Explore the vast range of titles available.

Ebola virus causes irregular outbreaks of severe hemorrhagic fever in equatorial Africa. Case mortality remains high; there is no effective treatment and outbreaks are sporadic and unpredictable. Studies of Ebola virus vaccine platforms in non-human primates have established that the induction of protective immunity is possible and safety and human immunogenicity has been demonstrated in a previous Phase I clinical trial of a 1st generation Ebola DNA vaccine. We now report the safety and immunogenicity of a recombinant adenovirus serotype 5 (rAd5) vaccine encoding the envelope glycoprotein (GP) from the Zaire and Sudan Ebola virus species, in a randomized, placebo-controlled, double-blinded, dose escalation, Phase I human study. Thirty-one healthy adults received vaccine at 2×109 (n=12), or 2×1010 (n=11) viral particles or placebo (n=8) as an intramuscular injection. Antibody responses were assessed by ELISA and neutralizing assays; and T cell responses were assessed by ELISpot and intracellular cytokine staining assays. This recombinant Ebola virus vaccine was safe and subjects developed antigen specific humoral and cellular immune responses.

Two injections of mRNA-1273, a lipid nanoparticle–encapsulated mRNA-based vaccine produced in collaboration with the NIAID that encodes the SARS-CoV-2 spike protein, conferred protection against Covid-19 illness in 94% of vaccinated patients. Adverse effects of the vaccine were mild, transient local reactions, and the incidence of systemic effects such as fever, headache, and fatigue was low.

Background: Despite the effectiveness of antiretroviral therapy, vertical HIV transmission continues. A potent, broadly neutralizing, monoclonal antibody (bNAb) administered to HIV-exposed infants might reduce transmission. VRC07-523LS is 5-fold more potent and has a prolonged half-life compared to VRC01. VRC07-523LS may provide therapeutic levels over the duration of breastfeeding with infrequent doses. Methods: This is an open-label study of VRC07-523LS administered to HIV-exposed infants. Non-breastfed infants receive 80 mg subcutaneous (SC) within 72 hrs of birth. Infants and mothers receive ART to prevent transmission. Infants have safety assessments and VRC07-523LS levels at 24 hrs, week 2, 4, 8, 12 and every 12 weeks through week 96. The target week 12 plasma level is 10 mcg/mL: the leve needed to neutralize > 90% of tier II viruses in a multiclade panel. Plasma VRC07-523LS levels are determined through week 12 and compared to previously reported levels of VRC01. Results: The non-breastfed cohort fully accrued (N = 11) from US sites Jan-Sep, 2019. All infants received 80 mg VRC07-523LS SC within 72 hours of birth (mean 1.5 days), resulting in an average dose of 28 mg/kg (range 23 to 32 mg/kg). Enrollees were 45% male, 73% Black, 18% Hispanic. One infant withdrew after 4 weeks. VRC07-523LS was well tolerated. Local reactions were rare and mild: 1 infant had injection site erythema of 0.5 cm and 1 had tenderness. Five infants developed Grade 3/4 events within 28 days of receipt of VRC07-523LS (vomiting [N = 2], neutropenia, hyperkalemia, and parainfluenza sepsis), none considered related to study treatment. Pharmacokinetic measures through week 12 show average levels of 68.7, 31.1, 16.3mcg/mL at weeks 4, 8, and 12, respectively. Mean VRC07-523LS levels exceeded those previously reported for VRC01 20 mg/kg SC at week 2, 4, and 8. Ongoing growth contributed to the fall in VRC07-523LS concentration but levels remain over the target of 10 mcg/mL at week 12. Conclusions: We identified no safety or tolerability findings when VRC07-523LS is administered to neonates. Week 12 is an appropriate time for a second dose in infants with ongoing breastmilk exposure. VRC07-523LS, with its enhanced potency and extended half-life, could achieve target levels for the duration of breastfeeding with dosing every 3 months.

