Live Attenuated Varicella Vaccine

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Anne A. Gershon

Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, N.Y., USA

The Virus and Its Diseases

Varicella-zoster virus (VZV) is the etiologic agent of varicella and zoster. Varicella is the primary infection, and zoster is due to reactivation of latent VZV acquired during chickenpox. Each disease is characterized by a macu-lopapular and vesicular skin eruption, which in varicella is generalized, and in zoster is unilateral and usually localized. Varicella is often mild and uncomplicated in otherwise healthy children, but it may unpredictably be associated with significant morbidity and even mortality. In the United States, in the pre-vaccine era, there were about 100 annual deaths from varicella and 11,000 hospitalizations [1]. Most deaths from varicella occurred in individuals who were healthy before contracting varicella. The risk of developing zoster is increased in the immunocompromised and the elderly, and zoster may be severe but is rarely fatal.

Live Attenuated Varicella Vaccine: Background

A live attenuated varicella vaccine, the Oka strain, was developed in Japan in the early 1970s [2]. This vaccine is now available worldwide. The most extensive published experience with varicella vaccine comes from the United States, where it was licensed in 1995 for routine use in healthy susceptible individuals over the age of 1 year [1]. The vaccine is extremely safe [3, 4]. The main adverse effects in healthy persons are both mild and transient: fever and a sore arm in less than 50%, and a very mild rash in about 5%, usually occurring a month after immunization [5]. VZV antibodies are demonstrable after about 2 weeks. In the United States, the epidemiology of varicella is changing, with a decreased incidence of chicken-pox in both the vaccinated and the unvaccinated [6].

Transmission of the Oka strain from healthy vaccinees with rash to other susceptibles is extremely rare. It has been reported only on four occasions, although over 30 million doses have been distributed in the United States alone. There is no clinical evidence of reversion of the vaccine strain to virulence. Contact cases are usually very mild or even subclinical [4, 7]. There are many mutations in the vaccine compared to the parental viral strains, although which are responsible for attenuation is unknown [8-10]. Although a few cases of immunodeficiency have been unmasked by complications following varicella vaccination, there have been no reported fatalities from the Oka varicella strain [4].

In the United States, contraindications to varicella vaccine include pregnancy, allergy to vaccine components, and immunodeficiency. Children receiving steroids at a dose of 2mg/kg/day of prednisone or greater (or of its equivalent) should not be immunized. It is safe to immunize HIV-infected children, as long as their levels of CD4 lymphocytes are relatively well-preserved [11]. Healthy persons who have close contact with susceptible individuals who are at high risk to develop severe varicella, such as pregnant women and children with malignant disease, should be immunized to protect them because transmission of vaccine is rare. The vaccine has been shown to be cost effective in the United States and abroad [12-17].

Efficacy and Effectiveness of the Vaccine

Studies in vaccinated leukemic children showed not only that the vaccine was safe but also that it was highly protective against varicella [18]. About 85% of vaccinated leukemic children were completely protected against varicella after household exposure, and those who developed breakthrough infection had mild infections. Early studies in healthy children indicated a similar degree of protection [19].

Two double-blind placebo controlled studies in healthy children were conducted, indicating protection of about 90% [20-22]. Better protection resulted from higher doses (roughly 3,000 plaque forming units {pfus} vs. 10,000 pfus per dose). A post-licensure case-control effectiveness study in healthy children indicated that the vaccine in the United States is about 85% effective in preventing varicella [23]. The best evidence of protection from varicella vaccine, however, is the reported decline in disease since 1995, in the United States [6].

Does Immunity to Varicella Wane with Time after Immunization?

There are two types of vaccine failure, primary and secondary. Primary vaccine failure means there is no immune response to a vaccine. When a positive immune response after vaccination is lost with time, secondary vaccine failure has occurred. There is little evidence for secondary vaccine failure after immunization of healthy children with the Oka vaccine. Persistence of VZV antibodies and cellular immunity for up to 20 years after vaccination has been reported [24-26]. Studies involving over 400 vaccinated adults for up to 20 years revealed no decrease in immunity to varicella with time. It is disquieting, however, that about 10% of children may develop a modified form of varicella despite vaccination. In some studies, the breakthrough rate of varicella ranged between 18 and 34% [27-30].

