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Our take —

This prospective cohort study examined the vaccine effectiveness of two mRNA vaccines (Pfizer-BioNTech and Moderna) among 3,950 health care personnel, first responders, and other essential/frontline workers across 8 US-based sites between December 14, 2020 and March 13, 2021. Through weekly and symptom-based screening, 205 PCR-confirmed SARS-CoV-2 infections were identified. The observed 90% vaccine effectiveness estimate among fully immunized individuals (≥14 days after second dose) was consistent with clinical trial data. The study also noted 80% vaccine effectiveness among partially immunized individuals, but caution is warranted given exclusion of infections within 14 days of second dose.

Study design

Prospective Cohort

Study population and setting

This study describes the interim results of a prospective cohort study that examined the vaccine effectiveness of two messenger RNA (mRNA) vaccines – BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) – in real-world settings. The study collected data across 8 locations in the US between December 14, 2020 and March 13, 2021 on 3,950 health care personnel, first responders, and other essential and frontline workers (e.g. hospitality, delivery, retail, teachers) without prior laboratory confirmed SARS-CoV-2 infection. Participants self-collected a nasal swab weekly regardless of symptoms, and self-collected additional swabs if experiencing symptoms consistent with COVID-19; all swabs were tested for SARS-CoV-2 via RT-PCR. COVID-19 vaccination status was documented via self-report, telephone interviews, vaccine card upload at all sites, and medical records at some sites. Participants additionally self-reported COVID-19 associated symptoms weekly via text messages, email, or medical record reports.

Summary of Main Findings

Of the 3,950 participants (62% female, 86% white, 72% < 50 years old, 69% without self-reported chronic conditions), 205 were diagnosed with SARS-CoV-2 infection during the study period (11% asymptomatic). The incidence rates of SARS-CoV-2 infection were 1.38 per 1000 person-days among unvaccinated individuals, 0.19 per 1000 person-days among partially immunized individuals (≥14 days after first dose but before second dose), and 0.04 per 1000 person-days among fully immunized individuals (≥14 days after second dose), corresponding to site-adjusted vaccine effectiveness estimates of 80% (95% CI: 59-90%) and 90% (95% CI: 68-97%) among partially immunized individuals and fully immunized individuals, respectively. Vaccine effectiveness estimates individually adjusting for sex, age, ethnicity and occupation were similar to the main results. Notably, 33 PCR-confirmed infections occurring with 13 days of first or second dose of vaccination (67,483 person-days) were excluded from analyses.

Study Strengths

This was a prospective and moderately sized cohort study. Individuals self-collected nasal swabs to test for SARS-CoV-2 infection weekly, regardless of symptom status which enabled capture of asymptomatic infection and assessment of the impact of vaccine on overall infection, rather than just symptomatic illness.

Limitations

33 PCR-confirmed infections that occurred within 13 days of either vaccine dose were excluded, and it was not clear why the 13 days following second dose were considered a period of indeterminate immune status rather than partial immunization. Depending on how many of the 33 excluded infections occurred within 13 days of the second dose, the estimate of vaccine effectiveness among partially immunized individuals may be overestimated. Individuals with prior laboratory confirmed SARS-CoV-2 infection were excluded, so vaccine effectiveness estimates are unlikely to be generalizable to that group. Nasal swabs were self-collected, and symptoms were self-reported, which may have influenced the sensitivity of the test (especially if vaccination reduces viral shedding) or lead to misclassification. Only 3 infections occurred among people in the fully immunized group and 8 among people in the partially immunized group, which limited the ability to adjust for other potential confounders and led to wide confidence intervals.

Value added

This is one of the first real-world examinations of vaccine effectiveness for the Pfizer-BioNTech and Moderna mRNA vaccines.

Our take —

In a small study, available as a preprint and thus not yet peer-reviewed, of 66 COVID-19 patients with persistent COVID-19 symptoms 8 months after hospital discharge, receipt of at least one dose of Pfzier-BioNTech or AstraZeneca SARS-CoV-2 vaccinations was not significantly associated with symptom exacerbation or improvement. Findings, however, are subject to various limitations, including possible misclassification of symptom persistence in participants, a short observation period, and questionable generalizability to patients not requiring hospitalization during their acute COVID-19 infections.

Study design

Prospective Cohort

Study population and setting

Patients hospitalized for COVID-19 infections between April and May 2020 were recruited into a prospective cohort study measuring quality of life and recovery status at 3 and 8-month intervals from discharge date. Cohort participants who received at least one dose of the Pfizer-BioNTech or AstraZeneca SARS-CoV-2 vaccines in December 2020 were contacted one month later to assess symptom persistence, mental health, and quality of life. A control participant from the parent cohort study was matched to two vaccinated participants based on symptom persistence and quality of life measures 8 months post-hospitalization. Symptomatology and quality of life were compared in vaccinated participants and unvaccinated controls.

