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Panorama of Breakthrough Infection Caused by SARS-CoV-2: History
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Contributor: Qinglu Fan , Zhihao Nie , Songping Xie

Since the outbreak of the novel coronavirus disease 2019 (COVID-19) in 2019, many countries have successively developed a variety of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, with the continuous spread of SARS-CoV-2, it has evolved several variants; as a result, prevention and control of the pandemic of SARS-CoV-2 has become more important. Among these variants, the Omicron variant has higher transmissibility and immune escape ability and is the main variant causing a large number of COVID-19 breakthrough infection, thus, presenting new challenges to pandemic prevention and control.

  • COVID-19
  • SARS-CoV-2
  • variants
  • Omicron
  • breakthrough infection

1. Introduction

From the outbreak of novel coronavirus disease 2019 (COVID-19) in 2019 to 18 October 2022, the number of infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was 624 million and the number of death was nearly 6.56 million worldwide [1]. Meanwhile, with the spread of SARS-CoV-2, which is susceptible to mutation, including changing the affinity of the virus to host cells, the virus has mutated into five variants of concern (VOCs) [2]: Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and the Omicron variant (B.1.1.529). In order to control the COVID-19 pandemic, various vaccines have been developed and administered [3][4]. However, the number of reported cases with breakthrough infection caused by the Omicron variant is increasing. The Omicron variant, the main variant now, not only has enhanced transmissibility and infectivity but also improved immune escape ability, which results in a large number of SARS-CoV-2 breakthrough infections and poses a huge medical burden on global public health security [5]. 

2. Characteristics of the Omicron Variant

Since the Omicron variant was first reported in South Africa and Botswana on 24 November 2021, it has rapidly replaced Delta as the dominant strain worldwide. Compared with other VOCs, Omicron has significantly evolutionary characteristics [5][6][7][8][9][10][11][12], such as: higher infectivity, transmissibility and immune escape ability but reduced pathogenicity. These characteristics have changed the situation of the pandemic and posed a great threat to the global economy, normal life and public health.

2.1. Higher Infectivity and Transmissibility

At the end of November 2021, South Africa’s National Institute for Communicable Diseases (NICD) reported that the basic reproduction number (R0) of the Omicron variant in Gauteng Province was vastly higher than that of the Delta variant prevalent in Septemberf 2021, indicating that Omicron may be more infectious than Delta [13]. An artificial intelligence model, which had been trained with tens of thousands of experimental data and extensively validated by experimental results on SARS-CoV-2, revealed that Omicron may be over 10 times more infectious than the original virus and approximately 2.8 times as infectious as Delta [12]. That means that Omicron could be the most contagious variant ever. Liu et al. found that the average R0 of the Omicron variant was 9.5 (95% CI: 5.5–24), which was 2.5 times higher than that of Delta [14]. In addition, the UK Health Security Agency reported that the secondary attack rates among contacts of Omicron cases in households (13.6%; 95% CI: 13.1–14.1%) and non-household settings (7.6%; 95% CI: 7.2–8.0%) were higher than those for Delta (household: 10.1%; 95% CI: 10.0–10.2%, non-household: 2.8%; 95% CI: 2.7–2.9%) [6]. Moreover, the transmissibility of Omicron is 8 times higher than the D614G original strain of SARS-CoV-2 [15]. In addition, Omicron is approximately 3.2 times more transmissible than Delta, and the doubling time is proximately three days [6][16]. Of note, the Omicron variant has been shown to result in a higher proportion of asymptomatic infections than other variants, which may be one of the reasons for its rapid spread [17].

