Use of statistical models for evaluating antibody response as a correlate of protection against varicella

Abstract

In vaccine clinical trials, humoral antibody responses are often used to measure the effect of a vaccine because they correlate with a vaccine's protective efficacy against the target disease. While the concept of a correlate of protection usually refers to establishing a protective level of antibody titre, identifying a clear-cut value is often impossible because vaccine efficacy is not related solely to the antibody titre. We propose examining the relationship between disease protection and the whole distribution of antibody responses rather than a single cut-off level. In particular, we use failure-time models to estimate the relationship between long-term disease breakthroughs and primary antibody responses after vaccination. We apply these models to show that the varicella antibody response measured by glycoprotein enzyme-linked immunosorbent assay 6 weeks after vaccination strongly correlate with protection against varicella (chickenpox); we used 7-year follow-up data from children who received one dose of a live attenuated varicella (Oka/Merck) vaccine. In addition, we explore the potential use of these models to predict long-term disease breakthrough rates and to estimate the predicted vaccine efficacy of a similar varicella vaccine made with a modified manufacturing process.

Preventing Varicella-Zoster Disease

“…These data are supported by a further prospective study of varicella in 11 day care centers in North Carolina (23,25). Between 1995 and 1999, the rate of vaccine coverage increased from 4.4 to 63.1% while the incidence of varicella fell markedly among both vaccinated and unvaccinated groups.…”

“…The absence of a sensitive and specific measure of immunity to VZV has posed a problem in evaluating the success of varicella vaccine. Over long-term follow-up, the magnitude of the initial postvaccination antibody response, as measured by gpELISA, is correlated with protection against varicella (25,96,143). A 6-week antibody titer of at least 5 gpELISA units/ml has been proposed as a "reasonable correlate of protection" following vaccination, since it defines a low-responding group with a 3.5-fold excess risk of breakthrough varicella (96).…”

Prevention of Varicella: Recommendations for Use of Varicella Vaccines in Children, Including a Recommendation for a Routine 2-Dose Varicella Immunization Schedule

“…49 The concentration of varicella antibody as measured by gpELISA 6 weeks after immunization correlates with neutralizing antibody concentration, VZV-specific Tlymphocyte proliferative responses, and protection against breakthrough varicella after exposure to VZV. [50][51][52][53][54] Among children who have varicella antibody titers of Ն5 gpELISA units per mL 6 weeks after immunization, the vaccine efficacy rate is 95.5%, compared with an efficacy rate of 83.5% in children with Ͻ5 gpELISA units per mL. 51 Approximately 76% to 90% of children who are immunized with a single dose of varicella-containing vaccine achieve varicella titers of Ն5 gpELISA units per mL.…”

A Framework for Assessing Immunological Correlates of Protection in Vaccine Trials

“…If these predictions are reliable, then use of such immune correlates provides an efficient way to guide the development, evaluation, and utilization of vaccines. However, empirically validating such predictions is challenging.Despite the importance of identifying immunological correlates of protection (CoPs) and the extensive literature reporting attempts to find them, the methodology available for their quantitative assessment is limited [1,[5][6][7]. Moreover, at least 3 different conceptual definitions have been implicitly used for CoPs, which has created confusion and controversy in the literature.…”