Summary of Main Findings

A total of 44 vaccinated patients were matched to 22 unvaccinated controls in the cohort study. Vaccinated patients were older (median age: 64 years) than unvaccinated control (median age: 55 years) and were more likely to have underlying health conditions, specifically heart (25% vs. 9.1%) and chronic lung (32% vs. 9.1%) diseases, respectively. A majority (82%) across both groups reported at least one persistent COVID-19 symptom 8 months after hospital discharge, the most common being fatigue (61%) and shortness of breath (50%). Eight months after hospital discharge, unvaccinated controls reported more persistent symptoms (median: 4.1 symptoms) per patient than vaccinated participants (median: 3.6 symptoms). Persistent COVID-19 symptoms remained unchanged in most vaccinated participants (70%) and unvaccinated controls (71%) 30 days after vaccination, irrespective of vaccine candidate received. Adjusting for participant age and gender, no significant differences in physical or mental health were observed 30 days after vaccination comparing vaccinated patients to unvaccinated controls.

Study Strengths

Investigators matched vaccinated participants to unvaccinated controls on factors that would likely affect the observed association between vaccination status and physical mental health outcomes. Investigators also measured changes (improvement, maintenance, or aggravation) in individual symptoms in the one month after vaccination.

Limitations

While the investigators elicited information about changes in individual symptoms in the one-month period following vaccination, participants were discretely classified in regression analyses as having improved, unchanged, or exacerbated physical and mental health. As a result, outcomes may have been misclassified if, for example, some symptoms improved while others worsened over the observation period. Additionally, study participants included in the analytic cohort were followed for a median duration of 32 days; any changes in symptom persistence or severity beyond the observation period would not have been captured in the short follow-up window. Study procedures were also susceptible to response biases, as vaccinated participants may have been more likely to recall any changes in their symptoms since vaccination compared to unvaccinated controls. Inferences about the relationship between vaccination status and symptom persistence, aggravation, or attenuation are additionally limited by the study’s small sample size, resulting in low statistical power to detect differences between vaccinated participants and unvaccinated controls. Lastly, because the parent cohort included only adults with hospitalization history for COVID-19, results may not be generalizable to patients with persistent COVID-19 symptoms that did not require hospitalization during their acute infections.

Value added

This is among the first studies to assess safety and physiological responses to SARS-CoV-2 vaccines in patients with persistent symptoms from prior COVID-19 infections.

Our take —

This study, available as a preprint and thus not yet peer-reviewed, followed 13,109 healthcare workers in the UK from April 2020 through February 2021. Authors found that a single dose of either the Pfizer-BioNTech or the Oxford-AstraZeneca vaccine conferred an estimated 67% protection against symptomatic SARS-CoV-2 infection beginning 14 days after vaccination, and there were no cases 14 days after two doses of either vaccine. Evidence of prior infection from a positive antibody test was associated with an apparent 98% protection, though it is unclear how often HCWs received antibody testing. No differences were observed in apparent protection (either from vaccination or prior infection) when comparing the B.1.1.7 variant against non-B.1.1.7 lineages. Rates of SARS-CoV-2 infection increased during the first 14 days after infection, but this time was not included in analyses.

Study design

Prospective Cohort

Study population and setting

This observational study assessed protection from symptomatic PCR-confirmed SARS-CoV-2 infection conferred by vaccination and/or prior infection among 13,109 healthcare workers (HCWs, 74% female, median age 39 years) in a hospital network in the UK from April 23, 2020 to February 28, 2021. HCWs were classified by their vaccination status (1 dose vs. 2 doses of either the Pfizer-BioNTech or Oxford-AstraZeneca vaccines) and antibody status (any previous positive test for anti-spike IgG antibodies). Person-time was classified into five groups: 1) unvaccinated, seronegative; 2) unvaccinated, seropositive; 3) vaccinated once, seronegative; 4) vaccinated twice, seronegative; and 5) vaccinated once or twice, seropositive. HCWs could contribute person-time at risk to multiple exposure groups. Vaccinated follow-up time began 14 days after vaccination, while seropositive follow-up time began 60 days after initial positive antibody result. Asymptomatic HCWs were offered voluntary PCR testing for SARS-CoV-2 infection every two weeks and antibody testing every two months beginning April 23, 2020. Risks of infection were compared across vaccination and antibody status, and were compared between the B.1.1.7 variant and non-B.1.1.7 variants. The B.1.1.7 variant was identified via PCR test results indicative of S gene target failure (SGTF) as of November 16, 2020; all positive samples starting on December 1, 2020 were sequenced to identify the viral lineage. The authors used Poisson regression to test for differences in incidence rates in each exposure group, adjusted for month, age, sex, ethnicity, occupational role, amount of patient contact, and whether the HCW worked in a non-ICU ward caring for COVID-19 patients. Sensitivity analyses were conducted to test for differences by vaccine type, by time since vaccination, by SGTF, and by B.1.1.7 vs. non-B.1.1.7 lineage.

