RESUMO
BackgroundEpidemiological data regarding differences in durability and its determinants of humoral immunity following 2- and 3-dose COVID-19 vaccination are scarce. MethodsWe 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. ResultsA 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. ConclusionsThe 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.
RESUMO
BackgroundData 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. MethodsFirst 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. ResultsAmong 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. ConclusionsThe 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. SummaryThe third vaccine dose reduced SARS-CoV-2 infection risk during the Omicron wave. Higher neutralizing antibody levels may not reduce Omicron infection risk in third-dose patients. On the contrary, it may be associated with fewer symptoms of infection.
RESUMO
BackgroundLongitudinal data are lacking to compare booster effects of Delta breakthrough infection versus the third vaccine dose on neutralizing antibodies (NAb) against Omicron. MethodsParticipants 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. ResultsPersons 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. ConclusionsSymptomatic 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. Key pointsSymptomatic, not asymptomatic, SARS-CoV-2 breakthrough infection after the second BNT162b2 vaccination during the Delta-predominant wave enhanced neutralizing antibodies against Wuhan, Delta, and Omicron comparable to the three vaccine doses, although immunity against Omicron was much lower than Wuhan and Delta.
RESUMO
BNT162b2, an mRNA-based SARS-CoV-2 vaccine (Pfizer-BioNTech), is one of the most effective COVID-19 vaccines and has been approved by more than 130 countries worldwide. However, several studies have reported that the COVID-19 vaccine shows high interpersonal variability in terms of humoral and cellular responses, such as those with respect to SARS-CoV-2 spike protein immunoglobulin (Ig)G, IgA, IgM, neutralizing antibodies, and CD4+ & CD8+ T cells. The objective of this study is to investigate the kinetic changes in anti-SARS-CoV-2 spike IgG (IgG-S) profiles and adverse reactions and their associations with HLA profiles among 100 hospital workers from the Center Hospital of the National Center for Global Health and Medicine (NCGM), Tokyo, Japan. DQA1*03:03:01 (P = 0.017; Odd ratio (OR) 2.80, 95%Confidence interval (CI) 1.05-7.25) was significantly associated with higher IgG-S production after two doses of BNT162b2 while DQB1*06:01:01:01 (P = 0.028, OR 0.27, 95%CI 0.05-0.94) was significantly associated with IgG-S declines after two doses of BNT162b2. No HLA alleles were significantly associated with either local symptoms or fever. However, C*12:02:02 (P = 0.058; OR 0.42, 95%CI 0.15-1.16), B*52:01:01 (P = 0.031; OR 0.38, 95%CI 0.14-1.03), DQA1*03:02:01 (P = 0.028; OR 0.39, 95%CI 0.15-1.00) and DPB1*02:01:02 (P = 0.024; OR 0.45, 95%CI 0.21-0.97) appeared significantly associated with protection against systemic symptoms after two doses of BNT162b2 vaccination. Further studies with larger sample sizes are clearly warranted to determine HLA allele associations with the production and long-term sustainability of IgG-S after COVID-19 vaccination.
RESUMO
IntroductionThe humoral and cellular immune responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon coronavirus disease 2019 (COVID-19) vaccination remain to be clarified. Hence, we aimed to investigate the long-term chronological changes in SARS-CoV-2 specific IgG antibody, neutralizing antibody, and T cell responses during and after receiving the BNT162b2 vaccine. MethodsWe performed serological, neutralization, and T cell assays among 100 hospital workers aged 22-73 years who received the vaccine. We conducted seven surveys up to eight months after the second vaccination dose. ResultsSARS-CoV-2 spike protein-specific IgG (IgG-S) titers and T cell responses increased significantly following the first vaccination dose. The highest titers were observed on day 29 and decreased gradually until the end of the follow-up period. There was no correlation between IgG-S and T cell responses. Notably, T cell responses were detected on day 15, earlier than the onset of neutralizing activity. ConclusionsThis study demonstrated that both IgG-S and T cell responses were detected before acquiring sufficient levels of SARS-CoV-2 neutralizing antibodies. These immune responses are sustained for approximately six-ten weeks but not for seven months or later following the second vaccination, indicating the need for the booster dose (i.e., third vaccination).
