Abstract
Despite the extraordinary speed and success in SARS-Cov-2 vaccine development, the emergence of variants of concern perplexed the vaccine development community. Neutralizing antibodies waned antibodies waned and were evaded by viral variants, despite the preservation of protection against severe disease and death across vaccinated populations. Similar to other vaccine design efforts, the lack of mechanistic correlates of immunity against Coronavirus Disease 2019, raised questions related to the need for vaccine redesign and boosting. Hence, our limited understanding of mechanistic correlates of immunity - across pathogens - remains a major obstacle in vaccine development. The identification and incorporation of mechanistic correlates of immunity are key to the accelerated design of highly impactful globally relevant vaccines. Systems-biology tools can be applied strategically to define a complete understanding of mechanistic correlates of immunity. Embedding immunological dissection and target immune profile identification, beyond canonical antibody binding and neutralization, may accelerate the design and success of durable protective vaccines.