Influenza vaccines for preventing cardiovascular disease.

BACKGROUND: This is an update of the original review published in 2008. The risk of adverse cardiovascular outcomes is increased with influenza-like infection, and vaccination against influenza may improve cardiovascular outcomes. OBJECTIVES: To assess the potential benefits of influenza vaccination for primary and secondary prevention of cardiovascular disease. SEARCH METHODS: We searched the following electronic databases on 18 October 2013: The Cochrane Library (including Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Economic Evaluation Database (EED) and Health Technology Assessment database (HTA)), MEDLINE, EMBASE, Science Citation Index Expanded, Conference Proceedings Citation Index - Science and ongoing trials registers (www.controlled-trials.com/ and www.clinicaltrials.gov). We examined reference lists of relevant primary studies and systematic reviews. We performed a limited PubMed search on 20 February 2015, just before publication. SELECTION CRITERIA: Randomised controlled trials (RCTs) of influenza vaccination compared with placebo or no treatment in participants with or without cardiovascular disease, assessing cardiovascular death or non-fatal cardiovascular events. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. We carried out meta-analyses only for cardiovascular death, as other outcomes were reported too infrequently. We expressed effect sizes as risk ratios (RRs), and we used random-effects models. MAIN RESULTS: We included eight trials of influenza vaccination compared with placebo or no vaccination, with 12,029 participants receiving at least one vaccination or control treatment. We included six new studies (n = 11,251), in addition to the two included in the previous version of the review. Four of these trials (n = 10,347) focused on prevention of influenza in the general or elderly population and reported cardiovascular outcomes among their safety analyses; four trials (n = 1682) focused on prevention of cardiovascular events in patients with established coronary heart disease. These populations were analysed separately. Follow-up continued between 42 days and one year. Five RCTs showed deficits in at least three of the risk of bias criteria assessed. When reported (seven studies), vaccination provided adequate immunogenicity or protection against influenza. Cardiovascular mortality was reported by four secondary prevention trials and was significantly reduced by influenza vaccination overall (risk ratio (RR) 0.45, 95% confidence interval (CI) 0.26 to 0.76; P value 0.003) with no significant heterogeneity between studies, and by three trials reporting cardiovascular mortality as part of their safety analyses when the numbers of events were too small to permit conclusions. In studies of patients with coronary heart disease, composite outcomes of cardiovascular events tended to be decreased with influenza vaccination compared with placebo. Generally no significant difference was found between comparison groups regarding individual outcomes such as myocardial infarction. AUTHORS' CONCLUSIONS: In patients with cardiovascular disease, influenza vaccination may reduce cardiovascular mortality and combined cardiovascular events. However, studies had some risk of bias, and results were not always consistent, so additional higher-quality evidence is necessary to confirm these findings. Not enough evidence was available to establish whether influenza vaccination has a role to play in the primary prevention of cardiovascular disease.

Association between influenza vaccination and cardiovascular outcomes in high-risk patients: a meta-analysis.

