Summary Background A preventive vaccine for HIV is a crucial public health need; adeno-associated virus (AAV)-mediated antibody gene delivery could be an alternative to immunisation to induce sustained expression of neutralising antibodies to prevent HIV. We assessed safety and tolerability of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralising antibody against HIV. Methods This first-in-human, proof-of-concept, double-blind, phase 1, randomised, placebo-controlled, dose-escalation trial was done at one clinical research centre in the UK. Healthy men aged 18–45 years without HIV infection were randomly assigned to receive intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps in one of four dose-escalating cohorts (group A, 4 × 10 12 vector genomes; group B, 4 × 10 13 vector genomes; group C, 8 × 10 13 vector genomes; and group D, 1·2 × 10 14 vector genomes). Volunteers were followed up for 48 weeks. The primary objective was to assess safety and tolerability. A secondary objective was to assess PG9 expression in serum and related HIV neutralisation activity. All volunteers were included in primary and safety analyses. The trial is complete and is registered with ClinicalTrials.gov , number NCT01937455 . Findings Between Jan 30, 2014, and Feb 28, 2017, 111 volunteers were screened for eligibility. 21 volunteers were eligible and provided consent, and all 21 completed 48 weeks of follow-up. Reactogenicity was generally mild or moderate and resolved without intervention. No probably or definitely related adverse events or serious adverse events were recorded. We detected PG9 by HIV neutralisation in the serum of four volunteers, and by RT-PCR in muscle biopsy samples from four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in ten volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1-specific T-cell responses were detected. Interpretation Future studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralising HIV antibodies. Funding International AIDS Vaccine Initiative, United States Agency for International Development, Bill & Melinda Gates Foundation, US National Institutes of Health.

Plasma artemether and dihydroartemisinin levels were measured using liquid chromatography-mass spectrometry. Population compartmental pharmacokinetic models were developed. In study 1, sublingual artemether absorption was biphasic, with both rate constants being greater than that of the artemether tablets (1.46 and 1.66 versus 0.43/h, respectively). Relative to the tablets, sublingual artemether had greater bioavailability (>1.24), with the greatest relative bioavailability occurring in the 30.0-mg dose groups (>1.58). In study 2, there was evidence that the first absorption phase accounted for between 32% and 69% of the total dose and avoided first-pass (FP) metabolism, with an increase in FP metabolism occurring in later versus earlier doses but with no difference in bioavailability between the dose actuations. Sublingual artemether is more rapidly and completely absorbed than are equivalent doses of artemether tablets in healthy adults. Its disposition appears to be complex, with two absorption phases, the first representing pregastrointestinal absorption, as well as dose-dependent bioavailability and autoinduction of metabolism with multiple dosing.

A lthough parenteral artesunate is the recommended initial treatment for severe malaria (1), intramuscular (i.m.) artemether is an acceptable and practical alternative (1, 2). Artemether is also a recommended first-line oral therapy in combination with the longer half-life partner drug lumefantrine for uncomplicated Plasmodium falciparum (3) and Plasmodium vivax (4) infections. There are, however, few detailed studies assessing the pharmacokinetics of artemether and its active metabolite dihydroartemisinin (DHA) in either of these settings in children.Artemether-lumefantrine is a safe and effective treatment for uncomplicated pediatric malaria (3, 4), but there is evidence of significant between-dose variability in absorption even when coadministered with a small amount of fat to improve bioavailability (5). In addition, the nausea and vomiting that are frequently associated with malaria, together with an unwell child's refusal to feed or take medications by mouth (6), can reduce the effectiveness of oral treatment through reduced adherence to the World Health Organization (WHO) recommended 3-day regimen (7). In cases of more severe malaria, there is evidence of substantial between-patient variability in the absorption of i.m. artemether (8, 9), with some acidotic children likely exposed to subtherapeutic concentrations when the recommended doses are given (9). Rectal artesunate administration is associated with more rapid absorption and initial parasite clearance than is i.m. artemether administration in severely ill children (8). However, there is also marked between-patient variability in the dispositions of artesunate and DHA, and there is evidence that some children are able to expel artesunate suppositories even in the context of close monitoring as part of a formal pharmacokinetic evaluation (10). This might help explain why artesunate suppositories do not improve mortality compared to that with a placebo in older relative to younger pediatric age groups (11).There is a clear need for a prereferral formulation of an artemisinin derivative that can be easily administered and adequately absorbed in a child who may be unconscious or uncooperative or in whom nausea and vomiting preclude oral dosing. ArTiMist (Essential Nutrition Ltd., Brough, England) is an artemether formulation in neutral oil that can be administered as a metered sublingual spray and which is more rapidly and completely absorbed than is artemether given in tablet form in healthy adult volunteers (see accompanying paper [12]). In the present study, we assessed the pharmacokinetics of ArTiMist in African children with severe malaria or in whom gastrointestinal symptoms prevented the administration of artemether-lumefantrine tablets.

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)

dThe efficacy of sublingual artemether (ArTiMist) was investigated in two studies. In study 1, 31 children were randomized to sublingual artemether (n ‫؍‬ 16) or intravenous (i.v.) quinine (n ‫؍‬ 15). In study 2, 151 children were randomized to sublingual artemether (n ‫؍‬ 77) or i.v. quinine (n ‫؍‬ 74). For both studies, patients weighed between 5 and 15 kg and had either severe or complicated malaria based on WHO criteria, or they had uncomplicated malaria but were unable to tolerate oral medication as a result of nausea, vomiting, or diarrhea. Patients received either 3 mg/kg of body weight of sublingual artemether or a loading dose of 20 mg/kg of i.v. quinine followed by 10 mg/kg every 8 h i.v. thereafter. The primary endpoint was parasitological success, defined as a reduction in parasite count of >90% of that at baseline at 24 h after the first dose. Other endpoints based on parasite clearance and clinical response were evaluated. In study 1, there were parasitological success rates of 93.3% (14/15) and 66.7% M alaria remains a major health challenge in developing countries, especially in sub-Saharan Africa (SSA). Approximately 207 million cases of malaria were reported worldwide, of which 80% were in sub-Saharan Africa. Overall, 90% of the reported 627,000 deaths, of which 77% were in children under five years of age, were in SSA (1). The overwhelming majority (98%) of malaria cases in the African region are due to Plasmodium falciparum (1).In countries where the disease is highly endemic, 20% to 46% of child deaths can be attributed to malaria or febrile illness (2). In moderate-to high-transmission settings, such as is found in most SSA countries where malaria is endemic, young children are disproportionately affected by malaria (3). A child presents with an average 1.6 to 5.4 episodes of febrile malaria per year, with about 5% of malaria episodes becoming severe disease (4). Less than one-third attend clinics, and many receive malaria treatment outside the health care system. The majority of treatments are initiated on a presumptive diagnosis, with a high false-positive rate, resulting in challenges in accurate monitoring of the malaria burden in SSA (5).Despite advances in the treatment of malaria in children, "the majority of deaths from severe malaria in childhood are caused by the delayed administration of effective antimalarial treatment. There is a relentless deterioration in the clinical condition of a young child with malaria who fails to get effective treatment, with death ensuing in a matter of hours or days. Any successful attempt to reduce mortality from malaria will have to explore novel possibilities for minimizing such delays" (6).There is a clear need for a formulation of an artemisinin derivative that can be easily administered and adequately absorbed in a child who may be unconscious or uncooperative, or in whom nausea and vomiting preclude oral dosing. Artemether can be used as initial intramuscular (i.m.) monotherapy for severe malaria in children (7). It is also a recommended first...