Summary of Main Findings

A total of 13,109 healthcare workers (HCWs) contributed 2,835,260 person-days of time to the study. Over the study period, 1,273 HCWs tested positive for IgG anti-spike antibodies; 8,285 HCWs received the Pfizer-BioNTech vaccine and 2,738 received the Oxford-AstraZeneca vaccine. There was an increase in the incidence rate above baseline levels, even after adjustment, during the first 14 days after vaccination; these cases were excluded from analysis. There were 294 symptomatic infections among unvaccinated seronegative HCWs during follow-up, 32 among vaccinated HCWs (31/32 were previously seronegative), and 1 in an unvaccinated seropositive HCW. Relative to unvaccinated seronegative HCWs, the adjusted incidence rate ratio (IRR) for seropositivity was 0.02 (95% CI: <0.01 to 0.18). Among previously seronegative HCWs, the adjusted IRR for a single vaccine dose was 0.33 (95% CI: 0.21 to 0.52), and there were no infections among HCWs who had received a second dose. There were 16 COVID-19 hospitalizations among unvaccinated seronegative HCWs, and no hospitalizations among vaccinated HCWs. When considering any SARS-CoV-2 infection regardless of symptoms, the IRR for seropositivity was 0.15 (95% CI: 0.08 to 0.26); among seronegative HCWs, the IRR was 0.36 (0.26 to 0.50) for the first vaccine dose and 0.10 (95% CI: 0.02 to 0.38) for the second dose. There were no statistically significant differences in incidence by vaccine type. Viral loads were highest among unvaccinated previously seronegative cases, followed by vaccinated previously seronegative cases, and lowest among unvaccinated seropositive cases. There was no evidence that SGTF or B.1.1.7 lineage altered the incidence rate among seropositive or vaccinated HCWs, though the confidence intervals were wide.

Study Strengths

Frequent testing of HCWs allowed consideration of COVID-19 incidence across person time for a wide range of exposures (defined by antibody and vaccination status). A high proportion of infections was assessed for SGTF and/or sequenced to determine viral lineage.

Limitations

Follow-up time after vaccination, particularly the second vaccination, was short and few events were observed. There were increases in incidence during the first two weeks after vaccination, but this person-time and these cases were not included in analyses: if these HCWs were systematically different from those remaining in the risk set, the ensuing selection bias would overestimate vaccine protection. Any prior positive antibody test was used as a proxy for previous infection, which is subject to several limitations. First, the frequency of testing among HCWs was not reported, and it appears that all person-time before a positive antibody test was classified as seronegative; thus, misclassification of person-time is likely and incidence among seropositive HCWs may be underestimated. If HCWs with prior symptoms were more likely to seek serological testing, and if asymptomatic infection confers less protection against re-infection, then this issue would be exacerbated. On the other hand, false positive results are not uncommon even with highly specific assays in low-prevalence populations, which would bias estimates of incidence among seropositive HCWs in the other direction. HCWs with positive PCR results for SARS-CoV-2 infection were removed from all risk sets; it is not clear why these events were not used as a better indicator of prior infection. Seropositive and vaccinated HCWs were less likely to be tested for SARS-CoV-2 infection, which may have underestimated incidence rates of asymptomatic infection in those groups.

Value added

This study took advantage of frequent PCR and serology testing among HCWs in an environment of high transmission to directly compare SARS-CoV-2 incidence rates by vaccination and antibody status, and was able to compare estimates of protection against the B.1.1.7 variant vs. non-B.1.1.7 lineages.

Our take —

This study used data from the COVID-19 Symptom Survey administered on Facebook. Among 576,051 reports of families in the US with school aged children, of which about half were attending some in-person schooling, the risk of living in a family with a child attending school in-person was associated with increased risk of COVID-like illness. This risk increased with the age of the child, but decreased with more mitigation measures, suggesting that in-person schooling can be made safe. In the absence of combination prevention measures, this study provides evidence that in-person school attendance may contribute to household spread; efforts to implement mitigation efforts while vaccination rollout continues are a priority in order to reopen schools safely.

Authors of this scientific article are also members of the Hopkins NCRC; therefore, this expert review was written by an NCRC member outside of Hopkins without current or past collaborations with authors.

