Looking back on the varicella zoster vaccine

August 2005

With the publication of our trial to prevent zoster (N Engl J Med. 2005;352[22]:2271-2284), I cannot help but look back over the past few decades. In 1961, I left practice to join the virology section at the CDC. One of the first things I did at the CDC was take some fetal tissues that were to be discarded and try to grow them in culture. Although this is now old hat, seeing human cells grow in test tubes was about the greatest thrill of my life at that point. The next was to see the cells in these tubes round up after vesicular fluid obtained from a child with chickenpox was added to it. Tom Weller, the Nobel laureate, had described this five years previously. At that time, there were only five of us working with the virus: Natalie Schmidt, Weller and me in the United States and David Taylor-Robinson, and Anne Caunt, in the United Kingdom. Now, there are more than 100 pages of citations on Medline.

As a clinician, I wanted to use this new knowledge to help patients. Thus, we developed a test to measure antibody, which we used to select patients convalescing from zoster with high titers of varicella zoster (VZ) antibody to prepare a globulin — zoster serum immune globulin (ZIG). We intended to use this to prevent varicella in children with malignancies who were at high risk of dying if they got chickenpox. Avron Ross, who had previously done studies on the prevention of chickenpox with regular immune globulin, was to become my collaborator along with Larry Miller, who is still my dermatologist here in Washington. You can imagine our excitement when only half of the household contacts got chickenpox, the controls, while those who got ZIG were completely protected. Varicella-zoster immune globulin, which was much easier to produce, subsequently replaced ZIG.

One of the unique characteristics of this virus was that it did not get out of cells and it grew very slowly. This is one of the main reasons it is so terribly expensive. It was extraordinarily difficult to obtain enough cell free virus for vaccine production. One of the first problems I tackled when coming to Saul Krugman’s department at New York University was to determine the best way of separating live virus from cells. We found that sonication, although terribly inefficient, was the best way, a method still used today about four decades after our original publication in Virology.

During a sabbatical year in England with Tony Allison, I learned about membrane fluorescence. Upon my return, we adapted this to the measurement of VZ antibody: the fluorescence antibody against membrane antigen (FAMA). This enabled us to finally have an antibody assay that could determine susceptibility to VZ. Sharon Steinberg, to whom I will be forever indebted, was instrumental in this and so many things we were able to accomplish. Unfortunately, I had to leave Sharon when I moved to Texas. Anne Gershon, who had just finished her fellowship and ran the lab during my sabbatical, went on to a spectacular career.

Michiaki Takahashi, who was to become a close friend, developed varicella vaccine in the 1970s. He was kind enough to provide me with some, which we were to evaluate in the prevention of chickenpox in children with leukemia. Supported by a National Institutes of Health (NIH) grant, we gave the first dose of his vaccine in San Antonio to an American child in 1978. Later, we were to evaluate the vaccine in normal children. Our first paper on a combined MMR-varicella vaccine appeared in 1988. Hopefully, this will be licensed shortly.

In 1998, at the invitation of Steve Straus, I left Los Angeles to take a position at the NIH. I was to be the principal investigator (PI) at this site for the evaluation of a vaccine to prevent zoster. In fact, I was the first of about 1,800 volunteers at this site (see photo at left). Unfortunately, I received the placebo. The fact that the PI had received placebo attests to the stringency which the study was conducted. As a pediatrician, I was always aware of chickenpox. As a senior pediatrician, I have been concerned about the devastating effect zoster may have on my contemporaries. Mike Oxman headed this monumental study of more than 38,000 people older than age 60. The results of our study showed that there was a 51.3% reduction in zoster, a 61.1% reduction in burden of illness and a 65.5% reduction in postherpetic neuralgia. The vaccine contained at least 14 times the amount of virus as the regular varicella vaccine so I do not recommend giving the regular vaccine to adults to prevent zoster. The FDA is now considering it for licensure. Subsequently, recommendations will be made for its use. This will probably be a much more important vaccine in reducing morbidity than chickenpox vaccine.

Finally, we should take note of the progress of the varicella vaccine program. Initially, there were two concerns: the length of immunity conferred by the vaccine and the effect on zoster. Both might be related to the decreased exposure to VZ as more and more individuals are immunized and the opportunities for immunologic boosting diminish. There may be an increase in breakthroughs in those immunized more remotely. This will be followed carefully. It is likely there will be a second dose of varicella vaccine recommended, especially if it can be combined with MMR. This is in the works.

There has been a marked decrease in cases of varicella since the advent of the vaccine program. Despite the decrease in cases of varicella nationally, there does not appear to be a change in the frequency of zoster (J Infect Dis. 2005;191[12]:2002-2007). Indeed, the vaccinees appear to have a lower risk of zoster than those who had natural disease.

As we look ahead, it is likely that we will have an measles-mumps-rubella-varicella vaccine, and it will be given twice. The zoster vaccine is expected to be licensed shortly. Given the difficulty in making this vaccine and the massive clinical trial it took to evaluate it, it is likely to be very expensive. However, having spent a lot of time listening to people suffering from postherpetic neuralgia, which had changed their whole lives, it should be worth a great deal. It is gratifying to look back these few decades and see what has been accomplished.