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Our take —

This study, available as a preprint and thus not yet peer-reviewed, assessed whether individuals vaccinated after a prior COVID-19 infection had better protection against future infection compared to vaccinated individuals who had never previously been infected. This was a large study conducted in Qatar using data from the country’s main public healthcare provider. Findings show that prior SARS-CoV-2 infection appears to further strengthen the already robust protection in individuals vaccinated with the Pfizer vaccine, but does not significantly influence the strong protection in those vaccinated with the Moderna vaccine.

Study design

Retrospective Cohort

Study population and setting

The aim of this study was to investigate whether individuals vaccinated after a prior COVID-19 infection had better protection against future infection compared to vaccinated individuals who had never previously been infected. Data from the Hamad Medical Corporation, Qatar’s main public healthcare provider and the national provider for all COVID-19 healthcare, was used to study the effect of prior infection in Qatar’s population. Data was pulled between December 21, 2020 through June 6, 2021. December 21, 2020 was the start of Qatar’s national immunization campaign, which began with the Pfizer vaccine and later added the Moderna vaccine. Consequently, the data came from two national, retrospective, matched-cohort studies; one for each vaccine. Cohorts were matched in a 1:1 ratio by sex, five-year age group, nationality, and calendar week of first vaccine dose in order to control for differences in risk of exposure, as well as differences in circulating variants at that time. During this time period, the Alpha and Beta SARS-CoV-2 variants were dominant in Qatar. The analysis compared the incidence of documented SARS-CoV-2 infection in people who were at least 14 days past their second dose of the Pfizer vaccine and who had experienced a prior PCR-confirmed infection, to the incidence among people at least 14 days after second dose of Pfizer vaccine and who had not experienced a prior infection. The same analysis was performed for the Moderna vaccine.

Summary of Main Findings

Both vaccines proved to be highly effective against the Alpha and Beta variants circulating at the time the data was collected, as seen by very low incidence of infection rates in these cohorts. However, prior infection enhanced protection of people vaccinated with the Pfizer vaccine, but not those vaccinated with the Moderna vaccine. Prior infection of individuals vaccinated with the Pfizer vaccine reduced their incidence rate by 85%, and this effect was not seen for people who received the Moderna vaccine. One potential explanation for this could be the fact that Moderna was slightly more effective in Qatar against the Alpha and Beta variants overall, so the existence of prior immunity may have had no additional benefit.

Study Strengths

This retrospective study had a large sample size, with over 500,000 individuals with Pfizer vaccine and over 200,000 individuals with Moderna vaccine. Another strength is the fact that two different vaccines were analyzed.

Limitations

Pfizer and Moderna were administered at different doses and in different intervals between doses, so it is difficult to make a direct comparison between the two vaccines. Prior infection was only identified via a positive PCR result, and therefore there could have been more infections undetected in the population due to mild symptoms or asymptomatic cases. The cohort studied was mainly composed of working-age adults, and therefore the results will not necessarily be generalizable to other age groups. Co-morbidities and other socio-demographic factors were not included in the analysis. Finally, the study was performed with retrospective data under the conditions of the Alpha and Beta variants, and right now the primary circulating virus is the Delta variant.

Value added

First study investigating the effect of prior SARS-CoV-2 infection on vaccine efficacy, for two different vaccines.

Our take —

This study provides a detailed analysis of antibody neutralization in vitro of the B.1.617.1 and B.1617.2 (Delta) SARS-CoV-2 variants of concern, which were first identified from cases in India in early 2021 and continue to spread rapidly across the globe. While the ability of both convalescent plasma and vaccine sera to neutralize these viruses was somewhat diminished, there was no evidence of widespread immune escape. Both doses of the Pfizer vaccine appeared to be required to maintain neutralizing responses against these variants, illustrating the importance of completing recommended vaccine regimens. Data also suggested that previous infection with B.1.351 (Beta variant) or P.1 (Gamma variant) may not be protective against reinfection with the Delta variant, indicating that these individuals may particularly benefit from vaccination. Additional studies are needed to determine the prevalence and severity of reinfection and vaccine breakthrough infection associated with B.1.617.1/B.1.617.2. However, initial data suggest that the current vaccines and antibody-based treatments remain effective for the treatment and prevention of SARS-CoV-2 infection caused by these variants of concern.

Study design

Retrospective Cohort

Study population and setting

Neutralizing antibodies targeting spike protein are elicited by natural infection with SARS-CoV-2 and vaccination against SARS-CoV-2. Viral variants harbor mutations that may allow for evasion of these neutralizing antibodies, resulting in reinfections and vaccine breakthrough infections. The highly transmissible B.1.617.1 and B.1.617.2 (Delta) variants originated in India in the spring of 2021. This study described the ability of these two variants to be neutralized by monoclonal antibodies (for both research and clinical use), convalescent plasma (collected post-infection with wild-type [n=34], B.1.1.7 Alpha [n=18], P.1 Gamma [n=17], and B.1.351 Beta [n=14] virus) and post-vaccination sera (Oxford-AstraZeneca [n=25] and Pfizer-BioNTech [n=25]). Neutralization was measured using either a pseudovirus or live virus assay; results were reported in comparison to the Victoria strain (highly similar to the original Wuhan strain). Neutralization assays were also performed with sera collected after only one dose of the Pfizer-BioNTech vaccine (n=20). Structural analysis of antibody binding to wild-type and variant SARS-CoV-2 was completed using x-ray crystallography. A new method, termed “antigenic cartography” was developed to estimate the antigenic distance between different viral lineages; this method used single value decomposition to return a graphical display of inter-strain antigenic relationships.

