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New concepts: Vaccines
GYNECOLOCXC ONCOLOGY
12, S341-S344 (1981)
New Concepts: Vaccines FRED RAPP Department
of Microbiology,
Pennsylvania State University Hershey, Pennsylvania 17033
College of Medicine,
The possibility of producing a vaccine against herpes simplex virus has been considered at a number of meetings. The NIH is quite interested in it, not because of the possible relationship to the etiology of cervical cancer, which is of considerable interest, but because of the widespread prevalence of the genital disease, especially as seen in venereal clinics. Many people make the mistake of translating knowledge based on experiences with other virus vaccines to herpesvirus vaccines but this might not be appropriate. The use of virus vaccines has been eminently successful in the prevention of many diseases. Perhaps the most notable is the vaccine for smallpox. The origin of this vaccine dates back hundreds of years and the vaccine has eliminated smallpox as a disease entity on an international level. The last case was apparently in 1978. Poliomyelitis, rubeola, rubella, mumps, and yellow fever vaccines are all live attenuated virus vaccines. They have all done their jobs in reducing the incidence of the diseases that they were meant to prevent. The one herpesvirus vaccine that is available and has been field-tested is Marek’s disease vaccine. It has been used all over the world to prevent Marek’s disease, a neoplastic disease of chickens. Again, it is a live attenuated vaccine. The chicken virus was attenuated by cell culture passage; there is a not-soclosely related but effective virus from turkeys found in the wild that does not harm the chicken and that, in fact, has been used to prepare a Marek’s disease vaccine and prevents the lymphoproliferative disease. Most of these vaccines do not prevent reinfection of the host. What they accomplish is prevention of the transfer of the wild-type or parental virus that is found under natural conditions to the target cell where most of the damage (i.e., disease) occurs. The well-studied poliovirus vaccine does not prevent reinfection of the gastrointestinal tract, but it does prevent the spread of the virus from the gastrointestinal tract to the central nervous system where the major damage occurs. This involves some understanding of the pathogenesis of many of the diseases that we are discussing. The pathogenesis of herpesvirus infections is considerably different from that of those infections that we have treated in the past and this makes vaccine development a more difficult problem. One factor associated with that problem is the question of whether local s341 0090-8258/81/05S341-04$01.00/O Copyright Q 1981 by Academic Press. Inc. All rights of reproduction in any form reserved.
S342
FRED
RAP
reinfection can be prevented by a vaccine. Local reinfection, if it stays local, without attendant destruction of cells is not necessarily bad if the body resists spread. But it is a problem that must be considered. However, the biggest problem is probably latency. Will a vaccine prevent subsequent latent infections due to the same or similar viruses? If it does not, and there is some reason to believe that this will be a very big problem, then has much been accomplished in preventing the primary infection? Will vaccination prevent subsequent reactivation (either of the virus that is latent or of the virus that subsequently goes latent)? We should keep in mind that there are two steps involved. One is for the virus to originally go latent in the various neuronal cells and the other is the second phase, or reactivation. Preventing either one would fundamentally prevent recurrent disease. Components of immunity that are involved are poorly understood at the present time. The more general type of immunity that appears to function with the various other vaccines (that is, humoral antibody and T-cell sensitization), does not appear to be a major factor in herpetic infections. How many epidemiologic types are there? Will vaccination with one herpes simplex virus isolate prevent infection with other isolates? We already know that there are measurable differences in isolates from different family groups. In the case of polioviruses, we know that there are three major types and it is easy to vaccinate against all three. In the case of rubella and rubeola, there is only one major serologic type. But these are viruses with relatively lesser amounts of genetic information. Viruses with more information might show considerably more variation than smaller viruses. What kind of markers of attenuation are to be used? We read in the literature about investigators using a chickenpox vaccine and there is even a live cytomegalovirus vaccine being tried in this country in certain localities, primarily on patients at risk because of renal transplants. It is claimed that these viruses are attenuated. But, in fact, there are no animal hosts in which to measure such attenuation, including nonhuman primates. What are the long-term sequelae? Preventing a disease early in life (95% of the population is infected in the first few years with HSV-I and a significant percentage of the population is infected with HSV-2 shortly after puberty) may result in serious sequelae if reinfection can occur; the later disease may be more serious than the initial disease that would have been caused by natural infection. An example of that, and there are many examples in virology, is infectious mononucleosis. The virus disease in the susceptible adult is much more severe than when the disease affects a child. What will be the vaccination schedule? Many investigators prefer an inactive vaccine because of the problems with attenuated vaccines, but how many times will the susceptible population need to be vaccinated and how often will they come back? People in Public Health Laboratories know perfectly well how rarely people will come back for repeated inoculations and we have already heard at this meeting how difficult it is to get people to return for Papanicolaou tests. How will the population be surveyed? What kind of surveillance will be needed? There is, in fact, very little known about the natural history of herpetic infections, despite the many studies that have been presented. Then, of course, there is the cost versus benefit ratio. In the face of smallpox epidemics, a vaccine
