Vaccination for Recovered Inpatients With COVID-19 (VATICO)

In this Phase 4 trial, participants in the TICO master protocol who received certain pre-specified blinded investigational agents or matched placebos will be offered enrollment, with the understanding that this will require 2X2 randomized assignment of the timing and of the number of mRNA SARS-CoV-2 vaccinations to be received, via publicly-available mRNA SARS-CoV-2 vaccination sites or via other routes, in keeping with the 4 specified study arm assignments.

This will address the objective of evaluating if the vaccine is best administered early or deferred after recovery, and whether one injection provides comparable immune response to a two-injection course of vaccination. Participants (as well as the protocol team) will remain blinded to the interventions studied in TICO. Allocation to timing of vaccination and to one or two vaccinations is not blinded. Participants will be offered enrollment in this protocol at the Day 28 or Day 90 visits in TICO, or anytime between these visits.

Participants will have blood collected for research purposes at the time of enrollment and at Weeks 12, 24, and 48.

The study vaccine and regimen will not be blinded; there will be be no 'dummy/placebo' vaccine administered. Vaccines are expected to be made available either through the study directly, or through a reliable public vaccination program using vaccine available per the local regulatory mechanism (e.g., currently under Emergency Use Authorization (EUA) for the United States) or via other routes in case such local mechanisms are not available.

Participants will be equally allocated to 4 groups to inform each of two vaccine strategies:

• One injection versus two (for the immediate and deferred groups)
• Immediate versus deferred (for one and two vaccinations)

Hence, the outcome of the randomization will lead to one of the four following vaccination strategies for each study participant:

I1 - Immediate, one dose: vaccination at study entry only I2 - Immediate, two doses: vaccination at study entry and Week 4 D1 - Deferred, one dose: vaccination at Week 12 only D2 - Deferred, two doses: vaccination at Week 12 and Week 16

Randomization will be stratified by study site and by randomization assignment in TICO for certain pre-specified investigational agents or their matching placebo.

When addressing the two co-primary objectives, the following groups are combined:

• Immediate vs deferred vaccine: groups I1 and I2 versus D1 and D2
• One versus two vaccinations: groups I1 and D1 versus I2 and D2

Similar comparisons will be made separately for each of the two principal TICO arms, i.e., for those assigned to one of the investigational agents and for those assigned to the matching placebo. Both of these comparisons are protected by the randomization in the present study.

Given the factorial design, whether there is an interaction of one factor (timing of vaccination) with the other factor (number of doses) will need to be assessed although the study is not fully powered for this evaluation.

A key secondary objective is to address whether the investigational agent studied in TICO (versus matching placebo) is affecting the primary outcome in this protocol. Of note, this comparison may not always be protected by randomization, as there may be differential inclusion in this protocol between those receiving the investigational agent in TICO and those receiving its matching placebo. This is more likely to be the case if the investigational agent is demonstrated to affect the chance of achieving sustained recovery.

The primary endpoint, immune response specific to the vaccination received, will be assessed at Week 48. Participants will have blood collected at time of enrollment, and at Weeks 12, 24 and 48 after study entry. Approximately 640 participants will be recruited. The total sample size will depend on how many investigational agents/placebo are evaluated in ACTIV-3/TICO.