Copyright 1998 ©

1 Introduction *

2 Varicella disease *

3 Varicella vaccine *

4 Development of the U.S. routine varicella vaccine recommendation - a decision process *

5 Discussion *

6 Conclusion *

7 References *

The Advisory Committee on Immunization Practices (ACIP) recommended the routine varicella vaccination for all children at 12-18 months of age in their statement of July 12, 1996 (1). In addition they recommended "catch-up" vaccinations in all susceptible children from 19-months to 12 years of age. A first evaluation of the varicella vaccine use during July 1996 - June 1997 showed 19% (3% -33%) coverage among children aged 19-35 with a slowly increasing tendency. (2). The ACIP has recommended, that state legislatures should consider the inclusion of varicella vaccination in their requirements for entry into daycare and school programs, in order to assure rapid control of varicella and high vaccination coverage.

Massachusetts, for example, will require varicella vaccination for day care entrants from September 1998 and for school entrants from September 1999 (personal communication, Dr. Victoria Soler, Massachusetts, State Department of Public Health), and it may be assumed that other US states will implement similar measures. The announcement of these obligatory measures has stimulated a controversial discussion about the usefulness and the consequences of the planned vaccination program by parents and physicians (3,4). The following paper reviews the decision process which led to the recommendation of routine varicella vaccination. Furthermore the possible perceptions of such a program by society will be discussed.

Varicella, also known as chickenpox, is caused by varicella zoster virus (VZV) a double stranded DNA virus of the herpes class. It is currently the most common infectious exanthem of childhood (5).

Varicella is transmitted both by droplet infection and by direct contact. The incubation period averages 14-16 days; it can range from 10-21 days. The period of infectiousness is estimated to begin 1-2 days before the onset of rash and ends when the lesions are crusted, which is 4-5 days later. Lifelong immunity almost always develops after exposure to natural infection. There is immunologic evidence to suggest that subclinical reinfection with VZV is common, although it is unknown what role reinfection plays in the maintenance of protective antibody levels (6)

The annual incidence approaches the US birth cohort of four million, with an attack rate of 85-95% (7). Over 90% of the population attain seropositivity by the age of 20 years (8). Seasonality is apparent with most cases occurring in the winter and spring months.

National health interview surveys for the period 1980-1990 have estimated that school children between the ages of 5 and 9 years have the highest age-specific incidences. Two recent studies in the US, however, have shown a change in the age-specific incidences with higher rates among the 3-6 year olds (9,10). It has been suggested that early social interaction in this age group due to increased day care attendance may be responsible for this observation (11).

A higher varicella seroconversion rate and incidence of herpes zoster has been found in the white US population, when compared with the black US population. It has been suggested that genetics and social differences may play a role (12).

Chickenpox generally follows a benign course in normal children below the age of 14 years. Although this age group accounts for a large proportion of the 9300 annual varicella related hospitalizations in the US, complications are substantially more frequent for those below one year of age and older than the age of 15 (13).

The most common complications that lead to hospital admission are bacterial skin infections and pneumonia. Both these complications have increased over the last decade (13-15). Other complications include cerebellar ataxia, varicella encephalitis, hepatitis, purpura fulminans, fasciitis, thrombocytopenia, dehydration, gullain barre syndrome, and Reyes syndrome; the latter is now rare, since aspirin has been contra-indicated for the treatment of common fever in children (10,15-17).

Approximately 60-100 previously healthy individuals die from complicated varicella infections annually (1). The case fatality rate is lowest for children between 1-14 years (0.75 per 100,000 cases). Case fatality rates in infants < 1 year are 6.23 per 100,000 cases. Over the age of 15, complications and mortality increase with age. In the age groups between 15-19 and 30-49 years the case fatality rates are 2.7 and 25.2 per 100,000 cases respectively. Hospital admissions and mortality increase, when outbreaks of varicella coincide with outbreaks of invasive streptococcal group A infection (18).

Seronegative pregnant women are an additional high-risk group for varicella complications. The most common complication is varicella pneumonia, which occurs in 1-5 per 10,000 cases (19). Mortality is estimated to be as high as 40% in pregnant women without treatment (19). Congenital varicella syndrome occurs as a result of vertical transmission in the first and early part of the second trimester, with an incidence of 0.4% and 2% respectively (20,21). A further pregnancy-related complication is neonatal varicella infection, which occurs in 17%-30% of neonates born to mothers who develop chickenpox 5 days prior to or 2 days after delivery. Infected infants often develop severe varicella infection and mortality has been estimated to be as high as 30%(22).

Herpes zoster is caused by the reactivation of the latent entity of varicella zoster virus. Risk factors are increasing age, particularly over 60 years, immunosuppression and varicella infection in utero or during the first year of life (23).

