Varicella: Problems Posed by an Ubiquitous Persistent Virus
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Weller, Thomas H.
Thomas Huckle Weller won the Nobel Prize in Physiology or Medicine in 1954, sharing the prize with John F. Enders and Frederick C. Robbins. Five years previously, the three scientists had demonstrated that the poliomyelitis virus could be cultured in tissues outside of nerve cells, which galvanized the race for the polio vaccine. Time was not wasted. At the time of the Nobel Prize announcement, the vaccine was already subjected to clinical trials, leading to large-scale vaccination of schoolchildren in 1955. Weller remained in the field of clinical virology, and had a particular interest in viruses that usually occur in childhood; rubella, Coxsackie, or varicella zoster, known as the chicken pox. During this brief lecture, Weller focused on a “problem of increasing social significance”, but one that rarely makes the headlines despite its prevalence. Once the symptoms of varicella clear, usually in a child, the body never completely rids itself of the virus. Varicella lies dormant in nerve cells. By the time the child reaches middle age, there is a considerable chance the virus will reactivate in the form of “severe, painful herpes zoster”, in the words of Weller. It is estimated that half of those who live to the age of 85 will develop herpes zoster, also commonly known as shingles, while 10% will have had the disease twice. Weller cited these statistics in 1981, and they are still relevant today. Yet the incidence of herpes zoster is increasing, and this is simply as a result of a longer life expectancy. Weller and his colleagues isolated the varicella virus in 1952, effectively showing that varicella zoster and herpes zoster are caused by the same virus. The symptoms are different, however, and while varicella is often mild and quickly forgotten, zoster may result in various neurologic complications, which may linger for months or even years. The disease is particularly serious in the immunocompromised, such as patients with cancer or who are HIV positive, or those who have undergone organ transplants. Soon after this lecture was delivered, a vaccine against varicella became available, yet it is usually only advised for specific groups, such as young children in child care facilities, and not part of national immunisation programmes. In 2006, the first herpes zoster vaccine was introduced, which is recommended in many countries for adults over the age of 60. Despite the fact that there are vaccines for both varicella and zoster, there is still much debate over whether these are illnesses that warrant enough of our attention to rationalise widespread vaccination. It seems that most of Weller’s lecture could be delivered unchanged today. Hanna Kurlanda-Witek Baicus, A. (2012) History of Polio Vaccination. World J Virol. 1(4), pp. 108-114. Cohen, J.I. (2013) Herpes Zoster. N Engl J Med 369(3), pp. 255-263. Warren-Gash, C., Forbes, H., and Breuer, J. (2017) Varicella and herpes zoster vaccine development: lessons learned. Expert Rev Vaccines 16(12), pp. 1191-1201.
 Music Well, students and colleagues, my scientific life is a little bit different from that of some of my associates. I think most of the work I've carried out has been aimed at solving a definite problem, usually a clinical problem. Three years ago I talked about some of the problems of tropical diseases and development of developing areas of the world. That's one facet of interest. Another facet has been the common viral communicable diseases of children, and I've chosen today to talk about the one virus that I deliberately set out to isolate and had the pleasure of succeeding. Some of our other isolations had a much greater element of the serendipitous, but that's another story. Being the last presenter on this program, at a point when you're saturated with knowledge and perhaps slightly hypoglycemic, I think you'll probably judge my presentation by the brevity of its content, as well as the subject matter per se. I hope to get high marks on both counts. Applause Well, why should we be interested in varicella? It's a continuing problem. As in introduction, mentioned there's no vaccine, but there's one on the horizon, and it's going to challenge all of us to have it develop successfully, and it may well be that it'll be your generation with the techniques of genetic engineering that will produce a good immunizing material for this disease. I'm presenting varicella because of my personal interest, but also because it's a problem of increasing social significance. Here we have a relatively benign disease. May I have the first slide, please? Which in children manifests itself with a rash? They aren't very sick. Yet, as man, the physician, manipulates the human host, we now see increasingly an eatrogenic type of varicella that may be lethal. Now, this is not eatrogenic in the bad sense, as Professor Krebs alluded to yesterday. I'm talking about the modification of the human host, say, to treat cancer with cytotoxic or immunosuppressive drugs, and in the course of that modification, one has the unhappy complication of severe varicella. Now we typically have an individual with a primary attack of the virus that manifests successive crops on the skin of lesions, little vesicles that rapidly go on to become popular and then postular. One little point I want you to keep in mind is, where does the virus come from that spreads around the community so fast? And I'm going to very briefly summarize the present state of our knowledge, go a little bit into the historical background, and then point out some of these special problems, the unique characteristics that have made this virus so difficult to work with. From your standpoint, you all ought to be interested in it more or less on a selfish basis. You all expect to achieve 60 or 70 years of age? No doubt, you all will. 50% or more will have another encounter with a chickenpox virus that you had as a child, and then