VZV Foundation - A Decade Of Leadership In The Fight Against VZV Infections

	STUDY SHOWS DRAMATIC DECLINE IN VARICELLA FOLLOWING VACCINATION In 2002, the Council for State and Territorial Epidemiologists formally recommended that chickenpox, or varicella, become a nationally reportable disease. Assuming each of the 50 states adopts this recommendation, it will still take a few years to fully implement. It is precisely the lack of national surveillance data for chickenpox in 1995, the year of licensure of the vaccine by the Food and Drug Administration, made it especially challenging to monitor the impact of the varicella immunization program. This situation was in contrast with other diseases, such as measles, rubella and mumps, which were reportable under the National Notifiable Disease Surveillance System when their vaccination programs were implemented in the U.S. The lack of a monitoring mechanism prompted the Centers for Disease Control and Prevention (CDC), in collaboration with state and local health departments, to launch an active surveillance study in 1995. According to the study's lead investigator, Dr. Jane F. Seward, three communities were selected for the study: Antelope Valley, California; Travis County, Texas and West Philadelphia, Pennsylvania. Dr. Seward is Acting Chief, Child Vaccine Preventable Diseases Branch, of the CDC's National Immunization Program. According to the CDC, prior to licensure of the varicella vaccine in 1995, chickenpox was a universal childhood disease in the U.S., causing approximately 4 million cases each year. Chickenpox-related complications resulted in an annual average of 11,000 hospitalizations and 100 deaths. In designing the study, investigators wanted the data to be population-based, covering all groups. According to Dr. Seward, the communities chosen were fairly representative of different segments of the American population. In 1995, the populations of Antelope Valley, Travis County and West Philadelphia were 284,000, 666,127 and 291,608, respectively. In Antelope Valley and Travis County, the populations were predominantly white--89 and 85 percent of the total-- with approximately 20 percent of the white populations in each area reporting Hispanic ethnicity. The population of West Philadelphia was predominantly (69 percent) African-American. As reported in the February 6, 2002 edition of the Journal of the American Medical Association, the study examined surveillance data from January 1, 1995 through December 31, 2000. The investigators, goals were to, first, establish baseline data and, second, to monitor trends in varicella following introduction of the vaccine. Reporting sites in each community included: childcare centers; schools; universities; private health care providers; health maintenance organizations; emergency departments; hospitals; public health clinics and households. In 1997, among children aged 19 to 35 months, vaccine coverage in Los Angeles County, Texas and Philadelphia County was 40, 23 and 43 percent, respectively. By 2000, coverage had increased to 82.1, 73.6 and 83.8 percent respectively, which the study termed "moderate vaccine coverage". According to Dr. Seward, 90 percent coverage is considered high. "Vaccine coverage was higher at these three sites than in rest of country," said Dr. Seward. "Therefore, our findings may not be completely representative of the entire U.S.-which was 68 percent in June 2000-but rather ahead in terms of vaccine uptake and disease decline. This greater coverage rate may be due to heightened awareness of varicella and its consequences in these communities. However, there was no extensive effort in the three sites to educate the public about the disease and vaccination." The study found that, four years after implementation of the varicella vaccination program in the U.S., there was "dramatic evidence of vaccine impact with a marked decline in all age groups". From 1995 through 2000, in Antelope Valley, Travis County and West Philadelphia, chickenpox cases declined 71, 84 and 79 percent, respectively. Cases declined in all age groups, including infants and adults. The study noted this was indicative of a reduced transmission of varicella-zoster virus in these communities. The declines were greatest among preschool children aged one to four years. The study stated that, "in 1995, there were 2,934 verified varicella cases reported in Antelope Valley, 3,130 in Travis County and 1,197 in West Philadelphia. In all sites, the number of cases declined in 1996...remained fairly stable until 1998...(with) a marked decline in...1999. In 2000, there were 837, 491 and 250 reported cases in Antelope Valley, Travis County and West Philadelphia (respectively). From 1995 to 2000, varicella cases showed springtime seasonality, with the highest number of cases reported between March and May." Hospitalizations due to varicella also declined significantly. According to the study, "considering all surveillance areas together, from 1995 through 1998, varicella hospitalizations ranged from 34 to 53 per year (average 40 per year). In 1999 and 2000, 8 and 20 varicella hospitalizations were reported, respectively...50 to 80 percent lower than the average number of hospitalizations from 1995 through 1998." The study concluded the "...continued implementation of existing vaccine policies should lead to further reductions of varicella disease in these communities and throughout the United States...Our surveillance data underscores the importance of not only continuing efforts to achieve more than 90 percent vaccine coverage among young children, but also of implementing existing policy recommendations for catch-up vaccination of susceptible older children and adolescents to prevent increasing susceptibility in these groups." "The CDC's goal, by 2010, is for the U.S. to achieve a 90 percent reduction in disease, in addition to vaccine coverage of 90 percent among children aged two and 95 percent of children at school entry," said Dr. Seward. "We also seek to maintain these percentages as a means of achieving a continuous decline in disease, as was seen with measles and other vaccine-preventable diseases. However, we might require a higher than 90 percent vaccine coverage for varicella, because of the potential for exposure of children to the VZV virus through contact with individuals with shingles, and due to the fact varicella vaccine is not quite as effective as the measles vaccine." Alternatively, a two-dose vaccine policy, which may decrease rates of vaccine failure, may be needed in the future. According to Dr. Seward, "The study was an exciting project that gave us more detailed information concerning varicella cases than we normally obtain about diseases monitored under the National Notifiable Disease Surveillance System." She added that surveillance