Correlates of protection for inactivated enterovirus 71 vaccine: the analysis of immunological surrogate endpoints

ABSTRACT

Background: Inactivated Enterovirus 71 (EV71) vaccines showed significant efficacy against the diseases associated with EV71 and a neutralizing antibody (NTAb) titer of 1:16–1:32 was suggested as the correlates of the vaccine protection. This paper aims to further estimate the immunological surrogate endpoints for the protection of inactivated EV71 vaccines and the effect factors.

Methods: Pre-vaccination NTAb against EV71 at baseline (day 0), post-vaccination NTAb against EV71 at day 56, and the occurrence of laboratory-confirmed EV71-associated diseases during a 24-months follow-up period were collected from a phase 3 efficacy trial of an inactivated EV71 vaccine. We used the mixed-scaled logit model and the absolute sigmoid function by some extensions in continuous models to estimate the immunological surrogate endpoint for the EV71 vaccine protection, respectively.

Results: For children with a negative baseline of EV71 NTAb titers, an antibody level of 26.6 U/ml (1:30) was estimated to provide at least a 50% protection for 12 months, and an antibody level of 36.2 U/ml (1:42) may be needed to achieve a 50% protective level of the population for 24 months.

Conclusion: Both the pre-vaccination NTAb level and the vaccine protective period could affect the estimation of the immunological surrogate for EV71 vaccine. A post-vaccination NTAb titer of 1:42 or more may be needed for long-term protection.

Clinical trial registration: NCT01508247.

KEYWORDS:

• Enterovirus 71 vaccine
• correlate of protection
• statistics
• Prentice criterion
• surrogate endpoint

Declaration of interest

W Zhu and P Liu were supported by the Fundamental Research Funds for the Central Universities (SJLX15_0071). F Zhu, P Jin and J Li were supported by the key laboratory of enteric pathogenic microbiology. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by the Fundamental Research Funds for the Central Universities [SJLX15_0071] and the Key Laboratory of Enteric Pathogenic Microbiology.