Summary of Main Findings

Monoclonal antibodies from a panel designed for research use displayed a more than 5-fold decreased neutralization of B.1.617.1 (8/20 antibodies) and B.1.617.2 Delta (7/20 antibodies), likely due to the L452R mutation found in both variants. However, monoclonal antibodies currently approved for treatment (i.e., Regeneron) remained effective, with only slight reductions in neutralization activity; the one exception was LY-CoV555, which was not effective against either variant. Neutralization of both B.1.617.1 and B.1.617.2 with convalescent plasma collected from persons previously infected with either wild-type virus or the Alpha variant was only mildly reduced. In contrast, neutralization of B.1.617.2 with convalescent plasma from persons previously infected with the Beta or Gamma variants was profoundly diminished, suggesting that those persons may be at increased risk of reinfection. Mean neutralization titers against the B.1.617.1 and B.1617.2 (Delta) variants were mildly reduced (but still adequately protective) for both the Pfizer-BioNTech and Oxford-Astra-Zeneca post-vaccine sera. However, at 10 weeks post-vaccination, all 20 individuals who received only one dose of the Pfizer-BioNTech vaccine had inadequate neutralization titers against both variants, indicating an increased risk of vaccine breakthrough infection among persons with incomplete vaccine schedules. Using antigenic cartography, the largest antigenic distance was found between B.1.351/P.1 and B.1.617.2.

Study Strengths

This study provides a comprehensive analysis of the neutralization performance of monoclonal antibodies, convalescent plasma, and post-vaccination sera against the B.1.617.1 and B.1.617.2 (Delta) SARS-CoV-2 variants of concern.

Limitations

Neutralization of B.1.617.1 and Victoria was measured using a pseudovirus-based assay vs. live virus, and these results were compared with data collected using a live virus assay for B.1.617.2 (Delta). All neutralization assays were completed in the absence of other important components of the immune system (i.e., complement, T-cells) whose effector functions may remain intact in cases of infection with B.1.617.1 or B.1.617.2. Epitope-level analysis of cross-reactive protective responses was also not included in this study. The neutralization mechanism for some antibodies included in this study is also still poorly understood. Additional epidemiologic data is required to determine the prevalence of B.1.617.1/B.1.617.2 reinfection/vaccine breakthrough infection and the associated risk of severe disease, hospitalization, or death.

Value added

This study provides the first in-depth analysis of neutralizing antibody responses (from previous natural infection, vaccination, or as part of antibody-based treatment regimens) against the B.1.617.1 and B.1.617.2 (Delta) SARS-CoV-2 variants of concern.

Our take —

This study, available as a preprint and thus not yet peer-reviewed, included 394 patients with COVID-19 and 388 individually-matched controls, and evaluated brain imaging data from the UK Biobank collected prior to the COVID-19 pandemic and follow-up scans from February-June 2021. Of 297 hypothesis-driven imaging derived phenotypes (IDPs) and 2,022 exploratory IDPs, most longitudinal differences between the groups were in regions of the brain related to olfactory and gustatory systems, as well as some related to memory function, which are consistent with some of the common symptoms of COVID-19. Results may be limited by residual confounding and it’s not yet clear whether these are acute and reversible or longer-lasting changes due to COVID-19.

Study design

Case-Control, Retrospective Cohort

Study population and setting

This was an ambidirectional cohort study, leveraging existing imagining data from the UK Biobank imaging study, which had completed 42,729 brain scans before the COVID-19 pandemic and included follow-up imaging data on 798 participants after the beginning of the COVID-19 pandemic (782 of whom had usable data and 394 of whom had COVID-19 between visits). The follow-up imaging study included people who had a COVID-19 diagnosis based on primary care data, hospital records, antigen tests linked through the Public Health datasets in England, or two concordant positive home-based lateral flow kits, and a group of controls from the remaining UK Biobank imaging participants who didn’t have a history of COVID-19 and were individually matched by age, ethnicity, date of birth (+/- 6 months), location of imaging assessment, and date of first imaging assessment (+/- 6 months). 2,260 brain imaging-derived phenotypes were used to describe different aspects of brain structure and function, based on three structural MRI scans (T1, T2 fluid attenuation inversion recovery, and susceptibility weighted MRI) as well as diffusion MRI, resting MRI, and task MRI. The analysis focused primarily on analyzing 332 pre-specified brain regions of interest based on expectations from animal models and post-mortem findings, including those related primarily to olfactory and gustatory function. Beyond that, the full set of imaging derived phenotypes were explored. All analyses were focused on longitudinal differences, considering the difference in imaging between scans (adjusted for baseline function) and were adjusted for multiple comparisons.

Summary of Main Findings

The final study population included 394 patients who had COVID-19 (median age 59.1 years, 57% female) and 388 controls (median age 60.4 years, 57% female), all of whom had imaging prior to and during the COVID-19 pandemic (average time between scans was 3.1 years for both groups). Only 15 of the participants with COVID-19 were hospitalized during their infection. Of 297 olfactory and gustatory regions that passed quality assurance tests, only 8 showed significant differences between groups after adjusting for multiple comparisons. These included reduced grey matter thickness or volume over time in the primary or secondary cortical gustatory and olfactory areas in the left hemisphere in the COVID-19 patients compared to controls. In the exploratory analysis of 2,022 imaging derived phenotypes that passed initial quality checks, the longitudinal difference for COVID-19 cases vs. controls was only significant for four measures: patients with COVID-19 had more prominent reductions the ratio of brain volume to total intracranial volume, reductions in cortical thickness of the parahippocampal gyrus and lateral orbitofrontal cortex, as well as increases in lateral ventricle volume. Many of these changes are linked to memory or olfactory function.

