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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.

BackgroundCOVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern.MethodsWe 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]).ResultsBetween 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.ConclusionsA 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.ClinicalTrials.govNCT04904549

Background Crimean-Congo hemorrhagic fever (CCHF) is endemic in Africa and in areas below the 50th parallel of north (latitude 50°0' N) in Asia and Europe, but the epidemiology of CCHF needs to be better characterized in most regions. Methods We comprehensively searched scientific databases for studies on CCHF epidemiology in these regions. We used a One Health approach to describe disease burden through human cases, animal and human serology studies, and Crimean-Congo hemorrhagic fever virus (CCHFV) isolation from ticks. In addition, we leveraged a classification scheme tosort countries into five categories based on the level of evidence and the maturity of their CCHF surveillance systems. Results We identified 2,253 CCHF cases that occurred in the region during the period 1944–2021. Central Asian countries reported the majority of cases (1,966). China is the only country in Eastern and South-eastern Asia that reported CCHF cases (287). Six countries (China, Kazakhstan, Kyrgyzstan, Tajikistan, Turkmenistan, and Uzbekistan) were assigned to level 1 or level 2, based on the maturity of their surveillance systems. Two countries (Mongolia and Myanmar) were assigned to level 3, due to conclusive evidence of CCHFV circulation in the absence of reported CCHF cases. Subsequently, 13 countries in Eastern and South-eastern Asia were categorized in levels 4 and 5, based on CCHFV vector prevalence. Conclusion This paper describes past and present status of the CCHF reporting systems to inform international and local public-health agencies to strengthen or establish CCHF surveillance systems and address shortcomings in the region. Disclosures All Authors: No reported disclosures.

SummaryBackgroundThis study evaluated the safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein candidate vaccine, CoV2 preS dTM.MethodsThis Phase 2, modified double-blind, parallel-group study (NCT04762680) was conducted in adults, including those at increased risk of severe COVID-19. Participants were randomised 1:1:1, stratified by age (18–59/≥60 years), rapid serodiagnostic test (positive/negative) and high-risk medical conditions (yes/no), to receive two injections (day [D]1 and D22) of 5μg, 10μg or 15μg of CoV2 preS dTM antigen with fixed AS03 content. Interim safety and reactogenicity results (to D43) and neutralising antibodies (NAbs) against the D614G variant are presented (primary objectives).FindingsOf 722 participants enrolled and randomised between 24 February and 8 March 2021, 721 received ≥1 injections (5μg, n=240; 10μg, n=239; 15μg, n=242). Four participants reported unsolicited immediate adverse events (AEs), two were vaccine-related (investigator assessment). Five participants reported seven vaccine-related medically-attended AEs. No vaccine-related serious AEs and no AEs of special interest were reported. Solicited reactions (local and systemic) were reported at similar frequencies between study groups; these were mostly mild to moderate and transient, with higher frequency and intensity post-injection 2 than post-injection 1. In SARS-CoV-2 naïve participants at D36, 96·9%, 97.0% and 97·6% of participants had ≥4-fold-rise in NAb titres from baseline in the 5μg-, 10μg- and 15μg-dose groups, respectively. NAb titres increased with antigen dose in younger (GMTs: 2954, 3951 and 5142 for 5μg-, 10μg- and 15μg-dose groups) but not older adults (GMTs: 1628, 1393 and 1736, respectively). NAb titres in non-naïve adults after one injection were higher than titres after two injections in naïve adults.InterpretationTwo injections of CoV2 preS dTM-AS03 demonstrated acceptable safety and reactogenicity, and robust immunogenicity in SARS-CoV-2 naïve and non-naïve adults. These results informed antigen dose selection for progression to Phase 3 evaluation of primary and booster vaccination.

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.

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

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 (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.

Influenza immunization is recommended for older adults annually, and has been reported to have cardiovascular protective effects. TNF-related weak inducer of apoptosis (TWEAK), an inflammatory mediator implicated in the development of cardiovascular diseases, could be a mechanism for such effect. The objective of this study was to evaluate the effect of influenza vaccine on TWEAK levels. Older persons over 70 years of age were recruited during 2007-2008 influenza season and immunized with the standard dose trivalent inactivated influenza vaccine. Frailty was evaluated using a validated set of criteria. Sera were collected immediately before and during the 4th week after vaccination. Pre- and post-vaccination levels of TWEAK, soluble CD163 (sCD163) and strain-specific influenza antibody titers were measured in 69 participants. Multiple regression analyses were employed to examine the effect of influenza vaccine on TWEAK and sCD163, adjusting for age, sex, and hypertension. Post-vaccination TWEAK [mean ± standard deviation (SD) = 591.7 ± 290.1 pg/ml] was significantly lower than pre-vaccination level (690.6 ± 330.0 pg/ml) (p = .003). No significant difference was observed between pre and post-vaccination sCD163 levels (p = .71). Post-vaccination TWEAK levels were significantly higher in men (p = .01) and in participants with college or higher level of education (p = .044). There was no significant difference in post-vaccination TWEAK according to other demographics or pre-existing medical conditions. A 2-fold or greater antibody titer against H1N1 vaccine strain was associated with a more pronounced reduction in TWEAK at the p < .10 level (p = .091). A time by frailty interaction term (p = .091) indicated that the vaccination-induced reduction of TWEAK was greatest among frail individuals. These results of this observational study indicate that the impact of Influenza vaccine on TWEAK, including the role of specific antibody responses of specific vaccine strains and frailty status, warrants further investigation. Such investigation may elucidate whether this effect plays a role in mediating cardiovascular protection of influenza vaccination.

Background From 2004 to 2005, an outbreak of Marburg virus, a filovirus, in Angola led to a case-fatality rate of 90 percent. However, little information is available regarding the virulence of the Angola strain from this outbreak compared with the virulence of other strains. Therefore, we sought to assess time to selected outcomes in non-human primates (NHPs) experimentally infected with either Angola or Musoke Marburg strains. Methods Between 2012 and 2017, nine therapeutic trials at the US Army Medical Research Institute of Infectious Diseases were conducted in Macaca fascicularis monkeys challenged with 1 to 10,000 plaque forming units of Marburg virus administered intramuscularly. The current study population was comprised of 90 control NHPs, of which, 61 were administered Angola strain in four separate trials and 29 with Musoke strain in five trials. Clinical responses including development of rash and oral intake were collected following infection. The primary outcome of interest was time to death or euthanasia post-inoculation between strains evaluated using Cox proportional hazards regression. Secondary endpoints included time to development of a petechial rash and time to decreased appetite. Results Following Marburg virus challenge, all NHPs died and most NHPs experienced decreased food consumption (97%), and petechial rash (96%). The median time to death for Angola-infected NHPs was 8.9 days (25th, 75th percentiles: 7.9, 9.3), whereas Musoke-infected NHPs survived for a median of 10.0 days (25th, 75th percentiles: 9.0, 10.9) (Figure 1). Irrespective of strain, petechial rash was preceded by decreased food consumption by 0.7 days (SD 1.5) on average. Angola strain was associated with statistically significant earlier death (adjusted HR = 21.8; 95% CI: 8.9, 53.2), earlier development of petechiae (adjusted HR = 17.6; 95% CI: 7.0, 44.5) and earlier loss of appetite (adjusted HR = 5.8; 95% CI: 2.9,11.7). Conclusion This was the first study to compare survival and clinical characteristics in NHPs between these strains. Despite sharing the similar genetic lineage, our data strongly supports increased virulence of Angola strain compared with Musoke strain. Pathophysiological mechanisms involved in increased virulence require further study. Disclosures All authors: No reported disclosures.