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Our take —

This study from Israel describes rates of breakthrough COVID-19 cases in July of 2021 among people who received two doses of the Pfizer vaccine. Among people older than 60 years, the rate of breakthrough infection was 2.2 times higher among those who were vaccinated six months before the study period compared to those who were vaccinated two months before the study.  Similarly, among people aged 40-59 years, the infection rate was 2.1 times higher among those who were vaccinated four and five months before the study compared to those who were vaccinated two months before the study; among those aged 16-39 years, the rate was 1.6 times higher. In all age groups, the risk of infection increased with time since full vaccination, however, estimated vaccine effectiveness against severe COVID-19 disease only declined modestly in people aged 60 years and older (from 92% to 85%). Although the authors attempted to control for some possible sources of bias, such as differences in rates of PCR testing, they could not adjust for others (e.g., comorbidities, differences in health care access, and differences in risk behaviors), so results should be interpreted cautiously. This study provides further evidence that vaccine induced immunity to infection wanes over time, but protection against severe disease remained strong. 

 

Study design

Retrospective Cohort

Study population and setting

The study was conducted in Israel between July 11 and July 31, 2021 among 4,791,398 residents who had been fully vaccinated (with the Pfizer vaccine) between January 16 and May 31, 2021 with no history of prior SARS-CoV-2 infection. By the start of the study period, the Delta variant accounted for over 98% of all new SARS-CoV-2 infections in the country; July 31, 2021 was selected as the end date of the study because of the rollout of the booster dose.  The study modeled the rate of SARS-CoV-2 infections and severe COVID-19 cases using Poisson regression.  Participants were stratified into the following age categories; 16-39 years, 40-59 years, and 60 years and older. Participants in each age category were grouped into vaccination intervals (using two-week periods) starting from each group vaccination eligibility date. Full vaccination status was defined as 7 days after the second dose of Pfizer vaccine. Severe infections were defined as COVID-19 pneumonia with a respiratory rate of more than 30, oxygen saturation less than 94% on ambient air, or P arterial O2 over FiO2 of <300. An interaction term between each age group and vaccination period was included to evaluate differences in waning immunity by age.  Regressions were adjusted for the following possible confounders: week of infection, the number of PCR tests that were done for each individual before vaccination (to account for possible ascertainment bias), sex, and population groups (general Jewish, Arab, and ultra-Orthodox). In sensitivity analyses, models were adjusted for socioeconomic status, and were restricted to the general Jewish population.

Summary of Main Findings

Across all age groups of fully vaccinated individuals, 13,426 people tested positive for SARS-CoV-2 infection, and 403 had severe COVID-19. In the adjusted model among individuals above the age of 60 years, the rate of SARS-CoV-2 infection was 2.2 times (95% CI: 1.3-3.6) higher among those vaccinated more than six months prior, relative to those who had their vaccine two months before the study.  Similar trends were noted among age groups 16-39 and 40-59 years, with rates of infection 1.6 (95% CI: 1.3-2.0) and 2.1 (95% CI: 1.4-3.0) times higher, respectively, among those who were vaccinated four months or more before the study period compared to those who were vaccinated two months before the study period. Comparing rates of severe COVID-19 among those above the age of 60 years, vaccinated persons six months or more before the study period had 1.8 times (95% CI: 1.1-2.9) the risk of severe disease compared to those vaccinated four months before the study period.  Among individuals below the age of 60 years, there were no statistically significant differences in the rates of severe COVID-19 across different vaccination periods.  In an additional analysis that used an unvaccinated cohort of individuals above the age of 60 years, vaccine efficacy for severe COVID-19 disease declined from 92% to 85% during the vaccination period. and efficacy against SARS-CoV-2 infection across all age groups declined from 82% to 57%. 

Study Strengths

The study accounted for the possibility of differential detection among individuals by adjusting for the number of PCR tests for each individual before the vaccination campaign. Several sensitivity analyses were done, including adjustment for socioeconomic status, and using ten-year age groups. 

Limitations

The high risk of unmeasured confounding should result in caution when interpreting results as solely the consequence of waning immunity. No data regarding comorbid conditions were included in the study, which could have resulted in confounding.  Similarly, health-related behaviors may have differed between early and late vaccine recipients (e.g., mask-wearing, social distancing, etc.). Socioeconomic status was only included as a variable in sensitivity analysis, but this may have affected both exposure and outcome risk. The rates of severe COVID-19 disease among age groups below the age of 60 years were low, which limits the evaluation of vaccine effectiveness against severe COVID-19 disease. Also, the definition of severe COVID-19 disease included patients with oxygen saturation below 94%, which could overestimate disease severity if the prevalence of chronic lung disease was elevated in the study cohort.  

Value added

This study provides observational data that corroborate laboratory-based studies indicating a waning of immunity against SARS-CoV-2 infection after vaccination.