you will get a severe, painful, incapacitating attack of herpes zoster, decairle rosa, and perhaps with very severe post-zoster neurologic pain. This is one of the reasons that this disease is becoming more important, because we are an aging population. And the next slide, please. The prevalence of zoster is directly related to increasing age. These are some data that Hope Simpson corrected in the course of a study of a panel practice in England, and it was his estimation that if a cohort of 1,000 people were to live to age 85, half would have had one attack of zoster, and 10 would have experienced two attacks. Next slide, please. We mentioned that medical progress, per se, turns varicella into a lethal entity. This was first recognized and reported by us in 1956, where a child with malignancy being treated with cytotoxic and immunosuppressive drugs did not get the single little series of crops, two or three or four, of vesicles and lesions, but instead continued over a matter of four or five weeks to have vesicular lesions and then went on and died. Next slide, please. That's a systemic disease, a situation like that, and one has to think of varicella as a systemic process. There are lesions all through the body, ear, pox, and the lungs. Next slide, please. And if you focus down on one of those little areas, you'll see the typical intranuclear inclusion bodies characteristic of varicella and indeed of all of the members of the herpes group. Well, it's this situation that gives us great concern now about varicella virus. In one series of children treated with malignancy, varicella as a complication had a mortality rate of 7%. In patients who received marrow transplants, varicella infection flares up in some 50% of all such transplanted children with a 12% mortality rate. So as medicine progresses, we're creating new problems and we need new preventive measures and methods of treatment. Well, now just a brief word about the history. As Longgoes, 1888, in Vienna, Bouquet, suggested on epidemiologic grounds that varicella and zoster might be related. He saw outbreaks of varicella occurring in children exposed to adults with zoster. Now the next slide, please. And then the first sort of entree into modern virology came when Dr. Tisser, my predecessor at Harvard, in 1903, studied the evolution of varicellulose in the skin. And this is one of his slides stained back in 1903, beautifully preserved, pictured now, and it shows the characteristic features of the herpes group, malinucleot giant cells, inter-nuclear inclusions. Next slide, please. Now that's a vesicle on the first day of the rash. That vesicle has lots of virus in it, maybe 10 to 7, 10 to 8 per ml, in fact, some particles if you were titrated out. There's another Dr. Tisser's preparations. By day two or three, when inflammatory cells begin to migrate in, there is practically no virus there. Virus is very transient. Next slide, please. And to show you some of his meticulous drawings he made at that time here, typical inter-nuclear inclusions. He didn't know he was dealing with a virus at that time, but he laid the basic classical description of the cytopathology of the herpes group agents. Well, things move very slowly for many years. During the 20s and 30s, biologists and workers tried to get virus into animals and reluctantly had to conclude that there weren't any susceptible laboratory animals. About 1941, a fellow intern and I got the idea that maybe one could use human cell cultures and we started out to inoculate vesicle fluid into cultures of human cells. That had to be put aside in 1948. I was able to return to it and we first got inclusions like this and it in suspended cell cultures. And then the next slide, when we switched to sheets of fibroblasts, inoculated with vesicle fluid, either from varicella or from zoster, didn't make any difference. We got plaxous woman cells that got larger and larger, seventh day, tenth day, and the virus seemed to spread from cell to contiguous cell. Next slide, please. And if one stained edge of one of those plaxons, even with this power, you can see all the nucleic giant cells, internal conclusions. Here are normal fibroblasts. Next slide, please. And if you go up under higher power, under oil, at the edge of such an advancing legion, here are normal fibroblast nuclei. Here are nice big characteristic, inter-nuclear inclusions. Well, with that as a starter, we were rapidly able to work out serologic techniques, immunologic procedures, and show that the viruses of zoster and varicella were alike. And we coined the name varicella-zoster virus. But the virus growing in the tissue cultures proved to be most frustrating. Unlike other agents, the virus remains cell-associated, and very little would come out into the fluid phase of the tissue culture. And this situation obtains to the present. The arches develop some. We can get virus out by sonocating infected cells, concentrating, say, with polyethylene glycol, and maybe get as many as 6 to 7, 10 to 6 to 7, infectious particles per ml, but still a tighter, much inferior to the little vesicle in the skin. Now the next slide, please. Peculiarly, the best yields from the tissue culture system yield less than one cell-free, infectious virus particle per infected cell. Now, if one's going to think about using a killed viral vaccine, and you're going to need huge masses of antigen, then we're a long ways, technically, from getting the antigenic mass that we're going to have. Right now, the killed vaccine is out the window. But what's happening? What happens in the skin is different from growing the virus in vitro. We've worked for years now on trying to have different cells and trying to improve the system. Was this tipped or are we in the same position as Dr. D. D. was yesterday? Another 10 minutes or so? Okay. At least I was prepared. Well, with serologic tests now and tests for immunity or susceptibility, we can look at children and know whether they need a vaccine, or whether perhaps they might get a short-term passive prevention by the use of hyperimmune gamoglobulin that will prevent chickenpox. But we know so little about this agent. The next slide, please. It's been notorious that when a case of chickenpox appears on a hospital ward, it spreads rapidly through the ward to all susceptibles. And here is a summary of a paper published last year by Claire and co-workers from Study Dunn in Boston, index case here on the ward, and then here were the contact cases. Next slide, please. When they looked at this epidemiologically, here was the index case. Nine out of 10 patients, susceptibles got it there, three out of five over there, one out of one, and so on. They took chemical smokes, followed the airflow, and believe it or not, there was a flow outside through window air conditioners as well as a flow inside. So where did the virus come from? Faculately, in spite of thousands of attempts to isolate virus from the throat washings, respiratory secretions of patients with varicella, I know of only one success. Now, there's virus in the vesicles, but that is a very labile agent. And I'm not sure that it was vesicle virus that infected all these other susceptibles. Surprisingly, in the tropics, varicella is an adult disease. Apparently, the virus is relatively labile, and it spread from person to person is delayed. You would think in a poorly-sanitated, dense, little, heavily populated village hut in the tropics that all the kids would get varicella very soon, but they don't. It's an adult disease. So here are mysteries. We don't know how this thing really gets around. Well, there are other problems. Mention of latency. Next slide, please. All of the members of the Herpes virus group have this propensity for latency. Herpes simplex virus can be recovered from ganglia of man and experimental animals in between periods of viral clinical activity. We assume that the same thing obtains for herpes zoster that it hides out in the sensory ganglia. If the patient has zoster, one can look at that ganglia and find nerve cells degenerating, find the satellite cells with typical inclusions, but in hundreds of attempts to detect or rescue virus from the ganglia at autopsy of people dying of a variety of things, when they did not have acute zoster, they've all been negative. So we don't know how this virus stays latent. And that's one of the interesting challenges. We're learning a little more about the host response and what happens to the host that releases the virus from latency. And we have phenomena in the child, infant. Next slide, please. Here is zoster in a baby two and a half months old. That mother of that baby had varicella during the pregnancy, and here's a shortened period. This baby's immune responses were immature and it developed zoster a few months after the episode of varicella in utero. Next slide, please. Parenthetically, within the last five years, next, please, we have learned to recognize that there, like congenital rubella, there is now a congenital varicella syndrome. It's rare, but if a mother should happen to have varicella in the first or second trimester, the baby may be damaged, and there are characteristic deep deforming scars that developed for the lesions were. Now, if we look at the human host, say, in mid-age, and look at patients who have diseases such as Hodgkin's disease, then we very clearly can determine that cellular immune responses to varicella virus are depressed. And most recently, next slide, please, Miller did a study on adults, looked at the blastogenic lymphocytic response to varicella antigen, white cells taken from older people, white cells taken from younger middle-aged people, and showed very clearly that the person over 60 years of age has a relatively incapacit-ly to react at the cellular level. In other words, this is an indication of what I like to call immunologic senility. Now, one of the real problems has been, right along, that there's been no animal model for varicella. So there's nothing to do safety testing in, nothing to work out the pathogenesis of this virus, no non-human host. And it's not a surprise that because of the peculiar nature of this agent, it was not until 1974, 25 years after we isolated the virus that the first varicella vaccine was gingerly tried out and published about, Takahashi and his co-workers in Japan. Since then, two or three other groups are working with varicella vaccines, their live viral vaccines, but lacking a human host, I mean lacking an animal host, one has to test out whether a tenuator did not in children. That, of course, is a scary thing. Fortunately, some of the candidate vaccines look extremely promising, but there remains the problem perhaps of latency and of zoster developing years later. Then there's another new development. Many of the herpes group viruses have some transforming or oncogenic potential. And last year, Gelb and his co-workers published a paper in which he showed that hamster cells underwet transformation and exposure in vitro to varicella zoster virus. Injection of the transformed cells into hamsters produced malignant tumors. Now we have no evidence at all now that there's any relationship between varicella zoster virus and malignancy in man. But the idea of putting an attenuated virus of uncertain parentage into children when there might be some oncogenic potential gives one pause. Well, this is where we now stand. I think it'll be years before a definitive assessment of benefits and risks of such a vaccine can now be made, and therefore alternative approaches to live virus vaccines should be explored concurrently. The rapid developments in the area of molecular biology and genetic engineering should expedite the development and production of a subunit vaccine that would be devoid of the possible risks of a live viral product. I commend this problem to you and to your generation. Varicella, the last of the common communicable disease of children, assumes increasing social significance and deserves priority of attention. Thank you.
