Routine vaccination for influenza and pneumococcal disease and its effect on COVID-19 in a population of Dutch older adults

Objectives: Protective heterologous beneficial effects of vaccines have been reported, and in this study we aimed to assess the impact of routine pneumococcal and influenza vaccination on the incidence and symptom duration of COVID-19 in a population of Dutch older adults. Methods: This cohort study is a secondary analysis of the BCG-CORONA-ELDERLY study, a randomised controlled trial on the effect of BCG vaccination on the cumulative incidence of respiratory tract infections requiring medical intervention in adults ≥60 years. The primary outcome was the cumulative incidence of a self-reported positive SARS-CoV-2 PCR test, and was assessed using a Fine-Gray competing risks model adjusted for baseline characteristics at enrolment. We analysed data from November 1st 2020 until the end of the main study in May 2021. Results: Routine vaccination data 2020/2021 were available for 1963/2014 (97.5 %) participants; 44/1963 (2.2 %) were excluded due to COVID-19 before vaccination. 1076/1919 (56.1 %) had received the influenza vaccine and 289/1919 (15.1 %) the pneumococcal vaccine. The cumulative incidence of COVID-19 was 0.030 (95 %CI 0.021–0.041) in those vaccinated against influenza compared to 0.029 (95 %CI 0.019–0.041) in the unvaccinated group (subdistribution hazard ratio (SDHR) 1.018; 95 %CI 0.602–1.721). For pneumococcal vaccination the cumulative incidence was 0.031 (95 %CI 0.015–0.056) for the vaccinated and 0.029 (95 %CI 0.022–0.038) for non-vaccinated individuals (SDHR 0.961; 95 %CI 0.443–2.085). BCG vaccination in the previous year and sex were not significant effect modifiers in the primary analysis. Duration of fever, cough and dyspnoea was also not significantly different between treatment arms. Conclusion: Neither influenza nor pneumococcal vaccination was associated with a lower incidence or shorter duration of COVID-19 symptoms in older adults

Timing and sequence of vaccination against COVID-19 and influenza (TACTIC):a single-blind, placebo-controlled randomized clinical trial

Background: Novel mRNA-based vaccines have been used to protect against SARS-CoV-2, especially in vulnerable populations who also receive an annual influenza vaccination. The TACTIC study investigated potential immune interference between the mRNA COVID-19 booster vaccine and the quadrivalent influenza vaccine, and determined if concurrent administration would have effects on safety or immunogenicity. Methods: TACTIC was a single-blind, placebo-controlled randomized clinical trial conducted at the Radboud University Medical Centre, the Netherlands. Individuals ≥60 years, fully vaccinated against COVID-19 were eligible for participation and randomized into one of four study groups: 1) 0.5 ml influenza vaccination Vaxigrip Tetra followed by 0.3 ml BNT162b2 COVID-19 booster vaccination 21 days later, (2) COVID-19 booster vaccination followed by influenza vaccination, (3) influenza vaccination concurrent with the COVID-19 booster vaccination, and (4) COVID-19 booster vaccination only (reference group). Primary outcome was the geometric mean concentration (GMC) of IgG against the spike (S)-protein of the SARS-CoV-2 virus, 21 days after booster vaccination. We performed a non-inferiority analysis of concurrent administration compared to booster vaccines alone with a predefined non-inferiority margin of −0.3 on the log10-scale. Findings: 154 individuals participated from October, 4, 2021, until November, 5, 2021. Anti-S IgG GMCs for the co-administration and reference group were 1684 BAU/ml and 2435 BAU/ml, respectively. Concurrent vaccination did not meet the criteria for non-inferiority (estimate −0.1791, 95% CI −0.3680 to −0.009831) and antibodies showed significantly lower neutralization capacity compared to the reference group. Reported side-effects were mild and did not differ between study groups. Interpretation: Concurrent administration of both vaccines is safe, but the quantitative and functional antibody responses were marginally lower compared to booster vaccination alone. Lower protection against COVID-19 with concurrent administration of COVID-19 and influenza vaccination cannot be excluded, although additional larger studies would be required to confirm this. Trial registration number: EudraCT: 2021-002186-17 Funding: The study was supported by the ZonMw COVID-19 Programme.</p