Our take —

Since the start of the pandemic, surprisingly little data has emerged on how the risks of secondary SARS-CoV-2 transmission may depend on the masking status of infected individuals and their close contacts. This study, conducted through a contact tracing program in one Iowa county from October 2020 to February 2021, collected information from 431 infected cases and 969 of their close contacts to estimate differences in the transmission risk by masking status. The authors found that when at least one person was unmasked during the exposure, the risk of secondary transmission was double compared to when both the infected person and their close contact were masked (26% vs. 13%). The risk of transmission was higher when only the contact was unmasked, compared to when only the infected case was unmasked, but the sample sizes were too small to draw a firm conclusion about this difference. Although this observational study is subject to several possible sources of bias, it provides rare individual-level data supporting the effectiveness of masks in preventing infection by the wearer.

Study design

Retrospective Cohort

Study population and setting

This study, conducted by the public health department of Johnson County, Iowa, compared SARS-CoV-2 secondary attack rates (SARs) by the masking status of index cases and their close contacts from October 23, 2020 to February 28, 2021. Through the Iowa state contact-tracing program, the authors identified 969 close contacts of 431 cases (people who had tested positive for SARS-CoV-2 infection) who met inclusion criteria and for whom data were available on masking status during exposure and subsequent SARS-CoV-2 testing results. Close contacts were defined as: people who spent more than 15 minutes within 6 feet of a case during that case’s infectious period; who spent 2 hours or more in the same enclosed space as a case; or who experienced “substantial direct exposure” to the case (this latter criterion was evaluated on a case-by-case basis). The masking status of both case and contact during exposure was assessed via interviews with cases. Cases were also asked about dates and durations of exposure, symptoms during exposure, and the setting of the exposure (indoors vs. outdoors). Contacts were interviewed and asked for demographic information, date of symptom onset, previous COVID-19 history, and vaccination history. Contacts were excluded from the study if exposure occurred in a household, health care, or long-term care setting; or if no SARS-CoV-2 testing results from 2-14 days after the exposure were available. Secondary attack rates were calculated for combinations of masking status of the case and contact.  Multivariable logistic regression was used to estimate the association between mask score (the number of persons masked during an exposure: 0, 1, or 2) and SARS-CoV-2 transmission, adjusting for age, exposure setting, whether the case was symptomatic during exposure, and exposure duration. The study was initiated in response to a change in guidance from the Iowa Department of Health on September 29, 2020 in which close contacts were advised to perform symptom monitoring for 14 days instead of home quarantine if both the initial case and the contact were fully masked during exposure.

Summary of Main Findings

The average number of contacts per case was 2.25, and the median age of contacts was 18 years (range: 0 to 90 years). The overall secondary attack rate (SAR) was 20.5% (95% CI: 18.1 to 23.2), with the following SARs by masking status of case and contact, respectively: unmasked/unmasked 26.4% (95% CI: 22.9 to 30.7), unmasked/masked 10.0% (95% CI: 4.0 to 25.3), masked/unmasked 29.1% (95% CI: 19.3 to 43.9), masked/masked 12.5% (95% CI: 9.6 to 16.3). Among the 590 contacts (61%) in which at least one person was unmasked, the SAR was 25.6% (95% CI: 22.3 to 29.4). In multivariable logistic regression, an increase in mask score of 1 unit (representing one additional person masked, from 0-2) was associated with 30% lower odds of a secondary case (odds ratio 0.70, 95% CI: 0.57 to 0.84). Longer exposure and older age were associated with higher odds of secondary infection. Results were similar when restricted to children aged 5-18 years. Only 16 contacts had received at least one vaccine dose prior to exposure; all 16 tested negative to SARS-CoV-2. Of the 3 contacts with a prior positive SARS-CoV-2 test result, one tested positive after exposure.

Study Strengths

This study was able to measure masking status among both cases and contacts, and calculated secondary attack rates for each combination of masking status. Nesting the study within a contact tracing program allowed for standardized collection of covariates.

Limitations

The sample by definition did not include individuals who could not be contacted or who refused to participate in contact tracing investigation; the authors did not report the number of possible cases who were thus excluded from analysis. The resulting sample may not be representative of the wider population of cases and their close contacts. Additionally, an unknown number of contacts without testing results were excluded, which may have resulted in overestimation of the SARs. The sample size was too small to permit strong inference about differences in protection when the case vs. the contact was masked. Classification of mask use relied on self-report, which is subject to several possible biases including faulty recall, social desirability (i.e., individuals may have reported what they felt the interviewer wanted to hear), or a desire to protect contacts from the possibility of quarantine. Finally, this study took place before widespread vaccination; these results might or might not apply to a population with higher vaccination rates.

Value added

This is one of the very few studies to estimate and compare secondary attack rates among close contacts by the masking status of the initial case and the close contact during exposure.

Our take —

This observational study assessed myocarditis rates among Israelis 16 years and older between December 2020 to May 2021 by SARS-CoV-2 vaccination status in Israel by age and sex. Myocarditis cases were clinically adjudicated and incidences per 100,000 persons after first and second Pfizer-BioNTech mRNA vaccine doses were compared with unvaccinated individuals during the same time period and with myocarditis incidence observed before the COVID-19 pandemic. Vaccine-associated myocarditis cases were rare in all age and sex groups and over 90% of cases were mild and resolved quickly. Myocarditis was more likely after the second dose of the vaccine in all individuals, compared to both control groups. Adolescent males (aged 16-19 years) were at the highest risk of myocarditis after their second dose of the vaccine (15.07 cases per 100,000) compared to other age and sex groups. This study was not able to compare the incidence of vaccine-associated myocarditis with negative outcomes of SARS-CoV-2 infection (myocarditis, hospitalization, multisystem inflammatory syndrome, death, etc.).