RESUMO
BackgroundWhile increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infections. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity. MethodsWe described incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2,473 fully vaccinated staff (BNT162b2) for breakthrough infection and selected three matched controls. We measured pre-infection neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the two groups. ResultsNo COVID-19 cases occurred 1-2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2-4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and had returned to work early. There was no measurable difference between cases and controls in pre-infection neutralizing antibody titers against the wild-type, Alpha, and Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type. ConclusionsPre-infection neutralizing antibody titers were not decreased among patients with breakthrough infection under the Delta variant rampage. The result points to the importance of infection control measures in the post-vaccination era, irrespective of immunogenicity profile.
RESUMO
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.
RESUMO
BackgroundWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the features of immune response remain to be clarified. MethodsIn the present prospective observational study, 225 healthy individuals in Kumamoto General Hospital, Japan, who received two BNT162b2 doses in February 2021, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT50; assessed using infectious virions and live target cells) with SARS-CoV-2-S1-binding-IgG and -IgM levels, adverse effects (AEs), ages, and genders were examined. The average half-life of neutralizing activity and the average time length for the loss of detectable neutralizing activity were determined and the potency of serums against variants of concerns was also determined. FindingsSignificant rise in NT50s was seen in serums on day 28 post-1st dose. A moderate inverse correlation was seen between NT50s and ages, but no correlation was seen between NT50s and AEs. NT50s and IgG levels on day 28 post-1st dose and pain scores following the 2nd shot were greater in women than in men. The average half-life of neutralizing activity in the vaccinees was approximately 67.8 days and the average time length for their serums to lose the detectable neutralizing activity was 198.3 days. While serums from elite-responders (NT50s>1,500-fold: the top 4% among all participants NT50s) potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain. InterpretationBNT162b2-elicited immune response has no significant association with AEs. BNT162b2-efficacy is likely diminished to under detection limit by 6-7 months post-1st shot. High-level neutralizing antibody-containing serums potently to moderately block the infection of SARS-CoV-2 variants; however, a few moderate-level neutralizing antibody-containing serums failed to do so. If BNT162b2-elicited immunity memory is short, an additional vaccine or other protective measures would be needed. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWhile mRNA vaccines against SARS-CoV-2 have been exceedingly effective in preventing symptomatic viral infection, the salient features of immune response including the persistence of protection remain to be clarified. There is a report that anti-SARS-CoV-2 antibodies persist through 6 months after the second dose of mRNA-1273 vaccine (Doria-Rose et al. N Engl J Med. 2021;384:2259-2261); however, more definite immune kinetics following mRNA-vaccine-elicited protection have to be clarified. The mRNA-vaccine-elicited protection against SARS-CoV-2 variants are also to be determined. Added value of this studyIn the present prospective study, 225 twice-BNT162b2-dose-receiving individuals in Japan were enrolled. No significant correlation was seen between 50% neutralizing titers (NT50s), determined by using infectious SARS-CoV-2 virions and live target cells, and adverse effects. Largely, NT50s and IgG levels were greater in women than in men. Following 28 days post-2nd shot, significant reduction was seen in NT50s, IgG, and IgM levels. The average half-life of NT50s was [~]68 days and the average time-length for participants serums to lose the detectable activity was [~]198 days. Although serums from elite-responders potently to moderately blocked the infectivity of variants of concerns, some serums with moderate NT50s failed to block the infectivity of a beta strain. Implications of all the available evidenceBNT162b2 efficacy is likely to be diminished to under detection limit by 6-7 months post-1st shot on average. Individuals with moderate NT50s may fail to block beta variants. If BNT162b2-elicited immune memory is lost soon, additional vaccine(s) or other protective means would be needed.
RESUMO
High vaccine reactogenicities may reflect stronger immune responses, but the epidemiological evidence for coronavirus disease 2019 (COVID-19) vaccines is sparse and inconsistent. We observed that a fever of [≥]38{square} after two doses of the BNT162b2 vaccine was associated with higher severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike IgG titers.
