Breakthroughs, Boosters, and Beyond: Current Challenges with COVID-19
TOC Will Appear Here

Breakthroughs, Boosters, and Beyond: A Practical Primer on Current Challenges with COVID-19

Table of Contents


While all coronavirus disease 2019 (COVID-19) vaccines currently authorized for use in the United States are highly effective, they are not 100% effective. Breakthrough infections, which are defined as a new diagnosis of COVID-19 developing more than 14 days after completing the original immunization schedule, are known to occur; however, they rarely result in hospitalizations or deaths.1 Vaccines are proven to greatly reduce the severe morbidity and mortality associated with COVID-19. Vaccines may also reduce the risk for post-COVID conditions, which are defined as symptoms of COVID-19 persisting more than 28 days after a new diagnosis.2-4 Nonetheless, vaccines do not wholly prevent individuals from contracting and transmitting SARS-CoV-2, and breakthrough infections can contribute to chains of transmission.5 Identifying the extent to which breakthrough infections are contributing to the spread of COVID-19 can help guide vaccination policies and other infection prevention and control protocols to promote public health and safety.


Note: The opinions expressed are solely those of Dr. Firew and Dr. Caputo; and do not express the views or opinion of Dr. Firew and Dr. Caputo's employers.

Key Studies

The following tables summarize key studies on COVID-19 vaccine efficacy and effectiveness. Efficacy describes vaccine performance based on clinical trial data, while effectiveness describes vaccine performance based on real-world data. Studies are listed in chronological order from date of publication (or date of posting, for preprints and data obtained via presentations or press releases). Of note, unless otherwise stated, data presented in the tables refer to the relative risk reduction among fully vaccinated participants aged ≥16 years, and they are based primarily on wild-type strain and non-Delta variants. A discussion of the caveats to these studies follows the tables. Full descriptions of the study limitations are listed in the Appendix.

Table 1. Vaccine Efficacy

  Pfizer Moderna Johnson & Johnson




Viral vector

Overall efficacy
against infection

95% Pfizer clinical trial A

91% Pfizer clinical trial B

94% Moderna clinical trial A

93% Moderna clinical trial B

66% J&J clinical trial

Efficacy against
hospitalization or death

100% Pfizer clinical trial A

97% Pfizer clinical trial B

100% Moderna clinical trial A

98% Moderna clinical trial B

85% J&J clinical trial

Table 2. Vaccine Effectiveness

  Pfizer Moderna Johnson & Johnson

Overall effectiveness
against infection

80% Mayo Clinic A

85% NHS

97% Israel A

97% Israel B

94% CDC A

92% Scotland

86% Mayo Clinic B

89% Israel C

91% CDPH

91% CDC B

76% Mayo Clinic D*

92% NIHR*

88% ZOE**

91% CDC C

75% CDC D

97% Israel F*

92% CDC F

89% CDC H

80% Mayo Clinic A

94% CDC A

93% Mayo Clinic B

91% CDPH

91% CDC B

86% Mayo Clinic D*

91% CDC C

75% CDC D

92% CDC F

96% CDC H


77% Mayo Clinic C*

92% CDC F

Effectiveness against
hospitalization or death

97% Israel A

89% Mayo Clinic B

85% Mayo Clinic D*

95% CDC D

87% CDC E

88% CDC G

86% Mayo Clinic B

92% Mayo Clinic D*

95% CDC D

87% CDC E

93% CDC G

65% Sisonke**

71% CDC G

Studies are listed in order of release date, earliest to latest.
Abbreviations: CDC, Centers for Disease Control and Prevention; CDPH, California Department of Public Health; NIHR, National Institute for Health Research; NHS, National Health Service.
*Denotes data released in preprint format that have yet to be peer-reviewed.
**Denotes data released in presentation or press release format that has yet to be published and peer-reviewed.

Table 3. Vaccine Effectiveness Against Delta Variant

  Pfizer Moderna Johnson & Johnson

Overall effectiveness
against infection from
Delta variant

64% Israel D*

79% Scotland

39% Israel E*

42% Mayo Clinic D*

54% Qatar*

88% PHE

78% NIHR*

66% CDC C

53% CDC D

73% MCHD*

76% Mayo Clinic D*

85% Qatar*

66% CDC C

53% CDC D

73% MCHD*



Effectiveness against
hospitalization or death
from Delta variant

93% Israel D*

88% Israel E*

90% Qatar*

96% PHE

84% CDC E

100% Qatar*

84% CDC E

91-95% Sisonke*

Studies are listed in order of release date, earliest to latest.
Abbreviations: CDC, Centers for Disease Control and Prevention; MCHD, Multnomah County Health Department; N/A, not applicable; NIHR, National Institute for Health Research; PHE, Public Health England.
*Denotes data released in preprint format that have yet to be peer-reviewed.