Study design

Retrospective Cohort

Study population and setting

This observational study assessed myocarditis rates among individuals 16 years and older in Israel following the initiation of a national vaccination campaign (Pfizer-BioNTech vaccine) on December 20, 2020 through May 31, 2021. Myocarditis cases were initially identified via passive and active surveillance through the Israeli Ministry of Health. All cases were subject to adjudication from cardiologists and rheumatologists, and cases categorized as definitive or probable myocarditis were included in the analysis. Definitive and probable myocarditis case severity was described with available clinical data (length of stay, cardiac imaging, laboratory values, and time to symptom or imaging resolution). Myocarditis cases per 100,000 persons were compared by sex and age group among individuals after their first and second doses of the Pfizer-BioNTech SARS-CoV-2 vaccine (within 21 days of the first dose and 30 days of the second dose) with unvaccinated individuals during the same time period. Observed numbers of myocarditis cases were also compared with those seen among individuals 16 years and older in Israel from 2017-2019, before the COVID-19 pandemic. The study assessed myocarditis incidence per 100,000 persons, rate differences by group, and rate ratios between groups.

Summary of Main Findings

Approximately 9.2 million Israeli residents were included in the study period, about 5.1 million of whom received two doses of the Pfizer-BioNTech COVID-19 vaccine. They adjudicated 304 reported myocarditis cases and excluded 21 with a reasonable alternative diagnosis, 59 with insufficient data, and 4 suspected cases without sufficient information to classify them as probable. Of the remaining probable or confirmed cases (n=220), 107 occurred within 21 days of the first vaccine dose or 30 days of the second vaccine dose, 31 occurred in vaccinated individuals more than 21 days after the first dose or 30 days after the second dose (thereby classified as not vaccine-related), and 82 occurred in unvaccinated individuals (29 in individuals with diagnosed COVID-19). Of the 138 cases in vaccinated individuals, 129 (93.5%) were classified as mild with rapid resolution, 4 had severely-reduced ejection fraction (2.9%), and one died (0.7%).

Both male (RD 3.19 per 100,000 persons, 95% CI: 2.37, 4.02) and female (RD 0.39, 95% CI: 0.10, 0.68) participants were more likely to be diagnosed with myocarditis after their second dose compared to the first dose, with males aged 16-19 years experiencing the highest risk (15.07 cases per 100,000 persons). Overall, cases of myocarditis after vaccination were more common after the second dose than during the 2017-2019 reference period (standardized incidence ratio 5.34, 95% CI: 4.48, 6.40), with the highest incidence ratio in males aged 16-19 years (13.6, 95% CI: 9.3, 19.2). Overall, compared to the unvaccinated group, the second dose of the vaccine was associated with an increased rate of myocarditis (rate ratio 2.35, 95% CI: 1.1, 5.02), particularly among 16-19 year-old males (8.96, 95% CI: 4.50, 17.83).

Study Strengths

This study used population-level data with robust clinical adjudication to estimate the incidence of myocarditis after vaccination with the Pfizer-BioNTech vaccine by sex and age group. They also had access to baseline myocarditis incidence prior to the COVID-19 pandemic and incidence among unvaccinated individuals for comparison.

Limitations

While this study compared myocarditis incidence following vaccination to control individuals prior to the COVID-19 pandemic and unvaccinated individuals during the same time period, it did not include a comparison group of individuals diagnosed with SARS-CoV-2, which would have allowed readers to assess the risk of myocarditis following vaccination compared to the risk of myocarditis following COVID-19. It also did not have information on case severity among control participants, making it impossible to compare myocarditis severity following vaccination to other scenarios. Furthermore, this study did not provide information on myocarditis incidence in those younger than 16 years. Finally, given the small sample size, the analysis did not adjust for potential confounders beyond age and sex, such as underlying heart disease, immunological conditions, or medications that could cause myocarditis, all of which may be more common among vaccinated individuals.

Value added

This study provides evidence that adolescent males may be at increased risk of myocarditis following the second dose of the SARS-CoV-2 vaccine compared to baseline myocarditis incidence and incidence in similar unvaccinated individuals. However, it is unclear how clinically significant vaccine-associated myocarditis is compared to COVID-19 in this age group.

Our take —

This study, available as a preprint and thus not yet peer reviewed, used data from nationwide registries in the Netherlands to estimate vaccine effectiveness against COVID-19 hospitalization during periods when the Alpha and Delta variants were dominant. The study found that full vaccination (from the Pfizer, Moderna, AstraZeneca, and Janssen vaccines) was highly effective in both periods (94% and 95%, respectively), and found no evidence that effectiveness waned over a 5-month span after full vaccination or across different age groups. Although there are some possible sources of bias in this study, the use of nationwide registries provides strong evidence for persistently robust protection of vaccination against COVID-19-associated hospitalization, even with the dominance of the Delta strain.

