Betsy Herold, Albert Einstein College of Medicine
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Herpes Simplex Viruses or HSV cause cold sores and genital infections, and theyíre doubly unpleasant because the virus is carried for life within the nervous system. This allows it to reactivate periodically to cause new infectious skin lesions that are also exquisitely painful. And despite years of effort, scientists have not yet developed an effective vaccine to block the infection. But now, by removing a component of the virus coat, a protein called gD, Betsy Herold has made viruses that can fully protect animals against infection with either the cold sore, Type-1 strain of HSV, or HSV-2, the genital variant.
Betsy - The primary strategy that people used in the past really focused on one major protein that that the virus makes, glycoprotein D. That protein induces high levels of antibodies, and antibodies usually protect you from infection. But in this case, in the herpes case of the Herpes Simplex Virus, these antibodies protected animal models from infection but did not appear to protect humans in large clinical trials. So, we thought maybe those antibodies are interfering in some way with making the kind of immune response that would be more protective. So, we deleted that protein from the virus.
Chris - How then did you grow the virus, if you took that gene away from it so that it couldnít make that gD? How did you grow it?
Betsy - Glycoprotein D is essential for the virus to get into cells. So, what we did is we grew it on a cell line that provided the HSV-1 glycoprotein D. That just provides the protein on the outer surface of the viral envelope, allowing the virus to get in but once that virus is inside a cell it doesnít have the DNA to make more of that protein. And therefore, it also doesnít continue to spread and doesnít cause any kind of disease.
Chris - So, you get, effectively, a replication-defective virus. It goes in, it hits the cells once but nonetheless expresses all of the panoply of genes that HSV would normally express, showing to the immune system this is my genetic hand and making a diverse immune response. What critically, though, does that do to the ability of the animal to then be infected with a wild type, a normal virus that does have gD?
Betsy - That was the question Ė would this work as a protective vaccine? So, when we took mice and immunized them with this, and then challenged them with very high doses of wild type virus, we observed 100% complete protection. Not only do we protect them from disease, but unlike the previous vaccine candidates, we prevented the virus from establishing what we called latency Ė the ability of the virus to hide out inside your nerve cells and therefore cause persistent or recurring infections. This vaccine completely prevented that.
Chris - Is that because it just completely limited the ability of the agent to replicate at the mucosal surface and for that reason, it couldnít then access the nervous system, or was there some other reason why it was disabled in its ability to get into the nervous system?
Betsy - To answer that question, we did a different type of experiment, and thatís an important question. And so what we did is we asked, first of all, whether the immune protection that the vaccine was inducing was mediated by antibodies - whether it was mediated by T-cells, the other major half of your immune system. And when we only gave naÔve mice antibodies that came from the vaccinated animals, they were completely protected. So, that told us that it was those antibodies. And then to get at your question, we then used those antibodies and looked to see whether they got into the sites of infection. Did they get into the fluid in the genital tract and did they protect? And indeed, they did. So, the answer to your question is that it is immediately clearing the virus out of the genital tract.
Chris - Have you tried doing the experiment where, having used your vaccine candidate to protect your animals against HSV-2, you come along and challenge the animals with HSV-1, the relative that normally causes cold sores.
Betsy - Yes, and the vaccine protected against both HSV-2 and against HSV-1.
Chris - And what about the converse, which is that the majority of the population carry HSV-1. Theyíre infected very early in life, maybe by the age of 3, and up to 80% of people have already got it. Can you still protect people who have already got HSV-1 against HSV-2 using your candidate?
Betsy - The answer to that question is we donít know, and we do need to find that out. But that is a critical question because if we want to use this vaccine and give it to older children, letís say, we need to make sure that it would work if youíre already been exposed to HSV-1.
Chris - Have you any idea why removing this very potent and essential stimulus that the virus would normally use when it infects a cell, should release the immune response in this way and drive this very powerful immune effect? Do you think that the gD thatís normally there is having some other effect on the immune system other than just helping the virus to infect cells?
Betsy - I think thatís absolutely the right thought process, and thereís a couple of possibilities there. The first one is just that that glycoprotein D is such a strong immunogen itís able to make such a good immune response that all of your immune system is focused on that, and it forgets to make antibodies to other viral proteins, and thatís one possibility. And then it would be that those other viral proteins and the antibodies you make to them are the more important ones in protecting against human disease. The alternative is that glycoprotein D actually interferes with making the kind of response we want. Maybe it blocks that from happening, and thatís very likely because we already know that this glycoprotein has an ability to modify the human immune response.