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The Wide World of Vaccines

April 2019

No Doubt—Two Varicella Doses More Protective Than One

Christopher J. Harrison, MD, FAAP, FPIDS | Director, Infectious Diseases Research Laboratory | Director, Vaccine and Treatment Evaluation Unit | Professor of Pediatrics, UMKC School of Medicine

Varicella disease has decreased dramatically since introduction of varicella zoster virus (VZV) vaccine in 1995, and even more since the later addition of a second dose to the U.S. routine vaccine schedule in 2006. The two-step additions of VZV vaccine produced a two-step change in reported varicella disease. Prior to VZV vaccine use (before 1995), essentially the equivalent of the entire annual birth cohort got chickenpox each year (4 million cases annually) with 80% of cases being less than 8 years old. Now only about 3,500 cases are reported annually.

Figure 1. Varicella incidence, by age group — USA, 2005–2006 (pre-second dose use) versus 2013–2014.

Figure #1.png

Not only has there been a decrease in overall clinical chickenpox cases, the annual average age-adjusted mortality rate for VZV had dropped to just 0.03/million by 2012–2016.1 This was a 94% drop compared to the pre-vaccine era and a 47% drop from the one vaccine dose era. So epidemiological data suggested that the second dose was needed and added notable protection. A new 10-year prospective randomized blinded European study (begun in 2005-06) confirmed these epidemiologically derived conclusions about second-dose benefits.2

The authors evaluated vaccine efficacy in preventing confirmed varicella for three groups in a 3:3:1 ratio among 5,803 subjects who were 12-22 months old at first dose:

1. Two MMRV doses (2 VZV vaccine dose group)
2. One VZV and one MMR dose (1 VZV vaccine dose group)
3. Two MMR doses (No VZV vaccine doses)

Vaccines were given 42 days apart. This was a phase 3b follow-up of an observer-blinded, randomized, controlled trial with a median of 9.8 years’ patient follow-up.


Figure 2. Breakthrough Varicella and Relative Efficacy of One versus Two Varicella Vaccine Doses.

Figure #2.png


Breakthrough varicella occurred in 76 (3%) of the 2 VZV dose group; 469 (21%) in the one VZV dose group; and 352 (47%) in the no VZV vaccine subjects. Vaccine efficacy against any varicella was 95.4% (95% CI 94.0-96.4) for 2 VZV vaccine doses and 67.2% (62.3-71.5) for a single VZV vaccine dose. Vaccine efficacy against moderate/severe varicella was 99.1% (97.9-99.6) for 2 VZV vaccine doses, and 89.5% (86·1-92·1) for one dose.

Serious adverse events occurred at a similar rate among the three groups – N=290 (15%) for 2 VZV vaccine doses; N=317 (16%) for single VZV vaccine dose; and N=93 (15%) for no VZV vaccine, but 2 MMR doses.

This is strong scientifically rigorous evidence that one VZV vaccine dose gives pretty good protection, but a two-dose schedule of VZV vaccine yields even better long-term protection against varicella of all severities. So there is no doubt that the currently available live-attenuated VZV vaccine in a two-dose schedule is effective and the reason for the dramatic decrease in VZV disease, complications and mortality in the U.S.


1. Update on Trends in Varicella Mortality During the Varicella Vaccine Era—United States, 1990–2016. Leung J & Marin M. Hum Vacc & Immunother 2018 14(10):2460- 2465.

2. Protection Against Varicella with Two Doses of Combined Measles-mumps-rubella-varicella Vaccine or One Dose of Monovalent Varicella Vaccine: 10-year Follow-up of a Phase 3 Multicentre, Observer-blind, Randomised, Controlled Trial. Povey M, Henry O, Riise Bergsaker MA, et al. Lancet Infect Dis. 2019 Feb 11. S1473-3099(18)30716-3.