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Varicella vaccine

Summary and conclusions

Varicella (chickenpox) is an acute, highly contagious viral disease with worldwide distribution. While mostly a mild disorder in childhood, varicella tends to be more severe in adults. It may be fatal, especially in neonates and in immunocompromised persons. Varicella-zoster virus (VZV), the causative agent, shows little genetic variation and has no animal reservoir. Following infection, the virus remains latent in neural ganglia, and upon subsequent reactivation VZV may cause zoster (shingles), a disease mainly affecting the elderly and immunocompromised persons. Although individual cases may be prevented or modified by varicella-zoster immune globulin or treated with antiviral drugs, control of varicella can be achieved only by widespread vaccination. Varicella vaccines based on the attenuated Oka-strain of VZV have been marketed since 1974, and the positive results of extensive safety, efficacy and cost-effectiveness analyses have warranted the introduction of these vaccines into the childhood immunization programmes of several industrialized countries. After observation of study populations for periods of up to 20 years in Japan and 10 years in the United States, more than 90% of immunocompetent persons who were vaccinated as children were still protected from varicella.

Information concerning several aspects of varicella vaccination is still incomplete. The duration of protection against varicella and zoster without natural exposure to the virus, the epidemiological impact of childhood vaccination at various levels of coverage, and the zoster-preventive effect of vaccination of adults and elderly people with a history of varicella need to be better understood. Furthermore, there is little information from developing countries on the disease burden of varicella and zoster, and on the incidence and impact of secondary infections. It is unlikely, however, that varicella will be among the priority vaccine-preventable diseases in most developing regions.

Decision-makers considering the use of varicella vaccine in routine immunization programmes must take into account the epidemiology and the public health and socioeconomic impact of varicella relative to other health concerns competing for scarce resources. The following recommendations reflect current evidence, and are likely to be modified as additional information becomes available.

Most developing countries have other vaccine-preventable diseases that cause significantly greater morbidity and mortality, and varicella vaccine is not a high priority for routine introduction into their national immunization programmes.
Routine childhood immunization against varicella may be considered in countries where this disease is a relatively important public health and socioeconomic problem, where the vaccine is affordable, and where high (85%–90%) and sustained vaccine coverage can be achieved. (Childhood immunization with lower coverage could theoretically shift the epidemiology of the disease and increase the number of severe cases in older children and adults.)
Additionally, the vaccine may be offered in any country to individual adolescents and adults without a history of varicella, in particular to those at increased risk of contracting or spreading the infection. This use in adolescents and adults entails no risk of an epidemiological shift, as childhood exposure to VZV remains unaffected.


Public health impact

Varicella is a highly communicable viral disease with worldwide distribution. In temperate climates of the Northern Hemisphere, varicella occurs mainly in the period from late winter to early spring. Secondary attack rates reach close to 90% in susceptible household contacts. Varicella-zoster virus (VZV) is the causative agent and is transmitted by droplets, aerosol or direct contact, and patients are usually contagious from a few days before rash onset until the rash has crusted over. Once a case has occurred in a susceptible population, it is very hard to prevent an outbreak. As subclinical infection is rare, the disease is experienced by almost every human being. Sometimes, mild clinical infections may not be recognized or may be misdiagnosed. Thus, in temperate regions the majority of adults with a negative history for varicella are seropositive when tested.

In temperate climates most cases occur before the age of 10. The epidemiology is less well understood in tropical areas, where a relatively large proportion of adults in some countries are seronegative. Varicella is characterized by an itchy, vesicular rash, usually starting on the scalp and face, and initially accompanied by fever and malaise. As the rash gradually spreads to the trunk and extremities, the first vesicles dry out. It normally takes about 7–10 days for all crusts to disappear.

