 3 CYD14 (NCT01373281) and CYD15 (NCT01374516) CYD-TDV efficacy trials, which enrolled children aged 2-16 years in 2011-12 in five countries in the Asia-Pacific region (CYD14) and five Latin American countries (CYD15). Participants assessed had received at least one injection of study drug (CYD-TDV or placebo) and had baseline samples available. We tested baseline samples by IgG-based immunoassays to classify baseline dengue serostatus, using two ELISAs (EUROIMMUN and Panbio) and three rapid diagnostic tests (RDTs; TELL ME FAST, SD BIOLINE, and OnSite). Vaccine efficacy in preventing symptomatic, hospitalised, and severe virologically confirmed dengue was determined for participants who tested positive by each immunoassay. The specificity and sensitivity of each immunoassay was determined as percentage negative and positive agreement compared with the reference algorithm, which used dengue plaque reduction neutralisation test with 50% and 90% cutoffs and non-structural protein 1 IgG ELISA results to assign baseline serostatus. FINDINGS: Samples were available for 3967 participants, 2735 (69·0%) of whom were classified as seropositive by the reference algorithm. Vaccine efficacy against symptomatic virologically confirmed dengue in immunoassay-positive participants was high across all five immunoassays (EUROIMMUN ELISA 88·2% [95% CI 77·3 to 93·9], Panbio ELISA 87·6% [76·7 to 93·4], TELL ME FAST RDT 88·8% [67·0 to 96·2], SD BIOLINE RDT 82·8% [66·9 to 91·1], and OnSite RDT 89·7% [64·6 to 97·0]), as was vaccine efficacy against hospitalised virologically confirmed dengue (EUROIMMUN-ELISA 72·8% [38·9 to 87·9], Panbio ELISA 77·5% [52·8 to 89·3], TELL ME FAST RDT 92·4% [37·8 to 99·1], SD BIOLINE RDT 87·2% [54·5 to 96·4], and OnSite RDT 73·7% [-5·1 to 93·4]) and severe virologically confirmed dengue (EUROIMMUN ELISA 86·9% [-16·8 to 98·5], Panbio ELISA 91·3% [27·6 to 99·0], TELL ME FAST RDT 100·0% [not estimable to 100·0%], SD BIOLINE RDT 89·4% [9·6 to 98·8], and OnSite RDT 73·4% [-193·7 to 97·6]). The immunoassays exhibited high specificity (≥98·8% for all immunoassays apart from SD BIOLINE RDT) but variable sensitivities, with higher sensitivities observed for the ELISAs (EUROIMMUN 89·2% [87·9 to 90·3] and Panbio 92·5 [91·4 to 93·5]) than the RDTs (TELL ME FAST 52·5% [50·6 to 54·4], SD BIOLINE 71·1% [69·3 to 72·8], and OnSite 47·6% [45·7 to 49·5]). INTERPRETATION: Our findings suggest that these immunoassays could be used for pre-vaccination screening for CYD-TDV as tools to assist risk stratification until more sensitive and convenient tests become available. FUNDING: Sanofi Pasteur.

Immunobridging efficacy of a tetravalent dengue vaccine against dengue and against hospitalized dengue from children/adolescents to adults in highly endemic countries.

BACKGROUND: The recombinant tetravalent live-attenuated dengue vaccine based on the YF 17D vaccine virus backbone (CYD-TDV) demonstrated vaccine efficacy (VE) against symptomatic, virologically confirmed dengue of any serotype from month 13 to month 25 (VCD-DENV-AnyM13→M25) in the CYD14 (2-14-y-olds) and CYD15 (9-16-y-olds) phase 3 trials. Fifty percent plaque reduction neutralization test (PRNT50) titers are a potential surrogate for immunobridging VE to adults. METHODS: Using PRNT50 calibration datasets, we applied immunobridging approaches using baseline and/or M13 PRNT50 titers to estimate VE against VCD-DENV-AnyM0→M25 and against hospitalized VCD (HVCD)-DENV-AnyM0→M72 in hypothetical 18-45-y-old and 46-50-y-old CYD14 and CYD15 cohorts. RESULTS: Baseline and M13 geometric mean PRNT50 titers were greater in 18-45-y-olds and in 46-50-y-olds vs 9-16-y-olds for most comparisons. Estimated VE (95% CIs against VCD-DENV-AnyM0→M25 ranged from 75.3% to 90.9% (52.5% to 100%) for 18-45-y-olds and 74.8% to 92.0% (53.4% to 100%) for 46-50-y-olds. Estimated VE (95% CIs) against HVCD-DENV-AnyM0→M72 ranged from 58.8% to 78.1% (40.9 to 98.9%) for 18-45-y-olds and 57.2% to 78.4% (40.5 to 97.6%) for 46-50-y-olds. Corresponding predictions among baseline-seropositive individuals yielded comparable or higher VE estimates. CONCLUSIONS: VE M0→M25 against DENV-Any and VE against HVCD-DENV-AnyM0→M72 are both expected to be higher in 18-45 and 46-50-y-olds vs CYD14 and CYD15 9-16-y-olds.