would continue in Antelope Valley and West Philadelphia through 2004. Next year, the CDC will decide whether another five-year period of surveillance will be funded in these two sites or if it will rely on state-based surveillance. "We are also seeing clear evidence of vaccine impact in state surveillance data," said Dr. Seward. Study Data Source: Journal of the American Medical Association, February 6, 2002-Vol. 287, No. 5, Pp. 606-611 Varicella Disease After Introduction of Varicella Vaccine in the United States, 1995-2000 Jane F. Seward (1), Barbara M. Watson (2), Carol L. Peterson (3), Laurene Mascola (3), Jan W. Pelosi (4), John X. Zhang (1), Teresa J. Maupin (3), Gary S. Goldman (3), Laura J. Tabony (4), Kimberly G. Brodovicz (2), Aisha O. Jumaan (1), Melinda Wharton (1) (1) Centers for Disease Control and Prevention, Atlanta, Georgia (2) Philadelphia Department of Public Health, Philadelphia, Pennsylvania (3) Los Angeles County Department of Health Services, Los Angeles, California (4) Texas Department of Health, Austin, Texas THE SHINGLES PREVENTION STUDY: AN UPDATE The varicella vaccination study demonstrated a dramatic decline in chickenpox following vaccination. However, it remains unknown whether vaccination with a more potent form of the same vaccine can decrease the incidence and/or severity of shingles (herpes zoster) and post-herpetic neuralgia (PHN) in older adults. The Shingles Prevention Study seeks to find an answer to this question. The study is a double-blind, placebo-controlled, efficacy trial involving 38,546 subjects age 60 or older who have never had shingles. It is being conducted at 22 sites throughout the country by the Veterans Administration Cooperative Studies Program, with the scientific collaboration of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, and Merck & Co., Inc., the vaccine's manufacturer. The study is chaired by Dr. Michael N. Oxman, Professor of Medicine and Pathology at the University of California, San Diego, and a Staff Physician in the Infectious Diseases Section of the VA San Diego Healthcare System. He credits a paper written in 1965 by a British general practitioner as a major inspiration for this study. "It was all there in Dr. Edgar Hope-Simpson's landmark paper, in which he hypothesized that individuals develop shingles as they age because their immunity to the virus is weakening. He also concluded that people rarely develop shingles more than once because their first episode boosts their immunity to the virus, effectively immunizing them against another attack." According to Dr. Oxman, a member of the VZVRF Scientific Advisory Board, the Shingles Prevention Study is testing the theory that virus-specific cell-mediated immunity is a key determinant of shingles and its severity. "Specifically, we are seeking to determine whether immunization with an investigational live-attenuated Oka/Merck varicella-zoster vaccine will, by boosting that immunity, reduce significantly the burden of illness due to shingles and, in addition, protect against PHN," he said. Study subjects were enrolled between early 1999 and September 2001. One-half received live-attenuated varicella-zoster vaccine, while the other half received a placebo. The vaccine was a cell-free preparation modified from the live attenuated Oka strain of varicella-zoster virus (VZV) employed in the chickenpox vaccine, VARIVAXÏ, that is used to prevent chickenpox in susceptible children and adults. The investigational varicella-zoster vaccine, which is designed to boost immunity to VZV in adults who have already had chickenpox, contains substantially more live attenuated virus and viral antigen than are present in the chickenpox vaccine. "The investigational varicella-zoster vaccine is produced in a manner similar to the chickenpox vaccine, which was developed by Dr. Takahashi, but it contains a lot more VZV," said Dr. Oxman. "Presumably, most adults 60 and over are already immune to chickenpox because they had it in childhood, and this vaccine is designed to boost their cellular immunity to VZV which, by age 60, has fallen off significantly from the level present just after they recovered from chickenpox. The waning of cellular immunity to VZV as one ages is probably why people get shingles more frequently and more severely when they get older." Study subjects are required to report in to the study once each month via an automated telephone response system on the anniversary of their vaccination (with vaccine or placebo). If a subject does not call in as scheduled, the local Study Coordinator who enrolled the subject will attempt to reach the subject. However, if a subject develops shingles, he/she must contact the local study site immediately. "We want subjects to come in as early as possible so that they can begin receiving state-of-the-art treatment without delay," said Dr. Oxman. "We then begin measuring the extent, severity and duration of the disease, as well as its impact on the subject's quality of life and activities of daily living. We assess these indicators repeatedly during the six-month period following the onset of their shingles." Dr. Oxman estimates that the last case of shingles to be tracked by the study will occur at the end of December 2003. As with all cases of shingles, it will be followed for six months, with the last data point being recorded at the end of June 2004. "We will then lock the data and break the code," he said. "We will compare the total burden of illness in the placebo group versus the vaccine group. If the vaccine is effective, most of the misery, including the shingles pain, will be in the placebo group. If the vaccine is not highly effective, the misery will be distributed more evenly." According to Dr. Oxman, the study will help determine whether the vaccine affects the incidence of shingles, or its severity, or both. "It might just reduce the number of cases, with the cases that do occur being just as devastating as cases in the placebo recipients," he added. "Alternatively, the vaccine might not reduce the number of cases at all, but markedly reduce their severity, or it might reduce both the incidence and the severity of shingles. Armed with this data, the vaccine manufacturer and regulatory bodies will then be able to determine whether the decrease in the incidence and/or severity of shingles achieved merits licensing the vaccine." It is estimated the study will conclude in June 2004, with findings released by the end of the year. As he immerses himself in the study's follow-up phase, Dr. Oxman notes that an added benefit of the study has been that thousands of subjects and their families have been educated about shingles and the importance of prompt diagnosis and treatment. And, like his fellow study subjects, he looks forward to finding out if he received vaccine or placebo.