IMPORTANCE: Among nontraditional cardiovascular risk factors, recent influenzalike infection is associated with fatal and nonfatal atherothrombotic events. OBJECTIVES: To determine if influenza vaccination is associated with prevention of cardiovascular events. DATA SOURCES AND STUDY SELECTION: A systematic review and meta-analysis of MEDLINE (1946-August 2013), EMBASE (1947-August 2013), and the Cochrane Library Central Register of Controlled Trials (inception-August 2013) for randomized clinical trials (RCTs) comparing influenza vaccine vs placebo or control in patients at high risk of cardiovascular disease, reporting cardiovascular outcomes either as efficacy or safety events. DATA EXTRACTION AND SYNTHESIS: Two investigators extracted data independently on trial design, baseline characteristics, outcomes, and safety events from published manuscripts and unpublished supplemental data. High-quality studies were considered those that described an appropriate method of randomization, allocation concealment, blinding, and completeness of follow-up. MAIN OUTCOMES AND MEASURES: Random-effects Mantel-Haenszel risk ratios (RRs) and 95% CIs were derived for composite cardiovascular events, cardiovascular mortality, all-cause mortality, and individual cardiovascular events. Analyses were stratified by subgroups of patients with and without a history of acute coronary syndrome (ACS) within 1 year of randomization. RESULTS: Five published and 1 unpublished randomized clinical trials of 6735 patients (mean age, 67 years; 51.3% women; 36.2% with a cardiac history; mean follow-up time, 7.9 months) were included. Influenza vaccine was associated with a lower risk of composite cardiovascular events (2.9% vs 4.7%; RR, 0.64 [95% CI, 0.48-0.86], P = .003) in published trials. A treatment interaction was detected between patients with (RR, 0.45 [95% CI, 0.32-0.63]) and without (RR, 0.94 [95% CI, 0.55-1.61]) recent ACS (P for interaction = .02). Results were similar with the addition of unpublished data. CONCLUSIONS AND RELEVANCE: In a meta-analysis of RCTs, the use of influenza vaccine was associated with a lower risk of major adverse cardiovascular events. The greatest treatment effect was seen among the highest-risk patients with more active coronary disease. A large, adequately powered, multicenter trial is warranted to address these findings and assess individual cardiovascular end points.

Influenza vaccination and cardiovascular events in patients with ischaemic heart disease and heart failure: A meta-analysis.

AIM: Randomized controlled trials (RCTs) enrolling patients at high cardiovascular risk have found that influenza vaccination may reduce the incidence of cardiovascular events. We performed an updated meta-analysis assessing the effect of influenza vaccination on the incidence of cardiovascular events in patients with ischaemic heart disease or heart failure. METHODS AND RESULTS: We searched PubMed, EMBASE and other sources to identify RCTs examining the effect of influenza vaccination on the incidence of cardiovascular events assessed as efficacy outcomes in patients with ischaemic heart disease or heart failure. Eligible studies followed patients for at least one influenza season, defined as a minimum duration of 6 months. The primary endpoint was a composite of cardiovascular death, acute coronary syndrome, stent thrombosis or coronary revascularization, stroke or heart failure hospitalization. The secondary endpoints were cardiovascular death and all-cause death. Two investigators independently identified and extracted data from studies. Results were compared using hazard ratios (HRs) in both random effects and fixed effects models. We included five peer-reviewed and one non peer-reviewed RCTs for a total of 9340 patients. Five trials included patients with ischaemic heart disease (n = 4211) and one trial included patients with heart failure (n = 5129). Influenza vaccination was associated with a reduced incidence of the primary composite endpoint (random effects HR [rHR] 0.74, 95% confidence interval [CI] 0.63-0.88, p < 0.001, I2 = 52%), cardiovascular death (rHR 0.63, 95% CI 0.42-0.95, p = 0.028, I2 = 58%) and all-cause death (rHR 0.72, 95% CI 0.54-0.95, p = 0.0227, I2 = 52%). Results were similar when non peer-reviewed data were excluded. CONCLUSION: In this meta-analysis of available RCTs in patients at high cardiovascular risk, influenza vaccination was associated with a reduced incidence of cardiovascular events, cardiovascular death and all-cause death as compared to placebo or no treatment.

Crimean-Congo hemorrhagic fever virus in Central, Eastern, and South-eastern Asia.