 Music  Well, students and colleagues,  my scientific life is a little bit different from that of some of my associates.  I think most of the work I've carried out has been aimed at solving a definite problem,  usually a clinical problem.  Three years ago I talked about some of the problems of tropical diseases  and development of developing areas of the world.  That's one facet of interest.  Another facet has been the common viral communicable diseases of children,  and I've chosen today to talk about the one virus that I deliberately set out to isolate  and had the pleasure of succeeding.  Some of our other isolations had a much greater element of the serendipitous,  but that's another story.  Being the last presenter on this program,  at a point when you're saturated with knowledge  and perhaps slightly hypoglycemic,  I think you'll probably judge my presentation by the brevity of its content,  as well as the subject matter per se.  I hope to get high marks on both counts.  Applause  Well, why should we be interested in varicella?  It's a continuing problem.  As in introduction, mentioned there's no vaccine,  but there's one on the horizon,  and it's going to challenge all of us to have it develop successfully,  and it may well be that it'll be your generation with the techniques of genetic engineering  that will produce a good immunizing material for this disease.  I'm presenting varicella because of my personal interest,  but also because it's a problem of increasing social significance.  Here we have a relatively benign disease.  May I have the first slide, please?  Which in children manifests itself with a rash?  They aren't very sick.  Yet, as man, the physician, manipulates the human host,  we now see increasingly an eatrogenic type of varicella that may be lethal.  Now, this is not eatrogenic in the bad sense,  as Professor Krebs alluded to yesterday.  I'm talking about the modification of the human host,  say, to treat cancer with cytotoxic or immunosuppressive drugs,  and in the course of that modification,  one has the unhappy complication of severe varicella.  Now we typically have an individual with a primary attack of the virus  that manifests successive crops on the skin of lesions,  little vesicles that rapidly go on to become popular and then postular.  One little point I want you to keep in mind is,  where does the virus come from that spreads around the community so fast?  And I'm going to very briefly summarize the present state of our knowledge,  go a little bit into the historical background,  and then point out some of these special problems,  the unique characteristics that have made this virus so difficult to work with.  From your standpoint, you all ought to be interested in it more or less on a selfish basis.  You all expect to achieve 60 or 70 years of age?  No doubt, you all will.  50% or more will have another encounter with a chickenpox virus that you had as a child,  and then you will get a severe, painful, incapacitating attack of herpes zoster,  decairle rosa, and perhaps with very severe post-zoster neurologic pain.  This is one of the reasons that this disease is becoming more important,  because we are an aging population.  And the next slide, please.  The prevalence of zoster is directly related to increasing age.  These are some data that Hope Simpson corrected in the course of a study of a panel practice in England,  and it was his estimation that if a cohort of 1,000 people were to live to age 85,  half would have had one attack of zoster, and 10 would have experienced two attacks.  Next slide, please.  We mentioned that medical progress, per se, turns varicella into a lethal entity.  This was first recognized and reported by us in 1956,  where a child with malignancy being treated with cytotoxic and immunosuppressive drugs  did not get the single little series of crops, two or three or four, of vesicles and lesions,  but instead continued over a matter of four or five weeks to have vesicular lesions  and then went on and died.  Next slide, please.  That's a systemic disease, a situation like that,  and one has to think of varicella as a systemic process.  There are lesions all through the body, ear, pox, and the lungs.  Next slide, please.  And if you focus down on one of those little areas, you'll see the typical intranuclear inclusion bodies  characteristic of varicella and indeed of all of the members of the herpes group.  Well, it's this situation that gives us great concern now about varicella virus.  In one series of children treated with malignancy, varicella as a complication had a mortality rate of 7%.  In patients who received marrow transplants, varicella infection flares up in some 50% of all such transplanted children  with a 12% mortality rate.  So as medicine progresses, we're creating new problems and we need new preventive measures and methods of treatment.  Well, now just a brief word about the history.  As Longgoes, 1888, in Vienna, Bouquet, suggested on epidemiologic grounds that varicella and zoster might be related.  