RESUMO
ObjectivesTo investigate the risk factors contributing to severity on admission. Additionally, risk factors on worst severity and fatality were studied. Moreover, factors were compared based on three points: early severity, worst severity, and fatality. DesignA observational cohort study utilizing data entered in a Japan nationwide COVID-19 inpatient registry, COVIREGI-JP. SettingAs of August 31, 2020, 7,546 cases from 780 facilities have been registered. Participating facilities cover a wide range of hospitals where COVID-19 patients are admitted in Japan. ParticipantsParticipants who had a positive test result on any applicable SARS-CoV-2 diagnostic tests, and were admitted to participating healthcare facilities. A total of 3,829 cases were identified from January 16 to May 31, 2020, of which 3,376 cases were included in this study. Primary and secondary outcoe measuresPrimary outcome was severe or non-severe on admission, determined by the requirement of mechanical ventilation or oxygen therapy, SpO2, or respiratory rate. Secondary outcome was the worst severity during hospitalization, judged by the requirement of oxygen and/or IMV/ECMO. ResultsRisk factors for severity on admission were older age, male, cardiovascular disease, chronic respiratory disease, diabetes, obesity, and hypertension. Cerebrovascular disease, liver disease, renal disease or dialysis, solid tumor, and hyperlipidemia did not influence severity on admission; however it influenced worst severity. Fatality rates for obesity, hypertension, and hyperlipidemia were relatively lower. ConclusionsThis study segregated the comorbidities driving severity and death. It is possible that risk factors for severity on admission, worst severity, and fatality are not consistent and may be propelled by different factors. Specifically, while hypertension, hyperlipidemia, and obesity had major effect on worst severity, their impact was mild on fatality in the Japanese population. Some studies contradict our results; therefore, detailed analyses, considering in-hospital treatments, are needed for validation. Trial registrationUMIN000039873. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000045453 Strengths and limitations of this studyO_LIIn this article, we studied the disease progression of COVID-19, by comparing the risk factors on three points: early severity, worst severity, and fatality. C_LIO_LIOur results are useful from a public health perspective, as we provide risk factors for predicting the severity on admission and disease progression from patients background factors. C_LIO_LIThis study pointed out the possibility that risk factors of the severity on admission, worst severity, and fatality are not consistent and may be propelled by different factors. C_LIO_LIOur data were collected from hundreds of healthcare facilities; thus data accuracy may be questionable. C_LIO_LIAlso, treatment type, dosage, duration, and combination varied immensely across the facilities and we did not consider treatments prior to and during hospitalization in the analysis. C_LI
RESUMO
ObjectivesAlthough several randomised controlled trials have compared the efficacy of remdesivir with that of placebo, there is limited evidence regarding its effect in the early stage of nonsevere COVID-19 cases. MethodsWe evaluated the efficacy of remdesivir on the early stage of nonsevere COVID-19 using the COVID-19 Registry Japan, a nationwide registry of hospitalised COVID-19 patients in Japan. Two regimens (start remdesivir therapy within 4 days from admission vs. no remdesivir during hospitalisation) among patients without the need for supplementary oxygen therapy were compared by a three-step processing (cloning, censoring, and weighting) method. The primary outcome was supplementary oxygen requirement during hospitalisation. Secondary outcomes were 30-day fatality risk and risk of invasive mechanical ventilation or extracorporeal membrane oxygenation (IMV/ECMO). ResultsThe data of 12,657 cases met our inclusion criteria. The start remdesivir regimen showed a lower risk of supplementary oxygen requirement (hazard ratio: 0.861, p < 0.001). Both 30-day fatality risk and risk of IMV/ECMO introduction were not significantly different between the two regimens (hazard ratios: 1.05 and 0.886, p values: 0.070 and 0.440, respectively). ConclusionsRemdesivir might reduce the risk of oxygen requirement during hospitalisation in the early stage of COVID-19; however, it had no positive effect on the clinical outcome and reduction of IMV/ECMO requirement.
RESUMO
The development of therapeutic agents is important for controlling emerging infectious diseases. However, looking back into our experiences for the last three decades, there were no effective treatments at the beginning of the pandemics. Generally, the first step to develop therapeutic agents for emerging infectious diseases is to search for already existing agents that might have therapeutic effects, and so did with COVID-19. Many candidates have been examined with hopes of success for the past year. Up to now, only two agents, remdesivir and dexamethasone, which were anti-viral and anti-inflammatory agents, respectively, were approved as therapeutic agents. The two drugs are approved based on the results of clinical trials performed overseas and not in Japan. Though many other candidate drugs have been proposed and clinical trials have been carried out in Japan, few studies have reached clear conclusions. The reasons for these ineffective study-progress are not clear, but it appears that high hurdles may exist for doctors to participate in RCTs, probably due to the lack of human resources that can be invested in implementing RCTs. Based on the lessons learned from this pandemic, to proceed RTCs effectively, a new organization with the role of a command tower to manage and support RCTs is eagerly awaited.