Phase I studies of volunteers not infected with human immunodeficiency virus type 1 HIV-1) have shown that immunization with envelope subunit vaccine products elicits antibodies that neutralize laboratory-adapted (prototype) HIV-1 strains in vitro. Prototype strains are adapted to grow in continuous (neoplastic) cell lines and are more susceptible to neutralization than are primary isolates cultured in human peripheral blood mononuclear cells. In this study, 50 sera from nine phase I vaccine trials and 16 from HIV-1-infected persons were evaluated for neutralizing antibody activity against 3 laboratory-adapted and 5 primary HIV-1 isolates. Of 50 sera, 49 neutralized at least 1 of the prototype strains; however, none displayed neutralizing activity against primary isolatesof HIV-1. Serum from most HIV-1-infected persons neutralized both laboratory-adapted and primary HIV-1 isolates. These data demonstrate a qualitative, or large quantitative, differencein the neutralizing antibody response induced by envelope subunit vaccination and natural HIV-1 infection.

Doc number: P87

IntroductionNew HIV prevention strategies are urgently required. The discovery of broadly neutralising antibodies (bNAbs) has provided the opportunity to evaluate passive immunisation as a potential prevention strategy and facilitate vaccine development. Since 2014, several bNAbs have been isolated from a clade C-infected South African donor, CAPRISA 256. One particular bNAb, CAP256-VRC26.25, was found to be extremely potent, with good coverage against clade C viruses, the dominant HIV clade in sub-Saharan Africa. Challenge studies in non-human primates demonstrated that this antibody was fully protective even at extremely low doses. This bNAb was subsequently structurally engineered and the clinical variant is now referred to as CAP256V2LS.Methods and analysisCAPRISA 012B is the second of three trials in the CAPRISA 012 bNAb trial programme. It is a first-in-human, phase I study to assess the safety and pharmacokinetics of CAP256V2LS. The study is divided into four groups. Group 1 is a dose escalation of CAP256V2LS administered intravenously to HIV-negative and HIV-positive women. Group 2 is a dose escalation of CAP256V2LS administered subcutaneously (SC), with and without the dispersing agent recombinant human hyaluronidase (rHuPH20) as single or repeat doses in HIV-negative women. Groups 3 and 4 are randomised placebo controlled to assess two (CAP256V2LS+VRC07-523LS; CAP256V2LS+PGT121) and three (CAP256V2LS+VRC07-523LS+PGT121) bNAb combinations administered SC to HIV-negative women. Safety will be assessed by the frequency of reactogenicity and adverse events related to the study product. Pharmacokinetic disposition of CAP256V2LS alone and in combination with VRC07-523LS and PGT121 will be assessed via dose subgroups and route of administration.Ethics and disseminationThe University of KwaZulu-Natal Biomedical Research Ethics Committee (BREC) and the South African Health Products Regulatory Authority (SAHPRA) have granted regulatory approval (trial reference numbers: BREC00000857/2019 and SAHPRA 20200123). Trial results will be disseminated through conference presentations, peer-reviewed publications and the clinical trial registry.Trial registration numberPACTR202003767867253; Pre-results.

Doc number: O40

In an efficacy trial, 2504 persons at high risk for HIV-1 acquisition received either a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine or placebo. The vaccine regimen did not reduce either HIV-1 acquisition or viral load. The epidemic infection caused by the human immunodeficiency virus type 1 (HIV-1) is now in its fourth decade, with an estimated 2.5 million new infections occurring annually worldwide. 1 The number of newly infected persons, although diminishing, outpaces the number of patients who initiate antiretroviral therapy. Despite a number of successful prevention interventions that have been reported, including preexposure prophylaxis and treatment as prevention, 2 – 9 ultimate control of the HIV epidemic will most likely come only with the development of a safe and effective preventive vaccine. This goal has proved to be elusive. Of the efficacy trials of HIV vaccines that . . .