STUDY SHOWS DRAMATIC DECLINE IN VARICELLA FOLLOWING VACCINATION

In 2002, the Council for State and Territorial Epidemiologists formally recommended that chickenpox, or varicella, become a nationally reportable disease. Assuming each of the 50 states adopts this recommendation, it will still take a few years to fully implement.

It is precisely the lack of national surveillance data for chickenpox in 1995, the year of licensure of the vaccine by the Food and Drug Administration, made it especially challenging to monitor the impact of the varicella immunization program. This situation was in contrast with other diseases, such as measles, rubella and mumps, which were reportable under the National Notifiable Disease Surveillance System when their vaccination programs were implemented in the U.S.

The lack of a monitoring mechanism prompted the Centers for Disease Control and Prevention (CDC), in collaboration with state and local health departments, to launch an active surveillance study in 1995. According to the study's lead investigator, Dr. Jane F. Seward, three communities were selected for the study: Antelope Valley, California; Travis County, Texas and West Philadelphia, Pennsylvania. Dr. Seward is Acting Chief, Child Vaccine Preventable Diseases Branch, of the CDC's National Immunization Program.

According to the CDC, prior to licensure of the varicella vaccine in 1995, chickenpox was a universal childhood disease in the U.S., causing approximately 4 million cases each year. Chickenpox-related complications resulted in an annual average of 11,000 hospitalizations and 100 deaths.

In designing the study, investigators wanted the data to be population-based, covering all groups. According to Dr. Seward, the communities chosen were fairly representative of different segments of the American population. In 1995, the populations of Antelope Valley, Travis County and West Philadelphia were 284,000, 666,127 and 291,608, respectively. In Antelope Valley and Travis County, the populations were predominantly white--89 and 85 percent of the total-- with approximately 20 percent of the white populations in each area reporting Hispanic ethnicity. The population of West Philadelphia was predominantly (69 percent) African-American.

As reported in the February 6, 2002 edition of the Journal of the American Medical Association, the study examined surveillance data from January 1, 1995 through December 31, 2000. The investigators, goals were to, first, establish baseline data and, second, to monitor trends in varicella following introduction of the vaccine. Reporting sites in each community included: childcare centers; schools; universities; private health

care providers; health maintenance organizations; emergency departments; hospitals; public health clinics and households.

