Background
Both immunization and nirmatrelvir-ritonavir treatment (NMV-r) are known to lower the risk of severe COVID-19 including hospitalization or death. However, it is unclear whether the effect of NMV-r and acquired immunity (via vaccination or prior viral exposure indicated as serologic positivity) are additive or synergistic.
Methods
Non-hospitalized symptomatic adults infected with COVID-19 were enrolled into two similarly designed double-blind clinical trials, EPIC-HR and EPIC-SR, and randomized (1:1) to receive NMV-r or placebo for 5 days. All participants with risk factors for severe COVID-19 from these two published trials were included to evaluate synergy between NMV-r and acquired immunity, with synergy assessed as Relative Excess Risk due to Interaction (RERI) and Attributable Proportion (AP).
Results
2572 participants were divided into 4 groups based on acquired immunity (vaccinated/sero-positivity) and NMV-r (or placebo). Relative to the group with no acquired immunity and treated with placebo, the risk of COVID-19 related hospitalization or all-cause death was reduced (95% CI) by 83% (71-90%) with acquired immunity alone, 85% (69-93%) with NMV-r alone, and 96% (88-98%) when both were present.
To assess the presence of synergistic effect, comparisons were made with reference to the group with greatest risk prevention, participants with both acquired immunity and NMV-r. The risk increased significantly (p<0.0001) to 3.4-fold without acquired immunity, 3.82-fold without NMV-r, and to 22.73-fold in the absence of both (Figure 1). This indicated that 16.5-fold risk increase was due to synergy (RERI), accounting for 72.7% of total risk (AP). The synergy was seen both in men and in women, and regardless of whether immunity was acquired through vaccination or due to prior viral exposure. Furthermore, the synergistic effect was reflected in the clearance pattern of SARS-CoV-2 and was supported by similar synergy observed in the proportion of participants with any COVID-related medical visits or in the proportion with severe COVID-19 symptoms post treatment.
Conclusions
Among participants at high risk to develop severe COVID-19, NMV-r and acquired immunity provided incremental protection against severe COVID including hospitalization or death in the presence of each other. More significantly, because of the synergistic effect between NMV-r and acquired immunity, participants with neither immunization nor treatment saw a deleterious risk increase in severe COVID of more than 20-fold.
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