Crimean-Congo hemorrhagic fever (CCHF), caused by Crimean-Congo hemorrhagic fever virus (CCHFV), is endemic in Africa, Asia, and Europe, but CCHF epidemiology and epizootiology is only rudimentarily defined for most regions. Here we summarize what is known about CCHF in Central, Eastern, and South-eastern Asia. Searching multiple international and country-specific databases using a One Health approach, we defined disease risk and burden through identification of CCHF cases, anti-CCHFV antibody prevalence, and CCHFV isolation from vector ticks. We identified 2313 CCHF cases that occurred in 1944-2021 in the three examined regions. Central Asian countries reported the majority of cases (2,026). In Eastern Asia, China was the only country that reported CCHF cases (287). In South-eastern Asia, no cases were reported. Next, we leveraged our previously established classification scheme to assign countries to five CCHF evidence levels. Six countries (China, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan) were assigned to level 1 or level 2 based on CCHF case reports and the maturity of the countries' surveillance systems. Two countries (Mongolia and Myanmar) were assigned to level 3 due to evidence of CCHFV circulation in the absence of reported CCHF cases. Thirteen countries in Eastern and South-eastern Asia were categorized in levels 4 and 5 based on prevalence of CCHFV vector ticks. Collectively, this paper describes the past and present status of CCHF reporting to inform international and local public-health agencies to strengthen or establish CCHFV surveillance systems and address shortcomings.

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.

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.

Immune correlates analysis of the PREVENT-19 COVID-19 vaccine efficacy clinical trial.

In the PREVENT-19 phase 3 trial of the NVX-CoV2373 vaccine (NCT04611802), anti-spike binding IgG concentration (spike IgG), anti-RBD binding IgG concentration (RBD IgG), and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks post-dose two are assessed as correlates of risk and as correlates of protection against COVID-19. Analyses are conducted in the U.S. cohort of baseline SARS-CoV-2 negative per-protocol participants using a case-cohort design that measures the markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases. All markers are inversely associated with COVID-19 risk and directly associated with vaccine efficacy. In vaccine recipients with nAb ID50 titers of 50, 100, and 7230 international units (IU50)/ml, vaccine efficacy estimates are 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), and 96.8% (88.3%, 99.3%). The results support potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use.

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.

Unusual case of cutaneous and synovial Paecilomyces lilacinus infection of hand successfully treated with voriconazole and review of published literature.

Paecilomyces lilacinus infection is rare and is found worldwide. The majority of infections occur in immunocompromised people. Among immunocompetent patients, cutaneous infections are the second most common site of infection but are difficult to treat because of antifungal resistance. We report a case of hand cutaneous involvement with synovitis in an immunocompetent patient that improved after treatment with oral voriconazole. To the best of our knowledge, there are only five published cases of cutaneous P.lilacinus infection, all in immunocompromised patient, treated with oral voriconazole. We review all previously reported cases.

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study.

