Correlates of nucleocapsid antibodies and a combination of spike and nucleocapsid antibodies against protection of SARS-CoV-2 infection during Omicron XBB.1.16 and EG.5 predominant wave (preprint)

BackgroundThe role of nucleocapsid (N) antibodies and their combination with spike (S) antibodies against SARS-CoV-2 reinfection remains unclear. We aimed to examine the association between N antibodies, a combination of N and S antibodies, and protection against SARS-CoV-2 reinfection. MethodsWe conducted a prospective cohort study among staff at a national medical research center in Tokyo and followed them for the incidence of SARS-CoV-2 infection between June and September 2023 (Omicron XBB.1.16/EG.5 predominant wave). At baseline, participants donated blood samples to measure N-and S-specific antibodies in assays from three companies (Roche, Abbott, and Sysmex). Cox regression was used to estimate the hazard ratio (HR) and protection (1-HR*100) against subsequent SARS-CoV-2 infection across these antibody levels. FindingsOf the 2549 staff included in the analysis, 237 SARS-CoV-2 infections were identified during follow-up. Among participants with previous infection, higher pre-reinfection N antibodies were associated with a lower risk of reinfection even after adjusting S antibody levels (P for trend<0.01). Estimation of the protection matrix for N and S antibodies yielded that high levels in both N and S antibodies conferred robust protection (>90%) against subsequent infection. In addition, a pattern of low pre-reinfection N antibodies but high vaccine-enhanced S antibodies showed high protection (>80%). InterpretationPre-reinfection N antibody levels correlated with protection against reinfection, independent of S antibodies. If the N antibodies were low, vaccine-boosted S antibodies could enhance the reinfection protection. FundingNational Center for Global Health and Medicine and Japan Health Research Promotion Bureau Research Fund. Research in context Evidence before this studyWe searched published and preprinted literature with the following keywords: "COVID-19," "SARS-CoV-2," "nucleocapsid," "spike," "antibody," "protection," and "reinfection." We found few prospective or case-control studies examining the association between pre-reinfection anti-SARS-CoV-2 nucleocapsid (N) antibody levels and risk of SARS-CoV-2 reinfection; in particular, no studies were conducted for adults among Omicron-dominant phases. We also found no studies that examined the role of a combination of anti-spike (S) and anti-N antibodies in protection against SARS-CoV-2 infection. Added value of this studyThis study first revealed that pre-reinfection anti-N antibody levels correlated with protection against reinfection during the Omicron XBB.1.16 and EG.5 predominant waves even after adjusting S antibody levels. Further, we first estimated the protection matrix by combining anti-N and S antibody levels and showed that both high levels in N and S conferred robust protection (>90%). Vaccine-induced higher S antibody levels were associated with higher protection among previously infected individuals with low levels of N antibodies. Implications of all the available evidenceThe prolonged COVID-19 pandemic has resulted in diverse immune characteristics across individuals due to varying timing of infection and doses and timing of vaccination, making it challenging to decide the timing of additional vaccination. Our results suggest the utility of assessing both N and S antibody levels for considering the timing of additional vaccination for those with a history of COVID-19. If the N antibody level was low due to waning over time, additional vaccination enhances S antibodies and might improve the protection against reinfection.

COVID-19 severity and corticosteroid treatment have minimal effect on specific antibody production (preprint)

Background Dexamethasone is currently administered for Coronavirus disease 2019(COVID-19); however, there are concerns about its effect on specific antibodies’ production. The aim of this study was to evaluate whether specific antibodies were affected by COVID-19 severity and corticosteroid treatment.Methods Of 251 confirmed COVID-19 patients admitted to our hospital between January 26 and August 10, 2020, the early period of the pandemic, 75 patients with sera within 1 month of onset and 1month or longer were included in the research. A total of 253 serum samples from these patients were collected. The levels of specific antibodies for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), immunoglobulin G (IgG) and M (IgM), were measured retrospectively. The results were compared separately of each COVID-19 severity, and with or without corticosteroid treatment.Results Among the 75 patients, 47, 18, and 10 had mild, moderate, and severe disease, respectively. The median age was 53.0 years and 22 (29%) were women. The most common comorbidities were hypertension and dyslipidemia. Corticosteroids were administered to 20 (27%) and 10 (53%), patients with moderate and severe disease, respectively. The positivity rates IgM increased first, and IgG was almost always positive after day 16, regardless of the severity of COVID-19. On days 6–10, both IgG and IgM positivity rates were higher in patients with moderate disease than in those with mild or severe disease. In patients with moderate disease, IgG positivity was similar over time, regardless of corticosteroid treatment.Conclusions In COVID-19 patients, specific IgG is positive and maintained for a long period of time, even after corticosteroid treatment. The effect of corticosteroid treatment in a COVID-19 epidemiological study using specific IgG antibodies was considered minor. COVID-19 patients were more likely to receive oxygen if IgM was positive 1 week after onset, but not mechanical ventilation. IgM measurement 1 week after onset may predict COVID-19 severity.

Pre-infection neutralizing antibodies, Omicron BA.5 breakthrough infection, and long COVID: a propensity score-matched analysis (preprint)

Importance Investigating the role of pre-infection humoral immunity against Omicron BA.5 infection risk and long COVID development is critical to inform public health guidance. Objective To 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 Participants This 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. Exposures Live 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 Measures Symptomatic 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. Results Anti-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-naive individuals. Among the breakthrough cases, pre-infection antibody titers were not associated with the incidence of long COVID. Conclusions and Relevance Pre-infection immunogenicity against SARS-CoV-2 may play a role in protecting against the Omicron BA.5 infection, but not in preventing long COVID.

