Clinical development of variant-adapted BNT162b2 COVID-19 vaccines: the early Omicron era

Figures & data

Figure 1. Omicron-adapted BNT162b2 vaccine study designs. a) Monovalent BNT162b2 Omicron BA.1 vaccine (30 μg dose) in participants 18–55 years of age [41,42]; b) Monovalent BNT162b2 Omicron BA.1 vaccine (30 μg and 60 μg doses) and bivalent Original/Omicron BA.1 vaccine (30 μg and 60 μg doses) in participants >55 years of age [41,42]; c) Bivalent Original/Omicron BA.4–5 vaccine in participants >12 years of age [43].

Figure 2. Timeline for clinical development and approval of original and variant-adapted BNT162b2 vaccines in adults and older children.

*Approval of BNT162b2 Original/BA.4–5 initially based on preclinical/non-clinical data and data for other BNT162b2 vaccines.

CMA, conditional marketing authorization; EMA, European Medicines Agency; EUA, emergency use authorization; FDA, United States Food and Drug Administration; FMA, full marketing authorization; R&D, research and development.

Table 1. Regulatory authority guidance on clinical evaluation of variant-adapted COVID-19 vaccines [47,48].

Agency	FDA	EMA
Subjects	For primary vaccination: previously unvaccinated persons For booster vaccination: persons who previously completed primary vaccination with the parent vaccine	For primary vaccination: unvaccinated subjects with no serological evidence of prior SARS-CoV-2 infection For booster vaccination: Subjects with fully documented prior vaccination with the parent vaccine
Primary endpoints	Superiority of variant-adapted versus parent vaccine against variant, based on >1.5 or >1-fold margin for GMT ratio Non-inferiority of variant-adapted versus parent vaccine against variant, based on <5% margin for seroresponse* rate difference (alternatively, superiority based on >0% or >10% margin)	Lower bound of 95% CI for difference in seroconversion^† rate against variant ≤−10%, for variant-adapted versus parent vaccine Lower bound of 95% CI for GMT ratio against variant ≥0.67, for variant-adapted versus parent vaccine
Key secondary endpoints	Seroresponse* rates and GMTs, including against other clinically relevant variants Comparisons of immune responses post-variant-adapted booster with responses post-primary series of parent vaccine	GMTs and seroconversion^† rates elicited by parent vaccine versus variant-adapted vaccine virus, and vice versa
Safety	Safety assessments for ≥7 days post-vaccination (solicited events) and during immunogenicity evaluation period (serious/unsolicited events) Studies should plan for longer-term assessment of serious and medically attended events	In the absence of safety concerns for parent vaccine, safety data collected during immunogenicity trials with the variant vaccine suffice for approval

*Determination of appropriate seroresponse definition should be based on available data.

^†At least 4-fold increase in titer from pre- to post-vaccination (nominal value for pre-vaccination applied to subjects seronegative at baseline; actual values from previous trials for seropositive subjects, or data from a matched population).

CI, confidence interval; COVID-19, coronavirus disease 2019; EMA, European Medicines Agency; FDA, United States Food and Drug Administration; GMT, geometric mean titer; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

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