BACKGROUND: We evaluated our SARS-CoV-2 prefusion spike recombinant protein vaccine (CoV2 preS dTM) with different adjuvants, unadjuvanted, and in a one-injection and two-injection dosing schedule in a previous phase 1-2 study. Based on interim results from that study, we selected a two-injection schedule and the AS03 adjuvant for further clinical development. However, lower than expected antibody responses, particularly in older adults, and higher than expected reactogenicity after the second vaccination were observed. In the current study, we evaluated the safety and immunogenicity of an optimised formulation of CoV2 preS dTM adjuvanted with AS03 to inform progression to phase 3 clinical trial. METHODS: This phase 2, randomised, parallel-group, dose-ranging study was done in adults (≥18 years old), including those with pre-existing medical conditions, those who were immunocompromised (except those with recent organ transplant or chemotherapy) and those with a potentially increased risk for severe COVID-19, at 20 clinical research centres in the USA and Honduras. Women who were pregnant or lactating or, for those of childbearing potential, not using an effective method of contraception or abstinence, and those who had received a COVID-19 vaccine, were excluded. Participants were randomly assigned (1:1:1) using an interactive response technology system, with stratification by age (18-59 years and ≥60 years), rapid serodiagnostic test result (positive or negative), and high-risk medical conditions (yes or no), to receive two injections (day 1 and day 22) of 5 7mu;g (low dose), 10 7mu;g (medium dose), or 15 7mu;g (high dose) CoV2 preS dTM antigen with fixed AS03 content. All participants and outcome assessors were masked to group assignment; unmasked study staff involved in vaccine preparation were not involved in safety outcome assessments. All laboratory staff performing the assays were masked to treatment. The primary safety objective was to describe the safety profile in all participants, for each candidate vaccine formulation. Safety endpoints were evaluated for all randomised participants who received at least one dose of the study vaccine (safety analysis set), and are presented here for the interim study period (up to day 43). The primary immunogenicity objective was to describe the neutralising antibody titres to the D614G variant 14 days after the second vaccination (day 36) in participants who were SARS-CoV-2 naive who received both injections, provided samples at day 1 and day 36, did not have protocol deviations, and did not receive an authorised COVID-19 vaccine before day 36. Neutralising antibodies were measured using a pseudovirus neutralisation assay and are presented here up to 14 days after the second dose. As a secondary immunogenicity objective, we assessed neutralising antibodies in non-naive participants. This trial is registered with ClinicalTrials.gov (NCT04762680) and is closed to new participants for the cohort reported here. FINDINGS: Of 722 participants enrolled and randomly assigned between Feb 24, 2021, and March 8, 2021, 721 received at least one injection (low dose=240, medium dose=239, and high dose=242). The proportion of participants reporting at least one solicited adverse reaction (injection site or systemic) in the first 7 days after any vaccination was similar between treatment groups (217 [91%] of 238 in the low-dose group, 213 [90%] of 237 in the medium-dose group, and 218 [91%] of 239 in the high-dose group); these adverse reactions were transient, were mostly mild to moderate in intensity, and occurred at a higher frequency and intensity after the second vaccination. Four participants reported immediate unsolicited adverse events; two (one each in the low-dose group and medium-dose group) were considered by the investigators to be vaccine related and two (one each in the low-dose and high-dose groups) were considered unrelated. Five participants reported seven vaccine-related medically attended adverse events (two in the low-dose group, one in the medium-dose group, and four in the high-dose group). No vaccine-related serious adverse events and no adverse events of special interest were reported. Among participants naive to SARS-CoV-2 at day 36, 158 (98%) of 162 in the low-dose group, 166 (99%) of 168 in the medium-dose group, and 163 (98%) of 166 in the high-dose group had at least a two-fold increase in neutralising antibody titres to the D614G variant from baseline. Neutralising antibody geometric mean titres (GMTs) at day 36 for participants who were naive were 2189 (95% CI 1744-2746) for the low-dose group, 2269 (1792-2873) for the medium-dose group, and 2895 (2294-3654) for the high-dose group. GMT ratios (day 36: day 1) were 107 (95% CI 85-135) in the low-dose group, 110 (87-140) in the medium-dose group, and 141 (111-179) in the high-dose group. Neutralising antibody titres in non-naive adults 21 days after one injection tended to be higher than titres after two injections in adults who were naive, with GMTs 21 days after one injection for participants who were non-naive being 3143 (95% CI 836-11 815) in the low-dose group, 2338 (593-9226) in the medium-dose group, and 7069 (1361-36 725) in the high-dose group. INTERPRETATION: Two injections of CoV2 preS dTM-AS03 showed acceptable safety and reactogenicity, and robust immunogenicity in adults who were SARS-CoV-2 naive and non-naive. These results supported progression to phase 3 evaluation of the 10 7mu;g antigen dose for primary vaccination and a 5 7mu;g antigen dose for booster vaccination. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.

Epidemiology of Crimean-Congo Hemorrhagic Fever (CCHF) in Africa-Underestimated for Decades.

