Paediatric safety assessment of BNT162b2 vaccination in a multistate hospital-based electronic health record system in the USA: a retrospective analysis.

BACKGROUND: The emergency use authorisation of BNT162b2 (tozinameran; Comirnaty, Pfizer-BioNTech) for children aged 5-17 years has resulted in rapid vaccination in the paediatric population. However, there are few studies of adverse events associated with vaccination in children. The aim of this study was to systematically assess the adverse events of two-dose BNT162b2 vaccination in the paediatric population. METHODS: We conducted a retrospective analysis of patient electronic health records (EHRs) of children aged 5-17 years who received the primary two-dose series of the BNT162b2 vaccine between Jan 5, 2021, and Aug 5, 2022, at the Mayo Clinic Health System (MN, FL, AZ, IA, and WI), USA. Using natural language processing, we automatically curated adverse events reported by physicians in EHR clinical notes before and after vaccination. To determine significant adverse events after BNT162b2 vaccination, we calculated risk differences, which was defined as the percentage difference between the rate of children with an adverse event after a vaccine dose and the baseline rate of children with an adverse event before vaccination. 95% CIs and p values were calculated using the Miettinen and Nurminen score method. FINDINGS: 56 436 individuals aged 5-17 years (20 227 aged 5-11 years and 36 209 aged 12-17 years) with EHRs in the Mayo Clinic Health Systems were included in the study. Overall, the reporting of adverse events remained low in passive surveillance. Serious adverse events were rare after the first and second doses of BNT162b2, with rates of anaphylaxis (six [0·01%] of 56 436), myocarditis (five [0·01%]), and pericarditis (three [0·01%]) consistent with previous studies. Among the 20 227 5-11-year-olds, there were increased risks of fatigue (58 after second dose vs 41 before first dose; risk difference [RD]dose2 0·08% [95% CI -0·01 to 0·18], p=0·044) and fever (104 after second dose vs 77 before first dose; RDdose2 0·13% [0·00 to 0·27], p=0·022) after the second dose. Among the 36 209 12-17-year-olds, there were increased risks of arthralgia (69 after second dose vs 48 before first dose; RDdose2 0·06% [-0·00 to 0·12], p=0·026), chills (58 after second dose vs 40 before first dose; RDdose2 0·05% [-0·00 to 0·11], p=0·034), and myalgia (96 after second dose vs 73 before first dose; RDdose2 0·06% [-0·01 to 0·14], p=0·038) after the second dose. Although the overall incidence was low, there was an increased risk of myocarditis in males aged 12-17 years after the second dose (five after second dose vs zero before first dose; RDdose2 0·03% [0·01 to 0·07], p=0·013), with median age being 15 years (IQR 14 to 16). INTERPRETATION: Overall, this data suggests that vaccination with BNT162b2 in the paediatric population is generally safe and well-tolerated. Further research is warranted to investigate the basis for the increased risk of myocarditis in adolescent males. Additionally, further studies are needed to confirm whether the findings in our study population apply to the whole vaccinated paediatric population. FUNDING: nference.

Third dose vaccination with mRNA-1273 or BNT162b2 vaccines improves protection against SARS-CoV-2 infection.

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.

Continuous genomic diversification of long polynucleotide fragments drives the emergence of new SARS-CoV-2 variants of concern.

Highly transmissible or immuno-evasive SARS-CoV-2 variants have intermittently emerged, resulting in repeated COVID-19 surges. With over 6 million SARS-CoV-2 genomes sequenced, there is unprecedented data to decipher the evolution of fitter SARS-CoV-2 variants. Much attention has been directed to studying the functional importance of specific mutations in the Spike protein, but there is limited knowledge of genomic signatures shared by dominant variants. Here, we introduce a method to quantify the genome-wide distinctiveness of polynucleotide fragments (3- to 240-mers) that constitute SARS-CoV-2 sequences. Compared to standard phylogenetic metrics and mutational load, the new metric provides improved separation between Variants of Concern (VOCs; Reference = 89, IQR: 65-108; Alpha = 166, IQR: 149-181; Beta 131, IQR: 114-149; Gamma = 164, IQR: 150-178; Delta = 235, IQR: 217-255; and Omicron = 459, IQR: 395-521). Omicron's high genomic distinctiveness may confer an advantage over prior VOCs and the recently emerged and highly mutated B.1.640.2 (IHU) lineage. Evaluation of 883 lineages highlights that genomic distinctiveness has increased over time (R 2 = 0.37) and that VOCs score significantly higher than contemporary non-VOC lineages, with Omicron among the most distinctive lineages observed. This study demonstrates the value of characterizing SARS-CoV-2 variants by genome-wide polynucleotide distinctiveness and emphasizes the need to go beyond a narrow set of mutations at known sites on the Spike protein. The consistently higher distinctiveness of each emerging VOC compared to prior VOCs suggests that monitoring of genomic distinctiveness would facilitate rapid assessment of viral fitness.