Key Caveats

In order to understand the risk for fully vaccinated individuals to become infected with and transmit SARS-CoV-2, the true incidence of breakthrough infections must first be identified. Factors that influence the incidence of breakthrough infections include, but are not limited to, the age and underlying immunocompetency of the population at risk; the overall prevalence of disease within the community; vaccination rates and the durability of protection from vaccine-induced immunity; and emerging variants with increasing transmissibility or capacity for immune evasion.6-11 The incidence of breakthrough infections in the U.S. reported through the national surveillance system likely represents a substantial undercount due to reliance on passive and voluntary channels of data collection (eg, infected individuals who are asymptomatic or who experience mild to moderate illness are less likely to seek testing).12 In addition, as of May 1, 2021, the United States Centers for Disease Control and Prevention (CDC) no longer monitors or records breakthrough infections in asymptomatic cases or those with mild to moderate illness. While cases resulting in hospitalization or death continue to be investigated through the national surveillance system, this alteration in the reporting criteria will further obscure the true incidence of breakthrough infections in the U.S. and, consequently, our understanding of transmission risks among fully vaccinated individuals.

While the true incidence of breakthrough infections remains unknown, there is ancillary evidence to suggest a reduction in transmission risks among fully vaccinated individuals compared to those who are unvaccinated. In a study based on the HEROES-RECOVER data set of essential workers in the U.S., viral loads were 40% lower, with a shorter length of detection, in fully vaccinated participants who tested positive, compared to those who were unvaccinated.13 This suggests a lower risk for transmission among breakthrough infections. Another study based on the HOSTED data set in the United Kingdom showed the rate of infection among household members of positive cases was approximately 6% where the index case was fully vaccinated, compared to 10% where the index case was unvaccinated, also suggesting a lower risk for transmission among breakthrough infections.14 It should be noted that both of these studies were based on data sets that did not include the Delta variant.

Emerging Variants

Emerging variants remain potential drivers of breakthrough infections and may impact vaccine effectiveness against transmission.15-17 Across the U.S. where the Delta variant is now dominant, COVID-19 cases are surging, most prominently in areas of lower vaccination rates.18 The preponderance of hospitalizations and deaths from COVID-19 in the U.S. are among unvaccinated individuals.19,20 However, several regional and global outbreaks of the Delta variant involving breakthrough infections highlight rising concerns regarding the risk for transmission among fully vaccinated individuals.21-30 Over two-thirds of cases from a recent cluster in Barnstable County, MA were fully vaccinated, and case samples showed minimal differences in viral loads (measured via mean Ct values) between vaccinated and unvaccinated individuals.31 Furthermore, an in vitro study examining vaccine-induced neutralizing antibodies revealed titer levels were 3- to 5-fold lower against Delta compared to Alpha.32 This cumulative data complements a recent CDC study reassessing the HEROES-RECOVER data set, which demonstrated vaccine effectiveness against infection decreased from 91% (95% confidence interval [CI], 81-96) before Delta predominance to 66% (95% CI, 26-86) when Delta was predominant.33 Downward trends were also reported by studies conducted in Scotland, Israel, and the U.K., which have all demonstrated reduced vaccine effectiveness against symptomatic infection with Delta.34-41

Waning Immunity

Waning vaccine-induced immunity may also contribute to the occurrence of breakthrough infections. The ZOE COVID Symptom Study, which was based on self-reported information from approximately 1 million participants in the U.K., released data suggesting protection from symptomatic infection after 2 doses of the Pfizer vaccine decreased from 88% at 1 month to 74% at 5 to 6 months.42 Public Health England (PHE) also reported declines in vaccine protection over time; a preprint of their test-negative study, which included 1,659,513 participants who had received 2 doses of the Pfizer vaccine, suggests vaccine effectiveness against symptomatic infection decreased from 92% (95% CI, 92.1-92.7) 1 week after receiving the second dose, to 70% (95% CI, 68.7-70.5) after more than 20 weeks.43 Notably, no waning against severe illness was reported, and vaccine effectiveness remained >90% against hospitalization (95% CI, 90.3-94.6) and death (95% CI, 85.1-93.8). In fact, vaccines remained highly effective against hospitalization and death during the Delta surge in the U.K.; the Office for National Statistics, which reviewed all deaths in the U.K. between January 2021 and July 2021, revealed that <1% of deaths from COVID-19 were among the fully vaccinated; of the >50,000 COVID-related deaths, only 256 were recorded as “breakthrough deaths.”44

Ongoing studies in the U.S. and Israel show similar trends in waning vaccine-induced immunity. Recent findings released by the University of California San Diego Health suggest an increased risk for infection associated with the timing of the primary series. Based on a sample of 130 fully vaccinated healthcare workers who tested positive for SARS-CoV-2, participants who were vaccinated between January and February (attack rate, 6.7 per 1000 persons) were twice as likely to become infected compared to those who completed vaccination between March through May (attack rate, 3.7 per 1000 persons).45 Data from Israel released in preprint also suggests some degree of waning vaccine-induced immunity. From a sample of 4,785,245 fully vaccinated participants, 12,927 experienced a breakthrough infection, of which, 348 participants developed severe illness; so far, no deaths were reported in this study.46 For participants aged ≥60 years (who represented the preponderance of positive cases), the attack rate was 3.2 per 1000 persons for participants who completed vaccination in January 2021 compared to an attack rate of 1.6 per 1000 persons for those who completed vaccination in March 2021.46 This coincides with additional data from Israel, also released in preprint, which demonstrated a decline in neutralizing antibody levels over time, which was most pronounced among individuals aged ≥60 years.47 This prompted Israel to embark on a national vaccination booster campaign during the recent surge of the Delta variant and to offer a third dose of the Pfizer vaccine after completion of the original immunization schedule.48