NEW
CONCEPTS:
VACCINES
S343
can be employed with some unwanted side effects; encephalitis was the result in some of the vaccinees. This was accepted as long as the virus was causing a very severe disease that infected large numbers of the population with severe consequences. However, when dealing with a disease that is not quite so severe (and especially with the incidence of cervical carcinoma), then the vaccine has to be almost perfect in terms of safety and, given a biologically varied population, that is probably impractical. We can discuss types of vaccine from the point of view of an activated (live) vaccine, or an inactivated vaccine. Viruses can be inactivated in many different ways. The Salk poliovirus vaccine was inactivated with formalin. Many of the influenza virus vaccines are similarly inactivated. However, the influenza vaccines, for example, have not proven particularly effective; a very large percentage of the population remains at risk even after vaccination. It is possible to utilize structural components of the virus and this has been done with herpes simplex virus. Merck, Sharp and Dohme has produced such an experimental vaccine, and so has Dr. Skinner in Birmingham, England. One can immunize not only with the whole inactivated vaccine, but with these proteins. The major reason for using component vaccines is to remove the possibility of dangers generated by nucleic acids that remain in an inactivated whole virus vaccine. But obviously, it is essential to know which proteins or glycoproteins are needed to cause long-term immunity, and that information is not yet available. Viable virus is another alternative. Attenuation of the virus is possible and was the backbone for the development of the Sabin poliovirus vaccine. It is of some interest that almost anything done to a virus once it is out of the body makes it less virulent than it was under natural conditions. It is in fact very difficult to go the other way, which is probably what saves our lives. This gives us more confidence in recombinant DNA technology and the modern methods used to change the biologic properties of viruses. There are two major possibilities to consider concerning a live herpes simplex virus vaccine. One is that the vaccine virus will replicate and go latent, and the other possibility is that it will replicate and not go latent. This question is made more complex because some individuals might react one way or the other. The next thing that will probably occur is that sooner or later the vaccinee will encounter the wild-type virus in nature. The wild-type virus could multiply and could also go latent. This then defeats the whole purpose of the vaccine, especially if that latent virus can be reactivated. The wild-type virus could multiply without going latent. That might be ideal because it should result in an anamnestic immune response (hopefully without disease). It is also possible that activation of the vaccine virus might result with unknown consequences. Genetic recombination between the vaccine and wild-type virus might well cause difficulty. Given these problems, how can we visualize a herpes simplex virus vaccine? Advancing technology once resembling science fiction is not that far from supplying some of the answers. One of the reasons why we so badly want to know what the transforming regions are and where we can map various proteins on
s344
FRED
RAPP
the virus genetic map is because it is now possible to selectively excise such regions and then selectively reconstruct the virus genome. It should be theoretically possible to construct a virus that no longer has transforming ability or virulence. If one or two genes are responsible for the ability of the virus to establish latency, it is possible to remove them. In fact, there is some evidence by Dr. Tenser in our department and by others that this is the case. In theory, if this is all possible, the population could be vaccinated with such a virus; the virus will replicate and cause an immune response but not go latent or cause disease. However, we are then still faced with the second problem, what will happen when that vaccinee encounters the natural wild-type virus? We do not presently have an answer. We already know, however, that people who have been exposed as children to HSV-1 can still be infected with HSV-2. What we do not know is whether those children, if infected early with HSV-2, could still be reinfected with another HSV-2. We need to know more about the pathogenesis of infection with these viruses and more about the specific properties that will allow us to genetically engineer a vaccine virus. Then we need a good model to ascertain the risks under what might be called simulated natural situations. If all goes well, the first use of such a vaccine would have to be in a very carefully selected population (preferably at high risk to herpes-induced disease) before we could administer it to the general population. Current studies are leading in that direction. I think you will hear more about them in the near future but I personally believe we are some years away before we can take the chance of using a virus of this type in the general population.