Zika and Dengue Interactions in the Context of a Large Dengue Vaccine Clinical Trial in Latin America.

A phase III dengue vaccine trial including 9- to 16-year-olds in Latin America (NCT01374516) was ongoing at the time of a Zika outbreak. We explored interactions between dengue and Zika, in the context of dengue vaccination. Symptomatic virologically confirmed Zika (VCZ) was evaluated using acute-phase sera from febrile participants (January 2013-March 2018). Neutralizing antibody geometric mean titers (GMTs) were evaluated pre- and post-Zika outbreak (months 25 and 72) in 2,000 randomly selected participants. Baseline dengue serostatus was determined using the plaque reduction neutralization test or inferred post hoc using nonstructural protein 1 IgG ELISA at M13 (case-cohort analysis). Vaccine efficacy against VCZ and serologically suspected Zika (SSZ) was estimated. Overall, 239/10,157 (2.4%) acute-phase samples were VCZ positive during the study. Dengue vaccine efficacy against VCZ was 27.8% (95% CI: 0.3; 47.7) among baseline dengue-seropositive participants. No vaccine effect was evident against SSZ. Zika antibody GMTs increased from pre- to post-Zika epidemic, with smaller increases observed for participants who were dengue seropositive at baseline than for those who were dengue seronegative: post-/pre-Zika GMT ratios for baseline dengue-seropositive participants were 21.5 (vaccine group) and 30.8 (placebo); and for dengue seronegatives, 88.1 and 89.5, respectively. Dengue antibody GMTs post-Zika were higher in dengue vaccine and placebo recipients with SSZ than those without SSZ in both dengue seropositives and seronegatives. Dengue vaccine did not enhance symptomatic Zika illness in dengue-seropositive individuals, rather it reduced the risk of VCZ. Zika infection boosted preexisting vaccine-induced or naturally occurring dengue-neutralizing antibodies.

Efficacy after 1 and 2 doses of CYD-TDV in dengue endemic areas by dengue serostatus.

A simplified dose regimen of the live, attenuated, tetravalent dengue vaccine (CYD-TDV) could have the potential to facilitate easier implementation of immunization programs against symptomatic virologically-confirmed dengue (VCD) in dengue seropositive individuals aged ≥ 9 years. This post-hoc analysis of two Phase III studies (CYD14 [NCT01373281] and CYD15 [NCT01374516]) in dengue endemic areas assessed the efficacy of CYD-TDV by dengue serostatus between dose 1 and 2 (at Month [M] 6), between dose 2 and 3 (at M12), and from dose 3 to M25. Baseline dengue serostatus (seropositive or seronegative) was determined based on measured dengue neutralizing antibody titers with the 50% plaque reduction neutralization test (PRNT50) or ascertained by logistic regression-based multiple imputation (MI) to predict PRNT50. Vaccine efficacy against symptomatic VCD was assessed by age and baseline dengue serostatus using a case-cohort framework. Dengue neutralizing antibody geometric mean titers (GMTs) were measured with the PRNT50 at 28 days post-dose 2 and 3. Vaccine efficacy estimates in seropositive participants aged ≥ 9 years at post-dose 1, 2, and 3 were 80.5% (95% CI, 66.2, 88.7), 82.0% (95% CI, 70.5, 89.0), and 75.2% (95% CI, 65.9, 81.9), respectively. In seropositive participants aged < 9 years, vaccine efficacy estimates were 48.5% (95% CI, -24.3, 78.6), 68.3% (95% CI, 34.5, 84.7), and 65.3% (95% CI, 40.2, 79.9), respectively. CYD-TDV efficacy was null to modest after any dose in seronegative participants, regardless of age group. Seropositive participants aged ≥ 9 years in the CYD-TDV group had GMTs post-dose 3 that did not exceed those observed post-dose 2. In conclusion, CYD-TDV has high efficacy against VCD from the first dose through to M25, with estimates at post-dose 1 and 2 similar to or higher than those at post-dose 3 in seropositive participants aged ≥ 9 years, consistent with immunogenicity data.

