O'Horo, John C

Abstract COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection after full vaccination with BNT162b2 against polymerase chain reaction (PCR)-confirmed symptomatic SARS-CoV-2 infection, in a national medical practice from January 2021 through January 2022. We fit conditional logistic regression (CLR) models stratified on residential county and calendar time of testing to assess the association between time elapsed since vaccination and the odds of symptomatic infection or non-COVID-19 hospitalization (negative control), adjusted for several covariates. There were 5,985 symptomatic individuals with a positive test after full vaccination with BNT162b2 (cases) and 32,728 negative tests contributed by 27,753 symptomatic individuals after full vaccination (controls). The adjusted odds of symptomatic infection were higher 250 days after full vaccination versus at the date of full vaccination (Odds Ratio [OR]: 3.62, 95% CI: 2.52 to 5.20). The odds of infection were still lower 285 days after the first BNT162b2 dose as compared to 4 days after the first dose (OR: 0.50, 95% CI: 0.37 to 0.67), when immune protection approximates the unvaccinated status. Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. The odds of non-COVID-19 associated hospitalization (negative control) decreased with time since vaccination, suggesting a possible underestimation of waning protection by this approach due to confounding factors. In summary, BNT162b2 strongly protected against symptomatic SARS-CoV-2 infection for at least 8 months after full vaccination, but the degree of protection waned significantly over this period.

Abstract COVID-19 vaccines are effective, but breakthrough infections have been increasingly reported. We conducted a test-negative case-control study to assess the durability of protection against symptomatic infection after vaccination with mRNA-1273. We fit conditional logistic regression (CLR) models stratified on residential county and calendar date of SARS-CoV-2 PCR testing to assess the association between the time elapsed since vaccination and the odds of symptomatic infection, adjusted for several covariates. There were 2,364 symptomatic individuals who had a positive SARS-CoV-2 PCR test after full vaccination with mRNA-1273 (“cases”) and 12,949 symptomatic individuals who contributed 15,087 negative tests after full vaccination (“controls”). The odds of symptomatic infection were significantly higher 250 days after full vaccination compared to the date of full vaccination (Odds Ratio [OR]: 2.47, 95% confidence interval [CI]: 1.19–5.13). The odds of non-COVID-19 associated hospitalization and non-COVID-19 pneumonia (negative control outcomes) remained relatively stable over the same time interval (Day 250 ORNon-COVID Hospitalization: 0.68, 95% CI: 0.47–1.0; Day 250 ORNon-COVID Pneumonia: 1.11, 95% CI: 0.24–5.2). The odds of symptomatic infection remained significantly lower almost 300 days after the first mRNA-1273 dose as compared to 4 days after the first dose, when immune protection approximates the unvaccinated state (OR: 0.26, 95% CI: 0.17–0.39). Low rates of COVID-19 associated hospitalization or death in this cohort precluded analyses of these severe outcomes. In summary, mRNA-1273 robustly protected against symptomatic SARS-CoV-2 infection at least 8 months after full vaccination, but the degree of protection waned over this time period.

Abstract As of 2021 November 29, booster vaccination against SARS-CoV-2 infection has been recommended for all individuals aged 18 years and older in the United States. A key reason for this recommendation is the expectation that a booster vaccine dose can alleviate observed waning of vaccine effectiveness (VE). Although initial reports of booster effectiveness have been positive, the level of protection from booster vaccination is unclear. We conducted two studies to assess the impact of booster vaccination, with BNT162b2 or mRNA-1273, on the incidence of SARS-CoV-2 infection between August and December 2021. We first compared SARS-CoV-2 infection incidence in cohorts of 3-dose vaccine recipients to incidence in matched cohorts of 2-dose vaccine recipients (cohort size = 24,539 for BNT162b2 and 14,004 for mRNA-1273). Additionally, we applied a test-negative study design to compare the level of protection against symptomatic infection in 3-dose recipients to that observed in recent 2-dose primary vaccine series recipients. The 3-dose recipients experienced a significantly lower incidence rate of SARS-CoV-2 infection than the matched 2-dose cohorts (BNT162b2 Incidence Rate Ratio: 0.11, 95% CI: 0.09 to 0.13 and mRNA-1273 IRR: 0.11, 95% CI: 0.08 to 0.15). Results from the test-negative study showed the third vaccine dose mitigated waning of VE, with the risk of symptomatic infection in 3-dose recipients being comparable to that observed 7 to 73 days after the primary vaccine series. These results show that 3-dose vaccine regimens with BNT162b2 or mRNA-1273 are effective at reducing SARS-CoV-2 infection and support the widespread administration of booster vaccine doses.

Abstract Antispike monoclonal antibody treatment of 180 B-cell-depleted patients with mild-to-moderate coronavirus disease 2019 (COVID-19) resulted in good outcomes overall, with only 12.2% progressing to severe disease, 9.4% requiring hospitalization, 0.6% requiring mechanical ventilation, no deaths within 30 days, and 1.8% developing persistent COVID-19. Antispike monoclonal antibodies appear effective in this immunocompromised population.