12, S341-S344 (1981)
New Concepts: Vaccines FRED RAPP Department
of Microbiology,
Pennsylvania State University Hershey, Pennsylvania 17033
College of Medicine,
The possibility of producing a vaccine against herpes simplex virus has been considered at a number of meetings. The NIH is quite interested in it, not because of the possible relationship to the etiology of cervical cancer, which is of considerable interest, but because of the widespread prevalence of the genital disease, especially as seen in venereal clinics. Many people make the mistake of translating knowledge based on experiences with other virus vaccines to herpesvirus vaccines but this might not be appropriate. The use of virus vaccines has been eminently successful in the prevention of many diseases. Perhaps the most notable is the vaccine for smallpox. The origin of this vaccine dates back hundreds of years and the vaccine has eliminated smallpox as a disease entity on an international level. The last case was apparently in 1978. Poliomyelitis, rubeola, rubella, mumps, and yellow fever vaccines are all live attenuated virus vaccines. They have all done their jobs in reducing the incidence of the diseases that they were meant to prevent. The one herpesvirus vaccine that is available and has been field-tested is Marek’s disease vaccine. It has been used all over the world to prevent Marek’s disease, a neoplastic disease of chickens. Again, it is a live attenuated vaccine. The chicken virus was attenuated by cell culture passage; there is a not-soclosely related but effective virus from turkeys found in the wild that does not harm the chicken and that, in fact, has been used to prepare a Marek’s disease vaccine and prevents the lymphoproliferative disease. Most of these vaccines do not prevent reinfection of the host. What they accomplish is prevention of the transfer of the wild-type or parental virus that is found under natural conditions to the target cell where most of the damage (i.e., disease) occurs. The well-studied poliovirus vaccine does not prevent reinfection of the gastrointestinal tract, but it does prevent the spread of the virus from the gastrointestinal tract to the central nervous system where the major damage occurs. This involves some understanding of the pathogenesis of many of the diseases that we are discussing. The pathogenesis of herpesvirus infections is considerably different from that of those infections that we have treated in the past and this makes vaccine development a more difficult problem. One factor associated with that problem is the question of whether local s341 0090-8258/81/05S341-04$01.00/O Copyright Q 1981 by Academic Press. Inc. All rights of reproduction in any form reserved.
S342
FRED
RAP
reinfection can be prevented by a vaccine. Local reinfection, if it stays local, without attendant destruction of cells is not necessarily bad if the body resists spread. But it is a problem that must be considered. However, the biggest problem is probably latency. Will a vaccine prevent subsequent latent infections due to the same or similar viruses? If it does not, and there is some reason to believe that this will be a very big problem, then has much been accomplished in preventing the primary infection? Will vaccination prevent subsequent reactivation (either of the virus that is latent or of the virus that subsequently goes latent)? We should keep in mind that there are two steps involved. One is for the virus to originally go latent in the various neuronal cells and the other is the second phase, or reactivation. Preventing either one would fundamentally prevent recurrent disease. Components of immunity that are involved are poorly understood at the present time. The more general type of immunity that appears to function with the various other vaccines (that is, humoral antibody and T-cell sensitization), does not appear to be a major factor in herpetic infections. How many epidemiologic types are there? Will vaccination with one herpes simplex virus isolate prevent infection with other isolates? We already know that there are measurable differences in isolates from different family groups. In the case of polioviruses, we know that there are three major types and it is easy to vaccinate against all three. In the case of rubella and rubeola, there is only one major serologic type. But these are viruses with relatively lesser amounts of genetic information. Viruses with more information might show considerably more variation than smaller viruses. What kind of markers of attenuation are to be used? We read in the literature about investigators using a chickenpox vaccine and there is even a live cytomegalovirus vaccine being tried in this country in certain localities, primarily on patients at risk because of renal transplants. It is claimed that these viruses are attenuated. But, in fact, there are no animal hosts in which to measure such attenuation, including nonhuman primates. What are the long-term sequelae? Preventing a disease early in life (95% of the population is infected in the first few years with HSV-I and a significant percentage of the population is infected with HSV-2 shortly after puberty) may result in serious sequelae if reinfection can occur; the later disease may be more serious than the initial disease that would have been caused by natural infection. An example of that, and there are many examples in virology, is infectious mononucleosis. The virus disease in the susceptible adult is much more severe than when the disease affects a child. What will be the vaccination schedule? Many investigators prefer an inactive vaccine because of the problems with attenuated vaccines, but how many times will the susceptible population need to be vaccinated and how often will they come back? People in Public Health Laboratories know perfectly well how rarely people will come back for repeated inoculations and we have already heard at this meeting how difficult it is to get people to return for Papanicolaou tests. How will the population be surveyed? What kind of surveillance will be needed? There is, in fact, very little known about the natural history of herpetic infections, despite the many studies that have been presented. Then, of course, there is the cost versus benefit ratio. In the face of smallpox epidemics, a vaccine