Quantifying the immunological distinctiveness of emerging SARS-CoV-2 variants in the context of prior regional herd exposure.

The COVID-19 pandemic has seen the persistent emergence of immune-evasive SARS-CoV-2 variants under the selection pressure of natural and vaccination-acquired immunity. However, it is currently challenging to quantify how immunologically distinct a new variant is compared to all the prior variants to which a population has been exposed. Here, we define "Distinctiveness" of SARS-CoV-2 sequences based on a proteome-wide comparison with all prior sequences from the same geographical region. We observe a correlation between Distinctiveness relative to contemporary sequences and future change in prevalence of a newly circulating lineage (Pearson r = 0.75), suggesting that the Distinctiveness of emergent SARS-CoV-2 lineages is associated with their epidemiological fitness. We further show that the average Distinctiveness of sequences belonging to a lineage, relative to the Distinctiveness of other sequences that occur at the same place and time (n = 944 location/time data points), is predictive of future increases in prevalence (Area Under the Curve, AUC = 0.88 [95% confidence interval 0.86 to 0.90]). By assessing the Delta variant in India versus Brazil, we show that the same lineage can have different Distinctiveness-contributing positions in different geographical regions depending on the other variants that previously circulated in those regions. Finally, we find that positions that constitute epitopes contribute disproportionately (20-fold higher than the average position) to Distinctiveness. Overall, this study suggests that real-time assessment of new SARS-CoV-2 variants in the context of prior regional herd exposure via Distinctiveness can augment genomic surveillance efforts.

On the Origins of Omicron's Unique Spike Gene Insertion.

The emergence of a heavily mutated SARS-CoV-2 variant (Omicron; Pango lineage B.1.1.529 and BA sublineages) and its rapid spread to over 75 countries raised a global public health alarm. Characterizing the mutational profile of Omicron is necessary to interpret its clinical phenotypes which are shared with or distinctive from those of other SARS-CoV-2 variants. We compared the mutations of the initially circulating Omicron variant (now known as BA.1) with prior variants of concern (Alpha, Beta, Gamma, and Delta), variants of interest (Lambda, Mu, Eta, Iota, and Kappa), and ~1500 SARS-CoV-2 lineages constituting ~5.8 million SARS-CoV-2 genomes. Omicron's Spike protein harbors 26 amino acid mutations (23 substitutions, 2 deletions, and 1 insertion) that are distinct compared to other variants of concern. While the substitution and deletion mutations appeared in previous SARS-CoV-2 lineages, the insertion mutation (ins214EPE) was not previously observed in any other SARS-CoV-2 lineage. Here, we consider and discuss various mechanisms through which the nucleotide sequence encoding for ins214EPE could have been acquired, including local duplication, polymerase slippage, and template switching. Although we are not able to definitively determine the mechanism, we highlight the plausibility of template switching. Analysis of the homology of the inserted nucleotide sequence and flanking regions suggests that this template-switching event could have involved the genomes of SARS-CoV-2 variants (e.g., the B.1.1 strain), other human coronaviruses that infect the same host cells as SARS-CoV-2 (e.g., HCoV-OC43 or HCoV-229E), or a human transcript expressed in a host cell that was infected by the Omicron precursor.

Durability analysis of the highly effective BNT162b2 vaccine against COVID-19.

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.

Surveillance of Safety of 3 Doses of COVID-19 mRNA Vaccination Using Electronic Health Records.