Vaccination Boosters

Vaccination boosters, which are defined as vaccine doses administered after a sufficient immune response from the primary series, have been proposed both to combat variants of concern that have increasing capacity for immune evasion as well as to correct waning vaccine-induced immunity. The Advisory Committee on Immunization Practices (ACIP) has already recommended an additional dose to the original immunization schedule for certain immunocompromised individuals, given that the primary series may not be sufficient to effectively reduce mortality in this population.49-53 However, the role of booster doses for the general population remains under consideration. Early data based on the Israeli booster campaign suggests a reduction in the risk for severe illness for individuals aged ≥60 years; among a sample of 13,009 fully vaccinated participants recently diagnosed with a breakthrough infection, 29 cases of severe illness were among those who received a booster dose of vaccine compared to 294 cases of severe illness among those who did not receive a booster dose.54 It is important to note that the follow-up time of the study was only 12 days after receiving a booster. In addition, no deaths were reported in either the boosted or nonboosted cohorts. In fact, there is still no evidence showing boosters significantly decrease the number of deaths due to COVID-19.

Multiple recent studies published in the Morbidity and Mortality Review Weekly Report confirm a recent decline in COVID-19 vaccine effectiveness against symptomatic infection; however, it should be emphasized that vaccines maintained a high level of protection against severe morbidity and mortality.33,39,55,56 This is corroborated by data published by Kaiser Permanente Southern California, which was cited by Pfizer in its application for authorization of booster doses. Although vaccine effectiveness against infection declined from 88% during the first month after full vaccination to 47% after ≥5 months, effectiveness against hospitalization remained high, at 93%.57 Despite the accumulation of reassuring data on vaccine effectiveness against severe outcomes from COVID-19, the U.S. is implementing boosters for certain high-risk populations. On September 23, 2021, after reviewing the available relevant data, the ACIP voted to recommend boosters for adults aged ≥65 years, as well as for all adults at high risk for severe illness from COVID-19 (individuals must have completed the primary series ≥6 months previously to qualify).58 In addition to these recommendations, the CDC approved boosters for groups at high risk for infection due to workplace exposures, including frontline healthcare workers.59 This aligns with guidance issued from the Vaccines and Related Biological Products Advisory Committee to the U.S. Food and Drug Administration on September 17, 2021.59

Effectiveness of Nonpharmaceutical Interventions

While the future role of boosters is being reassessed continuously, nonpharmaceutical interventions (NPIs) remain an invaluable tool to mitigate the spread of COVID-19. The recognition of aerosols as a principal source of transmission underscores the importance of masking within indoor environments.60,61 This is especially important in spaces with poor ventilation or where crowding is uncontrolled. Multiple studies have shown that masking can reduce the chances of both contracting and transmitting SARS-CoV-2, and there is some evidence to suggest that masking may be more impactful compared to physical distancing, though concurrent use of multiple NPIs provides the highest level of protection.62-68 Physical distancing may be unfeasible without a mechanism for enforcement, capacity limits, or other crowd-control measures, and the absence of these controls may inadvertently promote bottlenecks in throughput and, consequently, crowding. Given these barriers to operationalizing physical distancing requirements, masking presents a practical and reliable tool for infection prevention and control. Local, regional, and international jurisdictional guidance regarding masking will vary despite research demonstrating that mask mandates are associated with reduced spread of COVID-19.69,70 Given that breakthrough infections may be partially contributing to the transmission of SARS-CoV-2, implementation of universal masking protocols within indoor environments should be considered where vaccinated and unvaccinated individuals are commingling, in order to reduce the risk of airborne transmission for both groups.


Vaccines currently authorized for use in the U.S. are highly effective against hospitalizations and deaths from COVID-19. Nonetheless, breakthrough infections are known to occur and are likely underreported. Emerging variants with increasing transmissibility or immune evasion, as well as the potential waning of vaccine-induced immunity, may impact transmission dynamics, resulting in an increase in breakthrough infections. While boosters may provide additional protection against severe disease for certain high-risk populations, more research is needed to assess the broader utility and necessity of boosters for the general population. Furthermore, unvaccinated individuals remain more susceptible to developing severe disease and dying from COVID-19. Immunization campaigns targeting unvaccinated populations will likely provide a greater reduction in the severe morbidity and mortality associated with COVID-19. Finally, NPIs continue to provide demonstrable protection in addition to vaccination. Within indoor environments where poor ventilation and crowding cannot be controlled, the spread of COVID-19 may be mitigated through implementation of universal masking policies.

Appendix: Study Limitations

The Mayo Clinic A study (published 10 March 2021) used an observational design to analyze data from vaccinated and unvaccinated patients who underwent one-time testing before surgery and were asymptomatic at the time of testing.71 Effect size was calculated based on data from asymptomatic patients who tested positive for SARS-CoV-2 on RT-PCR. Given that this study focused on asymptomatic infections alone, results may not be comparable to studies examining rates of overall infection after vaccination. Furthermore, there was no longitudinal follow-up to monitor the development of subsequent symptoms, and presymptomatic cases may be inadvertently included in the data set, overstating the effect size for asymptomatic cases.

The National Health Service (NHS) study (published 23 April 2021) was based on the SARS-CoV-2 Immunity and Reinfection Evaluation (SIREN) data set, which utilized a prospective cohort of healthcare workers in the U.K. who were followed for 2 months and tested every 2 weeks. This testing cadence may increase the risk for missed cases and bias the short-term effect size toward vaccination.36

The Mayo Clinic C study (posted 30 April 2021) is a preprint that has yet to undergo peer review.72 The study was based on data collected from a single healthcare system, using a limited cohort size (2195 vaccinated patients) and a participant sample (>90% White) that was not demographically representative of the population at risk. This limits the generalizability of the findings from the study.