NEW
CONCEPTS:
VACCINES
S343
can be employed with some unwanted side effects; encephalitis was the result in some of the vaccinees. This was accepted as long as the virus was causing a very severe disease that infected large numbers of the population with severe consequences. However, when dealing with a disease that is not quite so severe (and especially with the incidence of cervical carcinoma), then the vaccine has to be almost perfect in terms of safety and, given a biologically varied population, that is probably impractical. We can discuss types of vaccine from the point of view of an activated (live) vaccine, or an inactivated vaccine. Viruses can be inactivated in many different ways. The Salk poliovirus vaccine was inactivated with formalin. Many of the influenza virus vaccines are similarly inactivated. However, the influenza vaccines, for example, have not proven particularly effective; a very large percentage of the population remains at risk even after vaccination. It is possible to utilize structural components of the virus and this has been done with herpes simplex virus. Merck, Sharp and Dohme has produced such an experimental vaccine, and so has Dr. Skinner in Birmingham, England. One can immunize not only with the whole inactivated vaccine, but with these proteins. The major reason for using component vaccines is to remove the possibility of dangers generated by nucleic acids that remain in an inactivated whole virus vaccine. But obviously, it is essential to know which proteins or glycoproteins are needed to cause long-term immunity, and that information is not yet available. Viable virus is another alternative. Attenuation of the virus is possible and was the backbone for the development of the Sabin poliovirus vaccine. It is of some interest that almost anything done to a virus once it is out of the body makes it less virulent than it was under natural conditions. It is in fact very difficult to go the other way, which is probably what saves our lives. This gives us more confidence in recombinant DNA technology and the modern methods used to change the biologic properties of viruses. There are two major possibilities to consider concerning a live herpes simplex virus vaccine. One is that the vaccine virus will replicate and go latent, and the other possibility is that it will replicate and not go latent. This question is made more complex because some individuals might react one way or the other. The next thing that will probably occur is that sooner or later the vaccinee will encounter the wild-type virus in nature. The wild-type virus could multiply and could also go latent. This then defeats the whole purpose of the vaccine, especially if that latent virus can be reactivated. The wild-type virus could multiply without going latent. That might be ideal because it should result in an anamnestic immune response (hopefully without disease). It is also possible that activation of the vaccine virus might result with unknown consequences. Genetic recombination between the vaccine and wild-type virus might well cause difficulty. Given these problems, how can we visualize a herpes simplex virus vaccine? Advancing technology once resembling science fiction is not that far from supplying some of the answers. One of the reasons why we so badly want to know what the transforming regions are and where we can map various proteins on
s344
FRED
RAPP
the virus genetic map is because it is now possible to selectively excise such regions and then selectively reconstruct the virus genome. It should be theoretically possible to construct a virus that no longer has transforming ability or virulence. If one or two genes are responsible for the ability of the virus to establish latency, it is possible to remove them. In fact, there is some evidence by Dr. Tenser in our department and by others that this is the case. In theory, if this is all possible, the population could be vaccinated with such a virus; the virus will replicate and cause an immune response but not go latent or cause disease. However, we are then still faced with the second problem, what will happen when that vaccinee encounters the natural wild-type virus? We do not presently have an answer. We already know, however, that people who have been exposed as children to HSV-1 can still be infected with HSV-2. What we do not know is whether those children, if infected early with HSV-2, could still be reinfected with another HSV-2. We need to know more about the pathogenesis of infection with these viruses and more about the specific properties that will allow us to genetically engineer a vaccine virus. Then we need a good model to ascertain the risks under what might be called simulated natural situations. If all goes well, the first use of such a vaccine would have to be in a very carefully selected population (preferably at high risk to herpes-induced disease) before we could administer it to the general population. Current studies are leading in that direction. I think you will hear more about them in the near future but I personally believe we are some years away before we can take the chance of using a virus of this type in the general population.