There are two types of vaccine failure Primary – No immune response to vaccine (No take) Secondary – Loss of positive immune response months to years after vaccination (Waning immunity)

Why does vaccine failure occur? (Breakthrough) Improper storage of vaccine < 15 months old when immunized –Lim 1998, Dworkin 2002, Galil 2002, Verstraeten 2003,Vazquez 2004 Asthma (Izurieta 1996) > 3 years since vaccination < 30 days between MMR and varicella Low vaccine dosage (Varis 1996, Clements, Johnson, Takayama)

Factors associated with successful vaccination (low breakthrough rate) High vaccine dose (over 10,000 pfu) – Weibel 1984, Varis 1996 Two doses of vaccine – Higher titers, which correlate with better protection

Two doses of vaccine Second dose after 4  6 years –GMT increased from 26 to 144 (Watson 1995) Second dose after 3 months –GMT 20 vs 31, 1 year after either 1 or 2 doses, respectively (Ngai, 1996) –Increased protection (98% vs 93%) after 10 yr (Kuter, PIDJ 2004 [3 months apart])

Will zoster increase in the unvaccinated? External boosting may decrease zoster –Decrease in zoster if exposed to children Thomas (London 2002) and Brisson (Canada 2002) –Less zoster in leukemics exposed to VZV (Gershon et al 1996) Brisson predicts doubling of incidence for next 40 years –Epidemic, increased mortality: (2  4 to 4  8/1000 p-y) Mortality from zoster is unusual, especially in middle age Don’t confuse death from zoster with death during zoster

Why do 15 % of people develop zoster? : They had varicella (or vaccine) They have latent VZV infection –Vaccinees may have less latency Their cell-mediated immune response to VZV declines –Due to ageing and/or illness

Cellular immunity to VZV is low prior to onset of zoster in vaccinees with underlying leukemia N=4 N=29 N=11 N=30

Zoster is less frequent in immunocompromised vaccinees Over 6  10 years, the rate of zoster was lower in vaccinated children than in similar children who had previous natural varicella (4 studies) Takahashi. Adv Med Biol 1990; Brunell, Pediatrics 1986; Hardy, N Engl J Med 1991; Broyer, Pediatrics 1997

Zoster in healthy adult vaccinees is unusual 362 vaccinated healthy adults: NYC Zoster incidence: 1.09 (0.3  3.9)/ 1000 p-y Active follow up 1  23 years –Mean 5 yr, median 3.4 yr, 52 over 10 yrs 42 cases of breakthrough varicella Two patients developed zoster; both had evidence of past varicella (1 WT, 1 unknown) (Gershon et al, unpublished)

Zoster incidence is low in adults whether or not they were vaccinated

Zoster in leukemic vaccinees is associated with prior VZV rash History of rashNZoster Rash27910 (3.6%) No rash2691 (0.4%) Vaccine-associated rash: 7 (10  )Vaccine-associated rash: 7 (10  150 lesions) Breakthrough varicella: 3 (20  36 lesions)Breakthrough varicella: 3 (20  36 lesions) No rash: 1 (zoster at vaccination site)No rash: 1 (zoster at vaccination site) The risk of zoster after VZV rash is increased 9.6-fold (p<0.02)The risk of zoster after VZV rash is increased 9.6-fold (p<0.02)

Two doses of varicella vaccine will alleviate many problems Will probably decrease incidence of breakthrough varicella In decreasing breakthrough, varicella will decrease zoster in vaccinees by keeping virus away from the skin (less latent infection) Give as 2 doses MMRV If zoster becomes a problem, give zoster vaccine to 40 year olds