Background
Currently, optimal timing and/or number of booster COVID19 vaccinations remains unclear. We compared immunogenicity and safety of mRNA booster vaccination at different time intervals.
Methods
In a randomised, controlled, multicentre, phase II trial, adults with >3 prior mRNA COVID19 vaccines, with last vaccine 3 to 7 months (M) prior, were randomized to one of five arms; no booster vaccine (control) or Comirnaty mRNA booster vaccine at M0, 2, 4 or 6. Plasma receptor binding domain (RBD) antibodies (IU/mL) were measured at each visit and 2 weeks post booster, along with solicited adverse events (AE). Composite primary endpoint was a two-fold increase in RBD titre at 2 weeks post boost and/or RBD titre ≥500IU/mL in those with pre-boost RBD<500IU/ml. Efficacy was met if >50% subjects in a booster arm met the primary endpoint using a 1 sample proportion test (adjusted 1-sided alpha 0.0125). We explored optimal booster vaccine timing by logistic regression with best fitting fractional polynomial. Data are mean (SD) unless specified.
Results
Of 255 subjects, mean age 52 (14) years, 154 (60%) female, 249 (98%) white, 130 (51%) with prior COVID19, time from last vaccine was 154 (44) days and baseline RBD was 15143 (16088) IU/mL. Arms were well matched. In the trial, 39 (20%) received Original, 125 (62%) Original/Omicron BA4-5 and 32 (16%) Omicron BXX.1.5 specific Comirnaty vaccines. Two weeks post boost, RBD titres increased in all four vaccine arms but then declined rapidly (Fig a). Only M2 booster arm achieved efficacy and no dose-response for time to booster vaccination was found (Fig b). 32 (13%) reported incident COVID19, with no difference in infection rates between vaccine arms and controls. Neither age nor prior COVID-19 were associated with the primary endpoint. However, those with a longer time since last pre-study vaccine and lower pre-boost RBD were more likely to reach a primary endpoint (P=0.005 and P<0.001), regardless of study arm (P=0.79 and P=0.16 for interaction). 144/169 (85%) subjects reported AE post-booster with tiredness, headache and muscle pain each reported in ≥20%. Of 7 serious AE, none causally linked to booster vaccine.
Conclusions
Booster COVID19 vaccination provided only short-lived increases in RBD titre but with systemic side effects commonly reported. Lower pre-booster RBD and time since last vaccine but not age was associated with greater likelihood of booster immune responses. These data suggest a saturable humoral response to repeated COVID-19 vaccinations.