The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections

BACKGROUND AND OBJECTIVE: A recent study has suggested that circadian rhythm has an important impact on the immunological effects induced by Bacillus Calmette-Guérin (BCG) vaccination. The objective of this study was to evaluate whether the timing of BCG vaccination (morning or afternoon) affects its impact on severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infections and clinically relevant respiratory tract infections (RTIs). METHODS: This is a post-hoc analysis of the BCG-CORONA-ELDERLY (NCT04417335) multicenter, placebo-controlled trial, in which participants aged 60 years and older were randomly assigned to vaccination with BCG or placebo, and followed for 12 months. The primary endpoint was the cumulative incidence of SARS-CoV-2 infection. To assess the impact of circadian rhythm on the BCG effects, participants were divided into four groups: vaccinated with either BCG or placebo in the morning (between 9:00h and 11:30h) or in the afternoon (between 14:30h and 18:00h). RESULTS: The subdistribution hazard ratio of SARS-CoV-2 infection in the first six months after vaccination was 2.394 (95% confidence interval [CI], 0.856-6.696) for the morning BCG group and 0.284 (95% CI, 0.055-1.480) for the afternoon BCG group. When comparing those two groups, the interaction hazard ratio was 8.966 (95% CI, 1.366-58.836). In the period from six months until 12 months after vaccination cumulative incidences of SARS-CoV-2 infection were comparable, as well as cumulative incidences of clinically relevant RTI in both periods. CONCLUSION: Vaccination with BCG in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning in the first six months after vaccination

Determinants of Systemic SARS-CoV-2-Specific Antibody Responses to Infection and to Vaccination: A Secondary Analysis of Randomised Controlled Trial Data

SARS-CoV-2 infections elicit antibodies against the viral spike (S) and nucleocapsid (N) proteins; COVID-19 vaccines against the S-protein only. The BCG-Corona trial, initiated in March 2020 in SARS-CoV-2-naïve Dutch healthcare workers, captured several epidemic peaks and the introduction of COVID-19 vaccines during the one-year follow-up. We assessed determinants of systemic anti-S1 and anti-N immunoglobulin type G (IgG) responses using trial data. Participants were randomised to BCG or placebo vaccination, reported daily symptoms, SARS-CoV-2 test results, and COVID-19 vaccinations, and donated blood for SARS-CoV-2 serology at two time points. In the 970 participants, anti-S1 geometric mean antibody concentrations (GMCs) were much higher than anti-N GMCs. Anti-S1 GMCs significantly increased with increasing number of immune events (SARS-CoV-2 infection or COVID-19 vaccination): 104.7 international units (IU)/mL, 955.0 IU/mL, and 2290.9 IU/mL for one, two, and three immune events, respectively (p < 0.001). In adjusted multivariable linear regression models, anti-S1 and anti-N log10 concentrations were significantly associated with infection severity, and anti-S1 log10 concentration with COVID-19 vaccine type/dose. In univariable models, anti-N log10 concentration was also significantly associated with acute infection duration, and severity and duration of individual symptoms. Antibody concentrations were not associated with long COVID or long-term loss of smell/taste

The impact of Bacillus Calmette-Guérin vaccination on antibody response after COVID-19 vaccination