Although varicella is usually a benign childhood disease, and rarely rated as an important public health problem, the course may occasionally be complicated by VZV-induced pneumonia or encephalitis, sometimes resulting in persistent sequelae or death. Disfiguring scars may result from secondary bacterial infections of the vesicles, and necrotizing fasciitis or septicaemia may occur from such infections. In Canada and the United States, invasive group A streptococcal infections complicating varicella have been described with increased frequency. Other serious manifestations include VZV-induced pneumonitis (more commonly in adults), the rare congenital varicella syndrome (caused by varicella during the first 20 weeks of pregnancy) and perinatal varicella of newborns whose mothers develop chickenpox from five days before delivery to 48 hours afterwards. In patients suffering from immunodeficiencies, including HIV infection, varicella tends to be severe and zoster may be recurrent. Severe and fatal varicella may also occur occasionally in children taking systemic steroids for treatment of asthma. In general, complications as well as fatalities from varicella are more commonly observed in adults than in children. Case-fatality ratios (deaths per 100 000 cases) in healthy adults are 30–40 times higher than among children five to nine years of age. Hence, if a vaccination programme is undertaken, it is important to ensure high vaccination coverage in order that prevention programmes do not cause changes in the epidemiology of varicella resulting in higher incidence rates in adults.

In about 10%–20% of the cases, varicella is followed later in life by herpes zoster, or shingles, a painful vesicular rash with dermatomal distribution. Most cases of zoster occur after the age of 50 or in immunocompromised persons. It is a relatively common complication in HIV-positive persons. Zoster may occasionally result in permanent neurological damage such as cranial nerve palsies and contralateral hemiplegia, or in visual impairment following zoster ophthalmia. Nearly 15% of zoster patients have pain or parasthesias in the affected dermatome for at least several weeks and sometimes permanently (postherpetic neuralgia). Disseminated, sometimes fatal zoster may occur in patients suffering from malignancies, AIDS or other conditions associated with immunodeficiency. Transmission of VZV from zoster patients may cause varicella in non-immune contacts.


The pathogen

VZV is a double-stranded DNA virus belonging to the herpesvirus family. Only one serotype is known, and humans are the only reservoir. VZV enters the host through the nasopharyngeal mucosa, and almost invariably produces clinical disease in susceptible individuals. The incubation period is usually 14–16 (10–21) days. Following varicella, the virus persists in sensory nerve ganglia, from where it may later be reactivated to cause zoster. Serum antibodies against viral membrane proteins and glycoproteins are utilized in diagnostic tests, but are less reliable as correlates of immunity, particularly to zoster. As with other human herpesviruses, nucleoside analogues such as acyclovir inhibit the replication of VZV, although less efficiently than in the case of Herpes simplex.


Immune response

Natural infection induces lifelong immunity to clinical varicella in almost all immunocompetent persons. Newborn babies of immune mothers are protected by passively acquired antibodies during their first months of life. Temporary protection of non-immune individuals can be obtained by injection of varicella-zoster immune globulin within three days of exposure. The immunity acquired in the course of varicella prevents neither the establishment of a latent VZV infection, nor the possibility of subsequent reactivation as zoster. Although antibody assays are conveniently used as an indication of previous infection or response to vaccination, failure to detect antibodies against VZV does not necessarily imply susceptibility, as the corresponding cell-mediated immunity may still be intact. On the other hand, about 20% of persons aged 55–65 show no measurable cell-mediated immunity to VZV in spite of persisting antibodies, and a history of previous varicella. Zoster is closely correlated to a fall in the level of VZV-specific T-cells, and an episode of zoster will reactivate the specific T-cell response.


The justification for vaccine control

Except for vaccination, no countermeasures are likely to control the dissemination of varicella or the frequency of zoster in a susceptible community. Varicella-zoster immune globulin and antiherpesviral drugs are very costly, and mainly applied for post-exposure prophylaxis or the treatment of varicella in persons at high risk of severe disease. Due to its extremely contagious nature, varicella is experienced by almost every child or young adult in the world. Each year from 1990 to 1994, prior to availability of varicella vaccine, about 4 million cases of varicella occurred in the United States. Of these cases approximately 10 000 required hospitalization and 100 died. Although varicella is not commonly perceived as an important public health problem, the socioeconomic consequences in industrialized countries of a disease that affects practically every child and causes the carer to be absent from work should not be underestimated.

The recently marketed varicella vaccines have been shown to be safe and effective. From a societal perspective, a recent cost-benefit analysis in the United States showed that routine chickenpox vaccination is likely to save five times the investment. Even when only direct costs were considered, benefits almost balanced the costs. Similar studies from developing countries are not available. However, the socioeconomic aspect of varicella is likely to be of less importance in countries with a different social organization. On the other hand, the public health impact of varicella and zoster may be increasing in regions with high rates of HIV endemicity.