Outbreaks of varicella in young vaccinated children have recently been reported in the United States [31-33]. There are a number of possible explanations for these outbreaks. Improper storage of this labile vaccine may account for primary vaccine failure in some children. The ability to mount a protective immune response may be impaired in children with asthma [34]. Children immunized at less than 14 months old may have higher rates of breakthrough varicella than those immunized when they were older [31, 32]. When varicella vaccine is administered less than 1 month after another live vaccine, the incidence of breakthrough varicella increases [35]. A recent outbreak of varicella in a day care center in New Hampshire identified an interval of over 3 years since vaccination as the only significant risk for developing breakthrough disease [33]. This small study is the only one that suggests that waning immunity may be a factor in breakthrough disease. However, the children involved were very young, and the age at vaccination could also have been a factor. Continued investigations are necessary to determine whether waning immunity is significant in developing breakthrough disease.

A second dose of varicella vaccine may prove useful to avoid possible primary and secondary vaccine failure [36]. Breakthrough varicella is almost always mild. The few reports of varicella of normal or increased severity in vaccines probably represent primary vaccine failure [4]. Zoster, however, may be more of a concern. Currently a second dose of varicella vaccine is being considered for all healthy children in the U.S. because of the realization that primary immune failure may be more of a concern than was originally thought [37].

Zoster: Effects and Potential Effects on Its Incidence in the Vaccine Era

In immunocompromised vaccines, the incidence of zoster was lower than after natural infection [25]. Therefore vaccination may also be protective against zoster in healthy children. Less than 50 cases of zoster have been reported after distribution of over 30 million doses of vaccine between 1995 and 2002 in the United States [4].

Recently, it has been proposed that exposure to varicella is protective against zoster, and there is concern that zoster may become more common as the incidence of varicella decreases in a population. Studies in vaccinated leukemic children with either household exposure and/or additional doses of varicella vaccine correlated with a lower incidence of zoster than one dose of vaccine [38]. A recent case-control study indicated that following natural varicella, there is a lower incidence of zoster in individuals who have exposures to children with VZV infections in comparison to those who do not [39]. It has been projected that an epidemic of zoster with accompanying significant mortality will occur in countries where varicella vaccination is routine [40]. These observations, even though theoretical, have led to reluctance to use varicella vaccine routinely in some countries. Since the possibility has been raised, it will be important to study the situation further.

It is important, however, to put the idea of an increase of zoster into perspective. The reported incidence of zoster in healthy individuals aged 40-50 in developed countries is 2-4 cases per 1,000 person-years of observation. It has been projected that the rate of zoster may double in countries with routine vaccination [40]. This could lead to an incidence of 4-8 cases per 1,000 person-years of observation in this age group. This incidence of zoster is still not very high and is about that seen in vaccinated leukemic children. In similar unvacci-nated children, the incidence is at least 3 times higher. In adults with AIDS it is 6 times higher. Thus the projected increase in the incidence of zoster based on computer modeling might represent a significant increase, but it is likely to be far from an epidemic. Moreover, the mortality of zoster is lower than that from the primary infection (varicella). As yet, no actual increase in the incidence of zoster has been observed in the United States.

References

1 Centers for Disease Control: Prevention of varicella: recommendations of the advisory committee on immunization practices (ACIP). MMWR Morb Mortal Wkly Rep 1996;45:1-36.

2 Takahashi M, Otsuka T, Okuno Y, Asano Y, Yazaki T: Live vaccine used to prevent the spread of varicella in children in hospital. Lancet 1974;2:1288-1290.

3 Baba K, Yabuuchi H, Takahashi M, Gershon AA, Ogra PL: Seroepidemiologic behavior of varicella zoster virus infection in a semiclosed community after introduction of VZV vaccine. J Pediatr 1984;105:712-716.

