. 2021 Apr 22;6:63. doi: 10.1038/s41541-021-00325-4

Table 1.

Strategies for accelerating clinical development.

Approach	Rationale	Other considerations
Aggressive initial human immunogenicity targets	Multiple candidates may proceed through phase 1 clinical trials. Thus, phase 2 should be designed to enable manufacturers to down-select to one lead candidate. Set immunogenicity endpoints to enable rapid down-selection of competing early-stage candidates and to decrease the likelihood of late-stage immunogenicity failures.	Immunogenicity targets should also determine if a single dose or multiple doses will be necessary, and if single dose vs. two-dose arms should be part of phase 2.
Aggressive initial human immunogenicity targets		If a prime-boost is needed, it may be advisable to assess if heterologous prime-boost could provide a more durable response⁴⁸.
Adaptive trial design	Allows for the evaluation of multiple candidates in parallel using pre-determined decision parameters and early efficacy signals to select which arms of the study continue enrollment and which are closed⁴⁹. This enables faster overall clinical assessments and increasing statistical power.	Adaptive trial design has not so far been used for initial vaccine development plans for current COVID-19 vaccine candidates because of the urgency to utilize the available population of clinical subjects but will be advantageous to follow-on vaccine candidates.
Novel biomarkers	Identifying relevant novel biomarkers early in clinical development can accelerate subsequent development.	Examples of useful novel biomarkers have been derived from vaccine studies in animal models of SARS-CoV-2 infection^50,51
Rapid age escalation and de-escalation	Data in both elderly populations and children will be needed due to the risk of COVID-19 morbidity and mortality in the elderly, and the role of children in spreading the disease^52,53	Utilize rapid age de-escalation strategies to obtain data in younger populations post-Phase 1⁵⁴.
		Given the lower responses to flu vaccines seen in the elderly, the use of adjuvants, higher dose levels, and/or or novel prime-boost regimens could be helpful to achieve protective immune responses in this population⁵⁵.
		It is important to work closely with regulators to ascertain whether the proposed age escalation to develop data in elderly (50 + years) and more elderly (70 + years) populations needs to be completed prior to EUL; or if the EUL can be amended with new information as the data becomes available.
Considering platform novelty in clinical development	The novelty of the proposed vaccine platform or vector will be key in determining the total number of exposures needed to meet the safety criteria for EUL; and whether regulatory authority alignment will be needed to determine the number of vaccinated subjects needed for the initial human safety database. This needs to be discussed with and agreed with the WHO PQ team and the primary regulator(s).	Novel platforms or vectors will likely require larger exposures/safety databases to allow for widespread use under the EUL, while established platforms may require perhaps only several hundred subjects⁵⁶.
Collecting long-term safety data	Phase 2 subject follow-up assessing response durability and long-term safety is invaluable, and should continue for at least one year after the final vaccine dose is administered.	A proactive plan to update the EUL submission with revised safety and immunogenicity data for long-term follow-up will aid in collecting these data during the EUL submission and review process.
Collecting long-term safety data		Follow-up studies should particularly look for any evidence of enhanced disease, and help identify correlates of protection for COVID-19 vaccines⁵⁷.