Serum lipid profiles among patients initiating ritonavir-boosted atazanavir versus efavirenz-based regimens

<p>Abstract</p> <p>Background</p> <p>Antiretrovirals used to treat HIV-infected patients have the potential to adversely affect serum lipid profiles and increase the risk of cardiovascular disease which is an emerging concern among HIV-infected patients. Since boosted atazanavir and efavirenz are both considered preferred antiretrovirals a head to head comparison of their effects on serum lipids is needed.</p> <p>Aim</p> <p>The primary objective of the study was to compare the effects of atazanavir (boosted and unboosted) and efavirenz based regimens on serum lipid profiles.</p> <p>Study Design</p> <p>Prospective cohort study nested within three ongoing cohorts of HIV-infected individuals.</p> <p>Study Population and Methods</p> <p>Participants initiating either atazanavir or efavirenz based regimens with documented pre- and post-initiation lipid values. Multivariate linear regression was conducted to estimate adjusted mean differences between treatment groups for high density lipoprotein cholesterol (HDL-c), non-HDL-c, and log total cholesterol (TC) to HDL-c ratio outcomes; log-linear regression models were used to estimate differences in prevalence of low HDL-c and desirable TC.</p> <p>Results</p> <p>The final study population was comprised of 380 efavirenz and 281 atazanavir initiators. Both atazanavir and efavirenz users had increases in serum HDL-c and decreases in TC/HDL ratio. In comparison to individuals initiating efavirenz, boosted atazanavir users on average had lower HDL-c (-4.12 mg/dl, p < 0.001) and non HDL-c (-5.75 mg/dl, p < 0.01), but similar declines in TC/HDL ratio.</p> <p>Conclusion</p> <p>Both efavirenz and atazanavir-based regimens (boosted and unboosted) resulted in similar beneficial declines in the TC/HDL ratio.</p

Therapeutic Vaccine for Genital Herpes Simplex Virus-2 Infection: Findings from a Randomized Trial

Background. Genital herpes simplex virus type 2 (HSV-2) infection causes recurrent lesions and frequent viral shedding. GEN-003 is a candidate therapeutic vaccine containing HSV-2 gD2∆TMR and ICP4.2, and Matrix-M2 adjuvant. Methods. Persons with genital herpes were randomized into 3 dose cohorts to receive 3 intramuscular doses 21 days apart of 10 µg, 30 µg, or 100 µg of GEN-003, antigens without adjuvant, or placebo. Participants obtained genital swab specimens twice daily for HSV-2 detection and monitored genital lesions for 28-day periods at baseline and at intervals after the last dose. Results. One hundred and thirty-four persons received all 3 doses. Reactogenicity was associated with adjuvant but not with antigen dose or dose number. No serious adverse events were attributed to GEN-003. Compared with baseline, genital HSV-2 shedding rates immediately after dosing were reduced with GEN-003 (from 13.4% to 6.4% for 30 μg [P < .001] and from 15.0% to 10.3% for 100 µg [P < .001]). Lesion rates were also significantly (P < .01) reduced immediately following immunization with 30 µg or 100 µg of GEN-003. GEN-003 elicited increases in antigen binding, virus neutralizing antibody, and T-cell responses. Conclusions. GEN-003 had an acceptable safety profile and stimulated humoral and cellular immune responses. GEN-003 at doses of 30 µg and 100 µg reduced genital HSV shedding and lesion rates

Multidrug-resistant Tuberculosis in Military Recruits

We conducted a tuberculosis contact investigation for a female military recruit with an unreported history of multidrug-resistant tuberculosis (MDRTB) and subsequent recurrence. Pertinent issues included identification of likely contacts from separate training phases, uncertainty on latent MDRTB infection treatment regimens and side effects, and subsequent dispersal of the contacts after exposure

577. COVI-VAC™, a Live Attenuated COVID-19 Vaccine, Provides Single Dose Protection Against Heterologous Challenge with SARS-CoV-2 Beta (B.1.351) in the Syrian Golden Hamster Model

Abstract Background Although multiple COVID-19 vaccines are currently in use, emergence of novel SARS-CoV-2 variants with reduced neutralization raises concern of future vaccine escape. COVI-VAC™ is a live attenuated SARS-CoV-2 strain based on WA/1 being developed as an intranasal COVID-19 vaccine. COVI-VAC is attenuated through removal of the furin cleavage site and introduction of 283 silent, deoptimizing mutations that maintain viral amino acid sequence but slow viral replication in vivo by up to 5 logs. Notably, COVI-VAC presents all viral antigens in their native conformation and is not limited to spike. COVI-VAC demonstrated attenuation, immunogenicity and single dose protection in both the Syrian golden hamster and non-human primate models and currently in Phase 1 clinical trials. In this study, we evaluated efficacy of COVI-VAC against challenge with the Beta/B.1.351 variant in Syrian golden hamsters. Methods Syrian golden hamsters, 7-10 weeks of age were, vaccinated intranasally with 8.25x104 PFU COVI-VAC (n=28) or vehicle control (n=16). Twenty seven days post-vaccination, animals were challenged intranasally with 3x104 PFU of wildtype (WT) SARS-CoV-2 Beta. Animals were weighed daily. Further analysis is being conducted with serum and key tissues from pre and post challenge timepoints to include neutralizing antibody, biodistribution (subgenomic qPCR) and histopathology. Results COVI-VAC prevented weight loss following challenge with the heterologous variant of SARS-CoV-2, B.1.351/Beta (Figure). Results of additional analyses will be available before the IDWeek meeting. Change in Weight following SARS-CoV-2 Beta Challenge Conclusion COVI-VAC is protective against heterologous challenge with SARS-CoV-2 Beta. By presenting all viral antigens, COVI-VAC may be less affected by viral evolution than spike-based vaccines. Disclosures Anna Kushnir, PHD, Codagenix Inc (Employee) Steffen Mueller, PhD, Codagenix Inc (Board Member, Employee, Shareholder) Sybil Tasker, MD, MPH, FIDSA, Codagenix Inc (Employee, Shareholder) J. Robert Coleman, PhD, Codagenix Inc. (Board Member, Employee, Shareholder) </jats:sec