Study Strengths

Brain imaging data was available from prior to the COVID-19 pandemic and during the COVID-19 pandemic. Controls were individually matched to COVID-19 cases based on several important characteristics.

Limitations

Follow-up imaging data during the COVID-19 pandemic were only available for a subset of the people originally evaluated in the UK Biobank imaging study. It is not clear how the COVID-19 cases or controls were selected for follow-up. They had limited power to evaluate differences in imaging between hospitalized and non-hospitalized COVID-19 patients. Despite matching and considering baseline differences, residual confounding, due to clinical comorbidities or other factors is still possible. It is not clear whether the observed changes are a long-term consequence of infection that will persist over time or if they are a more acute manifestation of COVID-19 that will resolve.

Value added

This is the first study that includes comprehensive brain imaging data on COVID-19 patients and control from before and during the COVID-19 pandemic.

Our take —

Between September and December 2020, there were 287 mucormycosis cases diagnosed across 16 healthcare centers in India, a two-fold increase compared to the same time period in 2019. Of these cases, 187 were COVID-19 associated mucormycosis (CAM). CAM was extremely rare (<0.3%) among hospitalized COVID-19 patients. Aside from CAM patients having more frequent hypoxia requiring ICU admission, CAM and non-CAM cases had similar clinical manifestations and outcomes. The majority of both CAM and non-CAM cases had uncontrolled diabetes. Most CAM cases were given glucocorticoids as part of their treatment for COVID-19, similar to previous smaller case series from India. It is possible that glucocorticoid treatment contributed to additional CAM cases in certain settings, but more research in larger sample sizes and with additional control for confounding is needed to further evaluate this finding.

Study design

Case Series, Retrospective Cohort

Study population and setting

This multicenter retrospective cohort study evaluated the prevalence, epidemiology, and outcomes of COVID-19 associated mucormycosis (CAM), a fungal disease, in India from September 1, 2020 to December 31, 2020, compared to mucormycosis not associated with COVID-19 (non-CAM) over the same time period. Mucormycosis was defined based on clinical and radiologic findings that showed fungi in tissue or sterile body fluids. COVID-19 diagnosis was based on detection of SARS-CoV-2 on RT-PCR or rapid antigen tests. The data from 16 health centers were used to evaluate predisposing factors and clinical manifestations of CAM and non-CAM patients, and data from 7 of these centers were used to estimate prevalence of CAM. Demographics, medical history, clinical presentation, and outcomes were extracted from patient medical records. Patients were treated for COVID-19 and mucormycosis in accordance with institutional protocols; inappropriate glucocorticoid use was defined as use of any steroid among non-hypoxic patients or when a dexamethasone-equivalent was used for 10 days or more with more than 6 mg/day.

Summary of Main Findings

Across the 16 participating centers, 295 cases of mucormycosis were diagnosed, among whom 287 had complete data and were included in the study population (mean age: 53.4 years, 25% women, 83% diagnosed on direct microscopy). Across the 7 centers with data on all hospitalized COVID-19 patients, the prevalence of CAM was 0.27% (28/10,517) in general wards and 1.6% (25/1579) in the ICU. The total number of mucormycosis cases between September 2020 and December 2020 was over twofold higher than the same time period in 2019, though the number of mucormycosis unrelated to COVID was relatively similar (92 in 2020 vs. 112 in 2019). Of the 187 CAM cases (65% of all mucormycosis cases), 61 (33%) did not have other underlying diseases, compared to only 19 of the 100 non-CAM cases without other underlying diseases. Among CAM and non-CAM cases, uncontrolled diabetes was common (63%) though newly diagnosed diabetes was more common among those with CAM (21% vs. 10%). Both groups experienced similar clinical manifestations and sites of involvement (~85% in each group with rhino-orbital or rhino-orbital-cerebral involvement), and mortality was similarly high (6-week mortality: 38%; 12-week mortality: 46%). However, patients with CAM were more likely to have hypoxia requiring ICU admission than non-CAM patients (31% vs. 9%). CAM patients were classified according to timing of onset (early: <8 days after COVID-19 diagnosis, n=29; late: ≥8 days after COVID-19 diagnosis, n=158), and although demographic, clinical characteristics, and outcomes were similar between early and late CAM groups, hypoxia and inappropriate or non-indicated glucocorticoid use was associated with development of late CAM as compared to early CAM (adjusting for age, sex, and underlying risk factors).

Study Strengths

This was a multisite study with detailed data on clinical characteristics, treatment history, and outcomes of COVID-19 associated mucormycosis, with a comparison group of adults with mucormycosis not associated with COVID-19.

Limitations

Despite its multi-site design, the sample size was still relatively small. Adjusted analyses, especially those among only CAM cases, were likely underpowered to detect associations or overfit. Consequently, many of the estimates had very wide confidence intervals and should be interpreted with caution. The study was retrospective and relied upon data available in the medical record, which may not have fully captured individual disease histories and comorbidities. The study did not report whether there was clustering of cases by healthcare center nor explore facility-level characteristics that might have enabled healthcare-associated sources of mucormycosis during the study period. Given the small sample size, analyses of mucormycosis and CAM outcomes were limited in their ability to fully adjust for treatment practices, which differed between sites.

Value added

This study is among the first and most detailed reports of COVID-19 associated mucormycosis, a rare fungal disease associated with high mortality.