He saw outbreaks of varicella occurring in children exposed to adults with zoster.  Now the next slide, please.  And then the first sort of entree into modern virology came when Dr. Tisser, my predecessor at Harvard,  in 1903, studied the evolution of varicellulose in the skin.  And this is one of his slides stained back in 1903, beautifully preserved, pictured now,  and it shows the characteristic features of the herpes group, malinucleot giant cells, inter-nuclear inclusions.  Next slide, please.  Now that's a vesicle on the first day of the rash.  That vesicle has lots of virus in it, maybe 10 to 7, 10 to 8 per ml, in fact, some particles if you were titrated out.  There's another Dr. Tisser's preparations.  By day two or three, when inflammatory cells begin to migrate in, there is practically no virus there.  Virus is very transient.  Next slide, please.  And to show you some of his meticulous drawings he made at that time here, typical inter-nuclear inclusions.  He didn't know he was dealing with a virus at that time, but he laid the basic classical description of the cytopathology of the herpes group agents.  Well, things move very slowly for many years. During the 20s and 30s, biologists and workers tried to get virus into animals  and reluctantly had to conclude that there weren't any susceptible laboratory animals.  About 1941, a fellow intern and I got the idea that maybe one could use human cell cultures and we started out to inoculate vesicle fluid into cultures of human cells.  That had to be put aside in 1948.  I was able to return to it and we first got inclusions like this and it in suspended cell cultures.  And then the next slide, when we switched to sheets of fibroblasts, inoculated with vesicle fluid, either from varicella or from zoster, didn't make any difference.  We got plaxous woman cells that got larger and larger, seventh day, tenth day, and the virus seemed to spread from cell to contiguous cell.  Next slide, please.  And if one stained edge of one of those plaxons, even with this power, you can see all the nucleic giant cells, internal conclusions.  Here are normal fibroblasts.  Next slide, please.  And if you go up under higher power, under oil, at the edge of such an advancing legion, here are normal fibroblast nuclei.  Here are nice big characteristic, inter-nuclear inclusions.  Well, with that as a starter, we were rapidly able to work out serologic techniques, immunologic procedures, and show that the viruses of zoster and varicella were alike.  And we coined the name varicella-zoster virus.  But the virus growing in the tissue cultures proved to be most frustrating.  Unlike other agents, the virus remains cell-associated, and very little would come out into the fluid phase of the tissue culture.  And this situation obtains to the present.  The arches develop some.  We can get virus out by sonocating infected cells, concentrating, say, with polyethylene glycol, and maybe get as many as 6 to 7, 10 to 6 to 7,  infectious particles per ml, but still a tighter, much inferior to the little vesicle in the skin.  Now the next slide, please.  Peculiarly, the best yields from the tissue culture system yield less than one cell-free, infectious virus particle per infected cell.  Now, if one's going to think about using a killed viral vaccine, and you're going to need huge masses of antigen,  then we're a long ways, technically, from getting the antigenic mass that we're going to have.  Right now, the killed vaccine is out the window.  But what's happening?  What happens in the skin is different from growing the virus in vitro.  We've worked for years now on trying to have different cells and trying to improve the system.  Was this tipped or are we in the same position as Dr. D. D. was yesterday?  Another 10 minutes or so?  Okay.  At least I was prepared.  Well, with serologic tests now and tests for immunity or susceptibility, we can look at children and know whether they need a vaccine,  or whether perhaps they might get a short-term passive prevention by the use of hyperimmune gamoglobulin that will prevent chickenpox.  But we know so little about this agent.  The next slide, please.  It's been notorious that when a case of chickenpox appears on a hospital ward, it spreads rapidly through the ward to all susceptibles.  And here is a summary of a paper published last year by Claire and co-workers from Study Dunn in Boston,  index case here on the ward, and then here were the contact cases.  Next slide, please.  When they looked at this epidemiologically, here was the index case.  Nine out of 10 patients, susceptibles got it there, three out of five over there, one out of one, and so on.  They took chemical smokes, followed the airflow, and believe it or not, there was a flow outside through window air conditioners as well as a flow inside.  So where did the virus come from?  Faculately, in spite of thousands of attempts to isolate virus from the throat washings, respiratory secretions of patients with varicella,  I know of only one success.  Now, there's virus in the vesicles, but that is a very labile agent.  