Varicella vaccines: background

A live attenuated varicella vaccine, the Oka strain, was developed by Takahashi and his colleagues in Japan the early 1970s (Takahashi et al., 1974). This vaccine is now being adminstered to varicella-susceptible healthy children and adults in many countries; it is produced by at least 3 manufacturers worldwide (Merck and Co., Glaxo SmithKline, and Biken Institute/Aventis Pasteur). Although the vaccine was developed in Japan, the largest experience with it comes from the United States, where the Merck formulation was licensed for routine use in healthy susceptible individuals over the age of 1 year in 1995 (Centers for Disease Control, 1996). In both pre- and postlicensure studies (Gershon et al., 1984a, b; White, 1997; Sharrar et al., 2000) the vaccine was demonstrated to be extremely safe. Adverse effects in healthy persons are few and quite transient: a sore arm after the injection in 20%–25%, and a very minor rash resembling mild varicella in about 5%, usually appearing a month after immunization (White, 1997). A small proportion of vaccinees (15%) may also experience mild fever. It takes about a week to demonstrate antibodies to varicella-zoster virus (VZV) after immunization, but protection often results even after an exposure has occurred. As a result of widespread immunization of children, the epidemiology of varicella has begun to change in the United States, with a reported marked decline in incidence in sentinel areas, where active surveillance for the disease is being carried out (Seward et al., 2002).

Throughout the years, there have been many scientists who have contributed to our knowledge of the varicella zoster virus and the prevention, diagnosis and management of VZV-related diseases. In recent years, four of them, including two Nobel Laureates, have had the distinction of receiving the VZV Research Foundation (VZVRF) Scientific Achievement Award, which recognizes lifetime achievements in VZV research. Established in 1991, the Foundation is the first and only nonprofit organization in the world dedicated to VZV research and education.

Thomas H. Weller, M.D.

Thomas H. Weller, M.D., professor emeritus of the Harvard School of Public Health, Boston, and a Nobel Laureate, was the recipient of the first VZVRF Scientific Achievement Award in 1993. He remarked that his VZVRF award was in a way more gratifying than his Nobel Prize. According to Dr. Weller, “Although my work in isolating and growing the poliomyelitis virus in tissue cultures was the most significant contribution I have made to medical science in terms of global impact, I am most proud of my work with the varicella-zoster virus. It's something I planned to do and worked for years to do.”

It was the work that Dr. Weller and his colleagues did on the poliomyelitis virus that garnered them the Nobel Prize in 1954, and led to the Sabin and Salk vaccines. Likewise, Dr. Weller's work on the varicella-zoster virus led to many important discoveries in VZV research, including Dr. Michiaki Takahashi's development of the varicella vaccine. In 1953, in addition to isolating VZV from cases of chickenpox and zoster, Dr. Weller was able to show that the same virus is responsible for both illnesses.

Introduction

Live attenuated varicella vaccine was developed in the early 1970s by Takahashi and his colleagues in Japan (Takahashi et al., 1974). The first described use of this vaccine, an attempt to halt an epidemic of varicella in a children's hospital ward, was, perhaps surprisingly, not greeted with acclaim, but rather with skepticism and controversy. The vaccine however became more and more accepted over a period of about 15 years as ongoing clinical trials indicated that it was safe and effective not only in healthy children but also in certain immunocompromised patients who were at high risk of developing severe varicella (Gershon et al., 1996a). The vaccine was licensed for use in Japan in 1989, for immunizing healthy children. Paradoxically, varicella vaccine has not been used extensively in Japan, where, almost 10 years after licensure, only about 20% of healthy children were immunized (Asano, 1996). In other areas of the world outside of the United States, testing of varicella vaccine has been sporadic, but at present there continues to be interest in Europe and Australia (Varis & Vesikari, 1996). There is also significant interest in immunizing susceptible adults in Southeast Asia, since varicella in childhood is unusual in these tropical countries.

In the United States clinical trials of varicella vaccine progressed from studies in high-risk individuals, in particular immunocompromised children and healthy adults, to studies in healthy children. This approach was the opposite from the sequence of testing in Japan, which progressed from healthy to immunocompromised children. Decisions regarding populations for clinical trials were complicated by the lack of a practical animal model for varicella, a deficiency that persists even today.

Major milestones in the understanding of varicella-zoster virus (VZV) occurred in the eighteenth century when varicella was recognized to be distinct from smallpox, and in the mid-twentieth century Weller and colleagues first succeeded in isolating the virus in cell culture. Nevertheless, as recently as 30 years ago only a handful of virologists were pursuing research on VZV, mainly because the diseases it caused were perceived as minor and it proved to be extremely difficult to propagate the virus in the laboratory. There were several achievements, however, that resulted in a veritable explosion in research on this pathogen, beginning in the early 1970s. First was development of a live attenuated varicella vaccine by Takahashi and colleagues. Other significant new interventions were introduced almost simultaneously, including passive immunization and antiviral therapy, along with the realization that diseases caused by VZV are not necessarily benign, especially in developed nations with aging populations and increasing numbers of immunocompromised patients. Next came the availability of molecular techniques, permitting bypass of propagation of the virus for its study, and allowing mutation of viral genes within the virus, leading to elucidation of the processes of VZV gene expression, latency, viral pathogenesis and immune responses. Finally the organization of the Varicella-Zoster Research Foundation by Richard Perkin led to improved communication between basic and clinical investigators studying VZV. In the brief period of about 10 years, this Foundation has hosted four international meetings on VZV, produced three volumes of Proceedings, presented four awards to premier senior scientists involved with VZV, and supported seven research fellowships for young investigators interested in VZV.