It is not yet sufficiently documented that the varicella vaccine, administered either in childhood or in adult populations, will protect against zoster. However, several indications, including the results of vaccination studies in certain immunodeficient groups, are encouraging in this regard. The public health as well as the socioeconomic impact of this vaccine would increase drastically if it was proved to protect against zoster in the general population. In industrialized countries considerable amounts are spent on medical care in complicated cases of zoster in immunocompromised or elderly persons, and the increasing incidence of zoster in HIV-affected areas is well documented.


Varicella vaccines

The currently marketed varicella vaccines are based on the so-called Oka strain of VZV, which has been modified through sequential propagation in different cell cultures. Various formulations of such live, attenuated vaccines have been tested extensively and are approved for use in Japan, the Republic of Korea, the United States and several countries in Europe. Some formulations are approved for use at nine months of age and older.

Following a single dose of the above-mentioned vaccines, seroconversion is seen in about 95% of healthy children. From a logistic as well as an epidemiological point of view, the optimal age for varicella vaccination is 12–24 months. In Japan and several other countries one dose of the vaccine is considered sufficient, regardless of age. In the United States, two doses, four to eight weeks apart, are recommended for adolescents and adults, in whom 78% were found to have seroconverted after the first, and 99% after the second dose of the vaccine. Children below 13 years of age receive only one dose.

Small studies, using formulations different to that currently licensed in the United States, show that when the vaccine is administered within three days after exposure to VZV, a post-exposure protective efficacy of at least 90% may be expected. Varicella in persons who have received the vaccine ("break-through varicella") is substantially less severe than the disease in unvaccinated individuals. Further studies are needed to clarify the post-exposure efficacy of the currently-licensed product, especially in outbreak situations.

When given at separate sites and with separate syringes, simultaneous vaccination of varicella with other vaccines is as safe and immunogenic as when the vaccines are given at intervals of several weeks. However, in order to induce the same immune response as the monovalent varicella vaccine, the dose of the varicella component had to be increased when included in a tetravalent vaccine with the combined measles-mumps-rubella vaccine. A multivalent vaccine is not yet licensed.

As judged from the Japanese experience, immunity to varicella following vaccination lasts for at least 10–20 years. In the United States, childhood vaccination against varicella provides 70%–90% protection against infection, and more than 95% protection against severe disease 7–10 years after immunization. From investigation of a varicella outbreak in a day-care centre, post-licensure efficacy was found to be 100% in preventing severe disease and 86% in preventing all disease. The attack rate in unvaccinated susceptible children was 88%. It is likely, but as yet not proved, that some protection is also achieved against zoster. However, in Japan as well as in the United States, the vaccine coverage in the population is quite limited, and the continued circulation of wild type VZV is likely to cause post-vaccination boosting. Hence, the long-term protection induced by the vaccine alone is difficult to assess at this time.

In immunocompromised persons, including patients with advanced HIV infection, varicella vaccination is currently contraindicated for fear of disseminated vaccine-induced disease. Vaccine safety is however being evaluated in asymptomatic HIV-infected children with CD4 counts of more than 1000, and a killed varicella vaccine has been studied in VZV-positive bone marrow transplant patients where a multiple-dose schedule has been shown to reduce the severity of zoster. Furthermore, in carefully supervised trials, patients with leukaemia in remission or solid tumours before chemotherapy, and uraemic patients waiting for transplantation, have received the vaccine. In most cases, one to two doses resulted in high rates of protection, with only moderate side-effects. A significant reduction in the rate of zoster has also been recorded in these patients.


Vaccine-associated adverse events

In healthy children the adverse effects of the vaccination are limited to some local swelling and redness at the site of injection during the first hours following vaccination (27%), and in a few cases (fewer than 5%) the vaccinees experience a mild varicella-like disease with rash within four weeks. In a placebo-controlled study involving 900 healthy children and adolescents, pain and redness at the site of vaccination were the only documented adverse events following vaccination. The vaccine was similarly well tolerated by already-immune persons who were inadvertently immunized. Rare occasions of mild zoster following vaccination show that the currently used vaccine strains may induce latency, with the subsequent risk of reactivation. Since licensure and distribution of more than 10 million doses of vaccine in the United States, the Vaccine Adverse Event Reporting System (VAERS) has received reports of encephalitis, ataxia, pneumonia, thrombocytopenia, arthropathy and erythema multiforme occurring after vaccination. These events may not be causally related and they occur at much lower rates than following natural disease.


