VARICELLA VACCINE


I. Varicella vaccine basics

  1. A live attenuated vaccine derived from a healthy Japanese boy with natural varicella by Dr. Takahashi in 1972; named "Oka" after the boy; attenuated by passage through human cell cultures. Initially used in kids with cancer, who are susceptible to severe disease from varicella
  2. Use of Oka-based vaccines in other countries
  1. Other strains of VZV (Oka) in use in Japan and Korea; 20% of Japanese kids (over 2 million) have been vaccinated (1)
  2. Licensed in Europe for use in immunocompromised patients and recently for use in healthy children (1)
  3. No plans to market in U.K. b/c most MD’s offices there don’t have freezers (2)
  1. Use in U.S.
  1. Oka/Merck strain, licensed 3/17/95
  2. U.S. would be first country to adopt universal immunization; # of American children likely to be immunized in first year of universal vaccination would exceet total # of all varicella vaccine recipients in history (1)
  3. AAP recommended universal vaccination for U.S. children at 12-18mos in May, 1995 (3)
  4. AAFP and Advisory Committee on Immunization Practices to CDC 1/96 (AFP 53:396, 1996)
  1. One 0.5 ml dose of licensed vaccine containes avg 3300PFU at time of manufacture and minimum of 1350 PFU 30min after reconstitution at time of product expiration
  2. Adverse effects
  1. No severe side effects attributable to vaccine in > 11,000 recipients
  2. Pain 19%
  3. Fever 15%
  4. Chickenpox-like rash 6% up to 3 wks later
  5. Note that rates for herpes zoster in recipients no greater than in kids with natural varicella

II. Guidelines for use

  1. For prevention of Chickenpox
    1. One dose SQ 12mo-12y; 2 doses 4-8 wks apart at older ages
      1. In 2006, ACIP recommended adding a 2nd dose of varicella vaccine (first dose at 12-15mos and booster at 4-6yo); Can give booster at older ages if initial dose given after age 4yo and at least 3mos has elapsed since first dose
    2. Recipients should avoid close contact with nonimmune pregnant women or immunocompromised persons, esp. if develop rash; ok to give if a household contact is immunocompromised, though
    3. OK to give at same time as all other routine vaccines, but give at different site
    4. Don’t give to immunocompromised individuals, inc. those on corticosteroids (see ref. 3 for details)
    5. Don’t give if pregnant; avoid pregnancy for 1mo after; ok to give to mom if nursing and risk for exposure to wild-type varicella is high
    6. Don’t give if h/o anaphylaxis to neomycin or if moderately to severely ill or if recently got immune globulin
    7. Don’t give salicylates for 6wks after
    8. May be useful for postexposure prophylaxis in child household contacts of children w/varicella (Ped. Inf. Dis. J. 17:256, 1998--AFP)
  2. For prevention of Herpes Zoster (Zostavax)
    1. Same vaccine as used for preventing chickenpox; intended for use after age 60
    2. Contraindicated in pts who are immunocompromised for any reason.

III. Efficacy of the vaccine in preventing chickenpox

  1. In unpublished clinical trials (1982-1991), including 11,000 kids and adults, short-term efficacy varied from <70% to >96% depending on dose and method of preparation (percentage based on ratio of cases with vaccine to expected cases without, cited in 1)
  1. Doses ranged from 950 to 17,430 PFU
  2. The one trial where doses were limited to range now licensed (1987 unpublished study) had >4000 kids and efficacy over first 2y of 61-67% for those followed "actively," 66-77% for those followed passively.
  3. i.e. rate of breakthrough varicella is 1-3%/yr for vaccinees c/w 7-8% for unvaccinated kids
  1. UPenn study (10)
  1. 914 healthy kids 1-14yo (mean 4.7y) seronegative for varicella randomized to Oka/Merck vaccine (8700 PFU) or placebo
  2. 9 mo f/u showed no cases of varicella in vaccinees; 8% of placebo recipients got varicella
  1. Multicenter Merck Study (12)
  1. 3303 healthy kids 12mos-17y, avg. age 4y
  2. 1000-1625 PFU/dose
  3. Parents reported sx to study personnel
  4. 59 cases of varicella = 1.79% in first year = 79% reduction vs. expected 8.3%/yr incidence; all were mild with fewer lesions and less fever than expected. 82% of these kids had had positive antibody response at 6wks post-vaccination!
  5. 87% reduction in varicella cases due to documented contacts compared with historical control attack rate
  6. Seroconversion rate 96% overall, highest (98%) in 12-15mo kids
  1. Combined results from 3 studies showed that rate of contraction of varicella for vaccine recipients with household exposure occurred in 20% of those exposed; would expect it to be 87% for unvaccinated nonimmuine kids
  2. In a case series of an outbreak of varicella at a day care center, in which vaccination history and details on the varicella course were obtained from cases, effectiveness of vaccination was est'd at 44% against any clinical disease and 86% against mod-severe disease.  Vaccine failure was sig. more likely in kids who had been vaccinated > 3y previously c/w kids vaccinated more recently (RR 2.6) (NEJM 347:1909, 2002--JW)
  3. In a case-control of 339 kids (13mo-16yo) with clinical varicella and 669 matched controls, protective effect of the vaccine appeared significantly lower with increasing time after vaccination (97% during first year, 81% after 7 years).  Also, protection from the vaccine was sig. greater if given at 15mos of age or later than if given earlier.  (JAMA 291:851, 2004--JW)