And I'm not sure that it was vesicle virus that infected all these other susceptibles.  Surprisingly, in the tropics, varicella is an adult disease.  Apparently, the virus is relatively labile, and it spread from person to person is delayed.  You would think in a poorly-sanitated, dense, little, heavily populated village hut in the tropics that all the kids would get varicella very soon, but they don't.  It's an adult disease.  So here are mysteries.  We don't know how this thing really gets around.  Well, there are other problems.  Mention of latency.  Next slide, please.  All of the members of the Herpes virus group have this propensity for latency.  Herpes simplex virus can be recovered from ganglia of man and experimental animals in between periods of viral clinical activity.  We assume that the same thing obtains for herpes zoster that it hides out in the sensory ganglia.  If the patient has zoster, one can look at that ganglia and find nerve cells degenerating, find the satellite cells with typical inclusions,  but in hundreds of attempts to detect or rescue virus from the ganglia at autopsy of people dying of a variety of things,  when they did not have acute zoster, they've all been negative.  So we don't know how this virus stays latent.  And that's one of the interesting challenges.  We're learning a little more about the host response and what happens to the host that releases the virus from latency.  And we have phenomena in the child, infant.  Next slide, please.  Here is zoster in a baby two and a half months old.  That mother of that baby had varicella during the pregnancy, and here's a shortened period.  This baby's immune responses were immature and it developed zoster a few months after the episode of varicella in utero.  Next slide, please.  Parenthetically, within the last five years, next, please, we have learned to recognize that there, like congenital rubella,  there is now a congenital varicella syndrome.  It's rare, but if a mother should happen to have varicella in the first or second trimester, the baby may be damaged,  and there are characteristic deep deforming scars that developed for the lesions were.  Now, if we look at the human host, say, in mid-age, and look at patients who have diseases such as Hodgkin's disease,  then we very clearly can determine that cellular immune responses to varicella virus are depressed.  And most recently, next slide, please, Miller did a study on adults, looked at the blastogenic lymphocytic response to varicella antigen,  white cells taken from older people, white cells taken from younger middle-aged people,  and showed very clearly that the person over 60 years of age has a relatively incapacit-ly to react at the cellular level.  In other words, this is an indication of what I like to call immunologic senility.  Now, one of the real problems has been, right along, that there's been no animal model for varicella.  So there's nothing to do safety testing in, nothing to work out the pathogenesis of this virus, no non-human host.  And it's not a surprise that because of the peculiar nature of this agent,  it was not until 1974, 25 years after we isolated the virus that the first varicella vaccine was gingerly tried out and published about,  Takahashi and his co-workers in Japan.  Since then, two or three other groups are working with varicella vaccines, their live viral vaccines,  but lacking a human host, I mean lacking an animal host, one has to test out whether a tenuator did not in children.  That, of course, is a scary thing.  Fortunately, some of the candidate vaccines look extremely promising,  but there remains the problem perhaps of latency and of zoster developing years later.  Then there's another new development.  Many of the herpes group viruses have some transforming or oncogenic potential.  And last year, Gelb and his co-workers published a paper in which he showed that hamster cells underwet transformation and exposure in vitro to varicella zoster virus.  Injection of the transformed cells into hamsters produced malignant tumors.  Now we have no evidence at all now that there's any relationship between varicella zoster virus and malignancy in man.  But the idea of putting an attenuated virus of uncertain parentage into children when there might be some oncogenic potential gives one pause.  Well, this is where we now stand.  I think it'll be years before a definitive assessment of benefits and risks of such a vaccine can now be made,  and therefore alternative approaches to live virus vaccines should be explored concurrently.  The rapid developments in the area of molecular biology and genetic engineering should expedite the development and production of a subunit vaccine  that would be devoid of the possible risks of a live viral product.  I commend this problem to you and to your generation.  Varicella, the last of the common communicable disease of children, assumes increasing social significance and deserves priority of attention.  Thank you.
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