Abstract The raging COVID-19 pandemic in India and reports of “vaccine breakthrough infections” globally have raised alarm mandating the characterization of the immuno-evasive features of SARS-CoV-2. Here, we systematically analyzed over 1.3 million SARS-CoV-2 genomes from 178 countries and performed whole-genome viral sequencing from 53 COVID-19 patients, including 20 vaccine breakthrough infections. We identified 116 Spike protein mutations that increased in prevalence during at least one surge in SARS-CoV-2 test positivity in any country over a three-month window. Deletions in the Spike protein N-terminal domain (NTD) are highly enriched for these ‘surge-associated mutations’ (Odds Ratio = 18.2, 95% CI: 7.53-48.7; p=1.465x10-18). In the recent COVID-19 surge in India, an NTD deletion (ΔF157/R158) increased over 10-fold in prevalence from February 2021 (1.1%) to April 2021 (15%). During the recent surge in Chile, an NTD deletion (Δ246-253) increased rapidly over 30-fold in prevalence from January 2021 (0.86%) to April 2021 (33%). Strikingly, these simultaneously emerging deletions associated with surges in different parts of the world both occur at an antigenic supersite that is targeted by neutralizing antibodies. Finally, we generated clinically annotated SARS-CoV-2 whole genome sequences and identified deletions within this NTD antigenic supersite in a patient with vaccine breakthrough infection (Δ156-164) and other deletions from unvaccinated severe COVID-19 patients that could represent emerging deletion-prone regions. Overall, the expanding repertoire of Spike protein deletions throughout the pandemic and their association with case surges and vaccine breakthrough infections point to antigenic minimalism as an emerging evolutionary strategy for SARS-CoV-2 to evade immune responses. This study highlights the urgent need to sequence SARS-CoV-2 genomes at a larger scale globally and to mandate a public health policy for transparent reporting of relevant clinical annotations (e.g. vaccination status) in order to aid the development of comprehensive therapeutic strategies.

Hospitalized patients with COVID-19 show increased serum concentrations of neurofilament light chain that correlate with worse clinical outcomes.

Objective To describe the process and outcome of creating a patient cohort in the early stages of the COVID-19 pandemic in order to better understand the process of and predict the outcomes of COVID-19. Patients and Methods A total of 1169 adults aged 18 years of age or older who tested positive in Mayo Clinic Rochester or the Mayo Clinic Midwest Health System between January 1 and May 23 of 2020. Results Patients were on average 43.9 years of age and 50.7% were female. Most patients were white (69.0%), and Blacks (23.4%) and Asians (5.8%) were also represented in larger numbers. Hispanics represented 16.3% of the sample. Just under half of patients were married (48.4%). Common comorbid conditions included: cardiovascular diseases (25.1%), dyslipidemia (16.0%), diabetes mellitus (11.2%), chronic obstructive pulmonary disease (6.6%), asthma (7.5%), and cancer (5.1%). All other comorbid conditions were less the 5% in prevalence. Data on 3 comorbidity indices are also available including the: DHHS multi-morbidity score, Charlson Comorbidity Index, and Mayo Clinic COVID-19 Risk Factor Score. Conclusion In addition to managing the ever raging pandemic and growing death rates, it is equally important that we develop adequate resources for the investigation and understanding of COVID-19-related predictors and outcomes.

Abstract Large Phase 3 clinical trials of the two FDA-approved COVID-19 vaccines, mRNA-1273 (Moderna) and BNT162b2 (Pfizer/BioNTech), have demonstrated efficacies of 94.1% (n = 30,420, 95% CI: 89.3-96.8) and 95% (n = 43,448, 95% CI: 90.3-97.6) in preventing symptomatic COVID-19, respectively. Given the ongoing vaccine rollout to healthcare personnel and residents of long-term care facilities, here we provide a preliminary assessment of real-world vaccination efficacy in 62,598 individuals from the Mayo Clinic and associated health system (Arizona, Florida, Minnesota, Wisconsin) between December 1st 2020 and February 8th 2021. Our retrospective analysis contrasts 31,299 individuals receiving at least one dose of either vaccine with 31,299 unvaccinated individuals who are propensity-matched based on demographics, location (zip code), and number of prior SARS-CoV-2 PCR tests. Administration of two COVID-19 vaccine doses was 89.0% effective in preventing SARS-CoV-2 infection (95% CI: 69.1-97.2%) with onset at least 36 days after the first dose. Furthermore, vaccinated patients who were subsequently diagnosed with COVID-19 had significantly lower 14-day hospital admission rates than propensity-matched unvaccinated COVID-19 patients (3.7% vs. 9.2%; Relative Risk: 0.4; p-value: 0.007). Building upon the previous randomized trials of these vaccines, this study demonstrates their real-world effectiveness in reducing the rates of SARS-CoV-2 infection and COVID-19 severity among individuals at highest risk for infection.

AbstractBackgroundNeutropenia is a risk factor for development of infections; however, the direct effect of neutropenia on development of bloodstream infection (BSI) is not known. D‐index, which is area between the neutrophil time curve and a neutrophil count of 0.5 × 109/L, incorporates the combined effect of severity and duration of neutropenia. We aimed to evaluate whether D‐index can be used as a marker for BSI in patients with allogeneic stem cell transplantation.MethodWe conducted a retrospective cohort study of patients undergoing allogeneic stem cell transplantation between January 1, 2005, and September 30, 2015. The primary outcome measure was the development of BSI within 30 days of transplantation.ResultsA total of 714 patients were included in the study of whom 101 developed BSI. Patients with BSI had a significantly higher median D‐index value compared with patients who did not have BSI (4990 vs. 3570, P < .001). As a marker, the performance of the D‐index was similar to that of the duration of profound neutropenia (P = .18) and significantly better than the total duration of neutropenia (P = .001).ConclusionThe D‐index performed better than the total duration of neutropenia as a marker for BSI in patients with allogeneic stem cell transplantation. There was no difference between D‐index and, a more easily calculable indicator, duration of profound neutropenia.