Assessment of the long-term efficacy of a dengue vaccine against symptomatic, virologically-confirmed dengue disease by baseline dengue serostatus.

CYD-TDV is a live, attenuated, tetravalent dengue vaccine licensed in 21 countries. We undertook a post-hoc analysis of the long-term efficacy of CYD-TDV during the surveillance expansion phase (SEP) of two Phase III studies (CYD14 in the Asia-Pacific region; CYD15 in Latin America). The SEP included approximately Year 5 and the entire Year 6 of follow-up after the first study injection. Vaccine efficacy against symptomatic virologically-confirmed dengue (VCD) was assessed by participant age (any age, ≥9, <9, 2-5, and 6-8 years at the time of the first injection) and baseline dengue serostatus using a case-cohort framework. Baseline dengue serostatus was estimated by several methods including logistic regression-based multiple imputation (MI) to predict PRNT50 with key predictor being Month 13 (M13) anti-non-structural protein (NS1) titers; superlearner-based imputation by targeted minimum loss based estimation (TMLE); and M13 anti-NS1 titer threshold 9 EU/mL (NS1 M13). There were 436 symptomatic VCD cases (CYD14: n = 360; CYD15: n = 76) during the SEP. Vaccine efficacy in seropositive participants aged ≥9 years was assessed by MI (47.9% [95% CI 19.4; 66.3]), TMLE (53.0% [95% CI 23; 71]), and NS1 M13 (52.4% [95% CI 30.8; 67.3]). Vaccine efficacy estimates were lower in seropositive individuals aged <9 years compared with individuals ≥9 years. Among seropositive individuals aged 2-5 and 6-8 years, vaccine efficacy across the different approaches for assessing serostatus ranged from between -25.7 to 36.9% and 44.4 to 64.7% during the SEP, respectively. In the pooled CYD14/15 data of seronegatives, vaccine efficacy was null to modest. In conclusion, CYD-TDV was shown to maintain efficacy against symptomatic VCD in seropositive participants aged ≥9 years up to six years after the first dose. Persistence of efficacy was also observed in seropositive participants aged 6-8 years.

Safety Overview of a Recombinant Live-Attenuated Tetravalent Dengue Vaccine: Pooled Analysis of Data from 18 Clinical Trials.

A recombinant live attenuated tetravalent dengue vaccine (CYD-TDV) has been shown to be efficacious in preventing virologically-confirmed dengue disease, severe dengue disease and dengue hospitalization in children aged 2-16 years in Asia and Latin America. We analyzed pooled safety data from 18 phase I, II and III clinical trials in which the dengue vaccine was administered to participants aged 2-60 years, including long-term safety follow-up in three efficacy trials. The participants were analyzed according to their age at enrollment. The percentage of participants aged 2-60 years reporting ≥1 solicited injection-site or systemic reactions was slightly higher in the CYD-TDV group than in the placebo group. The most common solicited injection-site reactions were pain. Headache and malaise were the most common solicited systemic reactions. In both groups 0.3% of participants discontinued for safety reasons. The most common unsolicited adverse events were injection-site reactions, gastrointestinal disorders, and infections. Reactogenicity did not increase with successive doses of CYD-TDV. The frequency and nature of SAEs occurring within 28 days of any dose were similar in the CYD-TDV and placebo groups and were common medical conditions that could be expected as a function of age. Baseline dengue virus serostatus did not appear to influence the safety profile. No vaccine-related anaphylactic reactions, neurotropic events or viscerotropic events were reported. In year 3 after dose 1, an imbalance for dengue hospitalization, including for severe dengue, observed in participants aged <9 years in the CYD-TDV group compared with the placebo group was not observed for participants aged ≥9 years. In Year 4, this imbalance in participants aged <9 years was less marked, giving an overall lower risk of dengue hospitalization or severe dengue from dose 1 to Year 4 in the CYD-TDV group. These results have contributed to the definition of the target population for vaccination (≥9 years old) for which CYD-TDV has a satisfactory safety profile. Long-term safety will continue to be monitored in the ongoing follow-up of efficacy trials. Safety and effectiveness in real-life settings will be assessed through post-licensure studies.

