This evidence synthesis has been compiled by members of the CITF Secretariat and does not necessarily represent the views of all CITF members.

By Varun C. Anipindi

Emergence of variants of concern (VOCs) may potentially impact efforts to end the COVID-19 pandemic, despite the ongoing continuation of the global vaccine rollout. Here, we summarize multiple published and pre-print articles which report increasing prevalence of breakthrough infections in individuals vaccinated with Pfizer or Moderna’s mRNA vaccines. VOCs such as the Alpha and Delta variants represent the prevailing cause of these breakthrough infections. Nevertheless, collectively, these reports strongly indicate that vaccination remains a highly effective public health strategy in mitigating the spread of SARS-CoV-2.

Key Points:

  • Multiple reports around the world including from the USA, Israel, Singapore and the UK have pointed to increasing evidence of breakthrough infections with VOCs. This may be associated with waning levels of neutralizing antibodies.

Vaccination has not eliminated the ability of individuals to be infected with SARS-CoV-2, albeit infections in these individuals may be associated with lower disease burden (mild or asymptomatic outcomes). This suggests the continued need for caution and use of masks in public gatherings and indoor spaces.

Recently, multiple reports (some of which are not yet peer-reviewed) have been published documenting the nature of breakthrough infections in several countries, namely the USA, Israel and Singapore [1-5]. The U.S. Centers for Disease Control and Prevention (CDC) reported that in an outbreak of 469 cases in Massachusetts in July 2021, nearly 74% of cases occurred in individuals fully vaccinated with either Pfizer or Moderna mRNA vaccines [2]. Researchers found that most infections were caused by the Delta variant (B.1.617.2). Similarly, researchers at the Houston Methodist Hospital reported that nearly 94% of all COVID-19 cases between March and July 2021 in Houston, Texas were caused by the Delta variant, and that this variant was also associated with increased breakthrough infections in fully vaccinated individuals [3]. In both cohorts, rtPCR testing, used to determine viral loads, indicated there was no difference in viral replication between unvaccinated, partially vaccinated, and fully vaccinated individuals. This key finding was also independently observed by researchers at the University of Wisconsin [5] and National Centre for Infectious Diseases in Singapore [4]; their pre-prints also indicate that viral loads in breakthrough infections amongst fully vaccinated individuals were similar to those seen in unvaccinated or partially vaccinated individuals. Collectively, these observations are significant in supporting the notion that fully vaccinated people are still capable at transmitting SARS-CoV-2 to others if infected [5]. This prompted the CDC to suggest that jurisdictions should consider expanding prevention strategies, including masking in indoor spaces or large public gatherings.

The emergence of these breakthrough infections has also been seen in Israel, where researchers have examined breakthrough infections amongst healthcare workers [1]. The majority of these cases (85%) were attributed to the Alpha variant (B.1.1.7). Researchers were also able to associate these breakthrough cases with reduced neutralizing antibodies within the sera of these individuals. This correlation between serological response and protection was also observed by researchers in Singapore [4] assessing breakthrough infections in vaccinated individuals. This suggests that neutralizing antibodies may represent a key correlate of vaccine-mediated protection, and that waning levels indicate reduced protection and increased susceptibility to breakthrough infections.

Collectively, this body of work demonstrates that breakthrough infections may occur in fully-vaccinated individuals. The majority of these infections appear to be linked with emerging VOCs and may be associated with waning levels of antibodies in vaccinated individuals, which can represent the key correlate of protection induced by vaccination. Yet, it is critical to emphasize that in all these studies, researchers indicated that breakthrough infections in fully vaccinated individuals were associated with relatively mild or asymptomatic outcomes. This suggests that vaccination remains highly effective at preventing serious COVID-19 disease, and that the rise of viral variants further stresses the need for mobilizing vaccination efforts across the world to resolve this pandemic.



  1. Bergwerk M, Gonen T, Lustig Y, et al. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. NEJM. July 28, 2021; DOI: 10.1056/NEJMoa2109072.
  2. Brown CM, Vostok J, Johnson H, et al. Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings — Barnstable County, Massachusetts, July 2021. MMWR Morb Mortal Wkly Rep. ePub: 30 July 2021. DOI:
  3. Musser JM, Christensen PA, Olsen RJ, et al. Delta variants of SARS-CoV-2 cause significantly increased vaccine breakthrough COVID-19 cases in Houston, Texas. July 22 2021. doi:
  4. Chia PY, Ong SWX, Chiew CJ, et. al., Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine-breakthrough infections: a multi-center cohort study. 2021.07.28.21261295; doi:
  5. Riemersma KK, Grogan BE, Kita-Yarbro A, et al. Vaccinated and unvaccinated individuals have similar viral loads in communities with a high prevalence of the SARS-CoV-2 delta variant. medRxiv 2021.07.31.21261387; doi: