Redefining Non-Inferiority in Anamnestic Antibody Responses Using the Mean Increase of Log-Transformed Antibody Titers after Revaccination: Secondary Analysis of a Randomized Controlled Rabies Vaccination Trial.

Lisanne A Overduin,Jelle J Goeman,Magdalena A Berkowska,Patrick H P Soentjens,Jacques J M Van Dongen,Leo G Visser

doi:10.3390/vaccines8040721

Abstract

Non-inferiority in the anamnestic antibody response is conventionally determined by comparing seroconversion rates after revaccination. However, this approach is inadequate in the case of high pre-booster antibody titers. Therefore, we propose an alternative method to determine non-inferiority of booster responses. We used anonymized data from a randomized controlled trial (NCT01388985; EudraCT 2011-001612-62) in 500 adults, comparing a two-visit primary vaccination schedule (two intradermal 0.1 mL rabies vaccine doses on day 0 and 7) with a three-visit schedule (single intradermal 0.1 mL dose on day 0, 7, and 28). Participants were revaccinated intradermally (single dose) 1 to 3 years later. Rabies virus neutralizing antibody titers were measured on day 0 and 7 after revaccination. After log3-transformation of antibody titers, the mean increase in titers after revaccination was compared between schedules. Non-inferiority was defined as the lower bound of the two-sided 95% confidence interval not exceeding −0.369. Four hundred and ten participants fulfilled the inclusion criteria. The mean increase in log3 titer was 2.21 and 2.31 for the two-visit and three-visit schedule, respectively. The difference between these increases was −0.10 [−0.28, 0.08], meeting the non-inferiority criterion. In conclusion, comparing mean increases in log-transformed titers after revaccination appears to be a feasible and more informative method of studying non-inferiority regarding the anamnestic antibody response.

Highlights

The main purpose of vaccination is to induce a robust immunological memory response that can be addressed by revaccination after possible exposure to the antigen
This anamnestic antibody response is primarily responsible for the protective immunity against infection with rabies virus, and it is vital to be able to establish whether a memory response is adequate for protection
410 out of 500 (82%) participants were included in this analysis: 200 participants had been randomized to the 3-visit schedule and 210 participants to the

Summary

Introduction

The main purpose of vaccination is to induce a robust immunological memory response that can be addressed by revaccination after possible exposure to the antigen. The definition of such an adequate anamnestic immune response, or ‘boostability’, is unclear. Vaccines 2020, 8, 721 for boostability, as they directly correspond to the memory B-cell response to revaccination [1,2,3,4,5]. This anamnestic antibody response is primarily responsible for the protective immunity against infection with rabies virus, and it is vital to be able to establish whether a memory response is adequate for protection.

Methods

Results

Discussion

Conclusion