Staphylococcus aureus: the current state of disease, pathophysiology and strategies for prevention.

Staphylococcus aureus is both a commensal organism and also an important opportunistic human pathogen, causing a variety of community and hospital-associated pathologies, such as bacteremia-sepsis, endocarditis, pneumonia, osteomyelitis, arthritis and skin diseases. The resurgence of S. aureus during the last decade in many settings has been facilitated not only by bacterial antibiotic resistance mechanisms but also by the emergence of new S. aureus clonal types with increased expression of virulence factors and the capacity to neutralize the host immune response. Prevention of the spread of S. aureus infection relies on the use of contact precautions and adequate procedures for infection control that so far have not been fully effective. Prevention using a prophylactic vaccine would complement these processes, having the potential to bring additional, significant progress toward decreasing invasive disease due to S. aureus.

Assessment of bivalent and tetravalent dengue vaccine formulations in flavivirus-naïve adults in Mexico.

UNLABELLED: Several ChimeriVax-Dengue (CYD)-based vaccination strategies were investigated as potential alternatives to vaccination with tetravalent CYD vaccine (CYD-TDV) in this phase IIa trial conducted in 2008-9 in 150 healthy adults. Participants were randomized and vaccinated on D0 and D105 (± 15 days). One group received bivalent CYD vaccine against serotypes 1 and 3 (CYD-1;3) on day 0 and CYD-2;4 on day 105 (± 15 days). Two groups received an injection at each timepoint of a tetravalent blend of CYD-1;3;4 and a VERO cell derived, live attenuated vaccine against serotype 2 (VDV-2), or the reference CYD-TDV. A fourth group received Japanese encephalitis (JE) vaccine on days -14, -7 and 0, followed by CYD-TDV on day 105. Viraemia was infrequent in all groups. CYD-4 viraemia was most frequent after tetravalent vaccination, while CYD-3 viraemia was most frequent after the first bivalent vaccination. Immunogenicity as assessed by 50% plaque reduction neutralisation test on D28 was comparable after the first injection of either tetravalent vaccine, and increased after the second injection, particularly with the blended CYD-1;3;4/ VDV-2 vaccine. In the bivalent vaccine group, immune response against serotype 3 was highest and the second injection elicited a low immune response against CYD 2 and 4. Immune responses after the first injection of CYD-TDV in the JE-primed group were in general higher than after the first injection in the other groups. All tested regimens were well tolerated without marked differences between groups. Bivalent vaccination showed no advantage in terms of immunogenicity. CLINICAL TRIAL REGISTRATION NUMBER: NCT00740155.

Preclinical and clinical development of a YFV 17 D-based chimeric vaccine against West Nile virus.

Substantial success has been achieved in the development and implementation of West Nile (WN) vaccines for horses; however, no human WN vaccines are approved. This review focuses on the construction, pre-clinical and clinical characterization of ChimeriVax-WN02 for humans, a live chimeric vaccine composed of a yellow fever (YF) 17D virus in which the prM-E envelope protein genes are replaced with the corresponding genes of the WN NY99 virus. Pre-clinical studies demonstrated that ChimeriVax-WN02 was significantly less neurovirulent than YF 17D in mice and rhesus and cynomolgus monkeys. The vaccine elicited neutralizing antibody titers after inoculation in hamsters and monkeys and protected immunized animals from lethal challenge including intracerebral inoculation of high dose of WN NY99 virus. Safety, viremia and immunogenicity of ChimeriVax-WN02 were assessed in one phase I study and in two phase II clinical trials. No safety signals were detected in the three clinical trials with no remarkable differences in incidence of adverse events (AEs) between vaccine and placebo recipients. Viremia was transient and the mean viremia levels were low. The vaccine elicited strong and durable neutralizing antibody and cytotoxic T cell responses. WN epidemiology impedes a classical licensure pathway; therefore, innovative licensure strategies should be explored.

Immunogenicity and safety of a recombinant tetravalent dengue vaccine in children and adolescents ages 9-16 years in Brazil.