Crimean-Congo hemorrhagic fever (CCHF) is endemic in Africa, but the epidemiology remains to be defined. Using a broad database search, we reviewed the literature to better define CCHF evidence in Africa. We used a One Health approach to define the impact of CCHF by reviewing case reports, human and animal serology, and records of CCHF virus (CCHFV) isolations (1956-mid-2020). In addition, published and unpublished collection data were used to estimate the geographic distribution of Hyalomma ticks and infection vectors. We implemented a previously proposed classification scheme for organizing countries into five categories by the level of evidence. From January 1, 1956 to July 25, 2020, 494 CCHF cases (115 lethal) were reported in Africa. Since 2000, nine countries (Kenya, Mali, Mozambique, Nigeria, Senegal, Sierra Leone, South Sudan, Sudan, and Tunisia) have reported their first CCHF cases. Nineteen countries reported CCHF cases and were assigned level 1 or level 2 based on maturity of their surveillance system. Thirty countries with evidence of CCHFV circulation in the absence of CCHF cases were assigned level 3 or level 4. Twelve countries for which no data were available were assigned level 5. The goal of this review is to inform international organizations, local governments, and healthcare professionals about shortcomings in CCHF surveillance in Africa to assist in a movement toward strengthening policy to improve CCHF surveillance.

Safety and immunogenicity of an inactivated eastern equine encephalitis virus vaccine.

BACKGROUND: Eastern equine encephalitis virus (EEEV) is a mosquito borne alphavirus spread primarily in Atlantic and Gulf Coast regions of the United States. EEEV is the causative agent of a devastating meningoencephalitis syndrome, with approximately 30% mortality and significant morbidity. There is no licensed human vaccine against EEEV. An inactivated EEEV vaccine has been offered under investigational new drug (IND) protocols at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) since 1976. METHODS: Healthy at-risk laboratory personnel received inactivated PE-6 strain EEEV (TSI-GSD 104) vaccine under two separate IND protocols. Protocol FY 99-11 (2002-2008) had a primary series consisting of doses on day 0, 7, and 28. Protocol FY 06-31 (2008-2016) utilized a primary series with doses on day 0 and 28, and month 6. Participants with an inadequate immune response, plaque reduction neutralization test with 80% cut-off (PRNT80) titer < 40, received booster vaccination. Volunteers with prior EEEV vaccination were eligible to enroll for booster doses based on annual titer evaluation. RESULTS: The FY06-31 dosing schema resulted in significantly greater post-primary series immune response (PRNT80 ≥ 40) rates (84% vs 54%) and geometric mean titers (184.1 vs 39.4). The FY 06-31 dosing schema also resulted in significantly greater cumulative annual immune response rates from 1 to up to 7 years post vaccination (75% vs 59%) and geometric mean of titers (60.1 vs 43.0). The majority of probably or definitely related adverse events were mild and local; there were no probably or definitely related serious adverse events. CONCLUSIONS: Inactivated PE-6 EEEV vaccine is safe and immunogenic in at-risk laboratory personnel. A prolonged primary series, with month 6 dose, significantly improved vaccine immunogenicity both post-primary series and longitudinally on annual titers. Despite decades of safe use under IND, full licensure is not planned due to manufacturing constraints, and ongoing development of alternatives.

The Western Equine Encephalitis Lyophilized, Inactivated Vaccine: An Update on Safety and Immunogenicity.

Background: Western Equine Encephalitis (WEE) is a naturally acquired infection and potentially devastating bioweapon, with no specific human countermeasures. An experimental inactivated Western Equine Encephalitis Vaccine (WEEV; WEE TSI-GSD 210) has been used under an IND (investigational New Drug) protocol at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) since 1976. Methods: Over 24 years from 1987 to 2011, 876 subjects received 3 primary vaccine doses under 3 studies with 1,537 booster doses administered (FY87-8, phase 2, laboratory workers, vaccine lots 1-81-1, 1-81-2, and 2-1-91; FY99-12, phase 2 laboratory workers, lot 2-1-91; and FY09-02, phase 1 healthy volunteer, lot 3-1-92). Post-vaccination safety and immunogenicity [plaque reduction neutralization test 80% (PRNT80) > 1:40] were analyzed. Results: Overall PRNT80 response to the primary series in FY87-8 was 42% (326/770) but dropped to 16% (14/87) in FY99-12, prompting study FY09-02, which achieved 89% (17/19). The first booster response rate was 68% (814/1194) in FY87-8, 53% (171/324) in FY99-12, and 100% (10/10) in FY09-02. The majority of definitely related adverse reactions (AEs) were mild and local with no definitely related serious AEs. No laboratory acquired WEE infection was documented during this period despite 4 reported exposures in vaccinated subjects. Conclusion: The TSI-GSD 210 WEE vaccine was immunogenic, safe and well tolerated. Use of this vaccine could be considered in an emergency setting. Despite decades of safe and effective use under IND, full licensure is not planned due to manufacturing constraints, and a strategic decision to develop alternatives. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT01159561.