Earlier studies showed that BCG vaccination improves antibody responses of subsequent vaccinations. Similarly, in older volunteers we found an increased IgG receptor-binding domain (RBD) concentration after SARS-CoV-2 infection if they were recently vaccinated with BCG. This study aims to assess the effect of BCG on the serum antibody concentrations induced by COVID-19 vaccination in a population of adults older than 60 years. Serum was collected from 1,555 participants of the BCG-CORONA-ELDERLY trial a year after BCG or placebo, and we analyzed the anti-SARS-CoV-2 antibody concentrations using a fluorescent-microsphere-based multiplex immunoassay. Individuals who received the full primary COVID-19 vaccination series before serum collection and did not test positive for SARS-CoV-2 between inclusion and serum collection were included in analyses (n = 945). We found that BCG vaccination before first COVID-19 vaccine (median 347 days [IQR 329-359]) did not significantly impact the IgG RBD concentration after COVID-19 vaccination in an older European population

Routine vaccination for influenza and pneumococcal disease and its effect on COVID-19 in a population of Dutch older adults

Objectives: Protective heterologous beneficial effects of vaccines have been reported, and in this study we aimed to assess the impact of routine pneumococcal and influenza vaccination on the incidence and symptom duration of COVID-19 in a population of Dutch older adults. Methods: This cohort study is a secondary analysis of the BCG-CORONA-ELDERLY study, a randomised controlled trial on the effect of BCG vaccination on the cumulative incidence of respiratory tract infections requiring medical intervention in adults ≥60 years. The primary outcome was the cumulative incidence of a self-reported positive SARS-CoV-2 PCR test, and was assessed using a Fine-Gray competing risks model adjusted for baseline characteristics at enrolment. We analysed data from November 1st 2020 until the end of the main study in May 2021. Results: Routine vaccination data 2020/2021 were available for 1963/2014 (97.5 %) participants; 44/1963 (2.2 %) were excluded due to COVID-19 before vaccination. 1076/1919 (56.1 %) had received the influenza vaccine and 289/1919 (15.1 %) the pneumococcal vaccine. The cumulative incidence of COVID-19 was 0.030 (95 %CI 0.021–0.041) in those vaccinated against influenza compared to 0.029 (95 %CI 0.019–0.041) in the unvaccinated group (subdistribution hazard ratio (SDHR) 1.018; 95 %CI 0.602–1.721). For pneumococcal vaccination the cumulative incidence was 0.031 (95 %CI 0.015–0.056) for the vaccinated and 0.029 (95 %CI 0.022–0.038) for non-vaccinated individuals (SDHR 0.961; 95 %CI 0.443–2.085). BCG vaccination in the previous year and sex were not significant effect modifiers in the primary analysis. Duration of fever, cough and dyspnoea was also not significantly different between treatment arms. Conclusion: Neither influenza nor pneumococcal vaccination was associated with a lower incidence or shorter duration of COVID-19 symptoms in older adults

Corrigendum: The impact of circadian rhythm on Bacillus Calmette-Guérin vaccination effects on SARS-CoV-2 infections (Front. Immunol., (2023), 14, 980711, 10.3389/fimmu.2023.980711)