Immunogenicity and safety of a recombinant, live-attenuated, tetravalent dengue disease vaccine (CYD-TDV) was evaluated in children/adolescents in Brazil. In this observer-blind, placebo-controlled, phase II single-center study, children/adolescents (ages 9-16 years) were randomized to receive CYD-TDV or placebo at 0, 6, and 12 months. Immunogenicity was assessed using a 50% plaque neutralization test. Overall, 150 participants were enrolled (CYD-TDV: N = 100; placebo: N = 50). Injection site pain and headache were the most common solicited injection site and systemic reactions. Unsolicited adverse events (AEs) and serious AEs were similar between groups. No serious AEs were vaccine-related. Geometric mean titers against all dengue virus serotypes increased with CYD-TDV vaccination and were 267, 544, 741, and 432 1/dil for serotypes 1-4, respectively, after dose 3, representing a mean fold increase from baseline of 5, 6, 6, and 20, respectively. CYD-TDV vaccination elicited a neutralizing antibody response against serotypes 1-4 and was well-tolerated in children/adolescents in a dengue-endemic region.

Safety and immunogenicity of three tetravalent dengue vaccine formulations in healthy adults in the USA.

BACKGROUND: A candidate recombinant, live-attenuated, CYD tetravalent dengue vaccine (CYD-TDV) has recently demonstrated immunogenicity, efficacy and good tolerability. This study was performed to evaluate three CYD-TDV formulations in adults. METHODS: This was a randomized, double-blind, multicenter, phase II trial. The vaccine formulations were: CYD-TDV 5555 (≈5log10 tissue culture infectious dose 50% [TCID50] of serotypes 1-4); CYD-TDV 5553 (≈5log10 TCID50 of serotypes 1-3 and ≈3log10 TCID50 of serotype 4); and CYD-TDV 4444 (≈4log10 TCID50 of serotypes 1-4). Vaccinations were administered at 0, 6 and 12 months. Immunogenicity was assessed using the plaque reduction neutralization test. RESULTS: In total, 260 individuals were enrolled. The 5555 formulation elicited a superior serotype 4 response versus the 5553 formulation, with seropositivity rates of 89.7% and 58.3%, respectively, after the second dose (between-group difference 31.4%; 95% confidence interval 18.2-43.2). After each of the three doses, seropositivity rates for serotypes 1-3 were numerically highest with CYD-TDV 5553 and lowest with the 4444 formulation; seropositivity rates for serotype 4 were similar with the 5555 and 4444 formulations, and much lower among recipients of CYD-TDV 5553. Geometric mean titers followed the same pattern as that seen with seropositivity rates. Safety/reactogenicity results were similar for all three vaccine formulations, although the percentage of participants reporting solicited injection site reactions was lower with CYD-TDV 4444 than with the other two formulations. All serious adverse events were unrelated to vaccination. CONCLUSIONS: Reducing the dose of serotype 4 antigen (5553 formulation) creates an imbalance in the immune response to CYD-TDV. Immune responses to CYD-TDV 5555 were slightly higher than to the 4444 formulation. Development of CYD-TDV 5555 has subsequently been pursued.

Safety and immunogenicity of a recombinant tetravalent dengue vaccine in 9-16 year olds: a randomized, controlled, phase II trial in Latin America.

BACKGROUND: The dengue virus is a member of the Flavivirus (FV) genus, which also includes the yellow fever virus. Dengue disease is caused by any 1 of 4 dengue virus serotypes and is a serious public health concern in Latin America. This study evaluated the safety and immunogenicity of a candidate recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) in 9-16 year olds in Latin America. METHODS: In this randomized, blinded, controlled study, volunteers received either 3 doses of CYD-TDV (n = 401) or placebo as first and second injection and tetanus/diphtheria/acellular pertussis vaccine as third injection (n = 199) at 0, 6 and 12 months. Adverse events were documented. Plaque reduction neutralization test antibody titers against the 4 CYD-TDV parental strains were measured before and 28 days after each dose. Seropositivity was defined as antibody titers ≥10 1/dil. RESULTS: The number of adverse reactions decreased after each successive CYD-TDV dose. After each CYD-TDV dose, antibody titers against all 4 serotypes were higher than baseline and respective predose titers. After the third dose of CYD-TDV, 100%, 98.6% and 93.4% of participants were seropositive for at least 2, at least 3 or all 4 serotypes, respectively. Higher antibody titers were observed in participants in the CYD-TDV group who were FV-seropositive at baseline compared with those who were FV-seronegative. CONCLUSIONS: CYD-TDV had a favorable safety profile and elicited antibody responses against all 4 dengue virus serotypes in 9-16 year olds in Latin America. These findings support the continued development of CYD-TDV.

The history of dengue outbreaks in the Americas.