Acyclovir is currently the drug of choice for the treatment of varicella infections and has been shown to be effective in reducing both the morbidity and mortality associated with varicella.

The Committee on Infectious Diseases of the American Academy of Pediatrics (AAP) has stated that acyclovir should not be used routinely in uncomplicated varicella infections, as this might possibly result in the development of resistant strains. However, its use is recommended in adolescents, adults and immunocompromised patients (1).

Varicella immunoglobulin (VZIG) has been available since 1978 and has been used to prevent varicella in exposed, susceptible individuals at risk for complications. The use of VZIG has been recommended for immunosuppressed individuals, for pregnant females, neonates and health personnel, who are seronegative and have been exposed to varicella recently (1).

Varicella zoster vaccine is a live attenuated virus vaccine, which was developed in Japan in 1970 from the vesicular fluid of a 3-year old Japanese boy with chickenpox, whose family name was Oka. The vaccine has been attenuated by 30-33 passages in human diploid cells and guinea pig fibroblasts. The original Japanese Oka strain vaccine has been licensed to various vaccine manufacturers world-wide and numerous studies have been undertaken in the past 15 years to investigate the safety, immunogenicity and efficacy of VZV (varizella zoster virus) vaccines (24,25).

VZV vaccine has been well tolerated in children. The most commonly observed adverse events in the 4-8 weeks post vaccination are mild tenderness (19.3%), redness at the injection site (3.8%) and low grade fever (14.7%). In one double blind, placebo-controlled trial, the only complaint that occurred more often in vaccinated children, than in those who received placebo, was pain and redness at the injection site (26).

Four to 10 percent of VZV vaccine recipients may develop a generalized maculo-papular rash within 7-21 days post vaccination, consisting of usually less than 50 lesions. Reactivation of the VZV virus, resulting in herpes zoster, has been reported in eight children (27). From this study the incidence of herpes zoster was estimated to be 1.8 /10,000 person-years after VZV vaccination. This is clearly lower than the incidence of 7.7/10,000 person-years following natural infection, found in an earlier study (28).

A rash occurs in up to 40% of children with acute lymphoblastic leukemia who have been vaccinated with VZV vaccine. This is more frequent in children on steroid therapy and ongoing chemotherapy. Reactivation of VZV vaccine virus, resulting in herpes zoster may be less frequent than after natural infection (29). No severe illness or dissemination in children with vaccine-caused herpes zoster has been reported.

Transmission of VZV vaccine strain to susceptible persons, diagnosed by seroconversion has been reported from normal recent vaccine recipients and from children with ALL, who developed a rash. In a double-blind, placebo controlled trial there were 1% asymptomatic seroconversions in susceptible household contacts in the eight weeks following vaccination. (26).

In the first 12 months after the licensure of VZV vaccine in March 1995 more than 2.3 million doses of the vaccine were distributed in the US. The Vaccine Adverse Events Reporting System (VAERS) and the vaccine manufacturer have received a limited number of spontaneous reports of serious medical events occurring within 6 weeks after varicella vaccination. These events include three cases of anaphylaxis, 4 cases of encephalitis, 7 cases of ataxia and 10 cases of erythema multiforme (1). The National Vaccine Injury Act of 1986 (30), which requires the maintenance of permanent immunization records and the report of adverse events for selected vaccines does currently not apply to varicella vaccine and underreporting of events may have occurred. Since 1995 more than 7 million doses have been administered. Further reports on the frequency of rare adverse events have not been published so far.

Normal children show a seroconversion rate of 94%-100% after one dose of the vaccine. The efficacy in normal children, who were exposed to wild-type varicella virus in the first year after vaccination, has been estimated in two randomized placebo-controlled trials to be 100% and 88% respectively (26,31). Several other studies have reported that each year post vaccination 1% to 3% of vaccinated children develop a mild varicella disease (mild varicella like syndrome, or MVLS) after exposure to wild-type varicella (31-33). These breakthrough infections are generally mild, with few skin lesions and do not result in dissemination or serious illness.

VZV vaccine seems to be less efficacious in adults and immunosuppressed children (34-36), who in general need two doses of VZV vaccine to have a seroconversion rate of 95% to 98%. For adults the efficacy of VZV vaccine was estimated to be 65%-70% after household-exposure (34).

The combined administration of the VZV together with mumps-measles-rubella vaccine would facilitate the introduction of a routine vaccine recommendation and would save an additional injection. However, a first comparative study (37) investigating the combined and separate administration of MMR and VZV vaccine found approximately 50% lower levels of VZV antibodies after the administration of the combined vaccine compared to separate administration.

