Evaluating the immunogenicity and safety of a BiondVax-developed universal influenza vaccine (Multimeric-001) either as a standalone vaccine or as a primer to H5N1 influenza vaccine: Phase IIb study protocol.

INTRODUCTION: Influenza is a major respiratory viral infection of humans with high mortality and morbidity rates and profound economic impact. Although influenza vaccines are generally updated yearly to match the viruses expected in the coming season, genetic mutation and reassortment can result in unexpected novel strains. Therefore, it is important to develop universal vaccines inducing protective immunity to such strains before they appear. This clinical trial is designed to evaluate the safety and immunogenicity of Multimeric-001 (M-001), which contains conserved epitopes of influenza A and B. M-001 is able to induce both humoral and cellular immunity and provides broad strain coverage. METHODS: In a multicenter, randomized, double-blind, and controlled phase IIb trial, 222 healthy volunteers aged 18 to 60 years will be randomized into 3 groups (1:1:1) to receive either 2 intramuscular injections of 0.5 mg M-001 (arm 1), 1.0 mg M-001 (arm 2), or saline (arm 3-placebo), before receiving an investigational (whole virus, inactivated, aluminum phosphate gel [AlPO4]-adjuvanted) prepandemic influenza vaccine (H5N1). Primary outcomes are safety and cellular immune responses (cell-mediated immunity [CMI]) induced by M-001, evaluated by multiparametric flow cytometry of intracellular cytokines. The secondary outcome is the serum hemagglutination inhibition (HAI) titer toward the H5N1 vaccine strain. Additionally, exploratory outcomes include evaluation of CMI by quantitative reverse transcription polymerase chain reaction of cytokine mRNA, HAI titers toward H5-drifted strains, serum single radial hemolysis titers toward the H5N1 study vaccine, and the association between CMI markers and antibody response. DISCUSSION: There is a need for influenza vaccines that give the population a broader protection against multiple strains of influenza virus. M-001 might be such vaccine which will be tested in this current trial as a standalone vaccine and as a pandemic primer. Both cellular and humoral immune responses will be evaluated. TRIAL REGISTRATION: EudraCT number: 2015-001979-46.

The effects of long-term testosterone, gonadotropin-releasing hormone agonist and pimozide treatments on testicular development and luteinizing hormone levels in juvenile and early maturing striped bass, Morone saxatilis.

The present study was conducted to test the responsiveness of the juvenile male reproductive axis to hormonal stimulation and to compare it to that of early maturing males. Long-term treatments with various combinations of T, GnRHa and pimozide did not result in an increased incidence of early maturing males, but did stimulate spermatogenesis slightly in juvenile fish. In early maturing males, the treatments appeared to be inhibitory since they resulted in a reduction of the GSI and a lower incidence of spermiating males. In early maturing males, pituitary LH content was elevated by GnRHa treatments alone while in juvenile males a combination of T and GnRHa was needed to increase the levels of LH in the pituitary. Thus, T may play an important role during puberty by potentiating the effects of GnRH on LH synthesis. In both juvenile and early maturing males, plasma LH levels could be increased only by high doses of GnRHa (in combination with T). Therefore, LH synthesis and release probably require different levels of GnRH stimulation. A GnRH challenge (single injection of 50 microg GnRHa/kg) at the end of the experiment resulted in a dramatic elevation of plasma LH levels in almost all animals. This finding demonstrates that pituitaries from juvenile and early maturing males were responsive to GnRHa stimulation, even after long-term hormonal treatments. The addition of pimozide did not affect the T- and GnRHa-induced increase in pituitary LH content but inhibited the release of LH in response to a GnRHa challenge. In conclusion, high doses of GnRHa in combination with T can increase plasma LH levels in juvenile males but do not induce complete testicular maturation. Factors other than T, GnRHa or LH are probably involved in the induction and completion of spermatogenesis.