Importance: Recent reports on waning of COVID-19 vaccine-induced immunity have led to the approval and rollout of additional doses and booster vaccinations. Individuals at increased risk of SARS-CoV-2 infection are receiving additional vaccine doses in addition to the regimen that was tested in clinical trials. Risks and adverse event profiles associated with additional vaccine doses are currently not well understood. Objective: To evaluate the safety of third-dose vaccination with US Food and Drug Administration (FDA)-approved COVID-19 mRNA vaccines. Design, Setting, and Participants: This cohort study was conducted using electronic health record (EHR) data from December 2020 to October 2021 from the multistate Mayo Clinic Enterprise. Participants included all 47 999 individuals receiving 3-dose COVID-19 mRNA vaccines within the study setting who met study inclusion criteria. Participants were divided into 2 cohorts by vaccine brand administered and served as their own control groups, with no comparison made between cohorts. Data were analyzed from September through November 2021. Exposures: Three doses of an FDA-authorized COVID-19 mRNA vaccine, BNT162b2 or mRNA-1273. Main Outcomes and Measures: Vaccine-associated adverse events were assessed via EHR report. Adverse event risk was quantified using the percentage of study participants who reported the adverse event within 14 days after each vaccine dose and during a 14-day control period, immediately preceding the first vaccine dose. Results: Among 47 999 individuals who received 3-dose COVID-19 mRNA vaccines, 38 094 individuals (21 835 [57.3%] women; median [IQR] age, 67.4 [52.5-76.5] years) received BNT162b2 (79.4%) and 9905 individuals (5099 [51.5%] women; median [IQR] age, 67.7 [59.5-73.9] years) received mRNA-1273 (20.6%). Reporting of severe adverse events remained low after the third vaccine dose, with rates of pericarditis (0.01%; 95% CI, 0%-0.02%), anaphylaxis (0%; 95% CI, 0%-0.01%), myocarditis (0%; 95% CI, 0%-0.01%), and cerebral venous sinus thrombosis (no individuals) consistent with results from earlier studies. Significantly more individuals reported low-severity adverse events after the third dose compared with after the second dose, including fatigue (2360 individuals [4.92%] vs 1665 individuals [3.47%]; P < .001), lymphadenopathy (1387 individuals [2.89%] vs 995 individuals [2.07%]; P < .001), nausea (1259 individuals [2.62%] vs 979 individuals [2.04%]; P < .001), headache (1185 individuals [2.47%] vs 992 individuals [2.07%]; P < .001), arthralgia (1019 individuals [2.12%] vs 816 individuals [1.70%]; P < .001), myalgia (956 individuals [1.99%] vs 784 individuals [1.63%]; P < .001), diarrhea (817 individuals [1.70%] vs 595 individuals [1.24%]; P < .001), fever (533 individuals [1.11%] vs 391 individuals [0.81%]; P < .001), vomiting (528 individuals [1.10%] vs 385 individuals [0.80%]; P < .001), and chills (224 individuals [0.47%] vs 175 individuals [0.36%]; P = .01). Conclusions and Relevance: This study found that although third-dose vaccination against SARS-CoV-2 infection was associated with increased reporting of low-severity adverse events, risk of severe adverse events remained comparable with risk associated with the standard 2-dose regime. These findings suggest the safety of third vaccination doses in individuals who were eligible for booster vaccination at the time of this study.

High diversity in Delta variant across countries revealed by genome-wide analysis of SARS-CoV-2 beyond the Spike protein.

The highly contagious Delta variant of SARS-CoV-2 has become a prevalent strain globally and poses a public health challenge around the world. While there has been extensive focus on understanding the amino acid mutations in the Delta variant's Spike protein, the mutational landscape of the rest of the SARS-CoV-2 proteome (25 proteins) remains poorly understood. To this end, we performed a systematic analysis of mutations in all the SARS-CoV-2 proteins from nearly 2 million SARS-CoV-2 genomes from 176 countries/territories. Six highly prevalent missense mutations in the viral life cycle-associated Membrane (I82T), Nucleocapsid (R203M, D377Y), NS3 (S26L), and NS7a (V82A, T120I) proteins are almost exclusive to the Delta variant compared to other variants of concern (mean prevalence across genomes: Delta = 99.74%, Alpha = 0.06%, Beta = 0.09%, and Gamma = 0.22%). Furthermore, we find that the Delta variant harbors a more diverse repertoire of mutations across countries compared to the previously dominant Alpha variant. Overall, our study underscores the high diversity of the Delta variant between countries and identifies a list of amino acid mutations in the Delta variant's proteome for probing the mechanistic basis of pathogenic features such as high viral loads, high transmissibility, and reduced susceptibility against neutralization by vaccines.