In the published article, there was an error. We stated that in the first six month after vaccination, BCG vaccination in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning. Given the lack of statistical significance in the analysis comparing the BCG-vaccinated individuals to those who received placebo in the morning and afternoon, it is not accurate to use ‘protection’ when describing the significant interaction hazard ratio in Table 2A. A correction has been made to the conclusion of the Abstract. This sentence previously stated: “Vaccination with BCG in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning in the first six months after vaccination.” The corrected sentence appears below: “Although there was a difference in effect between morning and afternoon BCG vaccination, the vaccine did not protect against SARS-COV-2 infections and clinically relevant RTI’s at either timepoint.” A correction has been made to the last three paragraphs of the results. The paragraphs previously stated: “In the first six months after vaccination, the cumulative incidence of SARS-CoV-2 infection was significantly lower in the BCG afternoon group compared to the BCG morning group (interaction hazard ratio [IHR] 8.966, 95% CI 1.366-58.836) (Table 2A). The cumulative incidence of SARS-CoV-2 infection in the BCG afternoon group also tended to be lower than in the respective placebo group, although not statistically significant (subdistribution hazard ratio [SDHR] 0.284, 95% CI 0.055-1.480). In the morning, results are in the opposite direction, and the placebo group tended to be better protected against SARS-CoV-2 (SDHR 2.394, 95% CI 0.856-6.696). In the period from six months after vaccination until 12 months after vaccination cumulative incidences were comparable (Table 2B). The SDHR of SARS-CoV-2 infections was 1.460 (95% CI 0.505-4.223) for the afternoon BCG group and 0.745 (95% CI 0.43-1.600) for the morning BCG group (IHR 0.530, 95% CI 0.149-1.881). A better protection of BCG vaccination in the afternoon against SARS-CoV-2 is also reflected in the analysis of the full 12 months follow-up (cumulative incidences 0.035 [95% CI 0.019-0.060] in the afternoon versus 0.067 [95% CI 0.044-0.097] in the morning), but neither statistically significant (Table 2C). Due to the interventions of the COVID-19 pandemic, such as quarantine, isolation, and social distancing, the number of clinically relevant RTIs was much lower than SARS-CoV-2 infections. The IHR of the morning BCG group was 0.351 (95% CI 0.025-4.978) in the first part of the year, 2.260 (95% CI 0.376-13.571) in the second part of the year and 1.218 (95% CI 0.295-5.037) in the analysis of the full 12 months (Tables 2A-C). In conclusion, BCG vaccination in the afternoon in the first six months offered better protection than BCG vaccination in the morning against SARS-CoV-2 infections, and potentially better protection than placebo vaccination in the afternoon.” The corrected paragraphs appears below: “In the first six months after vaccination, the cumulative incidence of SARS-CoV-2 infection was 0.014 (95% CI 0.005-0.031) in the placebo morning group and 0.034 (95% CI 0.018-0.056) in the BCG morning group (subdistribution hazard ratio [SDHR] 2.394, 95% CI 0.856-6.696) (Table 2A). In the afternoon results are in the opposite direction, but not statistically significant (SDHR 0.284, 95% CI 0.055-1.480). When comparing the BCG morning and afternoon group with each other, the interaction hazard ratio [IHR] is 8.966 (95% CI 1.366-58.836), indicating a difference in effect between the two timepoints. In the second part of the year, cumulative incidences were more comparable with SDHRs of 0.745 (95% CI 0.437-1.600) and 1.460 (95% CI 0.505-4.223) for the morning and the afternoon group, respectively (Table 2B). The IHR of the two BCG groups is 0.530 (95% CI 0.149-1.881). The analysis of the full 12 months follow-up is in line with the aforementioned and did not reveal any statistically significant differences in the cumulative incidence of SARS-CoV-2 infection (Table 2C). Due to the interventions of the COVID-19 pandemic, such as quarantine, isolation, and social distancing, the number of clinically relevant RTIs was much lower than SARS-CoV-2 infections. The SDHR was comparable in all time periods (Tables 2A–C). In conclusion, neither participants vaccinated with BCG in the morning nor in the afternoon were protected against respiratory infections including SARS-CoV-2.” A correction has been made to the first two paragraphs of the Discussion. The paragraphs previously stated: “The results of the present study show that, in the first six months after vaccination, BCG vaccination in the afternoon offered better protection against SARS-CoV-2 infections than BCG vaccination in the morning. In addition, BCG vaccination in the afternoon tended to offer better protection against SARS-CoV-2 than placebo. We did not observe those effects in the period from six months after vaccination until one year after vaccination. Our results should be interpreted with caution as this trial was not powered nor designed to analyze the effect of circadian rhythm. Consequently, the number of events per subgroup was low and confidence intervals were wide. Despite this limitation, the results argue against our initial hypothesis of a stronger heterologous effect of BCG in the morning. The time of BCG vaccination did not affect the impact on clinically relevant RTIs. Our finding of a potential better protection of BCG in the afternoon contradicts the experimental results from de Bree et al (7). Possible explanations may be that in the experimental study from de Bree et al. the time period between vaccination and blood collection was just three months, and that the morning group was vaccinated between 8:00 and 9:00 and the afternoon group at 18:00. …” The corrected paragraphs appears below: “The results of the present study show that the time of day of BCG vaccination did not affect the susceptibility to respiratory infections. We observed some differences in the cumulative incidence of SARS-CoV-2 infections, especially in the first six months after vaccination, but the number of events was too low and consequently confidence intervals were too wide to draw any conclusion. Notably, the direction of the effects was even in the opposite direction of our initial hypothesis that BCG vaccination offers better protection in the morning. It is important mentioning that the initial trial was not powered nor designed to analyze the effect of circadian rhythm. The most likely explanation for our findings is that BCG vaccination simply has no effect on the protection against RTIs and SARS-CoV-2 infections in this study. A protective effect has previously been demonstrated in several smaller studies (14, 20-22), but pathophysiological differences between SARS-CoV-2 infections and other RTIs (such as influenza) may account for these differential effects of BCG (23). Another explanation why our results contradict those from de Bree et al. may be that in their experiments the time period between vaccination and blood collection was just three months, and that the morning group was vaccinated between 8:00 and 9:00 and the afternoon group at 18:00 (7).” A correction has been made to the third paragraph of the Discussion. The following sentences were removed: “A trend towards lower incidence of SARS-CoV-2 infections in the BCG afternoon group compared to the placebo group in the first six months, may also point to a – if at all – better protection of BCG vaccination in the afternoon. An explanation for the absence of a clear effect may be that BCG vaccination has no effect on the protection against SARS-CoV-2 infections which makes the timing of the vaccination irrelevant.” A correction has been made to the third paragraph of the Discussion. The following sentence was moved further up: “A protective effect has previously been demonstrated in several (smaller) studies (14, 20-22), but pathophysiological differences between SARS-CoV-2 infections and other RTIs (such as influenza) may account for these differential effects of BCG (23).” A correction has been made to the fourth paragraph of the Discussion, paragraph 4. The following sentence was removed: “Interestingly, we only observed a trend towards protective effects of BCG only in the first six months after vaccination, which could mean that trained immunity effects are relatively short-lasting.” The authors apologize for these errors and state that this does not change the scientific conclusions of the article in any way. The original article has been updated