Study design

Prospective Cohort

Study population and setting

Evidence around whether transmission of SARS-CoV-2 occurs in schools has been challenging to generate. To answer this question, the authors used the COVID-19 Symptom Survey administered on Facebook which describes schooling behaviors and SARS-CoV-2 outcomes. Data from 2,142,887 respondents from November 24 to December 23, 2020 and January 11 to February 10, 2021 was analyzed. Of these, 576,051 had at least one child in school living in the household, of which in about half of households the child was attending either full or part time in-person schooling.

Summary of Main Findings

The study results showed that the risk of COVID-19-like illness was higher (adjusted OR 1.38, 95% CI 1.30-1.47) among those living with a child attending in person school compared to those who did not, and that the effect increased with increasing grade level of the child. Reports of mitigation measures at the school decreased the risk, with the strongest reduction associated with daily symptoms screens, teacher masking, and closure of extra-curricular activities. Implementation of 7 or more mitigation measures lead to almost no increased risk. In teachers, in-person teaching was associated with more COVID-19-related outcomes, but the risk was similar to that of other professions.

Study Strengths

The study used a large survey database that included respondents all over the United States. The authors were able to control for a number of geographic differences between areas, including background incidence rates, that could potentially confound results.

Limitations

Because the survey was administered through Facebook, results may not be fully generalizable to every part of the United States. Further the data are self-reported and may be subject to some mismeasurement. Finally, bias due to residual confounding remains possible as those areas that implemented the most mitigation measures may have had different risks before mitigation, even after adjusting for measured confounders.

Value added

This study is the largest to date in the US on transmission in schools, and suggests that in-person schooling does increase risk, but the risk can be minimized with strong mitigation measures.

Our take —

Much is still unknown about the extent and duration of immunity amongst individuals previously infected with SARS-CoV-2, and the rate and outcomes associated with reinfection, both in the general population and among vulnerable groups. This study described suspected reinfection among five permanent residents of a Kentucky skilled nursing facility during two separate outbreaks in July 2020 and October 2020. Although all five individuals were either asymptomatic or experienced mild symptoms during the first outbreak, illness was more severe during the second outbreak, including one death. Unfortunately, samples were not retained, so it was not possible to identify the phylogenetic strains that played a role in the outbreaks. Infection prevention and control measures remain important, even among populations with previous infection.

Study design

Case Series; Prospective Cohort

Study population and setting

This was a descriptive study carried out by the Kentucky Department of Public Health at a skilled nursing facility which had two COVID-19 outbreaks (in July 2020 and October 2020). In the first outbreak, which lasted from July 16 to August 11, 2020, 20 of 115 (17.4%) residents and five of the 143 health care professionals (3.5%) tested positive for SARS-CoV-2. Initially, testing was based on symptoms and contact, but was expanded to all residents and staff. Overall, eight residents with COVID-19 were hospitalized, of whom five died. Following the first outbreak, the facility monitored staff and residents for symptoms and tested symptomatic individuals, while health care personnel were tested at least every two weeks. Tests conducted in September and from October 1 to October 29 on facility residents and staff were all negative. On October 30, 2020, two symptomatic residents received positive test results, and all residents and staff were tested twice weekly. Subsequently, 85 of 114 (74.6%) residents and 43 of 146 (29.5%) personnel received positive results, of whom 15 residents died between October 30 and December 7, 2020. No health care professionals died during either outbreak.

Summary of Main Findings

Five permanent residents of the facility had positive reverse-transcription PCR SARS-CoV-2 tests at both outbreaks, even though all had at least four consecutive negative RT-PCR SARS-CoV-2 tests after the first outbreak. The five individuals ranged in age from 67 to 99 years; four were women, and all had more than three chronic underlying health conditions, although none had an immunosuppressive condition or were taking immunosuppressive medication. During the first outbreak, three of these individuals were asymptomatic, while two had mild symptoms. During the second outbreak, three of the five individuals had a roommate who tested positive to SARS-CoV-2, but no direct route of exposure was identified for the other two. All five experienced more severe disease in the second outbreak and one died. Investigators speculated that the findings could be due to true re-infection resulting from waning immunity in this aging population, or as a result of mild/asymptomatic cases not triggering a robust immune response to prevent reinfection. Alternatively, investigators noted the potential of false positive results during the first outbreak. However, they noted that the cycle threshold for all five of these residents met the cutoff for limit of detection during the first outbreak, supporting infection.

Study Strengths

Reverse-transcription PCR testing was used to confirm diagnoses during both outbreaks. Testing of all residents, including those who were asymptomatic, also strengthens our understanding of reinfection among residents overall.

Limitations

The investigators provided solid evidence to support their claim that residents were reinfected (versus experiencing prolonged disease). This evidence could have been bolstered even further by ruling out false positives during the first outbreak — with either repeat RT-PCR, antibody tests, or both — and using phylogenetic analyses to detect differences in the infecting virus. However, investigators were unable to ascertain phylogenetic strains between outbreaks because test samples had not been preserved and no further testing was performed on the residents until 10 or more days after the first RT-PCR positive test.