Our take —

This study, available as a preprint and thus not yet peer-reviewed, describes the rapid expansion of the B.1.617.2 (Delta) variant in India in April-May 2021, which resulted in significant fatalities due to a short-term collapse of the healthcare system. While B.1.617.2 appears to be 50% more transmissible than B.1.1.7, there is not yet evidence supporting increased symptom severity or case fatality. While B.1.617.2 is potentially associated with increased risk of vaccine breakthrough infection when compared to other lineages, rates of these infections are incredibly low and observed symptoms are mild. Some data indicate that prior SARS-CoV-2 infection may not provide sufficient protection against reinfection with B.1.617.2, illustrating the importance of widespread COVID-19 vaccination for the entire population, including previously infected individuals. This study clearly demonstrates the risk that highly transmissible variants pose to an effective SARS-CoV-2 public health response, even in the setting of high seroprevalence due to prior infections.

Study design

Retrospective Cohort

Study population and setting

This study describes the emergence and spread of the SARS-CoV-2 B.1.617.2 (Delta) variant of concern, which overwhelmed the healthcare system in Delhi and northern India in April-May 2021. Case, positivity, and death rates were obtained from the Integrated Disease Surveillance Programme (IDSP) database, which is maintained by India’s National Centre for Disease Control (NCDC). SARS-CoV-2 seroprevalence was determined using samples collected from laboratory personnel and their family members at over 40 sites across India in two phases: between May and September 2020 (n=10,427) and between February and March 2021 (n=9,918); positive samples were assayed for antibody titer and neutralizing response. Separately, through the NCDC’s Central Surveillance Unit of Integrated Disease Surveillance Programme, SARS-CoV-2 positive nasopharyngeal swab samples (n=11,001) were collected from nine states and territories across India between November 2020 and May 2021; this included samples from 27 persons with vaccine breakthrough infection. Cycle threshold (Ct) values were used to estimate variant-based differences in viral load. RNA was used to produce genomic sequences (n=8,477) for phylogenetic analysis and mutational profiling. Structural models for the B.1.617.2 spike protein were generated using established reference structures, modified to include variant mutations.

Summary of Main Findings

Prior to March 2021, India successfully managed multiple waves of SARS-Cov-2 infection using non-pharmaceutical interventions. SARS-CoV-2 seropositivity measured 42% at the end of March, with higher rates observed in large cities (i.e., Delhi, with a rate of 56%). However, median antibody titers and neutralization levels for seropositive individuals fell below accepted cutoffs, suggesting that prior infection may provide only limited protection. In this setting, cases of SARS-CoV-2 increased dramatically between the third week of March and the end of April, with positivity rates rising from 1% to 30% and daily cases peaking at ~30,000. This surge in infection paralleled the rapid expansion of the B.1.617.2 sublineage (seeded from the B.1.617 lineage, introduced in early February) to represent ~60% of cases in both Delhi and north India by the end of April. Transmissibility of B.1.617.2 was increased by 50% as compared to B.1.1.7, which may be driven by a 50-fold increase in viral load (as estimated by Ct values). At this time, there is no evidence of increased disease severity or fatality associated with B.1.617.2 infection. The variant was overrepresented among vaccine breakthrough cases (19/27 [76%]), but all were mild. The B.1.617.2 variant harbors a unique combination of seven mutations in spike protein. Three mutations (T19R, R158G, and ΔE156-F157) are found at key recognition sites for monoclonal antibodies. Another mutation (L452R) has been implicated in immune escape. One mutation (T478K) appears to improve viral interaction with the ACE2 receptor. Finally, three mutations (P681R, D950N, and D614G) are proximal to the S1/S2 and furin cleavage sites and may be responsible for increased transmissibility.

Study Strengths

This study integrates reported case data, serosurveillance data, genomic epidemiology, and structural modeling to thoroughly describe the emergence of the B.1.617.2 variant in India. Viral sequence analyses were completed using a large scale, geographically diverse, randomly collected sample set.

Limitations

Serosurveillance data was collected from a non-random sample of laboratory employees and their families, which may not be representative of the general population. While measures of antibody titer and neutralization capability suggest that prior infection may not be protective against future infection, no SARS-CoV-2 reinfection data was collected. The sample set used for sequencing overrepresented populated cities (i.e. Delhi) vs. rural areas. The subset of samples used to correlate B.1.617.2 with vaccine breakthrough infection was quite small (n=27). The functional relevance of lineage-defining mutations was assumed based on structural modeling and/or the impact of individual mutations in other variants, rather than on functional assays.

Value added

This study is the first to describe the genomic epidemiology of the B.1.617.2 variant of concern in India. In addition, a small subset of samples was used to explore the relationship between the variant and vaccine breakthrough infection.

Our take —

Some fully vaccinated individuals are expected to develop breakthrough SARS-CoV-2 infection, despite high vaccine efficacy. This report describes SARS-CoV-2 vaccine breakthrough infections in the United States through April 2021. At the time of this study, less than one third of the US population had been fully vaccinated, and new case rates exceeded 350,000 per week. Breakthrough infections represented only a small proportion of SARS-CoV-2 cases; only 0.01% (10,262 of 101 million) of fully vaccinated individuals tested positive for SARS-CoV-2 during the study period, supporting the very high efficacy data from clinical trials. Breakthrough cases were not more frequent based on age, sex, or infection with a variant of concern. In contrast with clinical trial data, a small number of deaths (n=160) were seen among older individuals with vaccine breakthrough infection; this is likely because the population observed in this study was much larger (millions vs. thousands). This report demonstrates that COVID-19 vaccines are highly effective for preventing SARS-CoV-2 infection, even in areas with a largely unvaccinated population, widespread community transmission, and a high variant prevalence.