Determinants of Systemic SARS-CoV-2-Specific Antibody Responses to Infection and to Vaccination: A Secondary Analysis of Randomised Controlled Trial Data

SARS-CoV-2 infections elicit antibodies against the viral spike (S) and nucleocapsid (N) proteins; COVID-19 vaccines against the S-protein only. The BCG-Corona trial, initiated in March 2020 in SARS-CoV-2-naïve Dutch healthcare workers, captured several epidemic peaks and the introduction of COVID-19 vaccines during the one-year follow-up. We assessed determinants of systemic anti-S1 and anti-N immunoglobulin type G (IgG) responses using trial data. Participants were randomised to BCG or placebo vaccination, reported daily symptoms, SARS-CoV-2 test results, and COVID-19 vaccinations, and donated blood for SARS-CoV-2 serology at two time points. In the 970 participants, anti-S1 geometric mean antibody concentrations (GMCs) were much higher than anti-N GMCs. Anti-S1 GMCs significantly increased with increasing number of immune events (SARS-CoV-2 infection or COVID-19 vaccination): 104.7 international units (IU)/mL, 955.0 IU/mL, and 2290.9 IU/mL for one, two, and three immune events, respectively (p 10 concentrations were significantly associated with infection severity, and anti-S1 log10 concentration with COVID-19 vaccine type/dose. In univariable models, anti-N log10 concentration was also significantly associated with acute infection duration, and severity and duration of individual symptoms. Antibody concentrations were not associated with long COVID or long-term loss of smell/taste