Background Waning antibody levels post-vaccination and the emergence of variants of concern (VOCs) capable of evading protective immunity has raised the need for booster vaccinations. However, which combination of COVID-19 vaccines offers the strongest immune response against Omicron variant is unknown. Methods This randomized, subject-blinded, controlled trial assessed the reactogenicity and immunogenicity of different COVID-19 vaccine booster combinations. 100 BNT162b2-vaccinated individuals were enrolled and randomized 1: 1 to either homologous (BNT162b2 + BNT162b2 + BNT162b2; ‘BBB’) or heterologous mRNA booster vaccine (BNT162b2 + BNT162b2 + mRNA-1273; ‘BBM’). Primary endpoint was the level of neutralizing antibodies against SARS-CoV-2 wild-type and VOCs at Day 28. Results 51 participants were allocated to BBB and 49 to BBM; 50 and 48 respectively were analyzed for safety and immunogenicity outcomes. At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBB (22,382  IU/mL 95% CI, 18,210 to 27,517) vs BBM (29,751  IU/mL 95% CI, 25,281 to 35,011, p = 0.034) as was the median level of neutralizing antibodies: BBB 99.0% (IQR 97.9 to 99.3%) vs BBM 99.3% (IQR 98.8 to 99.5%, p = 0.021). On sub-group analysis, significant differences in mean spike antibody titer and live Omicron neutralization titer was only observed in older adults. Median surrogate neutralizing antibody level against all VOCs was also significantly higher with BBM in older adults, and against Omicron was BBB 72.8% (IQR 54.0 to 84.7%) vs BBM 84.3% (IQR 78.1 to 88.7%, p = 0.0073). Both vaccines were well tolerated. Conclusions Heterologous mRNA-1273 booster vaccination induced a stronger neutralizing response against the Omicron variant in older individuals compared with homologous BNT123b2.

Background Ceftriaxone is the preferred treatment for bacteraemia caused by non-MDR (antibiotic-susceptible) Klebsiella pneumoniae. Excessive and widespread ceftriaxone use creates selection pressure for ESBLs. Cefazolin is an alternative, although there are theoretical concerns that SHV-1 β-lactamase in K. pneumoniae may inactivate cefazolin in an inoculum-dependent manner. Objectives In this retrospective study, we investigated the outcomes in K. pneumoniae bacteraemia patients treated with IV cefazolin versus IV ceftriaxone as definitive therapy. Methods A total of 917 patients infected with K. pneumoniae from 1 January to 31 December 2016 in three public acute care hospitals in Singapore were screened for study eligibility. Consecutive unique episodes of monomicrobial bacteraemia caused by cefazolin- and/or ceftriaxone-susceptible K. pneumoniae were analysed (n = 284). Results There were 143 patients (50.4%) in the cefazolin group and 141 patients (49.6%) in the ceftriaxone group. Demographics, baseline illness severity and risk factors for healthcare-associated bacteraemia were comparable in the two treatment groups. The primary outcome of 28 day all-cause mortality was not significantly different between the cefazolin and ceftriaxone groups (10.5% versus 7.1%, P = 0.403). Both in the crude analysis and using a multivariable logistic regression model with inverse probability weighting based on propensity score, cefazolin treatment was not associated with increased risk of 28 day mortality (OR 1.51 with ceftriaxone as the reference group, 95% CI 0.67–3.53; adjusted OR 1.55, 95% CI 0.33–7.40). Conclusions Cefazolin may be a ceftriaxone-sparing alternative treatment for antibiotic-susceptible K. pneumoniae bacteraemia. This observation may provide sufficient clinical equipoise for a randomized controlled trial.

Background Over 2021, COVID-19 vaccination programs worldwide focused on raising population immunity through the primary COVID-19 vaccine series. In Singapore, two mRNA vaccines (BNT162b2 and mRNA-1273) and the inactivated vaccine CoronaVac are currently authorized under the National Vaccination Programme for use as the primary vaccination series. More than 90% of the Singapore population has received at least one dose of a COVID-19 vaccine as of December 2021. With the demonstration that vaccine effectiveness wanes in the months after vaccination, and the emergence of Omicron which evades host immunity from prior infection and/or vaccination, attention in many countries has shifted to how best to maintain immunity through booster vaccinations. Methods The objectives of this phase 3, randomized, subject-blinded, controlled clinical trial are to assess the safety and immunogenicity of heterologous boost COVID-19 vaccine regimens (intervention groups 1–4) compared with a homologous boost regimen (control arm) in up to 600 adult volunteers. As non-mRNA vaccine candidates may enter the study at different time points depending on vaccine availability and local regulatory approval, participants will be randomized at equal probability to the available intervention arms at the time of randomization. Eligible participants will have received two doses of a homologous mRNA vaccine series with BNT162b2 or mRNA-1273 at least 6 months prior to enrolment. Participants will be excluded if they have a history of confirmed SARS or SARS-CoV-2 infection, are immunocompromised, or are pregnant. Participants will be monitored for adverse events and serious adverse events by physical examinations, laboratory tests and self-reporting. Blood samples will be collected at serial time points [pre-vaccination/screening (day − 14 to day 0), day 7, day 28, day 180, day 360 post-vaccination] for assessment of antibody and cellular immune parameters. Primary endpoint is the level of anti-SARS-CoV-2 spike immunoglobulins at day 28 post-booster and will be measured against wildtype SARS-CoV-2 and variants of concern. Comprehensive immune profiling of the humoral and cellular immune response to vaccination will be performed. Discussion This study will provide necessary data to understand the quantity, quality, and persistence of the immune response to a homologous and heterologous third booster dose of COVID-19 vaccines. This is an important step in developing COVID-19 vaccination programs beyond the primary series. Trial registration ClinicalTrials.govNCT05142319. Registered on 2 Dec 2021.