Study design

Retrospective Cohort

Study population and setting

This study in the Netherlands linked a nationwide vaccination registry with a nationwide hospitalization database to estimate vaccine effectiveness (VE) against COVID-19 hospitalization and ICU admission from April 4 to August 19, 2021. VE was estimated by vaccine (Pfizer, Moderna, AstraZeneca, and Janssen), age group (15-49 years, 50-69 years, 70 years and older), time since vaccination, and prevailing SARS-CoV-2 variant (April 4 to May 29, when 95% of sequenced SARS-CoV-2 isolates were Alpha, vs. July 4 – August 29, when 99% of sequenced isolates were Delta). COVID-19 hospitalizations and ICU admissions were taken from NICE, a nationwide registry of all hospitalized individuals with a positive SARS-CoV-2 test or COVID-19 diagnosis. Vaccination status was ascertained via the nationwide vaccine registry CIMS. Upon vaccination, informed consent was sought for CIMS registration; among the 84% of vaccinations provided through the Netherlands municipal health services, 7.3% declined to be registered in CIMS. The size of the unvaccinated group was calculated by subtracting the vaccinated group from the full population. Vaccination status was considered to be “partial” 14 days after the first dose and “full” 14 days after the second dose (or 28 days after the single dose of the Janssen vaccine). The median duration from symptom onset to hospitalization, by age group (3-7 days), was applied to each admission date to classify vaccination status. Incidence rates per 10,000 person-days were calculated and incidence rate ratios (IRRs) were calculated with negative binomial regression adjusted for calendar date.

Summary of Main Findings

Of the 15,571 patients hospitalized with COVID-19 during the study period, 6% were fully vaccinated, 7% were partially vaccinated, and 87% were unvaccinated. For full vaccination, the estimated VE against hospitalization during the Alpha period was 94% overall (95% CI: 93% to 95%) and was consistently high across all three age groups. The estimated VE against hospitalization during the Delta period was 95% (94% to 95%) and also above 90% across age groups. Estimated VE against hospitalization by vaccine during the Delta period was as follows: Pfizer 96% (95% to 96%), Moderna 84% (80% to 87%), AstraZeneca 94% (92% to 95%), and Janssen 91% (88% to 94%). Estimated VE against ICU admission was generally slightly higher than that for hospitalization across categories of age, vaccine, time since vaccination, and viral variant period. There was no evidence of waning VE in any age group up to 20 weeks after full vaccination.

Study Strengths

Linkage of national hospitalization and vaccination registries allowed for a full nationwide cohort analysis of vaccine effectiveness and a comparison of vaccine effectiveness across age and vaccine cohorts.

Limitations

Vaccine allocation was nonrandom; for example, the authors noted that the Moderna vaccine was provided to medically high-risk patients, which may explain the lower apparent VE for that vaccine relative to the other vaccines. Furthermore, individuals who received the Pfizer and Moderna vaccine received the doses with a median interval of five weeks, which is longer than the intervals tested in their clinical trials (three and four weeks respectively), but may have implications for long-term effectiveness. Additionally, other than age, no information on patient characteristics or comorbidities were available, so unmeasured confounding is likely. There were few hospitalizations in several strata, limiting precision of estimates. An unknown proportion (likely around 7%) of vaccinated individuals did not consent to CIMS registration, and the resulting misclassification would result in overestimation of VE. However, a sensitivity analysis showed minimal impact on VE estimates. The population at risk included people with prior SARS-CoV-2 infection, which may have also led to bias if prior infection was associated with both vaccination status and hospitalization. Finally, COVID-19 hospitalization may have included some people who were hospitalized for other reasons but who incidentally tested positive for SARS-CoV-2, which may have led to a slight bias in an unknown direction.

Value added

This study is one of the first nationwide cohort studies to estimate vaccine effectiveness in the era of dominance of the Delta strain of SARS-CoV-2.

Our take —

This retrospective study from Israel examined the effect of a third (booster) dose of the BNT162b2 (Pfizer) vaccine. The population studied included individuals ages 60 years and older who received their second dose of vaccine at least five months earlier. It was estimated that boosters decreased the rate of confirmed COVID-19 infection by a factor of 11.3, and reduced the rate of severe illness by a factor of 19.5. However, the rates of infection and severe disease were extremely low in both groups, and so while the factors of protection may be high, the overall real-world benefit of boosters may be somewhat limited.

Study design

Retrospective Cohort

Study population and setting

Administration of a third (booster) dose of the Pfizer BNT162b2 vaccine was approved on July 30, 2021 in Israel for individuals age 60 years and older who had received their second dose at least five months prior. This retrospective analysis extracted data from July 30 to August 31, 2021 from the Israeli Ministry of Health database on September 2, 2021. The goal of the study was to examine the effect of the booster dose on the rate of COVID-19 infections and severe illness in this population. Data was pulled only for individuals in the 60 years and older group who had their second dose at least five months earlier, which yielded information from 1,137,804 individuals. The rate of COVID-19 infection and severe illness was compared between those who received a booster at least 12 days earlier and those who did not (non-booster). COVID-19 illness was confirmed by PCR, and severe illness was defined as having a resting respiratory rate of more than 30 breaths per minute, oxygen saturation of less than 94% while breathing ambient air, or a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of less than 300. For the non-booster group, days at risk began 12 days after beginning of study (August 10, 2021) and ended at either time of occurrence of a study outcome, the end of study the period, or at the time of receipt of a booster dose. Finally, the rate of infection 4-6 days after receiving a booster was compared to the rate of infection at least 12 days after receiving a booster. A Poisson regression was used to calculate rates after adjusting for possible confounding factors, including age (60-69, 70-79, 80+), sex, demographic group (general Jewish, Arab, ultra-Orthodox Jewish), and date of second vaccination in half month intervals.