Value added

This study highlights the importance of continued infection prevention and control strategies, even among persons with previous COVID-19 diagnosis.

Our take —

Immunogenicity to a single dose of BNT162b2 nCoV-19 (Pfizer) vaccine was evaluated in a small cohort in the UK where timing of the 2nd dose was delayed to 12 weeks. Immunogenicity was considerably higher (26x in neutralizing antibody and 10x in T cell responses) in those previously infected with SARS-CoV-2 (n=21) compared to infection-naive adults (n=51). Antibodies decreased with increasing age only in the infection-naive vaccinated adults. One infection-naive adult over age 50 years whose post-vaccination anti-S was very low (62 AU/ml) had PCR-confirmed symptomatic infection 5 weeks after vaccination. Prioritization for the 2nd dose to those without prior infection over age 50 or with other risk factors might minimize cases.

Study design

Prospective Cohort

Study population and setting

This was a small cohort study in the UK of 72 health care workers (HCWs) who were vaccinated with BNT162b2 (Pfizer) between Dec 23 and 31, 2020 and who provided a blood sample both at the time of the first dose and 21-25 days later. Adults (n=21) were classified as previously infected if they had pre-existing antibody (n=16) or strong T-cell responses to non-spike protein antigens in the post-vaccination specimen (n=5) which the vaccine does not induce. Infection-naïve adults (n=51) were negative for both of these measures. Anti-S antibody titer, SARS-CoV-2 live virus neutralizing antibody titer, and T-cell responses to SARS-CoV-2 peptide pools were assessed and compared by pre/post vaccination status, age and previous infection status.

Summary of Main Findings

Anti-S antibodies after a single dose of BNT162b2 nCoV-19 vaccine was significantly higher in those previously infected with SARS-CoV-2 compared to infection-naïve HCWs. Antibodies among infection-naive HCWs were lower in those over age 50 years than in those less than 50 years. One infection-naïve HCW over 50 years old with very low (62 AU/ml) anti-S antibodies post-vaccination had PCR-confirmed symptomatic infection 5 weeks after vaccination. Vaccine induced very strong neutralizing titers even in those with no or low detectable NT at baseline. Previously infected HCWs mounted stronger (10x) T-cell responses to spike peptides than infection-naïve HCWs, of which 50% had T-cell responses considered negative.

Study Strengths

Multiple immunological markers were evaluated, all showing consistent results, which is critical given that the true correlate of protection is unknown. HCWs were prospectively enrolled with blood specimens collected at the time of vaccination, thus enabling assessment of pre-infection status, and post-vaccination at a time when antibody response is at peak. Individual results were shown, enabling assessment of heterogeneity of responses within sub-groups.

Limitations

This was a small study in a cohort that was not well characterized except for age and prior infection status, but the antibody responses were strikingly different by prior infection status suggesting the association is unlikely to be explained by another factor. Prior infection status was determined on immunological markers, not on confirmation of COVID-19 testing, which could account for some of the association; however, external data support their indication of prior infection status, and the immunological markers were infection-specific (i.e., not affected by vaccination). No correlates of immunity have been derived so implication for disease risk must be inferred, and the study was too small to evaluate impact on disease, but the one vaccine failure observed supported the findings that adults > age 50 years without prior infection may remain vulnerable after only a single dose. This study evaluated only the Pfizer vaccine; different findings (and thus recommendations) may be possible for ChAdOx1 (Oxford/AstraZeneca) in which observed no age effect on immunogenicity was observed in clinical trials.

Value added

This study showed clear evidence of lower antibody responses in individuals older than 50 years and in those without prior infection in adults immunized with a single dose of BNT162b2 (Pfizer) vaccine. Effectiveness studies should monitor the age and risk-factor status of breakthrough cases among those vaccinated as these finding suggest 2nd dose roll-out should consider prioritizing high-risk adults including those over 50 years of age.

Our take —

This study, available as a preprint and thus not yet peer-reviewed, describes the emergence of a new SARS-Cov-2 variant (B.1.526) in the New York metropolitan area in late 2020/early 2021. B.1.526 contains several mutations in spike protein, including E484K. Results indicate a rising prevalence of the B.1.526 variant in the population, increasing from 1% of randomly selected samples tested in November 2020, to over 12% in February 2021. In vitro studies demonstrated that E484K reduces the strength of antibody neutralization against the virus, raising concerns regarding the efficacy of vaccines and antibody-based treatments against variants with this mutation. However, recent clinical data from other studies indicates that the Johnson & Johnson COVID-19 vaccine still provides protection against the 501Y.V2 variant, which also contains the E484K mutation. This work highlights the value of genomic surveillance and illustrates that continued monitoring for viral genetic changes is an essential component of an effective public health response to COVID-19.

