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Artistic rendering of Viruses (green) floating within the blood stream.

Radical vaccine against herpes viruses

Researchers at Howard Hughes Medical Institute at Albert Einstein College of Medicine have created a powerful vaccine against herpes viruses.

Herpes simplex infections are an enormous global health problem with no viable vaccine. For nearly thirty years, immunologists' have put all their attention on manipulating a single protein, a glycoprotein called gD, on the outer surface of the virus known to produce antibodies.

Breaking away from this approach, Howard Hughes Medical Institute (HHMI) scientists at the Albert Einstein College of Medicine, Bronx, NY, created a genetic mutation of the virus which simply does not have the antibody producing protein.

The result is a powerful vaccine against herpes viruses.

"We have a very promising new candidate for herpes, which might also be a good vaccine vector for other diseases, particularly HIV and tuberculosis."

William Jacobs, HHMI investigator, Albert Einstein College of Medicine, Bronx, NY.

The new vaccine was found to be effective against the two most common forms of herpes: one that causes cold sores (HSV-1) and the second which causes genital ulcers (HSV-2). Both are known to infect the body's nerve cells, where the herpes virus can lay dormant for years before symptoms reappear.

The new vaccine is the first to prevent this type of latent infection. Jacobs: "With herpes sores you continually get them. If our vaccine works in humans as it does in mice, administering it early in life could completely eliminate herpes latency."

Jacobs and his colleagues reported their findings on March 10, 2015, in the journal eLife.

HSV-2, which causes recurring genital ulcers, is a lifelong, incurable infection of painful genital sores that increase carriers susceptibility to Human Immunodeficiency Virus or HIV. Current estimates suggest that 500 million people worldwide are infected with HSV-2, with approximately 20 million new cases annually.

Babies born to mothers with active genital herpes have a more than an 80 percent mortality rate.

While HSV-2 infection rates in the U.S. hover around 15 to 20 percent, it is highly viralent in sub-Saharan Africa. Nearly three in four sub-Saharan women have contracted HSV-2, contributing significantly to the region's HIV epidemic.

Although HSV-1 is primarily associated with oral lesions, it is also a major cause of corneal blindness and infects around 60 percent of the world's population.

HSV-1 is increasingly recognized as a cause of genital herpes in the United States and in other developed countries.

Prior attempts to construct a vaccine have focused on the glycoprotein, named gD, embedded in the virus's outer envelope. gD allows the microbe to enter and exit cells. In order to spread from cell-to-cell, gD elicits a vigorous antibody response on the part of the host carrying the virus. Many virologists believe it is needed to produce immunity.

However, no gD-based vaccine has been effective against HSV1 or 2.

"It was necessary to shake the field up and go another route," says Betsy Herold, a virologist and infectious disease physician at the Albert Einstein College of Medicine and co-study leader of the new research. Herold had been conducting a separate study of the signaling pathway that the herpes virus uses to enter cells, when she asked Jacobs's lab to engineer a mutant with gD deleted. Though not necessarily obvious, Herold adds: "once we had this mutant in our hands, it was a logical, scientifically driven hypothesis to say, 'This strain would be 100 percent safe and might elicit a very different immune response than the gD subunit vaccines that have been tried.'"

The hypothesis came from the increasing realization that, in addition to its critical role assisting the HSV virus being able to enter into a cell, gD changed the response of a host's immune response to infection.

In order to test the virus with the deleted gD as a vaccine, researchers grew it in cells with the HSV-1 version of gD. The HSV-2 virus with deleted gD grabbed onto any available HSV-1 gD proteins left in the cells. When inserted into a mouse, HSV-2 was able to use the HSV-1 gD to enter into its cells. Once inside, However, though HSV-2 replicated abundantly, it could not produce gD and no new cells were infected with the HSV-2 virus. According to Herold, HSV-2 infected cells became "little factories making viral proteins" producing antibodies to — HSV-2.

The vaccine completely immunized two common strains of lab mice against HSV-2, when exposed to intravaginal virus, and even became immune to 'on the skin' viruses. In fact, no virus could be detected in vaginal washes four days post-exposure. More importantly, no virus could be found in the nerve tissue, where HSV often latently hides. The vaccine produced no adverse health effects in mice with severely compromised immune systems, reflecting the vaccine's overall safety.

Blood serum transferred from immunized mice was found to protect wild-type (non-lab mice) providing a powerful demonstration of the vaccine's efficacy.

Jacobs: "No one has ever shown a skin disease that you can protect against with passive transfer."

Many vaccines provoke neutralizing antibodies that directly bind to and inactivate virus particles. This new vaccine, however, stimulates antibody-dependent cell-mediated cytotoxicity (ADCC) or antibodies that attach to a virus and flag it for destruction by the immune system.

The successful implementation of a vaccine based on ADCC could have profound implications for treatment of other infectious diseases.

"It's possible we could clone into this HSV vector pieces of other viruses, such as HIV, and maybe the immune system would produce the same types of ADCC antibodies for those viruses."

Herold says.

The robust response generated by the vaccine, has researchers creating more experiments in mice already infected by HSV-1 and HSV-2 to determine whether it can be eliminated after the infection has begun.

The next step in producing a herpes vaccine for use in humans is demonstrating its safety in an FDA-approved cell line. The researchers are looking for an industry partner to help make large quantities of the vaccine for future clinical tests.

Abstract
Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD−/+gD−1). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD−/+gD1 provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD−/+gD1 elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine. - See more at: http://elifesciences.org/content/4/e06054#sthash.XYNfuR5n.dpuf

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