Summary of Main Findings

From this retrospective cohort, there were 4,439 cases of infection out of 5,193,825 person-days at risk in the non-booster group compared to 934 cases out of 10,603,410 person-days at risk in the booster group. This amounted to a lower rate of infection in the booster group compared to non-booster group by factor of 11.3 (95% CI, 10.4 to 12.3) at least 12 days after receiving a booster. There were 294 cases of severe illness out of 4,574,439 person-days at risk in the non-booster group compare to 29 cases out of 6,265,361 person-days at risk in the booster group, which translates to a 19.5 fold lower rate of severe illness (95% CI, 12.9 to 29.5) in the booster group. Finally, the rate of confirmed infection at least 12 days after booster was lower than the rate of infection from 4-6 days after receiving a booster by a factor of 5.4 (95% CI, 4.8 to 6.1).

Study Strengths

The authors chose the cutoff of 12 days post-booster dose carefully, allowing for 7 days of immunity to build up plus 5 days of delay in detection of infection by PCR test. The date of second vaccine dose was included in the regression in order to account for waning effects of earlier vaccination, and the fact that high-risk groups received their vaccines earlier.

Limitations

Rates of infection in the 4-6 days post-booster time period could be underestimated due to booster recipients possibly undergoing less frequent PCR testing and behaving more carefully in the days following their booster dose. Next, the definition for severe illness may not be completely accurate. An oxygen saturation of 95% could be normal for some individuals, such as the elderly or people with COPD, so a saturation below 94% would not be severe in these cases. Additionally, deaths were not mentioned in this analysis. Finally, the rate ratio analysis is slightly unclear to the reader since the number of people in the booster and nonbooster groups was dynamic, and therefore one cannot calculate rates by dividing number of instances by number of people, in addition to the fact that the authors adjusted for specific factors within their model.

Value added

This is one of the first reports on the effectiveness of receiving a booster (third) dose of the Pfizer BNT162b2 vaccine in reducing rates of COVID-19 infection and severe illness in adults ages 60 years and older.

Our take —

This study from Israel, available as a preprint and thus not yet peer reviewed, found that the rates of SARS-CoV-2 breakthrough infections in vaccinated individuals, while very low (highest rate = 1.5%), were significantly higher than the rates of reinfection and hospitalization in previously infected individuals. In addition, individuals who were previously infected who received one dose of the Pfizer vaccine were even more protected from breakthrough infection than the naturally infected group. There were no deaths in any of the groups examined. Given that previously infected individuals may have had multiple infections prior to the study period, the overall applicability of the study to all populations needs more clarification. Lastly, these findings should not be taken as an endorsement that getting infected is a better overall option for protection than the highly effective vaccines that are available as only those who survived initial infection were eligible for analysis.

Study design

Retrospective Cohort

Study population and setting

This study compared the frequency of confirmed SARS-CoV-2 infections, COVID-19 disease, hospitalizations and deaths between individuals with three types of immunity: 1) SARS-CoV-2 naïve individuals who received two doses of the Pfizer vaccine by February 28, 2021 (vaccinated group); 2) people with RT-PCR confirmed SARS-CoV-2 infection prior to February 28, 2021 that had not been vaccinated at all by August 14 (natural immunity group); and 3) previously infected people who received one dose of Pfizer vaccine by May 25, 2021 (7 days before the study period began; infection-vaccine group). Data on outcomes were provided from June 1, 2021 to August 14, 2021 from the Maccabi Healthcare Services (MHS) database, Israel’s second largest Health Maintenance Organization that represents 26% of the population of Israel. The authors used three models to compare the groups while matching individuals from each group 1:1 on age, sex, and socioeconomic status. Model 1 only included people in the natural immunity group with confirmed infection who were matched in time to when vaccines were administered in the vaccine group. Model 2 compared the natural immunity and vaccination groups, but did not match on time of previous infection and vaccination. Model 3 compared the natural infection and infection-vaccine groups. All models were adjusted to account for possible confounders. During the time period examined for breakthrough and re-infections Israel was experiencing a surge in Delta variant related infections.

Summary of Main Findings

Overall, infections were very rare in all of the groups studied, and only 1.5% or less of study participants were infected in any of the analysis groups, regardless of how immunity was derived; there were no deaths in any group.

Model 1 compared 16,215 people in both the vaccinated and natural immunity groups and found that cases in the vaccinated group (n=238, 1.5%) were 13 fold more likely to experience a breakthrough infection than the natural immunity group (n=19, 0.12%). The majority of the cases were symptomatic. There were very few hospitalizations in either group with only 8 in the vaccine arm and 1 in the natural immunity arm.