The Israel A study (published 5 May 2021) analyzed aggregated data from Israel’s national surveillance system, comparing infection rates in vaccinated versus unvaccinated groups between January 17, 2021 and February 6, 2021.73 However, as the study authors noted, the testing criteria from the Ministry of Health exempted vaccinated people from requirements such as testing after travel or after close contact with a confirmed or suspected case of COVID-19, which may bias toward vaccination.

The Israel B study (published 6 May 2021) monitored 6710 healthcare workers over a median period of 63 days.74 Participants were tested either monthly or bimonthly, and vaccinated healthcare workers underwent fewer tests than unvaccinated healthcare workers. Because detection of infections (especially asymptomatic infection) increases with increasing frequency of testing, the transmission-blocking effect size may be overstated.

The CDC study A (published 21 May 2021) was limited by a sample size of approximately 623 case-patients and 1220 case-controls selected from a population of healthcare workers. Testing for infection was based on routine screening protocols at each healthcare facility, leading to reporting variability and a potential bias toward vaccination, given that many vaccinated healthcare workers are not routinely tested unless symptomatic.75

The Scotland study (published 14 June 2021) used an observational design to compare vaccine effectiveness.34 As a consequence, the analysis did not account for differences in the number of recipients vaccinated with AstraZeneca versus Pfizer, among other potential confounding factors. In addition, insufficient numbers of hospital admissions may have contributed to seemingly diminished protection of the vaccines against hospitalizations from Delta compared to those for Alpha, biasing against vaccination.

The Mayo Clinic B study (published 28 June 2021) is a retrospective analysis of participants who were either unvaccinated or vaccinated with the Pfizer or Moderna vaccines. Despite a large cohort, >90% of individuals were White; 60% of individuals who received the Pfizer vaccine were female; and >50% of individuals who received the Moderna vaccine were aged ≥65 years; therefore, the study cohort is not demographically representative of the population at risk. Furthermore, the study did not account for several potential confounding factors, including geographic and socioeconomic differences, specific comorbidities, and testing behavior.76

The Israel D study (posted 5 July 2021) is a preprint that has yet to undergo peer review.35 The effect size was calculated using a looser set of criteria that likely included near-asymptomatic cases captured via more frequent, systematic testing. As a result, the reported figures may not be comparable to peer-reviewed studies.

Israel C study (published 7 July 2021) was conducted using data from a single health system where the majority of the population are younger females and not demographically representative of the population at risk. Furthermore, the study used an observational design, and the analysis did not account for differences in testing behavior between those who were unvaccinated, partially vaccinated, and fully vaccinated, as well as other potentially confounding measures.77

The Israel E study (posted 20 July 2021) is comprised of data provided by the Israel Ministry of Health that has yet to undergo peer review. The methodology was consistent with that outlined previously for Israel A study and is therefore subject to the same limitations.78

The California Department of Public Health (CDPH) study (published 20 July 2021) did not include data beyond April 29, 2021. As a result, the positive cases do not reflect the bulk of the spread of the Delta variant and its impact on positive cases, hospitalizations, and deaths. The study also used an observational design, meaning that the analysis did not account for differences in testing behavior between those who were unvaccinated, partially vaccinated, and fully vaccinated, as well as other potentially confounding measures.79

The CDC B study (published 22 July 2021) references data collected until March 31, 2021, which was prior to escalation of Delta within the sampling regions.13 In addition, the study relied on a weekly testing cadence, which may not be sufficient in capturing the true burden of disease within the population at risk, leading to a bias toward vaccination.

The Mayo Clinic D study (posted 8 August 2021) is a preprint that has yet to undergo peer review. This study is a retrospective analysis of participants who were either unvaccinated or were vaccinated with the Pfizer or Moderna vaccines in a single health system that is not demographically representative of the general population. Although matched cohorts were used in the study design, impacts of potentially confounding factors may not be accounted for, including unknown underlying health conditions and unknown exposure risks. The vaccine effectiveness against infection for both Pfizer and Moderna declined to 42% and 76%, respectively, in the month of July when Delta was predominant. However, timing of vaccination and dose intervals were not examined, and results may also be attributed to waning protection over the 7-month study period from January to July 2021.38

The Sisonke study (posted 6 August 2021) reports on data released in a presentation that have yet to be published and undergo peer review. The overall vaccine effectiveness figure reported primarily reflects effectiveness against the Beta variant, which originated and was dominant in South Africa, where the data were collected.80

The Qatar study (posted 11 August 2021) is a preprint that has yet to undergo peer review. The study used an observational test-negative case-control design, which did not account for differences in exposure rate due to social contacts or adherence to safety measures. In addition, the Moderna vaccine was incorporated into the national immunization campaign approximately 3 months later than the Pfizer vaccine, biasing against the Pfizer vaccine. Finally, a large proportion of the study population is also elderly, which limits the generalizability of the findings from the study.37

The Public Health England study (published 12 August 2021) did not include data beyond May 17, 2021.81 As a result, positive cases were comprised mainly of Alpha variants; 12,675 sequenced cases were included in the analysis, of which only 1054 were identified as Delta. As a result, the effect size with respect to Delta may be overstated.36