In 1997, among children aged 19 to 35 months, vaccine coverage in Los Angeles County, Texas and Philadelphia County was 40, 23 and 43 percent, respectively. By 2000, coverage had increased to 82.1, 73.6 and 83.8 percent respectively, which the study termed "moderate vaccine coverage". According to Dr. Seward, 90 percent coverage is considered high.

"Vaccine coverage was higher at these three sites than in rest of country," said Dr. Seward. "Therefore, our findings may not be completely representative of the entire U.S.-which was 68 percent in June 2000-but rather ahead in terms of vaccine uptake and disease decline. This greater coverage rate may be due to heightened awareness of varicella and its consequences in these communities. However, there was no extensive effort in the three sites to educate the public about the disease and vaccination."

The study found that, four years after implementation of the varicella vaccination program in the U.S., there was "dramatic evidence of vaccine impact with a marked decline in all age groups". From 1995 through 2000, in Antelope Valley, Travis County and West Philadelphia, chickenpox cases declined 71, 84 and 79 percent, respectively. Cases declined in all age groups, including infants and adults. The study noted this was indicative of a reduced transmission of varicella-zoster virus in these communities. The declines were greatest among preschool children aged one to four years.

The study stated that, "in 1995, there were 2,934 verified varicella cases reported in Antelope Valley, 3,130 in Travis County and 1,197 in West Philadelphia. In all sites, the number of cases declined in 1996...remained fairly stable until 1998...(with) a marked decline in...1999. In 2000, there were 837, 491 and 250 reported cases in Antelope Valley, Travis County and West Philadelphia (respectively). From 1995 to 2000, varicella cases showed springtime seasonality, with the highest number of cases reported between March and May."

Hospitalizations due to varicella also declined significantly. According to the study, "considering all surveillance areas together, from 1995 through 1998, varicella hospitalizations ranged from 34 to 53 per year (average 40 per year). In 1999 and 2000, 8 and 20 varicella hospitalizations were reported, respectively...50 to 80 percent lower than the average number of hospitalizations from 1995 through 1998."

The study concluded the "...continued implementation of existing vaccine policies should lead to further reductions of varicella disease in these communities and throughout the United States...Our surveillance data underscores the importance of not only continuing efforts to achieve more than 90 percent vaccine coverage among young children, but also of implementing existing policy recommendations for catch-up vaccination of susceptible older children and adolescents to prevent increasing susceptibility in these groups."

"The CDC's goal, by 2010, is for the U.S. to achieve a 90 percent reduction in disease, in addition to vaccine coverage of 90 percent among children aged two and 95 percent of children at school entry," said Dr. Seward. "We also seek to maintain these percentages as a means of achieving a continuous decline in disease, as was seen with measles and other vaccine-preventable diseases. However, we might require a higher than 90 percent vaccine coverage for varicella, because of the potential for exposure of children to the VZV virus through contact with individuals with shingles, and due to the fact varicella vaccine is not quite as effective as the measles vaccine." Alternatively, a two-dose vaccine policy, which may decrease rates of vaccine failure, may be needed in the future.

According to Dr. Seward, "The study was an exciting project that gave us more detailed information concerning varicella cases than we normally obtain about diseases monitored under the National Notifiable Disease Surveillance System." She added that surveillance would continue in Antelope Valley and West Philadelphia through 2004. Next year, the CDC will decide whether another five-year period of surveillance will be funded in these two sites or if it will rely on state-based surveillance. "We are also seeing clear evidence of vaccine impact in state surveillance data," said Dr. Seward.

Study Data Source: Journal of the American Medical Association, February 6, 2002-Vol. 287, No. 5, Pp. 606-611
Varicella Disease After Introduction of Varicella Vaccine in the United States, 1995-2000
Jane F. Seward (1), Barbara M. Watson (2), Carol L. Peterson (3), Laurene Mascola (3), Jan W. Pelosi (4), John X. Zhang (1), Teresa J. Maupin (3), Gary S. Goldman (3), Laura J. Tabony (4), Kimberly G. Brodovicz (2), Aisha O. Jumaan (1), Melinda Wharton (1)
(1) Centers for Disease Control and Prevention, Atlanta, Georgia
(2) Philadelphia Department of Public Health, Philadelphia, Pennsylvania
(3) Los Angeles County Department of Health Services, Los Angeles, California
(4) Texas Department of Health, Austin, Texas

THE SHINGLES PREVENTION STUDY: AN UPDATE

The varicella vaccination study demonstrated a dramatic decline in chickenpox following vaccination. However, it remains unknown whether vaccination with a more potent form of the same vaccine can decrease the incidence and/or severity of shingles (herpes zoster) and post-herpetic neuralgia (PHN) in older adults.

