Table 4 Halting Rules

• One or more participants experience an SAE that is possibly, probably, or definitely related to the study agent or research procedure (except for neutropenia – see specific guidelines below).

• Two or more participants experience the same or similar grade 3 or greater AEs that are unexpected and possibly, probably, or definitely related to a study agent. There are two exceptions to this rule:

 ◦ Neutropenia: halting rules are specific and listed below

 ◦ Local reactions to vaccine: The study will not be halted for any Grade 3 or lower AEs classified as local reactions to the vaccine.

• One or more of the first 4–6 participants experience a mean peak viremia titer of ≥ 10⁶ PFU/mL by viral culture.

• Two or more participants experience an ANC ≥ 500/µL but < 750/µL for > 5 days duration.^a

• Two or more participants experience an ANC < 500/µL for any duration.^a

• Two or more participants experience a vaccine-associated dengue-like syndrome, defined as infection^b associated with fever and 2 or more of the following symptoms:

 ◦ Grade 2 or greater headache lasting ≥ 12 h.

 ◦ Grade 2 or greater photophobia lasting ≥ 12 h.

 ◦ Grade 2 or greater generalized myalgia lasting ≥ 12 h.

• Any safety issue that the principal investigator or the CSO determines should halt the study. The DSMB may recommend a pause to the CSO.