Study design

Retrospective Cohort

Study population and setting

Vaccines for COVID-19 are extremely effective in preventing SARS-CoV-2 infection. However, it is expected that some individuals will still become infected post-vaccination, especially in regions where community transmission remains high. This report describes SARS-CoV-2 vaccine breakthrough infections in the United States as monitored through April 30, 2021. Cases were voluntarily reported to the CDC by local health departments in 46 US states and territories. Breakthrough infection was defined as a positive test for SARS-CoV-2 (either RNA or antigen) >14 days after completion of all recommended vaccine doses. A subset of RNA-positive samples was used for genomic sequencing to identify breakthrough infections caused by variants of concern.

Summary of Main Findings

Of the 10,262 reported SARS-CoV-2 vaccine breakthrough infections, 63% (n=6,446) occurred in women, with a median patient age of 58 years (IQR: 40-74 years). These data were consistent with the distribution of sex and age in the population of vaccinated individuals at the time of the study. One quarter of breakthrough infections were classified as asymptomatic (n=2,725 [27%]). However, cases were also identified among hospitalized patients (n=995 [10%]), although many (n=289 [29%]) had been hospitalized for reasons unrelated to COVID-19 disease. Breakthrough infections were also identified in 160 (2%) patients who died (median age, 82 years), although some deaths (n=28 [18%]) were attributed to other causes. Genomic sequences were obtained for 555 (5%) breakthrough cases, 356 (64%) of which were caused by variants of concern (B.1.1.7, B.1.429, B.1.427, P.1, and B.1.351). These results are consistent with the proportion of all US cases attributed to variants of concern (70%) between March 28 and April 10, 2021.

Study Strengths

This study includes a review of SARS-CoV-2 vaccine breakthrough infections reported in the United States through April 2021.

Limitations

Sampling was completed via voluntary, passive reporting; data may not have been complete or adequately representative. Breakthrough cases may have included those where exposure took place prior to the 14-day cutoff, but symptoms developed, and testing took place after the 14-day cutoff. Vaccinated individuals are far less likely to experience symptomatic or severe illness, leading to lower rates of SARS-CoV-2 testing for this group vs. the unvaccinated population; the number of reported breakthrough cases was likely substantially undercounted as a result. Sequencing data were generated for only a small subset of breakthrough cases and may not be representative. Results were not stratified according to vaccine type, which may confound results because the Johnson & Johnson vaccine reaches maximum levels of effectiveness later than the Pfizer and Moderna vaccines.

Value added

This study describes SARS-CoV-2 vaccine breakthrough infections in the United States in early 2021. At the close of the study period, 101 million people in the United States had been fully vaccinated, and community transmission was still high (355,000 cases reported between April 24–30). The study therefore represents a measure of population level vaccine effectiveness in the United States at a time when ongoing risk of SARS-CoV-2 infection remained high.

Our take —

This study followed up 46 children in the UK who had a multisystem inflammatory syndrome associated with SARS-CoV-2 infection (called PIMS-TS or MIS-C), and assessed clinical, laboratory, and functional outcomes after six months. No children died, and there was significant normalization of organ-specific sequelae (i.e., the prevalence of gastrointestinal, neurologic, and echocardiogram abnormalities dropped considerably) for most children. Though all children had systemic inflammation on admission, all but one had normalized inflammatory biomarker values at six months. However, nearly half of children showed poor exercise tolerance at six months, and about one-fifth of children reported severe emotional difficulties. This study was from a single hospital with a small study population, which may not be representative of all children with this syndrome; additionally, it has not yet been possible to assess longer-term outcomes. The study nonetheless provides valuable data that may help guide provider and patient expectations regarding the course of this syndrome.

Study design

Case Series; Retrospective Cohort

Study population and setting

This study included 46 children (median age 10.2 years, 65% male, 80% from minority ethnic groups) who met the criteria for pediatric inflammatory multisystem syndrome (PIMS-TS; also called multisystem inflammatory syndrome in children, or MIS-C) admitted to a single hospital in the UK from April 4 to September 1, 2020. Outcomes were assessed 6 months after admission.  Included patients had evidence of SARS-CoV-2 infection from a positive PCR test, a positive antibody test, or an epidemiologic link to a confirmed case. All patients were seen by a multidisciplinary team of specialists at 6 weeks and 6 months after admission. Patients were assessed for a wide range of laboratory, clinical, and radiologic features at both follow-up times. Additionally, self-reported outcomes related to physical, emotional, social, and school function were assessed with the PedsQL 4.0 Generic Core Scales. Parents or guardians of patients also completed a structured interview. The authors compared patients older versus younger than 12 years and patients with versus without neurologic symptoms.

Summary of Main Findings

Eight (17%) children had baseline comorbidities; none died by six months after admission. Six weeks from admission, all participants were PCR-negative for SARS-CoV-2 infection. Of the 42 children who tested positive for anti-SARS-CoV-2 antibodies within six weeks of admission, 38 (90%) remained seropositive at six months. At admission, everyone had significantly elevated markers of inflammation, but only one child had systemic inflammation six months later. At baseline, 15 (33%) children had significant abnormalities on echocardiograms; at six months, 2 children (4%) had abnormal echocardiograms. The prevalence of gastrointestinal symptoms dropped from 98% at baseline to 13% at six months. Four of 43 (9%) participants with urinalysis had proteinuria at six weeks, and one of 44 (2%) had proteinuria at six months. Four of 42 (10%) had blood pressure above the 95th percentile at six months. There were abnormal neurological symptoms in 24 (52%) children at six weeks and 18 (39%) at six months; however, these abnormalities were largely minor, and the median Expanded Disability Status score to assess functionality at six months was 0 (interquartile range (IQR): 0 to 1). The median manual muscle-8 test score was 53/80 (IQR: 43 to 64) at admission, and this improved to 80/80 (IQR: 68 to 80) at six months. At six months, 18 of 40 (45%) children had six-minute walk test results below the 3rd percentile for their age and sex. Eight of 38 (22%) participants self-reported severe emotional difficulties at six months.