4 Sharrar RG, LaRussa P, Galea SA, Steinberg SP, Sweet AR, Keatley RM, Wells ME, Stephenson WP, Gershon AA: The postmarketing safety profile of varicella vaccine. Vaccine 2000;19:916-923.

5 White CJ. Varicella-zoster virus vaccine. Clin Infect Dis 1997;24:753-763.

6 Seward JF, Watson BM, Peterson CL, Mascola L, Pelosi JW, Zhang JX, Maupin TJ, Goldman GS, Tabony LJ, Brodovicz KG, Jumaan AO, Wharton M: Varicella disease after introduction of varicella vaccine in the United States, 1995-2000. JAMA 2000;287:606-611.

7 Tsolia M, Gershon AA, Steinberg SP, Gelb L: Live attenuated varicella vaccine: evidence that the virus is attenuated and the importance of skin lesions in transmission of varicella-zoster virus. J Pediatr 1990;116:184-189.

8 Gomi Y, Imagawa T, Takahashi M, Yamanishi K: Oka varicella vaccine is distinguishable from its parental virus in DNA sequence of open reading frame 62 and its transactivation activity. J Med Virol 2000;61:497-503.

9 Loparev VN, McCaustland K, Holloway BP, Krause PR, Takayama M, Schmid DS: Rapid geno-typing of varicella-zoster virus vaccine and wild type strains with fluorophore-labeled hybridization probes. J Clin Micro 2000;38:4315-4319.

10 Gomi Y, Imagawa T: Comparison of DNA sequence and transactivation activity of open reading frame 62 of Oka varicella vaccine and its parental viruses. Arch Virol 2001;S17:49-56.

11 Gershon A, Takahashi M, et al: Live attenuated varicella vaccine; in Plotkin S, Orenstein W (eds): Vaccines, ed 4. Philadelphia, WB Saunders, 2002.

12 Lieu T, Cochi S, Black SB, Halloran ME, Shinefield HR, Holmes SJ, Wharton M, Washington AE: Cost-effectiveness of a routine varicella vaccination program for U.S. children. JAMA 1994;271: 375-381.

13 Beutels P, Clara R, Tormans G, Van Doorslaer E, Van Damme P: Costs and benefits of routine varicella vaccination in German children. J Infect Dis 1996;174:S335-S341.

14 Burnham BR, Wells TS, Riddle JR: A cost-benefit analysis of a routine varicella vaccination program for United States Air Force Academy cadets. Mil Med 1998;163:631-634.

15 Coudeville L, Paree F, Lebrun T, Sailly J: The value of varicella vaccination in healthy children: cost-benefit analysis of the situation in France. Vaccine 1999;17:142-151.

16 Diez Domingo J, Ridao M, Latour J, Ballester A, Morant A: A cost benefit analysis of routine varicella vaccination in Spain. Vaccine 1999;17:1306-1311.

17 Brisson M, Edmunds WJ: The cost-effectiveness of varicella vaccination in Canada. Vaccine 2002;20:1113-1125.

18 Gershon AA, Steinberg SP, Gelb L, Galasso G, Borkowsky W, LaRussa P, Farrara A: Live attenuated varicella vaccine: efficacy for children with leukemia in remission. JAMA 1984;252: 355-362.

19 White CJ: Clinical trials of varicella vaccine in healthy children. Infect Dis Clin North Am 1996;10:595-608.

20 Weibel RB, Neff BJ, Kuter BJ, Guess HA, Rothenberger CA, Fitzgerald AJ, Connor KA, McLean AA, Hilleman MR, Buynak EB: Live attenuated varicella virus vaccine: efficacy trial in healthy children. N Engl J Med 1984;310:1409-1415.

21 Weibel R, Kuter BJ, Guess HA, Rothenberger CA, Fitzgerald AJ, Connor KA, McLean AA, Hilleman MR, Buynak EB: Live Oka/Merck varicella vaccine in healthy children: further clinical and laboratory assessment. JAMA 1985;245:2435-2439.