Comparative effectiveness of mRNA-1273 and BNT162b2 against symptomatic SARS-CoV-2 infection.

BACKGROUND: mRNA coronavirus disease 2019 (COVID-19) vaccines are safe and effective, but increasing reports of breakthrough infections highlight the need to vigilantly monitor and compare the effectiveness of these vaccines. METHODS: We retrospectively compared protection against symptomatic infection conferred by mRNA-1273 and BNT162b2 at Mayo Clinic sites from December 2020 to September 2021. We used a test-negative case-control design to estimate vaccine effectiveness (VE) and to compare the odds of symptomatic infection after full vaccination with mRNA-1273 versus BNT162b2, while adjusting for age, sex, race, ethnicity, geography, comorbidities, and calendar time of vaccination and testing. FINDINGS: Both vaccines were highly effective over the study duration (VEmRNA-1273: 84.1%, 95% confidence interval [CI]: 81.6%-86.2%; VEBNT162b2: 75.6%, 95% CI: 72.2%-78.7%), but their effectiveness was reduced during July-September (VEmRNA-1273: 75.6%, 95% CI: 70.1%-80%; VEBNT162b2: 63.5%, 95% CI: 55.8%-69.9%) as compared to December-May (VEmRNA-1273: 93.7%, 95% CI: 90.4%-95.9%; VEBNT162b2: 85.7%, 95% CI: 81.4%-88.9%). Adjusted for demographic characteristics, clinical comorbidities, time of vaccination, and time of testing, the odds of experiencing a symptomatic breakthrough infection were lower after full vaccination with mRNA-1273 than with BNT162b2 (odds ratio: 0.60; 95% CI: 0.55-0.67). CONCLUSIONS: Both mRNA-1273 and BNT162b2 strongly protect against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. It is imperative to continue monitoring and comparing available vaccines over time and with respect to emerging variants to inform public and global health decisions. FUNDING: This study was funded by nference.

FDA-authorized mRNA COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system.

BACKGROUND: Two US Food and Drug Administration (FDA)-authorized coronavirus disease 2019 (COVID-19) mRNA vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna), have demonstrated high efficacy in large phase 3 randomized clinical trials. It is important to assess their effectiveness in a real-world setting. METHODS: This is a retrospective analysis of 136,532 individuals in the Mayo Clinic health system (Arizona, Florida, Iowa, Minnesota, and Wisconsin) with PCR testing data between December 1, 2020 and April 20, 2021. We compared clinical outcomes for a vaccinated cohort of 68,266 individuals who received at least one dose of either vaccine (nBNT162b2 = 51,795; nmRNA-1273 = 16,471) and an unvaccinated control cohort of 68,266 individuals propensity matched based on relevant demographic, clinical, and geographic features. We estimated real-world vaccine effectiveness by comparing incidence rates of positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR testing and COVID-19-associated hospitalization and intensive care unit (ICU) admission starting 7 days after the second vaccine dose. FINDINGS: The real-world vaccine effectiveness of preventing SARS-CoV-2 infection was 86.1% (95% confidence interval [CI]: 82.4%-89.1%) for BNT162b2 and 93.3% (95% CI: 85.7%-97.4%) for mRNA-1273. BNT162b2 and mRNA-1273 were 88.8% (95% CI: 75.5%-95.7%) and 86.0% (95% CI: 71.6%-93.9%) effective in preventing COVID-19-associated hospitalization. Both vaccines were 100% effective (95% CIBNT162b2: 51.4%-100%; 95% CImRNA-1273: 43.3%-100%) in preventing COVID-19-associated ICU admission. CONCLUSIONS: BNT162b2 and mRNA-1273 are effective in a real-world setting and are associated with reduced rates of SARS-CoV-2 infection and decreased burden of COVID-19 on the healthcare system. FUNDING: This study was funded by nference.