IV. Efficacy of the vaccine in reducing severity of chickenpox

  1. Those who got "breakthrough" chickenpox had milder illness than unvaccinated controls
  2. 1/3 incidence of fever
  3. 1/6 # of lesions
  4. 1d shorter illness
  5. Too few cases to determine rate of serious varicella complications
  6. "95% effective" at preventing severe disease (1)

V. Efficacy of the vaccine in providing long-term protection against varicella

  1. Antibody titers actually increase with time after immunization (11), suggesting re-infection with wild-type varicella, boosting immune response, so "only after most children are immunized with Varivax will this booster effect diminish and an unequivocal analysis of the vaccine’s long-term efficacy become possible"—however, mean titers of antibodies were similar in vaccinees with and without hx of exposure to wild-type varicella in one study, suggesting that "continued exposure to natual infection may not be a prerequisite for persistence of immunity" (Peds 91:17, 1993, cited in 7)
  2. Studies on efficacy not designed to determine long-term protection
  3. Unpublished 1982 trial of 2000 kids included "passive" followup for 10y; assuming all cases of breakthrough varicella were reported, there was no evidence of waning protection over that time; this included many who got dose of 17,430 PFU! Subset of "actively" followed kids (contacted for info) had higher rates of breakthrough varicella.
  4. Unpublished 1987 trial showed decline in protective efficacy (i.e. increase in annual % of breakthrough cases) from year 1-5 (p < 0.01) but stable breakthrough rates in years 3-5; n.b. in this trial subjects who didn’t produce detectable antibodies were reimmunized 1y later!
  5. Followup study of Japanese kids (5, 9)
  1. 1994 paper: 244 healthy & sick kids (about 60/40) who got Oka vaccination (500-5000PFU) in Japan at ages 10mo-13yo, avg 4.4y (1/74-1/96)
  2. Observed 17-19y
  3. Questionnaires sent to parents’ asked about varicella and zoster in pts’ surroundings and pts; also tested for varicella Ab’s and skin test for VZV
  4. 96 questionnaires returned; 67 had well-documented contacts with varicella; only 2 got breakthrough varicella, both <12mos after immunization; had mild disease with few lesions and no fever; no cases of zoster
  5. All 26 who underwent immunologic testing had positive responses
  6. 1985 paper: 106 kids in same cohort; followed 7-10y; only 5 were reported by parents to have had, despite most having had been exposed; 97% had Ab’s and pos. skin tests. 4 cases occurred <1y after vaccination, the other 3y after.
  1. Followup of UPenn study (see above; 11)
  1. Followed vaccine recipients with questionnaires filled out by parents and followup of positive responses (i.e. mostly passive followup)
  2. Only 5% got varicella over 7y followup period
  3. Onset ranged from 2y to 6y post-vaccination
  4. No increase in incidence with time
  5. Cases were considerably milder, c/w data above
  1. 143 seronegative kids given Oka/Merck vaccine from a research lot (950 PFU x 1); 98% seroconverted; another 138 kids given vaccine from a production lot (1145-3265 PFU); 93.5% seroconverted. All kids' families were contacted by phone annually and seen by a study RN whenever varicella was suspected. In first group, 25/137 seroconverters had clinical varicella over 10y f/u. In 2nd group, 22/129 seroconverters had clinical varicella over 6y f/u (14)
  2. Merck will do phase IV studies on 7000 kids on long-term immunity and 40,000 kids on population patterns of varicella infection. CDC will also be monitoring.
  1. Efficacy of the vaccine in preventing Herpes Zoster when given to adults
    1. In one randomized trial in pts > 60yo, the Oka/Merck VZV vaccine, over median 3.12y f/u, was associated with a sig. reduction of herpes zoster (RR 38.9); absolute risk reduction was 1.7%  (NEJM 352:2271, 2005--abst)
  1. Arguments for use of vaccine
  1. Decrease in hosps/deaths
  2. Decrease in suffering from an annoying disease
  3. Reduction in costs from health care and time lost from work for parents
  1. Cost-effectiveness analysis suggested that universal vaccine administration would cost $88 million a year and save $80 million a year in medical costs; would save $392 a year in lost wages; so, wouldn’t be cost-effective from perspective of payer of medical care but would from a societal perspective (4)
  1. Reduction in wild-type cases would probably decrease intrauterine infections, unless vaccinees grew up to be pregnant women with lost immunity