Model 2 compared 46,035 people in both the vaccinated and natural immunity groups, and found that cases in the vaccinated group (n=640, 1.4%) were 6-fold more likely to experience a breakthrough infection than the natural immunity group (n=108, 0.23%). The majority of the cases were symptomatic. There were very few hospitalizations in either group with only 21 in the vaccine arm and 4 in the natural immunity arm.

Model 3 compared 14,029 people in both the natural immunity and infection-vaccine groups and found that cases in the infection-vaccine group (n=20, 0.14%) had about half the risk of experiencing a breakthrough infection than the natural immunity group (n=37, 0.26%). There was one hospitalization in the natural immunity group.

Study Strengths

Israel has a relatively high rate of COVID vaccination, and the nationalized healthcare database used represents an extremely large portion of the population. Limiting previous infections and vaccinations to only those which occurred by February 28 decreased the risk of continued viral shedding from the previously infected individuals, thereby ensuring that they are reporting true re-infections. The study was large and attempted to control for other factors that may affect COVID reporting in these individuals through a matched design.

Limitations

As the authors state the primary SARS-CoV-2 variant in Israel at this time was Delta, and therefore these results may not hold for other variants. In addition, Israel only used the Pfizer mRNA vaccine, so these results may not be applicable to other vaccine platforms. One important limitation of this study, that the authors do not address, is that it is possible that some of the previously infected individuals could have had multiple SARS-CoV-2 infections before their Feb 28 cut-off. It would be more applicable to treat anyone with multiple infections as a separate group or remove them from analysis. Lastly, more granular detail on the data used would be helpful to fully assess these findings.

Value added

This is one of the first studies to directly compare the protection against infection conferred through previous SARS-CoV-2 infection, vaccination, and a combination of both, in a large population with significant vaccine roll-out.

Our take —

This study linked contact tracing data, vaccination status, and SARS-CoV-2 testing results in Belgium from January to June 2021 to estimate the effectiveness of vaccines in a) preventing a vaccinated person from becoming infected, and b) preventing transmission from an infected vaccinated person to susceptible contacts. The authors found that the mRNA vaccines from Pfizer and Moderna were highly effective in preventing both infection (74% and 85%, respectively) and onward transmission (62% and 52%, respectively). The estimated effectiveness of the “viral vector” vaccines from AstraZeneca and Johnson & Johnson was lower, but too few people received these vaccines to permit precise estimation. There are two primary caveats with these results: first, the behavior of vaccinated and unvaccinated contacts may have differed from one another during exposures (e.g., mask use). Second, the study was conducted before the widespread emergence of the Delta variant and may not reflect vaccine effectiveness under the current mix of circulating strains. Despite these limitations, this study was able to estimate the effectiveness of vaccines to prevent both infection and onward transmission by leveraging data from a national contact tracing program.

Study design

Retrospective Cohort

Study population and setting

This was a study of SARS-CoV-2 vaccine effectiveness in Belgium from January 25 to June 24, 2021. The study population (52% female, mean age 33 years) was identified through the national contact tracing program and included all recorded contacts between infected and susceptible individuals within 1.5 meters lasting longer than 15 minutes. Susceptibility was defined by the absence of a positive PCR or antigen test result within the prior 90 days. There were 301,741 contact events arising from 131,283 index cases after excluding individuals with missing test results and those who were vaccinated within the previous 14 days. Vaccination status was classified by type of vaccine (AstraZeneca, Pfizer, Moderna, or Johnson & Johnson) and number of doses given (i.e., partial vs. full). In 91% of contact events, both the index case and the susceptible contact were unvaccinated. Among the remaining events, 2.7% of index cases were partially vaccinated and 0.8% were fully vaccinated, while 4% of susceptible contacts were partially vaccinated and 2.6% were fully vaccinated. The vast majority of vaccinated individuals received either the AstraZeneca or Pfizer vaccines. PCR testing of susceptible contacts was carried out as soon as possible and repeated 7 days after exposure (or sooner if symptoms developed). The authors fit Bayesian logistic regression models to test results, adjusting for previous infection, calendar week, and whether the exposure occurred in the household. Vaccine effectiveness was calculated with respect to preventing infection (from an index case to a vaccinated contact) and preventing onward transmission (from a vaccinated index case to a contact).

Summary of Main Findings

Vaccine effectiveness (VE) at preventing infection (from an unvaccinated index case to a fully vaccinated susceptible contact) was estimated at 74% (95% CI: 72 to 76) for the Pfizer vaccine and 85% (95% CI: 80 to 90) for the Moderna vaccine. For the viral-vector vaccines, estimated VE was lower with wider confidence intervals: 53% (95% CI: 12 to 84) for the AstraZeneca vaccine and 61% (95% CI: 29 to 84) for the Johnson & Johnson vaccine. There was no statistically significant difference between estimated VE and prior infection. For preventing onward transmission from a fully vaccinated index case to an unvaccinated susceptible contact, estimated VE was 62% (95% CI: 57 to 67) for the Pfizer vaccine and 52% (95% CI: 33 to 69) for the Moderna vaccine. The estimated VE for onward transmission for the viral-vector vaccines was not significantly different from zero.