The National Institutes of Health Research (NIHR) study (posted 16 August 2021) is a preprint that has yet to undergo peer review. The lower vaccine effectiveness against infection reported for Delta may also be attributed to waning protection over the 90-day period since receipt of the second dose of the vaccine. Participants were initially tested weekly, but were later tested monthly, which may lead to late detection of older infections that, in turn, impacts estimation of vaccine effectiveness over time.40

The ZOE Covid Symptom App study (posted 25 August 2021) reports on data released in a presentation that has yet to be published and undergo peer review. This study uses self-reported data, which is vulnerable to information bias, and does not control for other potential confounding factors such as behavior. Vaccine effectiveness against infection declined from 88% to 74% over 5 to 6 months after receiving the second vaccine dose.42

The CDC C study (published 27 August 2021) is limited by its observational study design, which can give rise to unmeasured and confounding factors. Testing for infection was based on routine screening protocols at each healthcare facility, leading to reporting variability and a potential bias toward vaccination, given many vaccinated healthcare workers are not routinely tested unless symptomatic. The lower vaccine effectiveness against infection reported for Delta may also be attributed to waning protection over the 35-week study period (December 14, 2020-August 14, 2021).33

The CDC D study (published 27 August 2021) is limited by its observational study design, which does not account for potential confounders such as age, presence of underlying health conditions, or history of prior SARS-CoV-2 infection. Of these, the older age of nursing home residents involved in the study limits the generalizability of the study’s findings. Furthermore, nursing home staff vaccination data, which were incomplete and may vary across the study sites, can be a potentially confounding factor impacting vaccine effectiveness. The lower vaccine effectiveness against infection reported for Delta may also be attributed to waning protection over the 22-week study period (March 1-August 1, 2021).39

The CDC E study (published 27 August 2021) is limited by its observational study design and short follow-up period of up to 24 weeks after full vaccination with an mRNA vaccine. The lower vaccine effectiveness against hospitalization reported for Delta may also be attributed to waning protection over the 24-week study period (March-July 2021).55

The Israel F study (posted 2 September 2021) is a preprint that has yet to undergo peer review. While the study involved weekly testing and use of electronic medical records to characterize participants’ demographic information, clinical history, and vaccination history, participation was voluntary. As a result, findings are potentially confounded by selection bias, thereby limiting generalizability.82

The Multnomah County Health Department (MCHD) study*(posted 3 September 2021) is a preprint that has yet to undergo peer review.41 This study is limited by its observational study design that is potentially confounded by testing behavior and disease severity, among other variables. Furthermore, while the study reports on reduced vaccine effectiveness during a period when the Delta variant achieved predominance, samples used in this analysis to estimate vaccine effectiveness were not sequenced for the Delta variant. As a result, the lower vaccine effectiveness may also be attributed to waning vaccine-induced protection.

The CDC F study (published 17 September 2021) is limited by potentially confounding factors such as testing behavior and social exposures, which may affect estimates of vaccine effectiveness. This study also did not estimate vaccine effectiveness by vaccine product, which may fail to account for differing time points at which the vaccines reached peak effectiveness. The vaccine effectiveness against infection also declined from 92% to 80% over 3 months (May 3 to July 25, 2021).56

The CDC G study (published 17 September 2021) was a case-control analysis among 3689 immunocompetent adults aged ≥18 years who were hospitalized at 21 U.S. hospitals across 18 states from March 11 to August 15, 2021. The small sample of patients who received the J&J vaccine (113 patients) may bias the effect size for this vaccine. Follow-up times were also limited to approximately 29 weeks after full vaccination, and long-term vaccine durability remains unknown. Finally, though vaccine effectiveness estimates were adjusted for relevant potential confounders, residual confounding is possible. Of note, vaccine effectiveness against Delta, which was predominant in the U.S. during the latter half of the study period, was not evaluated.83

The CDC H study (published 22 September 2021) is based on a test-negative case-control design, which did not account for differences in exposure rate due to social contacts or adherence to safety measures. In addition, the small sample size of the observed subgroups limits the generalizability of the findings. Longer follow-up times are also needed to understand the long-term durability of vaccines.84