Durability and determinants of anti-SARS-CoV-2 spike antibodies following the second and third doses of mRNA COVID-19 vaccine (preprint)

Background Epidemiological data regarding differences in durability and its determinants of humoral immunity following 2- and 3-dose COVID-19 vaccination are scarce. Methods We repeatedly assessed the anti-spike IgG antibody titers of 2- and 3-dose mRNA vaccine recipients among the staff of a medical and research center in Tokyo. Linear mixed models were used to estimate trajectories of antibody titers from 14 to 180 days after the last immune-conferred event (vaccination or infection) and compare antibody waning rates across prior infection and vaccination status, and across background factors in infection-naive participants. Results A total of 6901 measurements from 2964 participants (median age, 35 years; 30% male) were analyzed. Antibody waning rate (per 30 days [95% CI]) was slower after 3-dose (25% [23 - 26]) than 2-dose (36% [35 - 37]). Participants with hybrid immunity (vaccination and infection) had further slower waning rates: 2-dose plus infection (16% [9 - 22]); 3-dose plus infection (21% [17 - 25]). Older age, male sex, obesity, coexisting diseases, immunosuppressant use, smoking, and alcohol drinking were associated with lower antibody titers, whereas these associations disappeared after 3-dose, except for sex (lower in female participants) and immunosuppressant use. Antibody waning was faster in older participants, females, and alcohol drinkers after 2-dose, whereas it did not differ after 3-dose across except sex. Conclusions The 3-dose mRNA vaccine conferred higher durable antibody titers, and previous infection further enhanced its durability. The antibody levels at a given time point and waning speed after 2-dose differed across background factors; however, these differences mostly diminished after 3-dose.

Neutralizing antibodies following three doses of BNT162b2 vaccine, breakthrough infection, and symptoms during the Omicron predominant wave (preprint)

Background Data on the role of immunogenicity following the third vaccine dose against Omicron infection and coronavirus disease 2019 (COVID-19)-compatible symptoms of infection are limited. Methods First we examined vaccine effectiveness (VE) of the third-dose against the second dose during the Omicron wave among the staff at a tertiary hospital in Tokyo. In a case-control study of a cohort of third vaccine recipients, we compared the pre-infection levels of live-virus neutralizing antibodies (NAb) against Omicron between breakthrough cases and their controls, who had close contact with COVID-19 patients. Among these cases, we examined the association between pre-infection NAb levels and the number of COVID-19-compatible symptoms experienced during the Omicron wave. Results Among the 1456 participants for VE analysis, 60 (4%) breakthrough infections occurred during the Omicron wave (January to March 2022). The third-dose VE for infection, relative to the second dose was 54.6% (95% CI: 14.0-76.0). Among the recipients of the third vaccine, pre-infection NAb levels against Omicron did not significantly differ between the cases and controls. Among the cases, those who experienced COVID-19-compatible symptoms had lower pre-infection NAb levels against Omicron than those who did not. Conclusions The third vaccine dose was effective in decreasing the risk of severe acute respiratory syndrome coronavirus 2 infection during the Omicron wave compared with the second dose. Among third-dose recipients, higher pre-infection NAb levels may not be associated with a lower risk of Omicron infection. Contrarily, they may be associated with fewer symptoms of infection.

SARS-CoV-2 breakthrough infection during the Delta-dominant epidemic and neutralizing antibodies against Omicron in comparison with the third dose of BNT162b2: a matched analysis (preprint)

Background Longitudinal data are lacking to compare booster effects of Delta breakthrough infection versus the third vaccine dose on neutralizing antibodies (NAb) against Omicron. Methods Participants were the staff of a national research and medical institution in Tokyo who attended serological surveys on June 2021 (baseline) and December 2021 (follow-up); in between, the Delta-dominant epidemic occurred. Of 844 participants who were infection-naive and had received two doses of BNT162b2 at baseline, we identified 11 breakthrough infections during the follow-up. One control matched to each case was randomly selected from those who completed the booster vaccine and those who were unboosted by the follow-up. We used the generalized estimating equation model to compare live-virus NAb against Wuhan, Delta, and Omicron across groups. Results Persons who experienced breakthrough infection showed marked increases in NAb titers against Wuhan (4.1-fold) and Delta (5.5-fold), and 64% had detectable NAb against Omicron at follow-up, although the NAb against Omicron after breakthrough infection was 6.7- and 5.2-fold lower than that against Wuhan and Delta, respectively. The increase was apparent only in symptomatic cases and as high as in the third vaccine recipients. In contrast, these titers largely decreased (Wuhan, Delta) or remained undetected (Omicron) at follow-up in infection-naive and unboosted persons. Conclusions Symptomatic breakthrough infection during the Delta predominant wave was associated with significant increases in NAb against Wuhan, Delta, and Omicron, similar to the third BNT162b2 vaccine. Given the much lower cross-NAb against Omicron than other virus types, however, infection prevention measures must be continued irrespective of vaccine and infection history while the immune evasive variants are circulating.

Sex-associated differences between body mass index and SARS-CoV-2 antibody titers following the BNT162b2 vaccine among 2,435 healthcare workers in Japan (preprint)

Obesity may downregulate vaccine-induced immunogenicity, but the epidemiological evidence for the COVID-19 vaccine is limited, and the sex-associated difference is unknown. It was observed that a higher body mass index was associated with lower titers of spike IgG antibodies against SARS-CoV-2 in men but not in women.