Dengue is a viral disease usually transmitted by Aedes aegypti mosquitoes. Dengue outbreaks in the Americas reported in medical literature and to the Pan American Health Organization are described. The outbreak history from 1600 to 2010 was categorized into four phases: Introduction of dengue in the Americas (1600-1946); Continental plan for the eradication of the Ae. aegypti (1947-1970) marked by a successful eradication of the mosquito in 18 continental countries by 1962; Ae. aegypti reinfestation (1971-1999) caused by the failure of the mosquito eradication program; Increased dispersion of Ae. aegypti and dengue virus circulation (2000-2010) characterized by a marked increase in the number of outbreaks. During 2010 > 1.7 million dengue cases were reported, with 50,235 severe cases and 1,185 deaths. A dramatic increase in the number of outbreaks has been reported in recent years. Urgent global action is needed to avoid further disease spread.

Phase II, dose ranging study of the safety and immunogenicity of single dose West Nile vaccine in healthy adults ≥ 50 years of age.

INTRODUCTION: ChimeriVax-WN02 is a live, attenuated chimeric vaccine for protection against West Nile virus (WNV) produced by insertion of the genes encoding the pre-membrane (prM) and envelope (E) proteins of WNV (strain NY99) into the yellow fever 7D vaccine virus. This Phase II, randomized, double-blind, placebo-controlled, multi-center study in the US assessed the immunogenicity, viremia, and safety of the ChimeriVax-WN02 vaccine. METHODS: The study included adults in general good health. Subjects aged ≥ 50 years were randomized to one of four treatment groups: ChimeriVax-WN02 4 × 10(3) plaque-forming units (pfu) (n=122), 4 × 10(4)pfu (n=124), 4 × 10(5)pfu (n=113), or placebo (n=120). A subset of subjects was randomized to assess viremia after vaccination at three different dose levels. Subjects were followed for safety up to 6 months after vaccination. RESULTS: A total of 121 subjects for WN024 × 10(3), 122 for WN02 4 × 10(4), 110 for WN02 4 × 10(5), and 120 for the placebo group completed the study up to the 6-month safety follow-up. Seroconversion, as measured by plaque reduction neutralization test (PRNT), was achieved at Day 28 by 92.1%, 93.2%, and 95.4% of subjects in the WN02 4 × 10(3), the WN02 4 × 10(4), and the WN02 4 × 10(5) groups, respectively. Viremia was transient, detected between Days 2 and 14 but not at Day 28, and in most cases did not reach the quantification threshold. The percentage of subjects reporting at least one event of reactogenicity was similar in the placebo and active vaccine groups and showed no dose relationship. CONCLUSIONS: The ChimeriVax-WN02 vaccine was highly immunogenic and well tolerated among subjects ≥ 50 years old at all dose levels.

Mumps antibody levels among students before a mumps outbreak: in search of a correlate of immunity.

BACKGROUND: In 2006, a mumps outbreak occurred on a university campus despite ≥ 95% coverage of students with 2 doses of measles-mumps-rubella (MMR) vaccine. Using plasma samples from a blood drive held on campus before identification of mumps cases, we compared vaccine-induced preoutbreak mumps antibody levels between individuals who developed mumps (case patients) and those who did not develop mumps (nonpatients). METHODS: Preoutbreak samples were available from 11 case patients, 22 nonpatients who reported mumps exposure but no mumps symptoms, and 103 nonpatients who reported no known exposure and no symptoms. Antibody titers were measured by plaque reduction neutralization assay using Jeryl Lynn vaccine virus and the outbreak virus Iowa-G/USA-06 and by enzyme immunoassay (EIA). RESULTS: Preoutbreak Jeryl Lynn virus neutralization titers were significantly lower among case patients than unexposed nonpatients (P = .023), and EIA results were significantly lower among case patients than exposed nonpatients (P = .007) and unexposed nonpatients (P = .009). Proportionately more case patients than exposed nonpatients had a preoutbreak anti-Jeryl Lynn titer < 31 (64% vs 27%, respectively; P = .065), an anti-Iowa-G/USA-06 titer < 8 (55% vs 14%; P = .033), and EIA index standard ratio < 1.40 (64% vs 9%; P = .002) and < 1.71 (73% vs 14%, P = .001). DISCUSSION: Case patients generally had lower preoutbreak mumps antibody levels than nonpatients. However, titers overlapped and no cutoff points separated all mumps case patients from all nonpatients.