ALTRAVAX, INC — Department of Health and Human Services SBIR Phase I: NIAID

Description

DESCRIPTION provided by applicant Varicella zoster virus VZV is a neurotropic alpha herpesvirus that causes varicella chickenpox and establishes latency in the sensory ganglia Reactivation of VZV leads to herpes zoster shingles a painful and debilitating disease that is associated with post herpetic neuralgia Most cases of herpes zoster occur in persons over years of age with immunosuppression being an additional risk factor Two approved VZV vaccines are available both based on a live attenuated strain of VZV The high dose version is recommended for adults to reduce the incidence of shingles this reduction is on the order of However the long term efficacy of these live attenuated vaccines is inadequate and improved vaccines are desirable Reactivation of VZV with the attendant consequences of herpes zoster is thought to be due to inefficient T cell immunity Because VZV specific antibody titers do not significantly decline with age the increased risk of VZV reactivation among older individuals is likely due to an age associated decrease in T cell immunity Improved vaccines should therefore be efficient at inducing a robust cellular immune response The only animal model that recapitulates the human VZV induced disease is intrabronchial infection of young rhesus macaques with simian varicella virus SVV SVV and VZV are evolutionarily related and are co linear with respect to genome organization Immunization of patas monkeys with VZV can protect the animals from SVV challenge demonstrating substantial antigenic relatedness of the two viruses Recent studies by Dr Messaoudi the Co PI of this Proposal have examined the T cell responses given by each of the nearly open reading frames ORFs of SVV in infected macaques ORFs have been identified that are responsible for strong T cell responses during acute infection but are only weakly immunogenic in latent infection We hypothesize that these ORFs are candidates for an effective vaccine to prevent reactivation and thus herpes zoster In this Proposal we will create DNA vaccines expressing nine ORFs that are strongly immunogenic in acute infection but weakly so in latency Initial studies with mice will allow identification of those ORFs that are potent inducers of T cel responses We will select three ORFs for immunization of rhesus macaques with DNA vaccines delivered by electroporation Electroporation can increase the potency of DNA vaccines and is efficacious safe and well tolerated in human clinical trials it represents a realistic product modality for a VZV HZ vaccine destined for adults After several immunizations macaques will be challenged with live SVV and the viral titers evaluated Immune responses will also be measured after immunization and challenge in peripheral blood cells and bronchial lavage to characterize the kinetics and magnitude of T and B cell proliferation the frequency of antigen specific T cells and antigen specific antibody titer The immunization protocol will be considered a success if the vaccine produces a significant and large reduction of viral loads PUBLIC HEALTH RELEVANCE Previous infections by varicella zoster virus can lead to herpes zoster commonly known as shingles A complication of shingles is post herpetic neuralgia which is a severe disabling and persistent pain that can last for months or years Most cases of shingles occur in persons years of age or older Although vaccines are available for this age group they are of limited efficacy Thus the development of more effective vaccines would be highly desirable and is the objective of this Proposal