The Shingles Prevention Study seeks to find an answer to this question. The study is a double-blind, placebo-controlled, efficacy trial involving 38,546 subjects age 60 or older who have never had shingles. It is being conducted at 22 sites throughout the country by the Veterans Administration Cooperative Studies Program, with the scientific collaboration of the National Institute of Allergy and Infectious Diseases of the National Institutes of Health, and Merck & Co., Inc., the vaccine's manufacturer.

The study is chaired by Dr. Michael N. Oxman, Professor of Medicine and Pathology at the University of California, San Diego, and a Staff Physician in the Infectious Diseases Section of the VA San Diego Healthcare System. He credits a paper written in 1965 by a British general practitioner as a major inspiration for this study. "It was all there in Dr. Edgar Hope-Simpson's landmark paper, in which he hypothesized that individuals develop shingles as they age because their immunity to the virus is weakening. He also concluded that people rarely develop shingles more than once because their first episode boosts their immunity to the virus, effectively immunizing them against another attack."

According to Dr. Oxman, a member of the VZVRF Scientific Advisory Board, the Shingles Prevention Study is testing the theory that virus-specific cell-mediated immunity is a key determinant of shingles and its severity. "Specifically, we are seeking to determine whether immunization with an investigational live-attenuated Oka/Merck varicella-zoster vaccine will, by boosting that immunity, reduce significantly the burden of illness due to shingles and, in addition, protect against PHN," he said.

Study subjects were enrolled between early 1999 and September 2001. One-half received live-attenuated varicella-zoster vaccine, while the other half received a placebo. The vaccine was a cell-free preparation modified from the live attenuated Oka strain of varicella-zoster virus (VZV) employed in the chickenpox vaccine, VARIVAXÏ, that is used to prevent chickenpox in susceptible children and adults. The investigational varicella-zoster vaccine, which is designed to boost immunity to VZV in adults who have
already had chickenpox, contains substantially more live attenuated virus and viral antigen than are present in the chickenpox vaccine.

"The investigational varicella-zoster vaccine is produced in a manner similar to the chickenpox vaccine, which was developed by Dr. Takahashi, but it contains a lot more VZV," said Dr. Oxman. "Presumably, most adults 60 and over are already immune to chickenpox because they had it in childhood, and this vaccine is designed to boost their cellular immunity to VZV which, by age 60, has fallen off significantly from the level present just after they recovered from chickenpox. The waning of cellular immunity to VZV as one ages is probably why people get shingles more frequently and more severely when they get older."

Study subjects are required to report in to the study once each month via
an automated telephone response system on the anniversary of their vaccination (with vaccine or placebo). If a subject does not call in as scheduled, the local Study Coordinator who enrolled the subject will attempt to reach the subject. However, if a subject develops shingles, he/she must contact the local study site immediately. "We want subjects to come in as early as possible so that they can begin receiving state-of-the-art treatment without delay," said Dr. Oxman. "We then begin measuring the extent, severity and duration of the disease, as well as its impact on the subject's quality of life and activities of daily living. We assess these indicators repeatedly during the six-month period following the onset of their shingles."

Dr. Oxman estimates that the last case of shingles to be tracked by the study will occur at the end of December 2003. As with all cases of shingles, it will be followed for six months, with the last data point being recorded at the end of June 2004. "We will then lock the data and break the code," he said. "We will compare the total burden of illness in the placebo group versus the vaccine group. If the vaccine is effective, most of the misery, including the shingles pain, will be in the placebo group. If the vaccine is not highly effective, the misery will be distributed more evenly."

According to Dr. Oxman, the study will help determine whether the vaccine affects the incidence of shingles, or its severity, or both. "It might just reduce the number of cases, with the cases that do occur being just as devastating as cases in the placebo recipients," he added. "Alternatively, the vaccine might not reduce the number of cases at all, but markedly reduce their severity, or it might reduce both the incidence and the severity of shingles. Armed with this data, the vaccine manufacturer and regulatory bodies will then be able to determine whether the decrease in the incidence and/or severity of shingles achieved merits licensing the vaccine." It is estimated the study will conclude in June 2004, with findings released by the end of the year.

As he immerses himself in the study's follow-up phase, Dr. Oxman notes that an added benefit of the study has been that thousands of subjects and their families have been educated about shingles and the importance of prompt diagnosis and treatment. And, like his fellow study subjects, he looks forward to finding out if he received vaccine or placebo.