Study design

Retrospective Cohort

Study population and setting

This study described the recent emergence of a new SARS-CoV-2 variant of concern, B.1.526, in New York. Other variants of concern (B.1.1.7, B1.351, and P.1) carry mutations in spike protein (E484K and N501Y) that may lead to increased levels of transmission or immune escape. In order to better monitor the prevalence of these SARS-CoV-2 variants, researchers developed a PCR-based genotyping assay (targeting the E484K and N501Y mutations) that was used to screen a randomly-selected subset of SARS-CoV-2 positive samples (n=1,142) collected at Columbia University Irving Medical Center (New York City) between November 2020 and February 2021. Patient metadata were extracted from electronic health records stored in Columbia’s COVID-Care database. Whole genome sequencing was completed for all samples with cycle threshold [Ct] values <35 that had positive genotyping results and for a random subset of those with negative results. Sequences that were positive for either mutation (n=65, 5.7%) were used for phylogenetic analyses, along with a diverse set of SARS-CoV-2 global background sequences (n=140). Mutational profiling was completed by aligning variant spike sequences to the Wuhan-Hu-1 reference genome (NC_045512). A pseudovirus-based assay was used to quantify the effect of the E484K mutation on viral neutralization with monoclonal antibodies, convalescent plasma, and sera from vaccinated persons.

Summary of Main Findings

The genotyping assay identified 83 (9.0%) samples with the E484K mutation and 17 (1.8%) samples with the N501Y mutation; one sample had both mutations. The prevalence of cases that were positive for the E484K mutation increased over time from 1.3% in November to 12.3% in February. The results of the genotyping assay were successfully confirmed by whole genome sequencing for all samples tested. Patients infected with E484K variants vs. wildtype SARS-CoV-2 were older (58.1 vs 52.4 years) and were more likely to visit the emergency room or require hospital admission (85.9% vs 70.8%), but E484K status did not appear to impact overall rates of ICU admission. Phylogenetic analysis revealed that most samples with the E484K mutation (n=49) clustered together in a single, newly-identified lineage (B.1.526) with several mutations in spike protein (L5F, T95I, D253G, E484K, D614G, and A701V). Public SARS-CoV-2 sequence databases contained an additional ~140 genomes (from the Northeastern US) that were highly similar to the B.1.526 lineage, suggesting that it may be spreading throughout the region. Neutralizing antibody activity against a SARS-CoV-2 pseudovirus modified to contain the E484K mutation was significantly reduced for monoclonal antibody treatments (REGN10933, CB6, and LY-CoV555), convalescent plasma, and sera from persons vaccinated with either the Pfizer or Moderna vaccines. These results imply that spread of containing the E484K mutation (including B.1.526) could have significant clinical consequences, as this mutation may negatively impact the efficacy of antibody-based treatment and prevention modalities.

Study Strengths

Positive genotyping results for both mutations of interest (E484K and N501Y) were verified using whole genome sequencing. Further, functional impact of the E484K mutation on neutralization was quantified using an in vitro assay.

Limitations

Samples were collected at a single tertiary care center. Although B.1526 samples originated from diverse neighborhoods, the majority came from two distinct communities. A broader sample would provide more information about the spread of this new variant. Functional relevance of lineage-defining mutations was assessed based on the impact of a single mutation (E484K) in the context of an in vitro pseudovirus assay. Impact of all lineage-defining mutations in combination was not assessed, and no clinical data is presented confirming viral immune escape for patients infected with E484K variants.

Value added

This study describes the use of genomic surveillance to identify a newly-emergent SARS-CoV-2 variant of concern, B.1.526, in New York City between November 2020 and February 2021. This study also presents in vitro data suggesting that the E484K mutation (found in B.1.526 and other variants of concern) contributes to a loss of neutralizing antibody activity against viruses carrying the mutation.

Our take —

The study estimated the real-world effectiveness of the Pfizer vaccine in Israel’s mass vaccination campaign. Using data from 53% of the Israeli population, they found effectiveness rates similar to efficacy reported in the clinical trials. After receiving the second dose of the vaccine, the estimated effectiveness was 92% for infection, 94% for symptomatic COVID-19, 87% for hospitalization due to COVID-19, and 92% for severe COVID-19 disease. While there may be some selection bias in their estimates due to eligibility criteria and their matching pattern, this study shows that the COVID-19 vaccine is an important public health intervention that worked as well in the real-world as it did in trials, in this population and at this time, with the variants that were circulating in Israel from December 2020 to February 2021.