Contraindications for varicella vaccination

These include a history of anaphylactic reactions to any component of the vaccine (including neomycin), pregnancy (due to theoretical risk to the fetus; pregnancy should be avoided for four weeks following vaccination), ongoing severe illness, and advanced immune disorders of any type. Except for patients with acute lymphatic leukaemia in stable remission, ongoing treatment with systemic steroids (for adults more than 20 mg/day, for children more than 1mg/kg/day) is considered a contraindication for varicella vaccination. A history of congenital immune disorders in close family members is a relative contraindication. Fortunately, both varicella-zoster immune globulin (VZIG) and antiviral drugs are available should persons in the immunocompromised categories receive the vaccine by mistake. Administration of blood, plasma or immunoglobulin less than five months before immunization or three weeks afterwards is likely to reduce the efficacy of the vaccine. Due to the theoretical risk of Reye syndrome, the use of salicylates is discouraged for six weeks following varicella vaccination.


WHO position on varicella vaccines

The current varicella vaccines seem to meet the above WHO guidelines as far as their use in industrialized countries is concerned. However, from the global perspective, there are limitations in terms of price and storage. For example, one of the currently available vaccines requires storage at –15°C and use within 30 minutes of reconstitution.

The likelihood that every child will contract varicella, combined with a socioeconomic structure that implies high indirect costs for each case, make varicella relatively important in industrialized countries with temperate climates. Routine childhood vaccination against this disease is estimated to be cost-effective in such areas. Limited seroprevalence studies have suggested that susceptibility to varicella is more common among adults in tropical than in temperate climates. Thus, from the public health point of view, varicella could prove to be more important in tropical regions than previously assumed, in particular in areas where HIV is highly endemic. The impact of varicella in the global context requires further investigation. On the other hand, in most developing countries, other new vaccines, including hepatitis B, rotavirus, as well as conjugated Hib and pneumococcal vaccines, have the potential for a much greater public health impact, and should therefore be given priority over varicella vaccines. Hence, at the present time WHO does not recommend the inclusion of varicella vaccination into the routine immunization programmes of developing countries.

Varicella vaccine may be used either at an individual level to protect susceptible adolescents and adults, or at a population level, to cover all children as part of a national immunization programme. Vaccination of adolescents and adults will protect at-risk individuals, but will not have a significant impact on the epidemiology of the disease on a population basis. On the other hand, extensive use as a routine vaccine in children will have a significant impact on the epidemiology of the disease. If sustained high coverage can be achieved, the disease may virtually disappear. If only partial coverage can be obtained, the epidemiology may shift, leading to an increase in the number of cases in older children and adults. Hence, routine childhood varicella immunization programmes should emphasize high, sustained coverage.

Although observations in selected immunodeficient groups indicate that childhood varicella vaccination also reduces the risk of zoster, the period of observation since introduction of the vaccine is too short to permit firm conclusions about its zoster-preventive effect in the general population. Moreover, carefully conducted vaccination studies in adults and the elderly are required before recommendations may be made concerning the use of varicella vaccines for the prevention of zoster in those age groups.

Recommendations on possible use of this vaccine for persons in certain states of immunodeficiency are beyond the scope of this article. Advice is provided by several expert panels such as the Advisory Committee on Immunization Practices (ACIP) in the United States.


Administration summary

Type of vaccine Live attenuated virus, Oka strain
Number of doses One dose for persons aged under 13 years; two doses in adolescents and adults four to eight weeks apart, subcutaneous
Schedule 12–24 months of age for early childhood immunization*
Contraindications Pregnancy; reaction to previous dose (including reaction to a component such as gelatin); any advanced immune disorder or cellular immune deficiency; symptomatic HIV infection; severe illness
Adverse reactions Mild local reaction; mild illness with rash

Special precautions

Beware of confusion between vaccine and varicella-zoster immune globulin


*Not recommended for developing countries


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