Study Strengths

The study population was derived from the national contact tracing program, which meant the data collection and testing procedures were relatively standardized. A high proportion of identified contacts were tested for SARS-CoV-2 infection.

Limitations

A small proportion of the study population was fully vaccinated, which makes the model estimates relatively imprecise. Very few individuals received full doses of the AstraZeneca and Johnson & Johnson vaccines. Although there was a standard definition of a close contact, the nature of this contact could have systematically differed by vaccination status and this could have biased results. For example, if unvaccinated contacts were more likely to wear masks than vaccinated contacts, and if masks are partially effective in preventing infection, then the results would be biased against vaccine effectiveness. Actual numbers of positive test results among susceptible contacts were not reported, making interpretation of model results difficult. Data were not provided regarding the timing of testing relative to the date of exposure; if infections were missed due to late testing, results might be biased toward the null. The data also do not distinguish between symptomatic and asymptomatic infection. Finally, the emergence of more transmissible SARS-CoV-2 strains means that the results presented here may not be applicable to other calendar periods.

Value added

Because this study used data from a national contact tracing program, it was able to estimate vaccine effectiveness in both preventing infection and preventing onward transmission.

Our take —

Pediatric cases of SARS-CoV-2 have become more prevalent as the pandemic wears on, raising questions about the role this population plays in transmission. This study examined the impact of index case age on the risk of SARS-CoV-2 transmission in Canadian households between June and December 2020. Among households with pediatric SARS-CoV-2 index cases, 27.3% experienced secondary transmission to other household members. Researchers also found that the youngest children (aged 0-3 years) were the most likely to transmit infection, potentially because effective isolation is not feasible due to the basic parenting and care needs for this age group. These findings suggest that children can play a significant role in SARS-CoV-2 transmission, illustrating the importance of non-pharmaceutical interventions (i.e., masks, hand washing) for caregivers and other household members in the setting of pediatric infection. Data from this study preceded the rise of the Delta variant which is more infectious, and thus may underestimate current risks associated with household transmission related to pediatric index cases.

Study design

Retrospective Cohort

Study population and setting

The role of the pediatric population in SARS-CoV-2 transmission remains largely unexplored, in part due to the low proportion of symptomatic cases for this age group. This population-based cohort study examined the role of index case age in household transmission of SARS-CoV-2 in Ontario, Canada between June and December 2020. All data were collected from provincial public health databases. All cases were PCR-confirmed, and onset dates were determined based on timing of initial symptoms or specimen collection date. Index cases were defined as the earliest case in each household; index cases were grouped for analysis into four age categories (0-3, 4-8, 9-13, and 14-17). Secondary cases were defined as those among household members with disease onset 1 to 14 days following the index case. Odds of SARS-CoV-2 transmission according to index case age were determined using logistic regression, with stratified and sensitivity analyses.

Summary of Main Findings

Among 6,280 households with pediatric SARS-CoV-2 index cases (mean index case age = 10.7 years), 1,717 (27.3%) experienced secondary household transmission. Index cases occurred more frequently with increasing age (0-3: 776, 4-8: 1,257, 9-13: 1,881, 14-17 years: 2,376). However, index children between 0 and 3 years of age were more likely to transmit SARS-CoV-2 to other household members (OR: 1.43, CI: 1.17-1.75, compared to the 14-17 year age group), independent of symptomatic vs. asymptomatic infection, school/childcare opening dates, and documented school/childcare outbreaks. This association was maintained in sensitivity analyses, which included alternative secondary case windows (2-14 days, 4-14 days), adjustments for household size, and the inclusion of only symptomatic index cases. 

Study Strengths

Logistic regression models included relevant covariates (gender, household size, etc.), and the large study population allowed for stratified analyses. A python-based algorithm was used to address matching based on natural language, which allowed for more reliable household case grouping. Sensitivity analyses confirmed study results, increasing certainty of their validity.

Limitations

Secondary cases were assumed to originate from household index cases, but infection could have been acquired in the community; this would result in overestimates of household transmission. COVID-19 database systems evolved during the study period, which could have led to inconsistencies in reporting. Secondary attack rates could not be calculated, because the number of uninfected contacts for the full cohort was unknown. Finally, this study was completed prior to the rise of the Delta variant and does not capture its likely significant impact on household transmission.

Value added

This large, population-based study demonstrated an increased risk for household SARS-CoV-2 transmission by younger vs. older children.

Our take —

This study, available as a preprint and thus not yet peer-reviewed, is one of the first to investigate a potential decrease in effectiveness with increasing time since second dose of the Pfizer vaccine. Overall, very few breakthrough infections were detected, and some were caused by the Delta variant. However, experiencing a breakthrough infection was independently associated with being vaccinated >146 days (median time since vaccination) before the test date, and the odds were highest among those aged 60 years and older. The study did not investigate whether those experiencing breakthrough infections were more likely to have severe infections. These results suggest that there may be some reduction in the effectiveness of the vaccine to prevent infection over time, though more information on the frequency of severe disease among those infected would be helpful to determine whether there is any change in protection against hospitalization or death.