  1. Centers for Disease Control and Prevention. COVID-19 Breakthrough Case Investigations and Reporting | CDC. 2021.
  2. Brooks JT."The long haul: forging a path through the lingering effects of COVID-19.  2021 Congressional testimony from CDC." 2021. 
  3. Marshall M. The four most urgent questions about long COVID. Nature. 2021;594(7862):168-170.
  4. Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. The Lancet Infectious Diseases. DOI: 10.1016/S1473-3099(21)00460-6
  5. Kelley A. "Top health expert says vaccinated people are spreading delta variant." The Hill [Text]. 2021.
  6. Canaday DH, Carias L, Oyebanji OA, et al. Reduced BNT162b2 mRNA vaccine response in SARS-CoV-2-naive nursing home residents. Clin Infect Dis. 2021;ciab447. DOI: 10.1093/cid/ciab447
  7. Kustin T, Harel N, Finkel U, et al. Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2-mRNA-vaccinated individuals. Nature Medicine. 2021;27(8):1379-1384.
  8. Brosh-Nissimov T, Orenbuch-Harroch E, Chowers M, et al. BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel. Clin Microbiol Infect. 2021. DOI: 10.1016/j.cmi.2021.06.036
  9. Tenforde MW, Patel MM, Ginde AA, et al. Effectiveness of SARS-CoV-2 mRNA vaccines for preventing Covid-19 hospitalizations in the United States. medRxiv. 2021:2021.2007.2008.21259776. DOI: 10.1101/2021.07.08.21259776  
  10. Khan N, Mahmud N, Trivedi C, et al. Risk factors for SARS-CoV-2 infection and course of COVID-19 disease in patients with IBD in the Veterans Affair Healthcare System. Gut. 2021;70(9):1657-1664.
  11. Chodick G, Tene L, Rotem RS, et al. The effectiveness of the two-dose BNT162b2 vaccine: analysis of real-world data. Clin Infect Dis. 2021. DOI: 10.1093/cid/ciab438
  12. Centers for Disease Control and Prevention. COVID-19 vaccine breakthrough infections reported to CDC — United States, January 1–April 30, 2021. MMWR. Morbidity and Mortality Weekly Report. 2021;70(21):792-793
  13. Thompson MG, Burgess JL, Naleway AL, et al. Prevention and attenuation of Covid-19 with the BNT162b2 and mRNA-1273 vaccines. N Engl J Med. 2021;385(4):320-329.
  14. Harris RJ, Hall JA, Zaidi A, et al. Effect of vaccination on household transmission of SARS-CoV-2 in England. N Engl J Med. 2021;385(8):759-760.
  15. Ferreira I, Datir R, Papa G, et al. SARS-CoV-2 B.1.617 emergence and sensitivity to vaccine-elicited antibodies. bioRxiv. 2021.  DOI: 10.1101/2021.05.08.443253       
  16. Yadav PD, Sapkal GN, Abraham P, et al. Neutralization of variant under investigation B.1.617 with sera of BBV152 vaccinees. Clin Infect Dis. 2021. DOI: 10.1093/cid/ciab411
  17. Tada T, Zhou H, Dcosta BM, et al. The spike proteins of SARS-CoV-2 B.1.617 and B.1.618 variants identified in India provide partial resistance to vaccine-elicited and therapeutic monoclonal antibodies. bioRxiv. 2021. DOI: 10.1101/2021.05.14.444076   
  18. Centers for Disease Control and Prevention. COVID Data Tracker Weekly Review. CDC. 2021.
  19. United States White House. Press Briefing by White House COVID-19 Response Team and Public Health Officials. The White House. 2021.
  20. Sullivan B. "U.S. COVID Deaths Are Rising Again. Experts Call It A 'Pandemic Of The Unvaccinated'. "NPR. 2021.
  21. Stein L, Armitage R, Clarke C. "Taiwan and Singapore's current coronavirus surge should serve as a warning to Australia, experts say." ABC News 2021.
  22. Bengali S. Singapore announces new restrictions after vaccinated airport workers become infected. The New York Times. 05/14, 2021.
  23. Sim D. "Singapore’s Covid-19 hospital cluster, reinfections – causes for concern?" South China Morning Post 2021.
  24. Aravindan A, Lin C. Singapore races to find guests, hostesses in karaoke lounge virus cluster. Reuters. 2021/07/15/T09:13:06Z, 2021.
  25. Corder M. Dutch COVID-19 infections soar by 500% in a week. AP NEWS. 2021/07/13/T15:27:31Z, 2021.
  26. Ministerie van Volksgezondheid, Welzijn en Sport. Vaccines | Coronavirus Dashboard |
  27. ZOE COVID Symptom Study. New cases plateau ahead of Freedom Day.
  28. Guenot M. Almost half of UK COVID infections are in people who are at least partly vaccinated, study suggests. But the cases were much milder. Business Insider. 07/16, 2021.
  29. Jaffe-Hoffman M, Tercatin R. More than 1,000 Israelis test positive for COVID. The Jerusalem Post |
  30. Israel to Reinstate Indoor Mask Mandate Next Week as COVID Delta Variant Spreads. Haaretz. June 24, 2021.
  31. Abutaleb Y, Johnson CY, Achenbach J. ‘The war has changed’: Internal CDC document urges new messaging, warns delta infections likely more severe. Washington Post.
  32. Planas D, Veyer D, Baidaliuk A, et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature. 2021;596(7871):276-280.
  33. Fowlkes A, Gaglani M, Groover K, et al. Effectiveness of COVID-19 vaccines in preventing SARS-CoV-2 infection among frontline workers before and during B.1.617.2 (Delta) variant predominance - eight U.S. locations, December 2020-August 2021. MMWR Morb Mortal Wkly Rep. 2021;70(34):1167-1169.