Study Strengths

The six-month follow-up time provided useful data on longer-term outcomes for children afflicted with PIMS-TS/MIS-C. Participants were evaluated for a broad range of laboratory, clinical, and functional parameters by specialists at standardized follow-up times after initial presentation.

Limitations

The number of study participants was small, though this is understandable given the rarity of PIMS-TS/MIS-C in the general population. There was no comparison group of either healthy controls or children presenting with another inflammatory syndrome (e.g., Kawasaki disease). Participants were recruited from a single center and may not be representative of the broader population of children with the inflammatory syndrome. No data were available on laboratory, clinical, or functional parameters before hospital admission, preventing a comparison of 6-month outcomes with patients’ condition before SARS-CoV-2 infection. It is unclear from the data presented why functional outcomes were poor compared to other outcomes.

Value added

This study provides one of the highest-quality and longest-term assessments of outcomes associated with PIMS-TS/MIS-C to date.

Our take —

The Pfizer-BioNTech BNT162b2 mRNA vaccine proved to be very effective when implemented in real-life in Qatar’s national immunization campaign. Reduced effectiveness against the B.1.351 (South African) variant was seen compared to the B.1.1.7 (UK) variant, but this did not hinder the vaccine’s overall robust protection against severe infection, hospitalization, and death.

Study design

Retrospective Cohort

Study population and setting

This study looked at effectiveness of the Pfizer-BioNTech BNT162b2 mRNA vaccine in Qatar’s national vaccination campaign. Data from standardized national SARS-CoV-2 databases compiled at Hamad Medical Corporation, the principal public healthcare provider and designated provider for COVID-19 healthcare needs in Qatar, was used for the analysis. Vaccinations began on December 21, 2020, and by March 31, 2021 over 300,000 individuals had at least one dose of vaccine and over 250,000 individuals had two doses. The authors extracted data from February 1 to March 31, 2021, which coincided with the rapid scale-up of vaccinations in Qatar during its second and third waves of SARS-CoV-2 infection. Data included PCR testing results, antibody testing results, COVID-19 hospitalizations, vaccinations, infection severity, and COVID-19 deaths. Estimated vaccine effectiveness was calculated using a test-negative, case-control study design. Inclusion criteria were a B.1.1.7 case (UK variant), a B.1.351 case (South African variant), or a severe, critical, or fatal disease case. Cases and controls were matched one-to-one by age, sex, nationality, and reason for PCR testing.

Summary of Main Findings

The BNT162b2 vaccine’s effectiveness against the B.1.1.7 (UK) variant was estimated to be 89.5%, and 75% against the B.1.351 (South African) variant. Effectiveness against severe, critical, or fatal disease due to infection with any SARS-CoV-2 variant was estimated to be 97.4%, with B.1.1.7 and B.1.351 being most predominant variants in circulation. When comparing incidence of infection between vaccinated individuals and those who were antibody negative, it was estimated that there was an 87% effectiveness against the B.1.1.7 variant and 72.1% effectiveness against the B.1.351, confirming results from the previous analysis. Effectiveness against the B.1.351 variant specifically was approximately 20% lower than the >90% effectiveness seen in clinical trials and real-world conditions in Israel and the US, but this did not affect the overall effectiveness seen in Qatar, which was well over 90%.

Study Strengths

This retrospective analysis included a large sample size of over 200,000 individuals. Next, the test-negative, case-control study design is a widely accepted design used for assessing vaccine effectiveness against influenza. A key strength of this method is the ability to control for bias from different healthcare-seeking behaviors of vaccinated and unvaccinated people. Finally, Qatar has unusual demographics by sex and nationality, with 89% of the population comprised of expatriates from over 150 countries. The wide range in nationalities could have added strength to the real-world value of this analysis due to an increased variety of ethnicities.

Limitations

Due to the unique demographic of Qatar’s population, the median age included in the analysis was very low, with the median age in each group ranging from 32 to 43 years old and most included individuals under 40 years old. There was also a much greater proportion of males included in the analysis compared to females. Lastly, the effectiveness of the BNT162b2 vaccine against the B.1.351 variant was only assessed from March 8 – 31, during its wave of rapid expansion.

Value added

This is one of the first real-world vaccine effectiveness studies published about the Pfizer-BioNTech BNT162b2 mRNA vaccine, which documented Qatar’s national immunization campaign, and is yet another demonstrating that the vaccine is highly effective.

Our take —

This very large retrospective cohort study of Veteran Health Administration users from across the United States, involving more than 2 million person-years of follow-up, evaluated more than 800 incident outcomes indicative of post-acute sequelae of COVID-19 (PASC) among both non-hospitalized and hospitalized COVID-19 cases diagnosed between March 1 and November 30, 2020 and who survived ≥30 days, relative to well-matched control groups. Relative to individuals without COVID-19, individuals who were not hospitalized during their COVID-19 illness were significantly more likely to die or have additional outpatient encounters, and had an excess burden of numerous respiratory and non-respiratory complications. These findings are consistent with smaller studies that have reported post-acute sequelae among those with a mild initial COVID-19 course. The risk of death and other negative outcomes was further elevated among those hospitalized with COVID-19, and highest among those admitted to the ICU, reflecting a graded risk based on the severity of the initial COVID-19 disease course. The study also demonstrated a higher burden of death and new illnesses following hospitalization for COVID-19 compared to hospitalization for influenza, suggesting that PASC may be more severe than post-acute syndromes from comparable conditions. Though the findings from the VHA study population may not be generalizable to the general population, this rigorous study provides novel data on individual sequelae associated with COVID-19 within similar populations, specific to the severity of the initial disease course.