The decision to establish a routine VZV vaccination program starts from two basic prerequisites. First, an infectious disease, that affects most of the population and which contributes to morbidity in the population and second, a vaccine, that is safe and efficacious against this disease. Both the disease and the vaccine have characteristics (e.g. the vaccine efficacy under specific circumstances), that have to be considered and integrated into the decision process. Often these may be poorly known at the time, when the decision has to be taken. In an attempt to provide a rational basis for the decision, Halloran et al. (38) used an age-structured theoretical transmission model to estimate the effects of a routine vaccination program against varicella in the USA. This model allowed them to estimate the effects of a vaccination program for the next 10-50 years.

Under the assumption of a "best case scenario" (BCS: 97% coverage of all children at school entry; a catch-up vaccination program for 12-year olds) routine VZV vaccination could reduce the yearly number of approximately 3,960,000 varicella infections to 598,000 cases after 10 years and 4000 cases after 30 years (99% reduction). Under the assumption of a "worst case scenario" (WCS: 50% coverage of all children at school entry; no, or inefficient catch-up vaccination program for 12-year olds; vaccine efficacy including a 10% primary failure) routine VZV vaccination could reduce this number to 2,380,000 cases after 10 years and 2,316,000 cases after 30 years (41% reduction).

The fraction that vaccinated varicella cases constitute, out of the total number of varicella cases in the population is initially relatively low and varies between 1% and 3.6% under different assumptions. There is, however, a clear increase of vaccinated cases as the vaccine program progresses in time and with increasing vaccination coverage. A higher number of vaccinated cases might create doubt in the vaccine recipients about the usefulness of being vaccinated, even if the cases are milder compared to unvaccinated cases. The long term efficacy of VZV vaccine may also depend on the role of boosting by exposure to wild-type virus, and it is unknown whether vaccine-induced immunity against varicella may wane with decreasing circulation of natural VZV.

Under the assumption of BCS, routine VZV vaccination could reduce the number of hospitalization from 9,870 cases/year to 11 cases per year after 30 years (99% reduction). Under the assumption of a WCS, routine VZV vaccination could reduce this number to 6,800 cases/year respectively (31% reduction). If a primary vaccine failure of 10% is assumed, then susceptible persons will accumulate over time, and varicella outbreaks with relatively high hospitalization rates will occur after 5-25 years, dependent on the vaccination coverage.

The vaccination program would reduce first the incidence in the age groups between 1-14 years. The average age of onset for VZV infection would increase with time for persons who were not vaccinated or who did not contract the disease. Therefore a parallel "catch-up" program, which vaccinates susceptible 12-year olds has been suggested to prevent an increase of complications, which are known to be higher in older people and women of childbearing ages (19).

The first cost benefit analysis for the childhood varicella vaccine program was performed in 1985. This study reported that for every dollar invested, $7.00 was saved. Calculations were based on a vaccine cost price of $15 per vaccinee, assuming that it would be given together with measles (39). In 1994 Lieu et al presented the results of a detailed cost-effectiveness analysis; their results have been used as a major argument for the routine varicella vaccine program in the US. This model compared the costs, outcomes and cost-effectiveness of a routine vaccination program with no intervention (40). Direct medical costs for the routine vaccination program from the health payers’ perspective were estimated to be $2.00 per varicella case prevented. From a societal perspective, which included the cost of work loss by parents and medical costs, resulted in overall savings of $5.00 per case for every dollar invested in the vaccination program. In this latter model, calculations where based on a vaccine cost price of $35 per vaccinee. Vaccine costs and home cares costs were the most significant factors, that affected both models and adjustments in other costs made little or no difference.

In 1996, more than 25 years after the development of the varicella vaccine, the US was the first country in the world to recommend routine vaccination against varicella disease. The prolonged length of time prior to recommendation of the routine use of VZV vaccine was partly due to the fact that varicella infection in children has been regarded as a benign and self-limited illness. Therefore immunization has been limited to high-risk persons and their contacts in most countries so far.

During the last 15 years it has become clear, that the burden of varicella infection in the US population was higher than initially expected. Complications of varicella infection result currently in 9300 annual varicella-related hospitalizations and in 60 and 100 death cases per year in the US population. (1). A routine varicella vaccination program was estimated to cost the health care providers US $ 2 per varicella case prevented and to have a cost-saving effect of US $ 5 for every dollar invested in vaccination from the societal perspective. The savings were mainly due to the avoidance of work time loss by parents (40). The varicella complication rate and the expected cost-savings were the two major arguments for the introduction of the routine vaccine program. From a long-term perspective it has to be taken into account, that the program has to be continued for an unlimited time period. VZV vaccination cannot eradicate VZV infection, because varicella may remain in a dormant state in the human host for a lifetime.

Since the announcement of the varicella routine program various groups, including physicians and parents have published their concerns and differing opinions regarding the usefulness of the program and the implementation process in the US (3, 4).

