The use of correlates of protection (CoPs) in vaccination trials offers significant advantages as useful clinical endpoint substitutes. Vaccines with very high vaccine efficacy (VE) are documented in the literature (VE ? 95%). The rare events (number of infections) observed in the vaccinated groups of these trials posed challenges when applying conventionally-used statistical methods for CoP assessment. We describe the nature of these challenges, and propose easy-to-implement and uniquely-tailored statistical solutions for the assessment of CoPs in the specific context of high VE. The Prentice criteria and meta-analytic frameworks are standard statistical methods for assessing vaccine CoPs, but can be problematic in high VE cases due to the rare events data available. As a result, lack of fit and the problem of infinite estimates may arise, in the former and latter methods respectively. The use of flexible models within the Prentice framework, and penalized-likelihood methods to solve the issue of infinite estimates can improve the performance of both methods in high VE settings.