Study design

Prospective Cohort

Study population and setting

The study objective was to evaluate the effectiveness of a nationwide mass vaccination campaign in Israel (using the Pfizer vaccine) to reduce COVID-19 incidence, hospitalization, and death. The study used data from Clalit Health Services (CHS), an integrated health system with 4.7 million participants, equivalent to 53% of the population. Participants >16 years of age who did not have prior SARS-CoV-2 infection as determined by documented polymerase-chain-reaction (PCR) test, and who were members of CHS in the past year were eligible for the study. Each day from December 20, 2020 to February 1, 2021, newly vaccinated participants were matched 1:1 with unvaccinated participants on age, sex, sector, neighborhood of residence, history of flu vaccination in the past 5 years, pregnancy, and total number of comorbid conditions identified as risk factors for severe COVID-19. Follow-up continued until there was an outcome event, due to death unrelated to COVID-19, vaccination (for an unvaccinated control), vaccination of matched control (for vaccinated participant), or the end of the study. After an unvaccinated match was vaccinated, they were eligible for entry to the study as a vaccine recipient. Outcomes were SARS-CoV-2 infection by PCR test, reported symptoms of COVID-19, hospital admission for COVID-19, severe COVID-19, and death from COVID-19. They used a Kaplan-Meier estimator of risk of events with follow-up in days.

Summary of Main Findings

The study included 1,193,236 participants. The estimated vaccine effectiveness from 14 to 20 days after the first vaccine dose was 46% (95% CI: 40 – 51%) for SARS-CoV-2 infection, 57% for symptomatic COVID-19 illness (95% CI: 50 – 63%), 74% for hospitalization due to COVID-19 (95% CI: 56 – 86%), 62% for severe (95% CI: 39 –80%), and 72% for death due to COVID-19 (95% CI: 19 – 100%). Effectiveness increased in the 21 to 27 days after the first dose for all metrics. After the second dose, effectiveness was estimated at 92% for infection (95% CI; 88 – 95%), 87% for hospitalization (95% CI: 55 – 100%), and 92% for severe disease (95% CI: 75 – 100%). Death after 2nd dose was not estimated due to low observations. The study found lower effectiveness among participants with multiple comorbid conditions, and similar effectiveness across age strata.

Study Strengths

The primary study strength was the large sample size via the mass vaccination campaign, and the robustness of daily follow-up. Notably, CHS had prior medical data available for categorization of comorbid conditions and other sociodemographics, and patient follow-up both in the community and in the inpatient settings for more than half of the Israeli population. The study also used matching to reduce the likelihood of confounding based on a range of factors, including age and prior comorbidities. The study also had access to documented infection results, allowing them to also assess the effectiveness of preventing asymptomatic infections, providing greater generalizability of these results beyond the study population and to the general Israeli population.

Limitations

There may be residual confounding on factors beyond the matched sociodemographic factors, such as confounding due to specific health seeking behaviors. The study excluded healthcare workers and individuals confined to nursing homes due to high internal variability in the probability of vaccination or outcome, which may also limit the generalizability of the findings to these specific groups. Finally, the study did not report all variants, though they did find that the B.1.1.7 variant made up the majority of infections in the last days before data extraction, and that their study likely represented an average across multiple strains that may not be wholly applicable to any one given strain.

Value added

This is the largest COVID-19 vaccine effectiveness study conducted to date, making up over half of the population of Israel, demonstrating that the Pfizer vaccine has been highly effective in this population at preventing hospitalization and death.

Our take —

The clinical trial of the Pfizer/BioNTech vaccine showed that the vaccine is almost 95% effective in preventing COVID-19 1-2 weeks following administration of the second dose of the vaccine. With vaccine shortages and high SARS-CoV-2 infection rates world-wide, many have proposed postponing the second dose of the vaccine to expand the number of people getting their first dose to curb viral spread. This study shows that the Pfizer/BioNTech vaccine may be 85% effective in preventing symptomatic cases of COVID-19 15-28 days after following administration of first dose. Further studies are needed to determine the long-term protection after the first dose of the vaccine.

Study design

Case-Control, Prospective Cohort

Study population and setting

The study analyzed the SARS-CoV-2 infection rate among health care workers in The Sheba Medical Center, the largest hospital in Israel, after vaccination with Pfizer/BioNTech BNT162b2 vaccine. By the end of the study, among 9109 health care workers eligible for the vaccine, 7214 (79%) had received at least one dose and 6037 (66%) had received both doses of the vaccine. Most (91%) of the fully vaccinated workers received their second dose 21 or 22 days following the first dose. SARS-CoV-2 infection was detected through daily required symptom reporting and/or contact tracing followed by PCR lab diagnosis.