  34. Sheikh A, McMenamin J, Taylor B, et al. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. The Lancet. 2021;397(10293):2461-2462. DOI: 10.1016/S0140-6736(21)01358-1
  35. Israel Ministry of Health. Decline in Vaccine Effectiveness Against Infection and Symptomatic Illness. GOV.IL.
  36. Hall VJ, Foulkes S, Saei A, et al. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study. Lancet. 2021;397(10286):1725-1735. DOI: 10.1016/S0140-6736(21)00790-X
  37. Tang P, Hasan MR, Chemaitelly H, et al. BNT162b2 and mRNA-1273 COVID-19 vaccine effectiveness against the Delta (B.1.617.2) variant in Qatar. medRxiv. 2021:2021.2008.2011.21261885.  DOI: 10.1101/2021.08.11.21261885  
  38. Puranik A, Lenehan PJ, Silvert E, et al. Comparison of two highly-effective mRNA vaccines for COVID-19 during periods of Alpha and Delta variant prevalence. medRxiv. 2021:2021.2008.2006.21261707.
  39. Nanduri S, Pilishvili T, Derado G, et al. Effectiveness of Pfizer-BioNTech and Moderna Vaccines in preventing SARS-CoV-2 infection among nursing home residents before and during widespread circulation of the SARS-CoV-2 B.1.617.2 (Delta) variant - National Healthcare Safety Network, March 1-August 1, 2021. MMWR Morb Mortal Wkly Rep. 2021;70(34):1163-1166
  40. Pouwels KB, Pritchard E, Matthews PC, et al. Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK. medRxiv. 2021:2021.2008.2018.21262237. DOI: 10.1101/2021.08.18.21262237  
  41. Barlow RS, Jian K, Larson L. Effectiveness of COVID-19 vaccines against SARS-CoV-2 infection during a Delta variant epidemic surge in Multnomah County, Oregon, July 2021. medRxiv. 2021:2021.2008.2030.21262446. DOI: 10.1101/2021.08.30.21262446
  42. Study ZC. "Is COVID vaccine protection fading?" 2021.
  43. Andrews NT, E; Stowe J; Gower C. "Vaccine effectiveness and duration of protection of Comirnaty, Vaxzevria and Spikevax against mild and severe COVID-19 in the UK. " 2021.
  44. Office for National Statistics. Deaths involving COVID-19 by vaccination status, England: deaths occurring between 2 January and 2 July 2021.
  45. Keehner J, Horton LE, Binkin NJ, et al. Resurgence of SARS-CoV-2 infection in a highly vaccinated health system workforce. New Engl J Med. 2021.
  46. Goldberg Y, Mandel M, Bar-On YM, et al. Waning immunity of the BNT162b2 vaccine: a nationwide study from Israel. medRxiv. 2021:2021.2008.2024.21262423. DOI: 10.1101/2021.08.24.21262423
  47. Kertes J, Baruch Gez S, Saciuk Y, et al. Effectiveness of the mRNA BNT162b2 vaccine six months after vaccination: findings from a large Israeli HMO. medRxiv. 2021:2021.2009.2001.21262957. DOI: 10.1101/2021.09.01.21262957  
  48. Kozlov M. COVID-vaccine booster shot shows promise in Israeli study. Nature. 2021.
  49. Ducloux D, Colladant M, Chabannes M, et al. Humoral response after 3 doses of the BNT162b2 mRNA COVID-19 vaccine in patients on hemodialysis. Kidney Int. 2021;100(3):702-704. DOI: 10.1016/j.kint.2021.06.025
  50. Espi M, Charmetant X, Barba T, et al. Justification, safety, and efficacy of a third dose of mRNA vaccine in maintenance hemodialysis patients: a prospective observational study. medRxiv. 2021:2021.2007.2002.21259913. DOI: 10.1101/2021.07.02.21259913    
  51. Longlune N, Nogier MB, Miedougé M, et al. High immunogenicity of a messenger RNA-based vaccine against SARS-CoV-2 in chronic dialysis patients. Nephrology Dialysis Transplantation. 2021;36(9):1704-1709. DOI: 10.1093/ndt/gfab193
  52. Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and immunogenicity of a third dose of SARS-CoV-2 vaccine in solid organ transplant recipients: a case series. Ann Intern Med. 2021;174(9):1330-1332. DOI: 10.7326/L21-0282
  53. Harpaz R, Dahl RM, Dooling KL. Prevalence of immunosuppression among US adults, 2013. JAMA. 2016;316(23):2547-2548.
  54. Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 vaccine booster against Covid-19 in Israel. N Engl J Med. 2021.
  55. Tenforde MW, Self WH, Naioti EA, et al. Sustained effectiveness of Pfizer-BioNTech and Moderna vaccines against COVID-19 associated hospitalizations among adults - United States, March-July 2021. MMWR Morb Mortal Wkly Rep. 2021;70(34):1156-1162.
  56. Rosenberg ES, Holtgrave DR, Dorabawila V, et al. New COVID-19 cases and hospitalizations among adults, by vaccination status - New York, May 3-July 25, 2021. MMWR Morb Mortal Wkly Rep. 2021;70(34):1150-1155.
  57. Tartof SS, JM; Fischer H; Hong V. Six-month effectiveness of BNT162B2 mRNA COVID-19 vaccine in a large US integrated health system: a retrospective cohort study. Preprints with The Lancet. 2021.
  58. Soucheray S. "Following FDA, ACIP recommends COVID-19 booster shots."
  59. Pfizer. BNT162b2 [COMIRNATY (COVID-19 vaccine, mRNA)] evaluation of a booster dose (third dose) vaccines and related biological products advisory committee briefing document.