Halloran et al. showed impressively that the success of the program will largely depend on the vaccination coverage attained (38). If the vaccination coverage is insufficient, a reduced, but ongoing circulation of wild-virus will probably lead to a gradual increase of age of onset of varicella disease, and shift the disease towards older susceptible age groups, who are at higher risk for varicella disease complications (1, 7, 13).

There are three possible reasons for an insufficient coverage. First, all health care payers may not cover the vaccine costs. Second, there might be an insufficient vaccine delivery for people living in poverty. Third, parts of the population may raise objections against routine vaccination or even refuse the program, since they regard the disease to be of a lower risk than the vaccination (3).

The first two points may be regulated by responsible public health institutions, and most of the US states will probably introduce obligatory varicella vaccination before entry into daycare or school programs and hope to reach a coverage of about 90%, similar to measles vaccination by this measure.

It is more difficult, however, to assess the impact of the third point, which regards the risk perception of the routine vaccination and the disease in the "normal population". The risk perception depends primarily on the direct and instantaneous advantage-disadvantage perception at the individual level, which often does not necessarily overlap with the long-term cost-effectiveness calculations, provided by the health authorities.

The perception of the usefulness of varicella infection will be adversely affected, if the vaccine results to be less efficacious than expected. Increasing vaccination rates will lead to a substantial, overall decrease in varicella infection, but Halloran et al showed in their model, that a parallel proportional increase in breakthrough cases might be observed, due to the incomplete efficacy of the vaccine (38).

The long-term efficacy of the VZV vaccine is still unknown, even if several studies suggest, that immunity at least persists 10 years after vaccination (41). These studies, however, were done in populations continuously exposed to wild-type virus. It is yet not known, whether "natural boosters" by wild-type virus are necessary to maintain long-term immunity after vaccination and how long the protection of VZV vaccine will persist in absence of these "natural boosters".

Prelicensure trials have shown that VZV is a safe vaccine with very few side effects (27). Postlicensure reports (1), however, have reported very rare adverse events within 60 days post vaccination. These were not considered to be causally related to the vaccine, but one always has to take into account that the benefit perception of a routine vaccination program might be adversely affected by reports on single adverse events, especially if they are reported in the public mass media.

Presently, varicella is not a notifiable disease in the US, and surveillance data are limited (1). However, the monitoring of the vaccine efficacy using surveillance data, is an important tool to demonstrate the long-term effectiveness and possible limitations of the routine vaccination program. Furthermore the demonstration of the achievement of the program goals are important to stimulate the participation in the program and to justify the ongoing health care expenditures for it.

In addition post-licensure monitoring of rare varicella vaccine adverse events should be established. This could be done in the US by extending the requirements of the National Vaccine Injury Act of 1986 (30) and the Vaccine Adverse Event Reporting System (VAERS) to the VZV vaccine, as it has been recommended by CDC (1).

The United States is the first country in the world to recommend routine VZV immunization for all children. VZV immunization has been licensed in several countries, mainly for use in high-risk individuals and their contacts.

In Germany varicella vaccination has been recommended for susceptible persons at risk for varicella complications and their contacts (42). Routine recommendation for VZV vaccine will probably result in controversial discussions among large parts of the population, since varicella is commonly regarded as a mild disease and wild-type infections are often considered to confer higher and more "natural" immunity than vaccines in general. The implementation process of a routine program would be hindered by the fact, that parents in Germany have a free choice to decide, which of the recommended vaccinations their children will receive.

The vaccination coverage against measles is estimated to be only about 85%, and one might expect to get an even lower vaccination coverage against varicella, which is a less severe disease compared to measles. Under these circumstances routine vaccination against varicella may result in unexpected and worse outcomes in comparison to the present situation, for the reasons mentioned above.

Reports have documented that chickenpox is mainly a disease of adolescents and adults in the tropics and so a relatively higher complication rate is expected (43). From personal experience chickenpox is essentially a disease of school children in Africa (Ekundayo Ajayi-Obe). In Africa, there are more serious childhood vaccine preventable diseases than chickenpox, which are yet to attain the WHO goals for global coverage. Therefore varicella immunization is neither feasible nor a priority in the present times. An example of this is the measles vaccination coverage in Nigeria, which is presently below the WHO global goals, a reflection of the vaccination coverage of a large proportion of Africa.

The routine vaccination program against varicella disease is the first attempt to decrease the complications and the costs of ubiquitous varicella infection, which by the majority of the population has been regarded as an uncomplicated, self-limiting disease of childhood. The success of the program will largely depend on the vaccination coverage achieved and on the long-term immunity conferred by the vaccine. The program might result in adverse outcomes, if one or more of its assumptions are not be attained as expected. Careful monitoring of the changing epidemiology of varicella disease after the introduction of routine vaccination is therefore necessary to change or adjust the program in time and to justify its continuous costs for the public health system.

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