584. Phase 1 Placebo-Controlled Trial of COVI-VAC™, an Intranasal, Live Attenuated COVID-19 Vaccine

Abstract Background COVI-VACTM is an intra-nasal live-attenuated SARS-COV-2 synthetic viral vaccine being developed for the prevention of COVID-19. COVI-VAC is attenuated through deletion of the furin cleavage site and introduction of 283 silent deoptimizing mutations that maintain viral amino acid sequence but result in significant attenuation due to slow translation in the human host cell. Notably, COVI-VAC includes all viral antigens and is not limited to spike. COVI-VAC has demonstrated attenuation, immunogenicity and single dose protection in both Syrian golden hamster and non-human primate models. Methods 48 healthy young adults were enrolled in an inpatient quarantine setting to one of 3 dose escalating cohorts and randomized to COVI-VAC or saline placebo given as nose drops, as a single 0.5mL dose or 2 doses 28 days apart. Endpoints included solicited and unsolicited adverse events, serum cytokines, viral shedding and sequence stability, mucosal and serum antibody responses and IFN ELISpot. Subjects will be followed for 1 year for late safety events and durability of immune response. Results Dosing is complete. There has been no trend in solicited reactogenicity events, and all unsolicited adverse events reported to date have been mild. There have been no SAEs or Grade 3 or 4 events. Vaccine virus from anonymized subjects was shed at levels lower than that likely to result in onward transmission, and the deoptimized sequence of the shed virus remained unchanged compared to the original vaccine sequence. Unblinded data including immunogenicity will be available prior to the IDWeek meeting. Conclusion COVI-VAC appears safe and well tolerated in healthy young adults. Vaccination resulted in minimal viral shedding without sequence instability. Safety and shedding data supports continued development in a wider Phase 2/3 population. Disclosures Sybil Tasker, MD, MPH, FIDSA, Codagenix Inc (Employee, Shareholder) Daryl Bendel, MD, Codagenix Inc (Scientific Research Study Investigator) Melissa Bevan, MD, Codagenix Inc (Scientific Research Study Investigator) Steffen Mueller, PhD, Codagenix Inc (Board Member, Employee, Shareholder) Anna Kushnir, PHD, Codagenix Inc (Employee) Brandon Londt, PhD, Codagenix Inc (Other Financial or Material Support, contracted lab services) J. Robert Coleman, PhD, Codagenix Inc. (Board Member, Employee, Shareholder) </jats:sec

747 CodaLytic™, a novel codon-pair deoptimized influenza virus creates an immune-stimulatory tumor microenvironment leading to monotherapy efficacy in a preclinical model of breast cancer

BackgroundOncolytic viruses (OVs) of multiple species have been demonstrated to induce beneficial changes in the tumor microenvironment (TME), increasing immune cell infiltration and activating stimulatory immune responses, which ultimately support induction of an anti-tumor immune response. The majority of OVs are attenuated by either gene deletion or mutations and then armed with immunomodulatory transgenes to promote anti-tumor immune responses. Here, we describe a next-generation OV that is rationally attenuated via codon-pair deoptimization and capable of activating anti-tumor immune responses in a mouse model of triple-negative breast cancer without the need of transgenes.MethodsHemagglutinin and neuraminidase genes of influenza virus strain A/California/07/2009 were codon-pair deoptimized using an algorithm to design synthetic viral genomes, yielding CodaLytic, a genetically stable OV with over 600 silent mutations across the two genes. For in vivo studies, EMT6 cells were implanted into inguinal mammary fad pads and treated intratumorally with CodaLytic three times a week for up to 4 weeks for efficacy studies or for up to 5 doses for pharmacodynamic readouts. Tumor infiltrating immune cells were characterized by flow cytometry or RNA was isolated for transcriptomic analysis. Anti-tumor memory was assessed by intravenous EMT6 rechallenge and interferon-γ ELISpot in splenocytes of long-term survivors.ResultsCodaLytic treatment of orthotopic EMT6 tumors led to dose-dependent tumor growth retardation and increased survival with significant tumor growth inhibition of 60% and 40–60% complete regressions at 108 pfu/dose across repeat experiments. Intravenous rechallenge of long-term survivors led to a 27-fold reduction in lung nodule formation (colony mean 0.75 vs 19.92 in naïve control animals, p = 0.005). Anti-tumor efficacy after CodaLytic treatment was accompanied by a change in the composition of the tumor immune infiltrate with significant increases in CD4+ T, B and NK cells and increased gene expression of interferon-γ, MHC-II and CCL-5. Further evidence of induction of anti-tumor immunity was an EMT6-specific interferon-γ recall response in splenocytes from long-term survivors.ConclusionsThese data demonstrate the induction of innate and adaptive changes in the TME and anti-tumor efficacy after intratumoral treatment of EMT6 tumors with CodaLytic. Additional holistic gene expression analysis is ongoing to further characterize the mechanisms of immune activation. Taken together with preclinical safety data and demonstrated clinical safety and immunogenicity of this attenuated influenza virus after intranasal administration in healthy individuals, CodaLytic is a promising immunotherapeutic to be further developed as monotherapy and in combination with immune checkpoint inhibitors or other modalities.Ethics ApprovalAll animal studies were conducted in compliance with protocol 2019-01-17-COD-1, approved by the Mispro Biotech Services Institutional Animal Care and Use Committee.</jats:sec