  60. Mandavilli AM, B. C.D.C. Chief Overrules Agency Panel and Recommends Pfizer-BioNTech Boosters for Workers at Risk. New York Times. 2021.
  61. Cheng Y, Ma N, Witt C, et al. Face masks effectively limit the probability of SARS-CoV-2 transmission. Science. 2021.
  62. Hassan J, Bellware K, Kornfield M. CDC acknowledges airborne transmission. Washington Post. 2021/05/07/T06:56:05.107Z, 2021.
  63. Howard J, Huang A, Li Z, et al. An evidence review of face masks against COVID-19. Proc Natl Acad Sci U S A. 2021;118(4).
  64. Wilson AM, Jones RM, Lugo Lerma V, et al. Respirators, face masks, and their risk reductions via multiple transmission routes for first responders within an ambulance. J Occup Environ Hyg. 2021;18(7):345-360.
  65. Brooks JT, Butler JC. Effectiveness of mask wearing to control community spread of SARS-CoV-2. Jama. 2021;325(10):998-999.
  66. Kwon S, Joshi AD, Lo CH, et al. Association of social distancing and face mask use with risk of COVID-19. Nat Commun. 2021;12(1):3737.
  67. Rebmann T, Loux TM, Arnold LD, et al. SARS-CoV-2 transmission to masked and unmasked close contacts of university students with COVID-19 - St. Louis, Missouri, January-May 2021. MMWR Morb Mortal Wkly Rep. 2021;70(36):1245-1248.
  68. Abaluck J, Kwong L, Styczynski A, et al. "The impact of community masking on COVID-19: a cluster-randomized trial in Bangladesh. " EliScholar 2021. Accessed  September 27, 2021.
  69. Adenaiye OO, Lai J, de Mesquita PJB, et al. Infectious SARS-CoV-2 in exhaled aerosols and efficacy of masks during early mild infection. Clinical Infectious Diseases. 2021.
  70. Lyu W, Wehby GL. Community Use Of Face Masks And COVID-19: Evidence From A Natural Experiment Of State Mandates In The US. Health Aff (Millwood). 2020;39(8):1419-1425.
  71. Mitze T, Kosfeld R, Rode J, et al. Face masks considerably reduce COVID-19 cases in Germany. Proc Natl Acad Sci U S A. 2020;117(51):32293-32301.
  72. Tande AJ, Pollock BD, Shah ND, et al. Impact of the COVID-19 vaccine on asymptomatic infection among patients undergoing pre-procedural COVID-19 molecular screening. Clin Infect Dis. 2021.
  73. Corchado-Garcia J, Puyraimond-Zemmour D, Hughes T, et al. Real-world effectiveness of Ad26.COV2.S adenoviral vector vaccine for COVID-19. medRxiv. 2021:2021.2004.2027.21256193.
  74. Haas EJ, Angulo FJ, McLaughlin JM, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet. 2021;397(10287):1819-1829.
  75. Angel Y, Spitzer A, Henig O, et al. Association between vaccination with BNT162b2 and incidence of symptomatic and asymptomatic SARS-CoV-2 infections among health care workers. JAMA. 2021;325(24):2457-2465.
  76. Pilishvili T, Fleming-Dutra KE, Farrar JL, et al. Interim estimates of vaccine effectiveness of Pfizer-BioNTech and Moderna COVID-19 vaccines among health care personnel — 33 U.S. Sites, January–March 2021. MMWR. Morbidity and Mortality Weekly Report. 2021;70(20).
  77. Pawlowski C, Lenehan P, Puranik A, et al. FDA-authorized mRNA COVID-19 vaccines are effective per real-world evidence synthesized across a multi-state health system. Med. 2021;2(8):979-992.e978.
  78. Regev-Yochay G, Amit S, Bergwerk M, et al. Decreased infectivity following BNT162b2 vaccination: a prospective cohort study in Israel. The Lancet Regional Health – Europe. 2021;7.
  79. Israel Ministry of Health. "COVID-19. Dashboard IMoHC. " 2021. Accessed.
  80. Andrejko KL, Pry J, Myers JF, et al. Prevention of COVID-19 by mRNA-based vaccines within the general population of California. medRxiv. 2021:2021.2004.2008.21255135.
  81. Gray LB, L. "Sisonke Update on the Janssen®(JNJ) Ad26.COV2.S vaccine. " 2021. Accessed.
  82. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 vaccines against the B.1.617.2 (Delta) variant. New Engl J Med. 2021;385(7):585-594.
  83. Katz MA, Harlev EB, Chazan B, et al. Covid-19 Vaccine Effectiveness in Healthcare Personnel in six Israeli Hospitals (CoVEHPI). medRxiv. 2021:2021.2008.2030.21262465.
  84. Self WH, Tenforde MW, Rhoads JP, et al. Comparative effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) vaccines in preventing COVID-19 hospitalizations among adults without immunocompromising conditions - United States, March-August 2021. MMWR Morb Mortal Wkly Rep. 2021;70(38):1337-1343.
  85. Pilishvili T, Gierke R, Fleming-Dutra KE, et al. Effectiveness of mRNA Covid-19 vaccine among U.S. health care personnel. N Engl J Med. 2021.
Publication Information

Sonya Stokes, MD, MPH; Karen Shek, MHA; Michelle Hung

Publication Date

October 3, 2021

Get Permission

Content You Might Be Interested In

Emergency Department Clinical Operations During a Pandemic: Lessons Learned and Future Directions

COVID-19: The Impact on Pediatric Emergency Care

Get A Sample Issue Of Emergency Medicine Practice
Enter your email to get your copy today! Plus receive updates on EB Medicine every month.
Please provide a valid email address.