An Emerging Biothreat: Crimean-Congo Hemorrhagic Fever Virus in Southern and Western Asia.

Tick-borne Crimean-Congo hemorrhagic fever virus (CCHFV) is endemic in numerous countries, but the epidemiology and epizoology of Crimean-Congo hemorrhagic fever (CCHF) remain to be defined for most regions of the world. Using a broad database search approach, we reviewed the literature on CCHF and CCHFV in Southern and Western Asia to better define the disease burden in these areas. We used a One Health approach, moving beyond a focus solely on human disease burden to more comprehensively define this burden by reviewing CCHF case reports, human and animal CCHFV seroprevalence studies, and human and animal CCHFV isolations. In addition, we used published literature to estimate the distribution of Hyalomma ticks and infection of these ticks by CCHFV. Using these data, we propose a new classification scheme for organizing the evaluated countries into five categories by level of evidence for CCHF endemicity. Twelve countries have reported CCHF cases, five from Southern Asia and seven from Western Asia. These were assigned to level 1 or 2. Eleven countries that have evidence of vector circulation but did not report confirmed CCHF cases were assigned to level 3 or 4. This classification scheme was developed to inform policy toward strengthening CCHF disease surveillance in the Southern and Western Asia regions. In particular, the goal of this review was to inform international organizations, local governments, and health-care professionals about current shortcomings in CCHFV surveillance in these two high-prevalence regions.

Clinical and epidemiologic features of Crimean-Congo hemorrhagic fever among children and adolescents from southeastern Iran.

This study aimed to investigate the clinical and epidemiologic features of Crimean-Congo hemorrhagic fever among 34 children and adolescents (mean age, 13.3 +/- 4.6 years) from a highly endemic region. Clinical manifestations were similar to those in adults. The case-fatality ratio was 26.5% (9 of 34). Compared with adult patients, children and adolescents may be more vulnerable to severe and fatal Crimean-Congo hemorrhagic fever.

Antibody response to influenza immunization in kidney transplant recipients receiving either azathioprine or mycophenolate: a controlled trial.

AIMS: We aimed to assess humoral immune response to the influenza vaccine in adult kidney transplant recipients (KTRs) subjected to two immunosuppressive regimens containing either mycophenolate mofetil (MMF) or azathioprine (Aza). METHODS: 40 eligible KTRs (24 treated with Aza [KTRs-Aza] and 16 treated with MMF [KTRs-MMF]) and 40 matched healthy controls (HCs) were administered the trivalent 2006-2007 anti-influenza vaccine. Antibody (Ab) titers were measured before (pre-vacc) and 1 month after (post-vacc) vaccination. The proportion of protective Ab titers (i.e. >or=1:40), the serological response (i.e. >or=4-fold rise in titers) rates, and the magnitudes of change in titers were evaluated. RESULTS: KTRs and HCs were similar in serologic responses, magnitudes of change in Ab titers, and proportions of acquired protective titers against all antigens. Whereas KTRs-MMF and KTRs-Aza were identical in magnitude of rise in titers as well as in serologic responses, KTRs-MMF did poorer in developing post-vacc-protective titers against A/H1N1 (p < 0.05). The function of the transplanted kidney has not deteriorated after vaccination. CONCLUSIONS: Anti-influenza vaccination was safe in KTRs and evoked Ab responses comparable to those of HCs. KTRs-MMF and KTRs-Aza responded almost equally to the vaccine. Annual anti-influenza vaccination can be recommended to all stable KTRs.

