Dynamic immune landscape in vaccinated-BA.5-XBB.1.9.1 reinfections revealed a 5-month protection-duration against XBB infection and a shift in immune imprinting.

BACKGROUND: The impact of previous vaccination on protective immunity, duration, and immune imprinting in the context of BA.5-XBB.1.9.1 reinfection remains unknown. METHODS: Based on a 2-year longitudinal cohort from vaccination, BA.5 infection and XBB reinfection, several immune effectors, including neutralizing antibodies (Nabs), antibody-dependent cellular cytotoxicity (ADCC), virus-specific T cell immunity were measured to investigate the impact of previous vaccination on host immunity induced by BA.5 breakthrough infection and BA.5-XBB.1.9.1 reinfection. FINDINGS: In absence of BA.5 Nabs, plasma collected 3 months after receiving three doses of inactivated vaccine (I-I-I) showed high ADCC that protected hACE2-K18 mice from fatality and significantly reduced viral load in the lungs and brain upon BA.5 challenge, compared to plasma collected 12 months after I-I-I. Nabs against XBB.1.9.1 induced by BA.5 breakthrough infection were low at day 14 and decreased to a GMT of 10 at 4 months and 28% (9/32) had GMT ≤4, among whom 67% (6/9) were reinfected with XBB.1.9.1 within 1 month. However, 63% (20/32) were not reinfected with XBB.1.9.1 at 5 months post BA.5 infection. Interestingly, XBB.1.9.1 reinfection increased Nabs against XBB.1.9.1 by 24.5-fold at 14 days post-reinfection, which was much higher than that against BA.5 (7.3-fold) and WT (4.5-fold), indicating an immune imprinting shifting from WT to XBB antigenic side. INTERPRETATION: Overall, I-I-I can provide protection against BA.5 infection and elicit rapid immune response upon BA.5 infection. Furthermore, BA.5 breakthrough infection effectively protects against XBB.1.9.1 lasting more than 5 months, and XBB.1.9.1 reinfection results in immune imprinting shifting from WT antigen induced by previous vaccination to the new XBB.1.9.1 antigen. These findings strongly suggest that future vaccines should target variant strain antigens, replacing prototype strain antigens. FUNDING: This study was supported by R&D Program of Guangzhou National Laboratory (SRPG23-005), National Key Research and Development Program of China (2022YFC2604104, 2019YFC0810900), S&T Program of Guangzhou Laboratory (SRPG22-006), and National Natural Science Foundation of China (81971485, 82271801, 81970038), Emergency Key Program of Guangzhou Laboratory (EKPG21-30-3), Zhongnanshan Medical Foundation of Guangdong Province (ZNSA-2020013), and State Key Laboratory of Respiratory Disease (J19112006202304).

Comparison of Azvudine and Nirmatrelvir/Ritonavir and Combined Use in Patients with COVID-19.

Purpose: To compare the effectiveness of azvudine and nirmatrelvir/ritonavir for the treatment of coronavirus disease (COVID-19). Patients and Methods: We conducted a retrospective analysis of data from 576 patients with COVID-19, comprising 195 patients without antiviral therapy, 226 patients treated with azvudine, 114 patients treated with nirmatrelvir/ritonavir, and 41 patients were treated with azvudine and nirmatrelvir/ritonavir concurrently. We compared their symptoms, mortality rates, and the length and cost of hospitalization. Results: The incidence of symptoms was similar in patients treated with azvudine and in those treated with nirmatrelvir/ritonavir. However, among patients experiencing weakness, the duration of weakness was significantly shorter in the azvudine group than in the nirmatrelvir/ritonavir group (P=0.029). Mortality did not differ significantly between the azvudine group and the nirmatrelvir/ritonavir group (18.14% vs.10.53%, P=0.068). Among "severe patients", the mortality rate was markedly lower in patients treated with nirmatrelvir/ritonavir than in patients treated with azvudine (16.92% vs.32.17%, P=0.026). In patients with hepatic insufficiency, those treated with nirmatrelvir/ritonavir had substantially lower mortality than those treated with azvudine (15.09% vs.34.25%, P=0.016). In addition, patients treated with nirmatrelvir/ritonavir had longer hospital stays (P=0.002) and higher hospital costs (P<0.001) than those receiving azvudine. Compared with patients treated with nirmatrelvir/ritonavir or azvudine alone, patients taking nirmatrelvir/ritonavir and azvudine concurrently had no significant improvement in survival (P>0.05), length of stay (P>0.05), or hospital costs (P>0.05). Conclusion: Azvudine is recommended for patients with non-severe COVID-19 with weakness. Nirmatrelvir/ritonavir is recommended for patients with severe COVID-19, to reduce mortality, and it could be the best choice for patients with hepatic insufficiency. The concurrent use of nirmatrelvir/ritonavir and azvudine in patients with COVID-19 could be not recommended.