VII. Vaccine issues

  1. Varicella is a mild disease and not worth preventing
  2. "There is some concern that universal immunization might shift susceptibility to chickenpox from children to adults, in whom infection is more serious" (1)
  1. Immunity with wild-type infection appears to be lifelong
  2. Long-term immunity in vaccine recipients could be dependent on subclinical reinfection with wild-type virus; if immunity from vaccination wanes, and wild-type varicella becomes so uncommon that it ceases to boost vaccine-induced immunity, then vaccinees could become susceptible as adults
  3. "The main problem with immunization is that we do not know whether children who are immunized with chickenpox vaccine develop lifelong immunity. If the protective effect of immunizatio wanes, a program of universal immunization may create a population of adults who are at risk of serious illness and thus turn a relatively benign childhood illness into a major cause of illness and teratogenicity" (6)
  4. "If the immunity is not as long-lasting as that which occurs after natural infection, the vaccine may create the risk of the more severe disease frequently observed in adults following infection later in life" (9)
  5. "Only time will tell whether immunized children are protected for life" (7)
  6. Could occur if unvaccinated individuals didn’t contract varicella until adulthood
  7. Mathematical models suggest that increase in adult chickenpox cases wll be small, but "if these assumptions prove to be overly optimistic, the frequency of adult disease, hospitalizations, deaths, and congenital varicella sd. might increase" (1)
  8. "With fewer children actually contracting the disease in childhood because of the vaccine, the few unvaccinated kids may grow up with no immunity because they will not have come in contact with the virus"—negative effects of herd immunity (Edward A. Mortimer Jr. of CDC, quoted in "A Pox on the Pox. New Vaccine Raises Hopes and Doubts" Sci. Am. 10/95 p. 32)
  9. "This program may transform varicella from a mild disease of childhood to a severe disease of adulthood…This vaccine seems to be a case of technology gone amok in the name of societal expediancy and perhaps some other unstated agenda…a horrific experiment involving a captive populace who will receive neither adequate informed consent nor the moral right to refuse participation" (Martin Smuckler, M.D., Arcata, CA. Letter to JAMA 6.22/29.94 271:1906)
  10. Booster immunizations might solve the problem of waning immunity in vaccinees but might be hard to implement
  1. Epidemiologic issues
  1. "The effect of a universal immunization program on the long-term epidemiology of varicella is unknown" (1)
  2. Universal vaccination produces "herd immunity," i.e. even if not all who receive the vaccine become immune, nonimmune individuals are protected from second- or third-hand transmission by their immune contacts
  3. Complete eradication of varicella is unlikely because of reintroduction from other countries and maybe zoster as well
  1. Alternatives to universal immunization
  1. Immunization of immunocompromised kids and their close contacts, like in Europe (not licensed for this indication in U.S. as of 9/96)
  2. Vaccination on elective basis, e.g. when a family member is immunocompromised, or to kids at age 12 & adults who didn’t get varicella yet—this would cost less and protect those with highest risk of complications of wild-type varicella—unlike universal vaccination, probably would not decrease total amound of wild-type circulating virus. Might be difficult to implement, however; also, wouldn’t decrease rate of childhood chickenpox
  1. These issues matter more than with vaccine like measles and polio because those diseases are more serious in kids than varicella; in addition, they are often less severe in adults than kids; with varicella, it’s the reverse
  2. Like most vaccines, private health sector will probably start implementing reccs before public sector can devote $ to it; may, however, become mandatory for school.
  3. Is there a better way to spend public health $ (see abov cost-benefit)
  4. Doesn’t seem to be a sig. risk of transmission of vaccine strain to others or risk of H. Zoster with vaccine

 

  1. Krause, Philip R. and Klinman, Dennis M. Efficacy, Immunogenicity, Safety, and Usa of Live Attenuated Chickenpox Vaccine. J. Peds. 127:518, 1995
  2. Chartan, F.B. Chickenpox Vaccine Gets Approval in U.S. BMJ 4/1/95
  3. Committee on Infectious Diseases, American Academy of Pediatrics. Recommendations for the Use of Live Attenuated Varicella Vaccine. Pediatrics 95:791, 1995
  4. Lieu, Tracy A. et al. Cost-effectiveness of a Routine Varicella Vaccination Program for U.S. Children JAMA 271:375, 1994
  5. Asano et al. Experience and Reason: Twenty-Year Follow-Up of Protective Immunity of the oka Strain Live Varicella Vaccine. Pediatrics 94:524, 1994
  6. Ross, L. and Lantos, J. Immunization Against Chickenpox. BMJ 310:2, 1995
  7. Watson, B. and Starr, S. Varicella Vaccine for Healthy Children Lancet 343:928, 1994
  8. Plotkin, S. Varicella Vaccine Pediatrics 97:251, 1996
  9. Asano, et al. Long-Term Protective Immunity of Recipients of the OKA Strain of Live Varicella Vaccine Pediatrics 75:667, 1985
  10. Weibel et al. Live Attenuated Varicella Virus Vaccine New England Journal of Medicine 310:1409, 1984
  11. Kuter et al. Oka/Merck Varicella Vaccine in Healthy Children: Final Report of a 2-year Efficacy Study and 7-year Follow-up Studies Vaccine 9:643, 1991
  12. White et al. Varicella Vaccine (VARIVAX) in Healthy Children and Adolescents: Results from Clinical Trials, 1987 to 1989 Pediatrics 87:604, 1991
  13. Guess et al. Population-Based Studies of Varicella Complications Pediatrics 76:723, 1986
  14. Johnson et al. Pediatrics 100:761, 1997