Effect of eradication of Helicobacter pylori on platelet recovery in patients with chronic idiopathic thrombocytopenic purpura: a controlled trial.

Several recent studies have suggested that an association exists between Helicobacter pylori (HP) eradication and improvement in platelet count in a significant proportion of patients with idiopathic thrombocytopenic purpura (ITP). In this controlled study, we prospectively examined adult patients with chronic ITP for HP infection, and assessed the effect of HP eradication on platelet count. One hundred forty-two consecutive Iranian patients with chronic ITP were assessed. Those who met the criteria and had platelet counts >30 x 10(9)/L within the medication-free screening month were enrolled (n = 129; 66 females; mean age, 29.2 +/- 7.0 years). HP-positive patients received a 2-week course of triple HP eradication therapy (i.e., amoxicillin, clarithromycin, and omeprazole) and were followed for 48 weeks. An ITP response was defined as a platelet count of >100 x 10(9)/L 24 weeks after treatment, together with an increase in the platelet count >30 x 10(9)/L over the baseline value. HP infection was detected in 79 (61%) patients. HP-positive patients were significantly older than HP-negative subjects (P = 0.018). HP eradication was successful in 87% (62/71) of those who completed the eradication therapy. Whereas 48% (30/62) of HP-eradicated patients showed an ITP response, no HP-negative patient had an ITP response. The ITP response persisted for 48 weeks in 93% (28/30) of the responders. The ITP responders had a shorter disease duration than the nonresponders (P = 0.002). The management of mild-to-moderate chronic ITP in Iranian patients, especially those with a recent onset of disease, should include an investigation for and eradication of infection with HP.

Treatment-focused Ebola trials, supportive care and future of filovirus care.

INTRODUCTION: During the 2014-2016 Ebolavirus (EBOV) outbreak, several candidate therapeutics were used in EBOV-infected patients in clinical trials and under expanded access for emergency use. This review will focus briefly on medications used during the outbreak. We will discuss current therapeutic candidates and their status and will then turn to a related and essential topic: supportive care and the standard of care for filovirus infected patients. Potential benefits and pitfalls of combination therapies for filoviruses will be discussed. Areas covered: Clinical trials of therapeutics targeting EBOV; clinical usage of therapeutics during recent EBOV outbreak; potential need for combination therapy; role of supportive care in treatment of Ebola virus disease (EVD). Expert commentary: In the absence of another large scale EBOV outbreak, the path to therapeutic product licensure in the United States of America (USA) would need to be via the FDA Animal Rule. However, human data may be needed to supplement animal data. The future of filovirus therapeutics may therefore benefit by establishing the ability to implement clinical trials in an outbreak setting in a timely fashion. Supportive care guidelines for filovirus infection should be defined and established as standard of care for treatment of EVD.

Dengue Fever as an Emerging Infection in Southeast Iran.

Dengue fever (DF) is a mosquito-borne acute viral disease presenting with hemorrhagic manifestations in severe cases. Southeast Iran is in close proximity to Pakistan, an endemic country for DF. This cross-sectional study was conducted in the Sistan and Baluchestan province in the southeast of Iran to investigate possibility of DF (immunoglobulin M [IgM], immunoglobulin G [IgG], and nonstructural protein 1 [NS1] antigen tests) in 60 clinically suspected patients (April 2013 to August 2015). NS1 protein was detected in 5% (N = 3), at least one of the antibodies (IgM and/ or IgG) was detected in 11% (N = 7) of the samples. Five patients identified as of acutely infected. There was a simultaneous presence of NS1 protein and IgG or IgM antibodies in 4% (N = 2) of patients. Previous studies show establishment of potential vectors in this area. These evidences support the hypothesis that DF can be a health concern in Southeast Iran with potential future outbreaks.