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Pertussis upsurge, age shift and vaccine escape post-COVID-19 caused byptxP3macrolide-resistantBordetella pertussisMT28 clone in China: a genomic epidemiology study

百日咳博德特菌 流行病学 医学 百日咳 病毒学 儿科 公共卫生 生物 接种疫苗 内科学 遗传学 病理 细菌
作者
Pan Fu,Gangfeng Yan,Yijia Li,Li Xie,Yuehua Ke,Shuxiang Qiu,Shuang Wu,Xiaolu Shi,Jie Qin,Jinlan Zhou,Guoping Lu,Chao Yang,Chuanqing Wang
出处
期刊:Cold Spring Harbor Laboratory - medRxiv
标识
DOI:10.1101/2024.04.16.24305932
摘要

Summary Background The upsurge of pertussis post-COVID-19 and expansion of macrolide-resistant Bordetella pertussis (MRBP) pose significant public health challenges worldwide. China has experienced notable pertussis upsurge post-COVID-19, alongside an age shift to older children, vaccine escape and a notable rise in MRBP prevalence. We describe the genomic epidemiological investigation of these events. Method We did a retrospective, population-based study using culture-positive B. pertussis from Children’s Hospital of Fudan University (CHFU), the exclusive referral hospital for childhood notifiable infectious diseases, in Shanghai, China between June 2016 and March 2024. We analysed strain and pertussis epidemiology dynamics by integrating whole-genome sequencing of 723 strains with antimicrobial susceptibility, transcriptomic proflie, and clinical data. We compared the genome sequences of Shanghai strains with 6450 Chinese and global strains. Findings Coincident with national situtation, pertussis cases upsurged post-COVID-19 in Shanghai. At CHFU, the number of confirmed cases (n=349) in the first three months of 2024 exceeded the total case of previously years (n≤177). Post-COVID-19, patients shifted from predominantly infants (90%, 397/442) to widespread infection among older children (infant: 16%, 132/844), with vaccinated individuals surging from 31% (107/340) to 88% (664/756); MRBP prevalence increased from 60% (267/447) to 98% (830/845). The emergence and expansion of a ptxP3 -linage, macrolide-resistant novel clone with MLVA type 28, MR-MT28, uniquely capable of causing substantial infections among older children and vaccinated individuals, temporally strongly associated with the pertussis upsurge and epidemiological transition. MR-MT28 exhibited increased expression of antigen genes including pertussis toxin genes, along with high incidence of abnormal C-reactive protein, but associated with siginicantly milder clinical symtoms (e.g. wheezing, facial blushing, p <0·01), higher proportion of normal chest computed tomography ( p <0·05) and lower hospitalization rate ( p <0·01). Phylogenomic clustering analysis revealed a higher proportion of MR-MT28 strains grouping into clusters representing putative transmission. We reconstructed the evolutionary history of MR-MT28, and showed that it most likely originated in China around 2016 (95% highest probability density: 2013-2017) after acquring several mutations, including a novel antigen allele prn150 and 23S rRNA A2047G mutation. Approximately one quarter (26%, 50/195) of MR-MT28 has evolved into predicted PRN-deficient strains. MR-MT28 has been identified in four regions (Anhui, Shanghai, Beijing and Guangdong) of China and continuously detected in Shanghai and Beijing, suggesting domestic spread and colonization. Interpretation We identified a ptxP3 -linage, macrolide-resistant novel clone, MR-MT28, and provide evidence that pathogen evolution is more likely the primary factor driving pertussis upsurge, age shift and vaccine escape. MR-MT28 potentially poses a high global spread risk and warrants global surveillance. Macrolides may no longer be suitable as first-line drugs for pertussis treatment in China. Funding National Key Research and Development Program of China (2021YFC2701800 and 2022YFC2304700), National Natural Science Foundation of China (82202567 and 32270003), Youth Innovation Promotion Association, Chinese Academy of Sciences (2022278), Shanghai Rising-Star Program (23QA1410500), and Shanghai municipal three-year action plan for strengthening the construction of the public health system (2023-2025) GWVI-2.1.2. Research in context Evidence before this study In the first two months of 2024, an unexpected upsurge in pertussis was seen in both China and Europe. Furthermore, the pertussis upsurge in China exhibited atypical patterns, including an age shift to older children, vaccine escape and a notable increase in macrolide-resistant Bordetella pertussis (MRBP) prevalence. We aimed to test the hypothesis linking pertussis upsurge and epidemiological transition to pathogen evolution. We searched PubMed for molecular epidemiology studies of macrolide-resistant Bordetella pertussis using the terms (" Bordetella pertussis " OR "pertussis” OR “whooping cough”) AND ("macrolide resistant" OR "erythromycin resistant”) for articles before March 2024 and identified 40 studies. MRBP has been reported in eight counties, including United States, United Kingdom, France, Iran, Cambodia, Vietnam, Japan and China. While MRBP incidence in other countries remained low, it was notably high in China, accounting for 50% and even 90% of strains across various regions. The risk of MRBP spreading out of China was previously considered low, primarily because Chinese strains predominantly belonged to ptxP1 -lineage, whereas the globally prevalent lineage was ptxP3 . However, the situation is changing, as ptxP3 -MRBP strains have been identified in multiple regions of China since 2017. In Shanghai, we identified a sharply increase of ptxP3 -MRBP prevalence post-COVID-19, coinciding with pertussis age shift to older children and vaccine escape. A similar scenario was independently observed in Beijing. Additionanlly, there is a significant rise in pertussis cases since the beginning of 2024. Currently, there is a lack of study testing the link between pertussis upsurge, epidemiological transition, and the evolution of its causative pathogen. Added value of this study Our study identified a ptxP3 -linage, macrolide-resistant novel clone, MR-MT28, which is uniquely capable of causing substantial infections among older children and vaccinated population, suggesting enhanced vaccine escape. The emergence and rapid expansion of MR-MT28 temporally strongly associated with the upsurge of pertussis cases, age shift, vaccine escape and notable rise in MRBP prevalence. MR-MT28 was characterized by increased expression of antigen genes long with high incidence of abnormal C-reactive protein, but associated with siginicantly milder clinical sytmptoms, which may prolong the interval before seeking medical care, thereby amplifying transmission opportunities. Phylogenomic clustering analysis indicated that MR-MT28 may have increased transmissibility. Therefore, MR-MT28 may have competitive advantages due to antimicrobial resistance, enhanced vaccine escape, increased opportunities for transmission and transmissibility. We reconstructed the evolutionary history of MR-MT28 and showed that it most likely originated in China around 2016 after the acquisition of several mutations, and COVID-19 may have promoted its expansion. Approximately one quarter of MR-MT28 strains has evolved into predicted PRN-deficient strains. Our results showed the domestic spread and colonization of MR-MT28. Implications of all the available evidence Our study provides evidence that pathogen evolution, rather than the widely accepted notion of wanning immunity or ‘immunity debt’, is more likely the primary factor driving pertussis upsurge, age shift and vaccine escape. MR-MT28 potentially poses a high global spread risk, due to its consistent ptxP3 allele and epidemiology across many counties, together with resistance to first-line drugs and potentially competitive advantages, which warrants global surveillance and research efforts. Macrolides may no longer be suitable as first-line drugs for pertussis treatment in China.
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