Study design

Retrospective Cohort

Study population and setting

This retrospective cohort study evaluated post-acute sequelae of laboratory-confirmed COVID-19 (PASC, also termed Long-COVID) among non-hospitalized and hospitalized individuals in the Veteran Health Administration (VHA), a large national healthcare system serving military veterans with 1,255 health facilities across the United States. Individuals were included if they had a health system encounter in 2019, were alive on March 1, 2020, had a positive COVID-19 test between March 1 and November 30, 2020, and survived at least 30 days following their positive test. Follow-up for post-acute sequelae of COVID-19 occurred through January 31, 2021. Individuals with COVID-19 who survived without hospitalization for 30 days following their first positive test (non-hospitalized COVID-19 cases; N=73,435) were selected and individually matched to 70 VHA users without a positive COVID-19 test (N=4,990,835). A second set of analyses compared individuals who were hospitalized from 5 days before to 30 days after their first positive COVID-19 test (hospitalized COVID-19 cases; N=13, 654) to individuals who were hospitalized within the 5 days before and 30 days after a positive test for seasonal influenza between October 1, 2016 and February 29, 2020 (hospitalized influenza cases; N=13,997). The outcomes for both sets of comparisons were the incident risk of death, outpatient admission, 379 diagnoses from ICD-10 codes, 380 medication classes, and 62 laboratory tests (all from beyond 30 days from positive test). A third analysis compared the risk of pre-specified acute COVID-19 outcomes (based on the joint CDC/NIH workshop on PASC) for three mutually exclusive groups (all compared to the same VHA reference group without COVID-19): non-hospitalized COVID-19 patients, hospitalized COVID-19 patients not requiring ICU admission, and COVID-19 patients requiring ICU admission. All analyses were weighted by propensity scores constructed from pre-defined covariates, including age, race, sex, receipt of long-term care, proxies of healthcare utilization, and deprivation index at patients’ residency address, and algorithmically identified covariates from the diagnoses, medications, and laboratory testing values that showed evidence of difference between the comparison groups.

Summary of Main Findings

In the non-hospitalized group, individuals with COVID-19 (median follow-up: 126 days, IQR: 81-203; 88% male; median age 60.7 years) compared to VHA users without COVID-19 (median follow-up 130 days, IQR: 82-205; 90% male; median age 66.7 years) had increased risk of death (hazard ratio (HR): 1.59, 95% CI: 1.46-1.73) and outpatient encounters (HR: 1.20, 95% CI: 1.19-1.21), corresponding to 8.39 (95% CI: 7.09-9.58) excess deaths and 33.22 (95% CI: 30.89-35.58) excess outpatient encounters, each per 1000 patients at 6 months. The most pronounced absolute differences in incident diagnoses were for respiratory signs and symptoms (excess burden per 1000 people at 6 months (EB): 28.5 episodes), hypertension (EB: 15.2), sleep-wake disorders (EB: 14.5), nervous system signs and symptoms (EB: 14.3), musculoskeletal pain (EB: 13.9), malaise and fatigue (EB: 12.6), and disorders of lipid metabolism (EB: 12.3). The COVID-19 group was also more likely to have been prescribed many medications, including bronchodilators, opioid analgesics, and anticoagulants, and had pronounced differences in laboratory values, such as lower hemoglobin, lower hematocrit, and higher hemoglobin A1c.

In the hospitalized group, individuals hospitalized with COVID-19 (median follow-up: 150, IQR: 84-217; 94% male; median age 70.3 years) compared to individuals hospitalized for season influenza (median follow-up: 157, IQR: 87-220; 94% male; median age 70.1 years) also had increased risk of death (HR: 1.51; 95% CI: 1.30-1.76) and outpatient encounters (HR: 1.12; 95% CI: 1.08-1.17), corresponding to 28.79 (95% CI: 19.52-36.85) excess deaths and 6.37 (95% CI: 4.01-9.03) excess outpatient encounters, each per 1000 patients at 6 months. Additionally, compared to hospitalized influenza cases, hospitalized COVID-19 cases had an EB (per 1000 people at 6 months) for several diagnoses, including respiratory failure (EB: 70.4), disorders of lipid metabolism (EB: 43.5), fluid and electrolyte disorders (EB: 40.2), malaise and fatigue (EB: 36.5), as well as increased use of anticoagulants, laxatives, vitamin C, vitamin D, gastric medications, and lower levels follow-up levels of serum albumin, serum total protein, higher platelet counts, and higher serum calcium, among others.

When comparing the outcomes for the three mutually exclusive groups (non-hospitalized COVID-19, hospitalized COVID-19 without ICU admission, COVID-19 with ICU admission) compared to VHA users, many incident diagnoses were at heightened risk in all groups, including acute coronary disease, arrhythmias, acute kidney injury, chronic kidney disease, memory problems, and thromboembolic events. For each of these, the magnitude of risk increased with the severity of the initial clinical course of COVID-19.

