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Date: 2022-11-30 10:43:57
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The FWT data indicated that the antibody titers surged rapidly after the third-dose booster vaccination, possibly achieving a peak around 6–7 days after receiving the booster dose of the vaccination. Lower pre-booster antibody titers were significantly associated with lower post-booster antibody titers, suggesting the presence of weak responders to the SARS-CoV-2 mRNA vaccination. All these data were demonstrated by FWT, which was highly correlated with the antibody titers of VST measured by established high-performance equipment.
The antibody titers of HCWs seemed to achieve their peaks one week after the third-dose vaccination, while those after secondary vaccination reached their peak in 2 weeks3,8. This clearly indicates the rapid efficacy of the third dose of the mRNA vaccine to boost serum antibody levels. However, the antibody titers after the third dose of the vaccine decay over time in a few months24. Notably, the positive correlation between the antibody titers before and after receiving the booster implied that a certain population would weakly react to the SARS-CoV-2 mRNA vaccination. The presence of weak responders to the vaccine is well known regarding the HBV vaccine25, for which several immunization series are provided individually as needed. Therefore, the development of a booster vaccination schedule for COVID-19 is individually required in the future.
Our data verified the clinical utility of FWT as a point-of-care test for measuring the neutralizing antibody titers against SARS-CoV-2. Due to its handy size and simple measurement process, as well as its very high correlation with VST, the testing device would be available at healthcare facilities with poor resources. This will enable us to measure the SARS-CoV-2 neutralizing antibodies in various clinical settings, even in outpatient clinics or long-term care facilities for the elderly, promoting antibody-based preventive and treatment strategies. For instance, to maintain herd immunity throughout society, individuals with decayed antibody titers can be screened on the spot when visiting a clinic and selectively boosted with additional vaccine doses at the same time by using point-of-care testing. It will also be useful to detect weak responders to vaccination to prioritize treatment indications, especially in long-term care facilities where vulnerable individuals reside in groups.
The appropriate antibody levels to be achieved to halt the COVID-19 pandemic or prevent infection at the individual level remain unknown. Generally, antibody titers are divided into three categories: infection prevention level, disease-onset prevention level, and severe-disease prevention level. Antibody titers at the infection prevention level are defined to those to prevent viral infection itself. Those over the disease-onset prevention level may contract the infection, but the infected individuals do not manifest any clinical symptoms. Severe-disease prevention level is explained as the antibody titer lower than these prevention levels that can prevent disease severity, such as hospitalization and fatal outcomes. To date, many cases of breakthrough infection after receiving an mRNA vaccine booster have been reported22,23. Therefore, we believe that the infection prevention level or disease-onset prevention level of antibody titers cannot be defined in the case of COVID-19 patients. To overcome the COVID-19 pandemic and normalize social functions, we rather need to determine the antibody titers for preventing the disease severity and build a vaccine strategy to maintain that optimized level.
The evaluation of antibody titers measured using our FWT method is yet to be established. In vitro data suggest that an FWT antibody titer of 125 U/mL can achieve a lethal dose (LD50) for wild-type SARS-CoV-2 (unpublished data). Previously spreading major variant strains, such as the Alpha and Delta variants, did not have genetic mutations in the receptor-binding domain of the spike protein of SARS-CoV-2. Thus, we presumed that the threshold of neutralizing activity against these variant strains would be 100–200 U/mL based on the FWT antibody titer. However, the Omicron variant has approximately 30 mutations in the receptor-binding domain19,20, resulting in reduced efficacy of acquired humoral immunity, known as immunoevasion. Recent in vitro biological experiments suggested that at least a ten-fold higher antibody titer is required to neutralize the Omicron variant when compared with the Delta variant26, potentially indicating that FWT antibody titers of 1000–2000 U/mL would be necessary for the neutralization of the Omicron variant, and those whose FWT antibody titers after the booster were less than these levels may be considered weak responders. Our data suggest that approximately 10% of HCWs participating in the study might be regarded as weak responders.
The limitations of this study should be mentioned. The vaccine response can be influenced by several factors, including age, sex, smoking history, and underlying diseases. However, these potentially associated factors were not adjusted for in this study, and future study is warranted to reveal this point in future studies. In addition, although we examined the vaccine response at an early stage after administering the mRNA vaccine booster, the testing points were arbitrary, and the timing and frequency of blood sampling were left at the participants’ discretion. However, the post-vaccination day after the third-dose booster was individually and precisely counted depending on the date of the booster, so as we can evaluate their vaccine responsiveness, or antibody titers, in detail. Then, the self-reported history taking of COVID-19 may have influenced on the data evaluation. Finally, threshold levels of the FWT antibody titers for infection prevention or onset prevention are not yet uncertain. The LD50 data is based on the wild-type variant and that in the newer variants should be evaluated as well. A high antibody titer does not necessarily endorse a high neutralizing ability because it depends on the specific epitope, the binding affinity, and the cross-reactivity. Despite these limitations, our results indicate that rapid reactivation of memory B cells leads to the robust production of antibodies immediately after receiving the third dose of the BNT162b2 vaccine. Moreover, given the rapid immune response subsequent to the administration of the third-dose of the vaccine, the booster dose for close contacts might be clinically applicable in preventing disease progression instead of administering other preventive drugs.
In summary, the FWT data demonstrated that the third-dose of the BNT162b2 vaccine administered to Japanese HCWs rapidly increased the antibody titer. However, a comparison of the pre- and post-booster antibody titers suggested the presence of weak responders to the mRNA vaccine. Therefore, the development of a selective strategy for the vaccination and treatment of COVID-19 is required to overcome and terminate the global pandemic. The active utilization of FWT-based point-of-care testing possibly takes us to a new stage of COVID-19 countermeasures that selectively target at-risk individuals.