Pre-Erythrocytic Vaccine Candidates in Malaria

A vaccine providing sterile immunity against malaria has been shown to be possible with antigens from the pre-erythrocytic stages of malaria. Therefore, it is reasonable to focus vaccine development efforts on the pre-erythrocytic stages, consisting of both sporozoites and liver stage parasites, where it is expected that sterile immunity against the parasite can be elicited to block the development of blood stage infection, clinical disease, and resulting parasite transmission. Accordingly, we will review the preclinical and clinical studies of malaria pre-erythrocytic efforts as well as highlight the advances, trends, and roadblocks encountered in these efforts

The Production of Antibody by Invading B Cells Is Required for the Clearance of Rabies Virus from the Central Nervous System

Every year over 50,000 people die from rabies worldwide, primarily due to the poor availability of rabies vaccine in developing countries. However, even when vaccines are available, human deaths from rabies occur if exposure to the causative virus is not recognized and vaccination is not sought in time. This is because rabies virus immunity induced by the natural infection or current vaccines is generally not effective at removing disease-causing rabies virus from brain tissues. Our studies provide insight into why this is the case and how vaccination can be changed so that the immune response can clear the virus from brain tissues. We show that the type of immune response induced by a live-attenuated rabies virus vaccine may be the key. In animal models, live-attenuated rabies virus vaccines are effective at delivering the immune cells capable of clearing the virus into CNS tissues and promote recovery from a rabies virus infection that has spread to the brain while conventional vaccines based on killed rabies virus do not. The production of rabies-specific antibody by B cells that invade the CNS tissues is important for complete elimination of the virus. We hypothesize that similar mechanisms may promote rabies virus clearance from individuals who are diagnosed after the virus has reached, but not extensively spread, through the CNS

Viral delivery of a peptide-based immunomodulator enhances T cell priming during vaccination

Modern, subunit-based vaccines have so far failed to induce significant T cell responses, contributing to ineffective vaccination against many pathogens. Importantly, while today’s adjuvants are designed to trigger innate and non-specific immune responses, they fail to directly stimulate the adaptive immune compartment. Programmed cell death 1 (PD-1) partly regulates naïve-to-antigen-specific effector T cell transition and differentiation by suppressing the magnitude of activation. Indeed, we previously reported on a microbial-derived, peptide-based PD-1 checkpoint inhibitor, LD01, which showed potent T cell-stimulating activity when combined with a vaccine. Here we sought to improve the potency of LD01 by designing and testing new LD01 derivatives. Accordingly, we found that a modified version of an 18-amino acid metabolite of LD01, LD10da, improved T cell activation capability in a malaria vaccine model. Specifically, LD10da demonstrates improved antigen-specific CD8+ T cell expansion when combined prophylactically with an adenovirus-based malaria vaccine. A single dose of LD10da at the time of vaccination is sufficient to increase antigen-specific CD8+ T cell expansion in wild-type mice. Further, we show that LD10 can be encoded and delivered by a Modified Vaccinia Ankara viral vector and can enhance antigen-specific CD8+ T cell expansion comparable to that of synthetic peptide administration. Therefore, LD10da represents a promising biologic-based immunomodulator that can be genetically encoded and delivered, along with the antigen, by viral or other nucleic acid vectors to improve the efficacy and delivery of vaccines for ineradicable and emerging infectious diseases

Failure To Open the Blood-Brain Barrier and Deliver Immune Effectors to Central Nervous System Tissues Leads to the Lethal Outcome of Silver-Haired Bat Rabies Virus Infection

Rabies is a lethal disease caused by neurotropic viruses that are endemic in nature. When exposure to a potentially rabid animal is recognized, prompt administration of virus-neutralizing antibodies, together with active immunization, can prevent development of the disease. However, once the nonspecific clinical symptoms of rabies appear conventional postexposure treatment is unsuccessful. Over the last decade, rabies viruses associated with the silver-haired bat (SHBRV) have emerged as the leading cause of human deaths from rabies in the United States and Canada as a consequence of the fact that exposure to these viruses is often unnoticed. The need to treat SHBRV infection following the development of clinical rabies has lead us to investigate why the immune response to SHBRV fails to protect at a certain stage of infection. We have established that measurements of innate and adaptive immunity are indistinguishable between mice infected with the highly lethal SHBRV and mice infected with an attenuated laboratory rabies virus strain. While a fully functional immune response to SHBRV develops in the periphery of infected animals, the invasion of central nervous system (CNS) tissues by immune cells is reduced and, consequently, the virus is not cleared. Our data indicate that the specific deficit in the SHBRV-infected animal is an inability to enhance blood-brain barrier permeability in the cerebellum and deliver immune effectors to the CNS tissues. Conceivably, at the stage of infection where immune access to the infected CNS tissues is limited, either the provision or the development of antiviral immunity will be ineffective

The T cell response to CVS-F3 infection in the absence of B cells mediates enhanced BBB permeability and long-term survival.

<p>The extent of BBB permeability in the cerebellum of wild-type, JHD^−/− and RAG-2^−/− mice, infected i.n. with CVS-F3 10 days previously, is shown in panel A. Weight loss over the course of infection in JHD^−/− and RAG-2^−/− mice is shown in panel B, while the number of copies of rabies virus nucleoprotein mRNA at different times of infection in these animals is presented in panel C. BBB permeability changes are shown as the mean±S.E.M. fold increase in Na-Fluorescein uptake in the tissues with the levels from uninfected mice taken as 1. Weight is expressed as the mean±S.E.M. percent body weight with the weight on day 0 being taken as 100% and copies of nucleoprotein mRNA in the tissues are expressed per copy of L13 mRNA in the same sample.</p

Factors Supporting Intrathecal Humoral Responses following Viral Encephalomyelitis▿

Central nervous system (CNS) infections and autoimmune inflammatory disorders are often associated with retention of antibody-secreting cells (ASC). Although beneficial or detrimental contributions of ASC to CNS diseases remain to be defined, virus-specific ASC are crucial in controlling persistent CNS infection following coronavirus-induced encephalomyelitis. This report characterizes expression kinetics of factors associated with ASC homing, differentiation, and survival in the spinal cord, the prominent site of coronavirus persistence. Infection induced a vast, gamma interferon (IFN-γ)-dependent, prolonged increase in chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, and CXCL11 mRNA, supporting a role for chemokine (C-X-C motif) receptor 3 (CXCR3)-mediated ASC recruitment. Similarly, CD4 T cell-secreted interleukin-21, a critical regulator of both peripheral activated B cells and CD8 T cells, was sustained during viral persistence. The ASC survival factors B cell-activating factor of the tumor necrosis factor (TNF) family (BAFF) and a proliferating-inducing ligand (APRIL) were also significantly elevated in the infected CNS, albeit delayed relative to the chemokines. Unlike IFN-γ-dependent BAFF upregulation, APRIL induction was IFN-γ independent. Moreover, both APRIL and BAFF were predominantly localized to astrocytes. Last, the expression kinetics of the APRIL and BAFF receptors coincided with CNS accumulation of ASC. Therefore, the factors associated with ASC migration, differentiation, and survival are all induced during acute viral encephalomyelitis, prior to ASC accumulation in the CNS. Importantly, the CNS expression kinetics implicate rapid establishment, and subsequent maintenance, of an environment capable of supporting differentiation and survival of protective antiviral ASC, recruited as plasmablasts from lymphoid organs