Kexin-Derived Vaccines to Prevent or Treat Fungal Infections

Abstract

A vaccine is disclosed that promotes CD4+ T cell-independent host defense mechanisms to defend against infection by fungi such as Pneumocystis spp. The vaccine may be used to prevent or to treat fungal infections. The novel vaccine can provide protective immunity, even for immunocompromised individuals such as HIV patients having reduced levels of CD4+ T cells.

Description

[0001]The benefit of the Jan. 12, 2010 filing date of U.S. provisional patent application Ser. No. 61 / 294,252 is claimed under 35 U.S.C. §119(e) in the United States, and is claimed under applicable treaties and conventions in all countries.[0002]This invention was made with government support under grant P01-HL076100 awarded by the National Institutes of Health. The United States Government has certain rights in this invention.TECHNICAL FIELD[0003]This invention pertains to certain proteins derived from kexin, nucleic acids encoding those proteins, and the use of the proteins or nucleic acids as vaccines, for example as vaccines against Pneumocystis jerovici or other Pneumocystis spp.BACKGROUND ARTEpidemiology of Pneumocystis Infection[0004]Despite advances in highly active anti-retroviral therapy (HAART), opportunistic pulmonary infection with Pneumocystis (PC) remains the most common opportunistic infection for HIV patients. Indeed, Pneumocystis pneumonia (PCP) is the index infec...

AI Technical Summary

Benefits of technology

This patent describes a new vaccine for preventing a specific infection called Pneumocystis jirovecii, which can cause life-threatening pneumonia in individuals with HIV or other immuppressed states. The vaccine uses a DNA vaccine that is improved by adding a molecular adjuvant called CD40L, which is a type of protein that helps jump-start the immune system. The vaccine also targets a specific part of the virus called mini-kexin, which is conserved across different species of fungus. When the vaccine is given with CD40L, it can even help generate protective immune responses in mice with CD4+ T-cells, which are often the first cells to be infected in HIV infection. The vaccine can be used either therapeutically in early HIV infection or to provide protective immunity in individuals with advanced HIV infection or other immunosuppressed states.

Problems solved by technology

In patients with established AIDS, prophylactic regimens have decreased the overall incidence of PCP, but in most patients this means that PCP is delayed rather than eliminated.

Unfortunately, not all AIDS patients respond to HAART, and drug resistance is emerging.

PCP is still a serious clinical problem in the third decade of the HIV epidemic.

In AIDS the depletion or dysfunction of CD4+ lymphocytes not only hinders the patient's immune response to infection, it also reduces or eliminates the ability to safely and effectively vaccinate a patient against PCP.

However, the most effective prophylactic treatment, TMP-SMX, has a high rate of adverse effects.

Second-line drugs may be used, but they typically have serious side effects and generally are less effective.

Definitive diagnosis of Pneumocystis pneumonia is relatively complex, requiring microscopy of tissues or fluids.

Organ transplant recipients are also at risk for PCP infection.

Most currently available antibiotic treatments have mild to severe side effects, leaving an unfilled need for alternative treatments.

The inability to reliably culture Pneumocystis organisms in vitro has limited experimental work with the pathogen to clinical specimens and animal models of infection.

Pneumocystis infections are a particular clinical problem in AIDS patients, whose progressive loss of CD4+ helper T lymphocytes results in profound suppression of cell-mediated immunity.

However, lymphocytes from AIDS patients have a reduced capacity to produce IFN after antigenic or mitogenic stimulation.

However, evidence for an in vivo role for IFN in host defense is conflicting.

It has been demonstrated that depletion of alveolar macrophages leads to delayed clearance of P. carinii from the rat lung.

Antimicrobial therapies are available, but emerging antimicrobial resistance is making treatments less effective.

Furthermore, high drug costs can preclude antimicrobial therapy in many third world countries have high rates of HIV infection.

PCP infection carries a high mortality rate.

Despite the long-standing need for a vaccine against Pneumocystis or other fungal pathogens, to our knowledge no fungal vaccine has yet reached Phase III clinical trials.

Images