Pre-infection neutralizing antibodies, Omicron BA.5 breakthrough infection, and long COVID: a propensity score-matched analysis
Authors: Yamamoto Shohei , Matsuda Kouki , Maeda Kenji , Horii Kumi , Okudera Kaori , Oshiro Yusuke , Inamura Natsumi , Nemoto Takashi , Takeuchi Junko S. , Li Yunfei , Konishi Maki , Tsuchiya Kiyoto , Gatanaga Hiroyuki , Oka Shinichi , Mizoue Tetsuya , Sugiyama Haruhito , Aoyanagi Nobuyoshi , Mitsuya Hiroaki , Sugiura Wataru , Ohmagari Norio 
Published: April 2023

AbstractImportanceInvestigating the role of pre-infection humoral immunity against Omicron BA.5 infection risk and long COVID development is critical to inform public health guidance.ObjectiveTo investigate the association between pre-infection immunogenicity after the third vaccine dose and the risks of Omicron BA.5 infection and long coronavirus disease.Design, Setting, and ParticipantsThis nested case-control analysis was conducted among tertiary hospital staff in Tokyo, Japan who donated blood samples in June 2022 (1 month before Omicron BA.5 dominant wave onset [July–September 2022]) approximately 6 months after receiving the third dose of the historical monovalent coronavirus disease 2019 mRNA vaccine.ExposuresLive virus-neutralizing antibody titers against Wuhan and Omicron BA.5 (NT50) and anti-SARS-CoV-2 spike protein antibody titers with Abbott (AU/mL) and Roche (U/mL) assays at pre-infection.Main Outcomes and MeasuresSymptomatic SARS-CoV-2 breakthrough infections during the Omicron BA.5 dominant wave vs. undiagnosed controls matched using a propensity score. Incidence of long COVID (persistent symptoms ≥4 weeks after infection) among breakthrough infection cases.ResultsAnti-spike antibody titers were compared between 243 breakthrough infection cases and their matched controls among the 2360 staff members who met the criteria. Neutralizing antibodies in 50 randomly selected matched pairs were measured and compared. Pre-infection anti-spike and neutralizing antibody titers were lower in breakthrough cases than in undiagnosed controls. Neutralizing antibody titers against Wuhan and Omicron BA.5 were 64% (95% CI: 42–77) and 72% (95% CI: 53–83) lower, respectively, in breakthrough cases than in undiagnosed controls. Individuals with previous SARS-CoV-2 infections were more frequent among undiagnosed controls than breakthrough cases (19.3% vs. 4.1%), and their neutralizing antibody titers were higher than those of infection-naïve individuals. Among the breakthrough cases, pre-infection antibody titers were not associated with the incidence of long COVID.Conclusions and RelevancePre-infection immunogenicity against SARS-CoV-2 may play a role in protecting against the Omicron BA.5 infection, but not in preventing long COVID.Key PointsQuestionDoes pre-infection anti-SARS-CoV-2 humoral immunity protect against Omicron BA.5 infection and long-COVID development?FindingsPre-infection neutralizing antibody titers against Omicron BA.5 were lower in subsequent Omicron BA.5 breakthrough infection cases than in matched controls in this nested case-control study of healthcare workers who received the third dose of historical COVID-19 mRNA vaccines approximately 6 months prior. Pre-infection antibody titers could not predict the incidence of long COVID among breakthrough infection cases.MeaningHigher pre-infection humoral immunity approximately 6 months after the third vaccination may correlate with protection against Omicron BA.5 infection but not against long-COVID development.