22 Varis T, Vesikari T: Efficacy of high titer live attenuated varicella vaccine in healthy young children. J Infect Dis 1996;174:330-334.

23 Vazquez M, LaRussa PS, Vazquez M, LaRussa PS, Gershon AA, Steinberg SP, Freudigman K, Shapiro ED: The effectiveness of the varicella vaccine in clinical practice. N Engl J Med 2001;344:955-960.

24 Asano Y, Suga S, Yoshikawa T, Kobayashi I, Yazaki T, Shibata M, Tsuzuki K, Ito S: Experience and reason: twenty year follow up of protective immunity of the Oka live varicella vaccine. Pediatrics 1994;94:524-526.

25 Arvin A, Gershon AA: Live attenuated varicella vaccine. Annu Rev Microbiol 1996;50:59-100.

26 Ampofo K, Saiman L, LaRussa P, Steinberg S, Annunziato P, Gershon A: Persistence of immunity to live attenuated varicella vaccine in healthy adults. Clin Infect Dis 2002;34:774-779.

27 Clements DA, Armstrong CB, Ursano AM, Moggio MM, Walter EB, Wilfert CM: Over five-year follow-up of Oka/Merck varicella vaccine recipients in 465 infants and adolescents. J Pediatr Infect Dis 1995;14:874-879.

28 Johnson, Stancin CT, Fattlar D, Rome LP, Kumar ML: A long-term prospective study of varicella vaccine in healthy children. Pediatrics 1997;100:761-766.

29 Takayama N, Minamitani M, Takayama M: High incidence of breakthrough varicella observed in healthy Japanese children immunized with live varicella vaccine (Oka strain). Acta Paediatr Jpn 1997;39:663-668.

30 Clements D, Moreira SP, Coplan PM, Bland CL, Walter EB: Postlicensure study of varicella vaccine effectiveness in a day-care setting. J Pediatr Infect Dis 1999;18:1047-1050.

31 Dworkin MS, Jennings CE: An outbreak of varicella among children attending preschool and elementary school in Illinois. Clin Infect Dis 2002;35:102-104.

32 Galil K, Fair E, et al: Younger age at vaccination may increase risk of varicella vaccine failure. J Infect Dis 2002;186:102-105.

33 Galil K, Lee B, et al: Outbreak of varicella at a day-care center despite vaccination. N Eng J Med 2002;347:1909-1915.

34 Shapiro E, LaRussa P: Vaccination for varicella - just do it. JAMA 1997;278:1529-1530.

35 Centers for Disease Control: Simultaneous administration of varicella vaccine and other recommended childhood vaccines - United States, 1995-1999. MMWR Morb Mortal Wkly Rep 2001;50:1058-1061.

36 Gershon A: Varicella vaccine: are two doses better than one? N Engl J Med 2002;347:1962-1963.

37 Gershon AA: Control of varicella: why is a two-dose schedule necessary? Pediatr Infect Dis J 2006;25:475-476.

38 Gershon A, LaRussa P, et al: The protective effect of immunologic boosting against zoster: an analysis in leukemic children who were vaccinated against chickenpox. J Infect Dis 1996;173:450-453.

39 Thomas S, Wheeler J, et al: Contacts with varicella or with children and protection against herpes zoster in adults: a case-control study. Lancet 2002;360:678-682.

40 Brisson M, Gay N, et al: Exposure to varicella boosts immunity to herpes-zoster: implications for mass vaccination against chickenpox. Vaccine 2002;20:2500-2507.

Anne A. Gershon, MD

Columbia University College of Physicians and Surgeons

650 W. 168th Street

New York, NY 10032 (USA)

Tel. +1 212 305 9445, Fax +1 212 342 5218, E-Mail [email protected]

Gross G, Doerr HW (eds): Herpes Zoster.

Monogr Virol. Basel, Karger, 2006, vol 26, pp 170-188

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