Breakthrough COVID-19 Infections in the US: Implications for Prolonging the Pandemic

Abstract

The incidence of COVID-19 breakthrough infections-an infection that occurs after you have been vaccinated-has increased in frequency since the Delta and now Omicron variants of the SARS-CoV-2 coronavirus have become the dominant strains transmitted in the United States (US). Evidence suggests that individuals with breakthrough infections, though rare and expected, may readily transmit COVID-19 to unvaccinated populations, posing a continuing threat to the unvaccinated. Here, we examine factors contributing to breakthrough infections including a poor immune response to the vaccines due to the fact of advanced age and underlying comorbidities, the natural waning of immune protection from the vaccines over time, and viral variants that escape existing immune protection from the vaccines. The rise in breakthrough infections in the US and how they contribute to new infections, specifically among the unvaccinated and individuals with compromised immune systems, will create the need for additional booster vaccinations or development of modified vaccines that directly target current variants circulating among the general population. The need to expedite vaccination among the more than 49.8 million unvaccinated eligible people in the US is critical.

Keywords: COVID-19; Delta variant; Omicron variant; SARS-CoV-2; breakthrough infections; coronavirus; vaccine.

Figure 1

SARS-CoV-2 replication in human airway epithelium: (a) initiation of infection is accomplished via binding of the viral spike glycoprotein to ACE-2/TMPRSS2 (serine protease); (b) membrane fusion, endosomal uptake and release of the viral genomic RNA; (c) translation of the pp1a/pp1b loci results in a polyprotein that is proteolytically cleaved to produce several proteins that assemble into the RdRP/replication complex; (d) RNA replication proceeds producing both genomic and sub-genomic RNAs that are positive sense for viral genome packaging and for translation of viral structural proteins as well sub-genomic RNAs that serve as a template for making more positive genomic RNAs; (e) translations and ER/Golgi processing of viral structural proteins and replication of full-length viral genomes leads to virion assembly and egress.

Figure 2

Mutations in the receptor-binding domain (RBD) of human coronaviruses contribute to the development of variants that may lead to breakthrough infections. These mutations in the RBD domain of the S1 subunit of the spike glycoprotein must bind to the ACE2 protein to initiate infection that can lead to viral transmission. The SARS-CoV-2 variant is shown and as well as the components of the virion structure that include the membrane protein, spike protein, nucleocapsid protein, the envelop protein, and RNA genome. The receptor-binding domain (RBD) of the S1 subunit of the spike protein is shown, which binds the ACE-2 protein to facilitate viral entry. The two heptad repeat (HR) regions of the S2 subunit HR1 and the HR2 are also shown.

Figure 3

US vaccination rates, immune surveillance, and the dynamics of COVID-19 breakthrough infections. The current state of vaccination in the US including the percentage of single doses given, completed vaccinations, adults boosted, and the current unvaccinated population. The approved vaccines administered in the US (J&J Pfizer and Moderna) are shown. The delta variant is shown to have increased infectivity and a waning of immune protection after 3–6 months. The dynamics of breakthrough infections are shown to include conditions that are associated with breakthrough infections such as the loss of immune protection over time, immune suppression, age, and genetics. The potential impact of the omicron variant is shown, and it could contribute to breakthrough infection. Although highly infectious, it has resulted in mild disease, limited hospitalizations, and reduced mortality.

Figure 4

COVID-19 infections: both the Delta and Omicron variants have mutations in the N-terminal domain that can contribute to their transmission and dissemination resulting high viral loads (A). The Delta and Omicron variants under certain conditions can cause cell-to-cell fusion of respiratory epithelial cells resulting in syncytia formation (B). These syncytia or multinucleated giant cells can release infection virus to infect neighboring cells without exiting the cell, thereby evading mucosal antibody responses that could contribute to breakthrough infections (C).

Figure 5

Peri-infection antibody titers as a potential biomarker for breakthrough infections. After the administration of FDA-approved vaccines in the US to health care workers, neutralizing antibody titers examined 5 days prior to PCR positivity (peri-infection period) compared in individuals with breakthrough infection (BT) and vaccinated controls. Individuals with high-neutralizing antibody titers during the peri-infection period were less likely to have a breakthrough infection. The full impact of the Omicron variant on breakthrough infections is unknown.