Summary of Main Findings

The study found that the vaccine reduced the infection rate (both symptomatic and asymptomatic) from 7.4/10,000 person-days in the unvaccinated group to 5.5/10,000 person-days (30% reduction) and 3/10,000 (75% reduction) on days 1-14 and 15-28 after administration of the first dose of the vaccine, respectively. The symptomatic cases were also reduced by 47% (2.8/10,000 person-days) and 85% (1.2/10,000 person-days) on days 1-14 and 15-28 after administration of the first dose of the vaccine, respectively, compared to the unvaccinated group (5/10,000 person-days).

Study Strengths

The study included 9109 health care workers with daily reporting of SARS-CoV-2 symptoms and contact tracing followed by same-day molecular diagnosis of the infection. This allowed for relatively high quality data. The high rate of SARS-CoV-2 infection in Israel at the time in which this study was conducted permitted detection of differences in infection rates among different groups tested in this study.

Limitations

One of the main limitations of this study is that it included health care workers only. This group has a higher exposure rate relative to the general population. The study also analyzed Pfize/BioNTech vaccine protection for up to 28 days after the first dose. Longer follow up to determine the protection level for one dose relative to two dases of the vaccine. For the effectiveness estimate of the window 15-28 days after vaccination, person-time from vaccinated individuals who had not been infected through 14 days were compared to all person-time contributed by unvaccinated individuals. It is possible that this could induce a selection bias that could overestimate effectiveness during this time window.

Value added

This study showed that Pfizer/BioNTech (BNT162b2) vaccine may provide up to 85% protection against symptomatic infection of COVID19 15-28 days after the first dose of the vaccine.

Our take —

This prospective cohort study was nested in a randomized controlled trial, and found that among 314 index patients with COVID-19, there were 753 contacts across 282 potential transmission clusters of which 32% had a transmission case. Increased viral load amongst the index case, household contacts, and age of contacts were associated with transmission; notably, respiratory symptoms of the index case were not associated with transmission. Additionally, among infected contacts testing positive but asymptomatic at first assessment, higher viral load within the contact was associated with their eventual onset of symptoms and time-to-symptom onset (higher viral load resulted in symptom onset in fewer days). A key limitation is that no asymptomatic index cases were included, however the study yielded important insights into the impact of viral load on transmission. Findings suggest that viral load, and not respiratory symptoms among index cases, predicts transmission, and that viral load amongst secondary infections impacts symptom onset.

Study design

Randomized Controlled Trial, Prospective Cohort

Study population and setting

The study objective was to identify transmission factors and clusters of COVID-19 in the Catalonia region of Spain using data from a randomized controlled trial conducted between March 17 and April 28, 2020 for hydroxychloroquine to reduce transmission of SARS-CoV-2. Eligibility criteria for cases included aged 18 years or older, not hospitalized, positive PCR results at baseline, an onset of mild symptoms within 5 days preceding enrollment, and no reported symptoms of COVID-19 at the home or workplace. Participants were identified using the Epidemiological Surveillance Emergency Service registry and their contacts were traced. Adult contacts were household members, nursing home residents, or healthcare worker contacts who had direct exposure to the index case for 15 or more minutes and no reported symptoms in the 7 days prior to index case enrollment. Contacts were followed for 14 days with visits on Day 1 and 14. The study used symptom questionnaires and collected age and sex information on cases and contacts. Authors assessed the relationship of viral load from PCR results and SARS-CoV-2 transmission.

Summary of Main Findings

From 314 patients with COVID-19, investigators identified 753 contacts from 282 (90%) of patients. Of these 282 potential connections across individuals, 90 (32%) had at least one transmission event documented by the study. Among the 125 index cases with viral load data available, viral load among the index case was associated with fever in the index case and was negatively associated with days since onset of symptoms (reinforcing that viral load is highest around timing of symptom onset). In terms of transmission, the viral load of the index case, being a household contact, and age of the contact were all positively associated with transmission. Age and sex of the index case, respiratory symptoms of the index case, and mask use of contacts were not associated with transmission. Further, among 421 contacts testing positive at their first visit and asymptomatic, viral load amongst contacts at first infection detection was associated with eventual development of symptoms and time to symptom onset.

Study Strengths

The study had viral load data available to understand differences in transmission related to viral load. It also had longitudinal follow-up for all contacts to track symptoms and positive tests. The study used epidemiologic surveillance systems that were coupled with mandated contact tracing to ensure a large sample size, though it was nested in a randomized controlled trial (RCT).

Limitations

By nesting this analysis in an RCT, investigators had stringent eligibility requirements for index cases that may not be representative of all or most cases in Catalonia at large. In particular, asymptomatic individuals were not enrolled as index cases. Finally, total time of exposure was not included in the analysis, which may have underestimated the protective nature of masks if household contacts used masks but also had a longer time period of exposure; further, mask use of the index cases was not factored into the analysis.

Value added

This is one of the largest studies investigating viral load, as opposed to just COVID-19 infection status. It has important insights into the impact viral load has on transmission.