Study Strengths

This was a very large and comprehensive study, evaluating data on diagnoses, medication use, and laboratory values following laboratory-confirmed COVID-19, ascertained from integrated electronic health records. The large VHA source population provided adequate power to assess the mid-term outcomes of COVID-19 by sub-categories of disease course severity, and also provided a large pool of individuals without COVID-19 diagnoses available for selection as appropriate controls. The authors used robust methods to control for potential confounding, including propensity score weighting of comparison groups and multivariable adjustment. The analytic plan was rigorous, e.g. accounting for competing risks, varying model assumptions in sensitivity analyses, testing negative outcome and exposure controls, and using Bonferroni-adjusted p-value to address spurious results arising from multiple comparisons. COVID-19 was not associated with any of the negative outcome controls–outcomes that were not expected to have a causal association with COVID-19; e.g. neoplasms or accidental injuries, strengthening confidence in the validity of the analyses. Likewise, there were no associations between the negative exposure controls (comparing the influenza cohorts tested in odd and even months), further reducing concern about unmeasured confounding and model misspecification. The study reported the incidence rate of each outcome among those with and without COVID-19, and the difference in the incidence rates between groups in addition to the hazard ratio, providing information not just on the magnitude of the relative hazard but also the extent of the excess burden of each outcome in the study population.

Limitations

The study population was primarily male (~90% across all groups), and may not reflect long-term outcomes or differences that are more pronounced in women. Further, these results are specific to a population with health insurance and access to care, and it is possible the post-acute outcomes might be worse among other populations impacted by COVID-19. The study evaluated all outcomes separately; therefore, it does not provide information on an overall incidence of PASC or of grouped organ-specific conditions among this population. The study was limited to patients diagnosed with COVID-19 before November 2020, prior to the widespread transmission of COVID-19 variants of concern in the US; it is possible that infection with these variants may lead to different long term sequelae. The authors do not mention missing data, so it is assumed that analyses are restricted to those with complete data and may be biased as a result. Although several methods were used to control for and evaluate confounding, residual confounding due to unmeasured factors is possible. While it is possible that some of the control participants may have had COVID-19 that was undiagnosed or tested outside the VHA system, this misclassification would minimize a true difference between populations, resulting in smaller estimates of the hazard ratio and excess burden.

Value added

This is one of the largest studies of post-acute COVID-19 to date, providing data on a range of mid-term outcomes following COVID-19, including among non-hospitalized patients, hospitalized patients, and those requiring care in the ICU, relative to a comparison group of similar veterans without COVID-19 diagnoses during the same time period. The study is also among the first to address questions about how the post-acute outcomes of COVID-19 compare to the syndromes following other viral infections, by directly comparing post-30 day outcomes of those hospitalized with COVID-19 to those hospitalized with influenza.

Our take —

This study supports national vaccination campaigns due to the fact that the campaign in Israel, one of the first countries to implement one, resulted in significantly lower rates of SARS-CoV-2 infections. A retrospective analysis of Israeli Ministry of Health data showed a decrease in new positive tests, positive test percentage, new hospitalizations, and severe hospitalizations after implementation of the vaccine campaign. These results indicate that the vaccine distribution strategy that Israel employed had a significant positive impact on the dynamics of the COVID-19 pandemic there.

Study design

Retrospective Cohort

Study population and setting

This study was a retrospective analysis using data on SARS-CoV-2 infections and vaccinations with the Pfizer BNT162b2 mRNA vaccine in Israel to investigate the impact of vaccination on transmission. Data from the Israeli Ministry of Health included age, sex, date of positive SARS-CoV-2 PCR test, date of hospitalization, clinical state during hospitalization, and date of death or recovery for all Israeli citizens from August 28, 2020 to February 24, 2021. Publicly available data from the national vaccination campaign included the number of daily vaccine doses broken down by which dose was received (first or second), city of residence, and age of vaccinees by 10-year age categories. Early vaccinated cities were defined as the top ten cities with the highest percentage of the population above 60 years who were vaccinated or recovered from COVID-19 by January 10, 2021, while late vaccinated cities were the ten bottom cities with the lowest percentage of these individuals. The study also compared the number of new positive tests, positive test percentage, new hospitalized cases and new severe cases between the second lockdown (imposed on September 18, 2020) and the third lockdown (imposed on January 8, 2021), which was after the national vaccination campaign began on December 20, 2020.

Summary of Main Findings

There was an approximate 77% drop in total cases, 45% drop in overall positive test percentage, and 68% drop in total hospitalizations two months following the initiation of the vaccination campaign compared to peak values. This was at a time that 85% of people age 60 years and older had already been vaccinated with two doses of the Pfizer vaccine. These drops were observed in each consecutive group that became eligible for the vaccine. There was approximately 10% less of a decrease in the number of COVID-19 cases and severe hospitalizations in late vaccinated cities compared to early vaccinated cities. When comparing these metrics between the second and third lockdowns, the same trends were not observed during the second lockdown, which was prior to initiation of the vaccination campaign. This lends support to the vaccine being the cause of the drops in cases and hospitalizations.

Study Strengths

The study used a large dataset from a universal healthcare system in Israel that enabled the authors to track all diagnosed cases and vaccinated individuals over time to compare before and after the vaccine campaign began.

Limitations

This was a single study, and therefore it is difficult to truly infer causality. All variables were not exactly the same between the second and third lockdown (i.e. circulating strains of COVID-19, behaviors, transmission prevention measures etc.), so these periods may not be comparable. Behavioral and social differences between cities were not accounted for when comparing different geographic regions. Finally, this study examined the effects of the Pfizer vaccine in the Israeli population, and therefore these results may not be generalizable to other COVID-19 vaccines.

Value added

This is the first analysis of the effect of a vaccination campaign on SARS-CoV-2 transmission dynamics at the population level.