Study design

Retrospective Cohort

Study population and setting

This study was a retrospective cohort study using data from Leumit Health Services (LHS), which is a large, nation-wide healthcare provider in Israel. The main objective of this study was to determine whether the amount of time elapsed since a person’s second dose of the BNT162b2 (Pfizer) vaccine was significantly associated with an increased risk of post-vaccination SARS-CoV-2 infection. Individuals included in the study were LHS members who were fully vaccinated with the Pfizer vaccine and who were tested for SARS-CoV-2 infection by PCR between May 15, 2021 and July 26, 2021. The PCR test had to be performed at least two weeks following the second dose of vaccination. These criteria yielded test results from 33,993 individuals for analysis, who were divided into three age groups to reflect vaccine rollout stages: 18-39, 40-59, and 60 years and older. Models were developed for each age group to identify whether the time since vaccination was independently associated with the risk of having a positive PCR test, after adjusting for sex, ethnicity, socioeconomic status, and comorbidities.

Summary of Main Findings

Of the 33,993 individuals tested, there were only 608 positive PCR tests. The median time between second dose of vaccine and PCR test, for both positive and negative tests, was 146 days. The only factor independently associated with having a positive test in each age group was the elapsed time since the second dose of vaccine. Individuals were more likely to test positive via PCR if the time elapsed since the second dose of the Pfizer vaccine was longer than 146 days, compared to those vaccinated less than 146 days prior. The odds ratio for individuals 18-39 years was 1.67, 2.22 for ages 40-59 years, and 2.76 for ages 60 years and older.

Study Strengths

This study included a large and well-defined cohort of fully vaccinated individuals (with the Pfizer vaccine) with similar health insurance, and therefore, similar access to healthcare services. Israel was one of the first countries to achieve high levels of vaccination within its population, so this population is optimal for assessing any potential waning of vaccine effectiveness over time. Finally, many infections during this time were attributed to the Delta variant, which allows for some interpretation of the ability of vaccines to protect against this variant.

Limitations

A major limitation of this study is that individuals who were vaccinated earlier may have been at higher risk for infection than those who elected to be vaccinated later, even after accounting for sex, ethnicity, socioeconomic status and comorbidities; although individuals were analyzed by age group, there could be differences by age even within age groups though no adjustments were made to account for this in the models. In addition, this study did not investigate whether longer elapsed time since second vaccine dose was associated with increased risk of severe disease when breakthrough infections occur.

Value added

This is one of the first studies investigating potential reductions in effectiveness of Pfizer vaccination over time.

Our take —

This study from Singapore, available as a preprint and thus not yet peer reviewed, found that patients who were fully vaccinated with an mRNA vaccine had lower risk of severe outcomes after SARS-CoV-2 infection with the variant of concern B.1.617.2 (Delta). The study also seems to suggest that vaccinated patients clear viral load at a faster rate compared to unvaccinated infected patients.

Study design

Retrospective Cohort

Study population and setting

Between April 1 and June 14, 2021, 218 patients hospitalized with the Delta variant were identified across the 5 study sites in Singapore, of whom 130 were unvaccinated, and 71 were fully (2 dose) mRNA vaccinated patients and included in the analyses. Those were not fully vaccinated or who did not receive an mRNA vaccine (n=17) were excluded from the study.  A subset of 69 fully vaccinated and 45 unvaccinated patients further had serologic data on record.

Summary of Main Findings

Those in the vaccine-breakthrough group tended to be older (56 years vs. 39.5 years) than the unvaccinated group.  Fully vaccinated breakthrough patients in the study had fewer symptoms (28% asymptomatic vaccinated vs. 9% asymptomatic unvaccinated) and better clinical outcomes (fewer cases with pneumonia, need for oxygen and ICU admissions).  Those who were vaccinated had similar peak Delta SARS-CoV-2 viral load but cleared virus at a faster rate compared to unvaccinated patients. In the subset of patients with serologic data, vaccinated breakthrough cases had earlier, more robust boosting of anti-spike SARS-CoV-2 protein antibodies than unvaccinated patients.

Study Strengths

This study is based on real-world evidence of viral kinetics in mRNA vaccine-breakthrough and unvaccinated patients after a SARS-CoV-2 Delta infection. 

Limitations

Although the manuscript states Singapore has a system where all identified COVID-19 cases, regardless of symptom status, are admitted to the hospital for evaluation, it is not clear where these cases are identified in the context of the study (e.g., whether they are representative of the Singapore population with the Delta variant infection or whether there are specific subgroups that tend to test more and end up in the hospital, especially in the asymptomatic cases).  It is also not clear how they accounted for immunocompromised patients, especially in the vaccine-breakthrough group.  As such, the viral kinetics mapped by the study may not be representative of all cases, especially undetected cases that may be more likely asymptomatic. Also, PCR ct values were used as a surrogate marker of viral load. Since only the viral kinetics of mRNA vaccines were examined, these findings cannot be generalized to other COVID-19 vaccine types.  It is also not clear whether there were differences in viral kinetics of Moderna versus Pfizer vaccine breakthrough cases or in older versus younger adults since the subgroup analyses were not shared.

Value added

This study suggests that mRNA vaccinated patients with breakthrough COVID-19 infection from the Delta variant had similar viral loads to unvaccinated patients at time of diagnosis but cleared the virus more quickly than unvaccinated cases.