2.2. Higher Immune Escape Ability but Reduced Pathogenicity

The Omicron variant can escape neutralization by antibodies induced by SARS-CoV-2 vaccines. Studies have confirmed that the activity of neutralizing antibodies in serum after vaccination for Omicron decreased, and the result of a South African real-word study showed that the effectiveness of SARS-CoV-2 vaccines against Omicron decreased to 70% 14 days after vaccination, indicating that Omicron has immune escape ability [18][19]. Moreover, Espenhain et al. found that the proportion of vaccinated or obtaining-booster patients with Omicron and Delta were 83.1% and 53.2%, respectively, based on data from Denmark [11]. Cele et al. found that the activity of neutralizing antibodies induced by the BNT162b2 vaccine against Omicron was approximately 22-fold lower than that of the wild strain [20]. Moreover, studies have confirmed that extensive mutations in the Omicron spike protein destroyed the activity of major potent monoclonal antibodies (mAbs), which leads to a severe reduction in the neutralizing ability of serum after natural infection or vaccination [20][21]. Fortunately, Redd et al. have shown that Omicron did not have many mutations conducive to escaping from T lymphocyte immunity, and SARS-CoV-2-specific CD8+T lymphocytes in recovered patients can still identify Omicron [22]. These studies suggest that the immune escape ability of Omicron from the humoral immunity induced by infection is stronger than that of Delta but has little effect on cellular immunity induced by infection.
Fortunately, Omicron results in milder clinical symptoms than Delta [23], including cough, fatigue, stuffy nose and runny nose, fever, nausea and vomiting, tachypnea and dyspnea, diarrhea, loss of taste or smell, etc., while loss of taste or smell was less common in Omicron [24]. Based on data from Denmark, Espenhain et al. found that the hospitalization rates of patients with Omicron and Delta were 1.2% and 1.5%, ICU occupancy rates were 0.13% and 0.11%, and case fatality rates were 0% and 0.07%, respectively [11]. Based on data from Gauteng Province, South Africa, Yang et al. found that the overall risk of death from infection during the Omicron wave (0.03%; 95% CI: 0.02–0.06%) was about 30% of that during the Delta wave (0.11%; 95% CI: 0.06–0.21%) [25]. Based on data from America, Tartof et al. demonstrated that the hospitalization rates of patients with Omicron and Delta were 0.5% and 1.3%, respectively. Among patients who were positive for Omicron in the outpatient clinic for the first time, compared to patients with Delta, the hazard ratio (HR) of hospitalization and symptomatic hospitalization were 0.48 (95% CI: 0.36–0.64) and 0.47 (95% CI: 0.35–0.62), respectively. In addition, the ICU occupancy rates and case fatality rates of patients with Omicron were 0.26 (95% CI: 0.10–0.73) and 0.09 (95% CI: 0.01–0.75) times than that of Delta, respectively. Moreover, compared to patients with Delta, the length of hospitalization in patients with Omicron decreased by 3.4 days (95% CI: 2.8–4.1), and the rate of change was 69.6% (95% CI: 64.0–74.5%) [8]. In fact, compared with other variants, studies have shown that Omicron infected lung cells less easily and its replication efficiency in lung parenchyma was also lower than other variants, which may explain the reduced severity in patients with Omicron [26][27]. Of note, it was found that the proportion of asymptomatic patients with Omicron was higher than patients with other VOCs with or without previous infection caused by SARS-CoV-2 [17]. In addition, through meta-analysis, Shang found that the pooled percentage of asymptomatic infections was 32.40% among Omicron-positive individuals and that vaccinated patients had a higher proportion of asymptomatic infection [28].

3. Status Quo of Breakthrough Infection Caused by the Omicron Variant

According to the US Centers for Disease Control and Prevention (CDC), a vaccine breakthrough infection is defined as the detection of SARS-CoV-2 RNA or antigen in a respiratory specimen collected from a person ≥ 14 days after the receipt of all recommended doses of an FDA-authorized COVID-19 vaccine [29]. With the further enhanced transmissibility and immune escape ability of the Omicron variant, breakthrough infection occurs continuously after vaccination(Table 1). Earlier, an outbreak of Omicron occurred at a party in Oslo, Norway, on 26 November 2021, and 81 of the 110 (74%) suffered Omicron breakthrough infection [30]. A genome sequencing study of SARS-CoV-2 in the Houston Methodist healthcare system identified that 2497 (55.9%) of 4468 symptomatic patients with Omicron from late November, 2021, to 5 January 2022, met the definition of a vaccine breakthrough infection and that the proportion of Omicron breakthrough infection is significantly higher than that of Delta [31]. On 31 December 2021, 58 (89.23%) of the 65 reported infections caused by Omicron had received all recommended doses of vaccination in Guangzhou, China [32]. Based on a multicenter study in 11 general hospitals in Israel, Cohen found that, as of 31 January 2022, 4802 (20%) of the 24,280 health care workers who received boosters and 368 (7%) of the 5331 health care workers who received the fourth dose of vaccine suffered a breakthrough infection during the peak of Omicron infection [33]. Moreover, based on data from Henan, China, in January 2022, Tang reported that the breakthrough infection rate was 17.8% in the Omicron chain [34]. Nowadays, the number of persons vaccinated with at least one dose per 100 population is approximately 89 in China, which is one of the countries with the highest vaccination rate in the world, but it is experiencing a surge in breakthrough infections caused by Omicron [1].
Table 1. Breakthrough infection caused by the Omicron variant in the literature.
References Type of Study Period of Study Country Sample Size Diagnosis Method Proportion of Breakthrough Infection Vaccine Type
Brandal [30] Cohort study 2021.11.26~2021.12.3 Oslo, Norway 110 PCR variant screening;
whole genome sequencing		 71.8% BNT162b2 (50.1%); mRNA-1273 (21.0%)
Christensen [31] Case-control study 2021.11.27~2022.1.5 Houston, America 4468 S-gene target-failure assay 55.9% BNT162b2(73%); mRNA-1273 (22%); JNJ-78436735 (5%)
Hu [32] Case-control study 2021.12.13~2021.12.31 Guangzhou, China 65 second-generation sequencing 89.2% ─
Cohen [33] Cohort study 2022.1 Israel 29,611 (the booster: 24,280; the fourth dose: 5331) polymerase chain reaction test the booster: 20.0%; the fourth dose: 5.0% BNT162b2 (100%)
Tang [34] Cohort study 2022.1.2~2022.1.23 Henan, China 2208 ─ 17.8% BBIBP-CorV and CoronaVac (91.8%); ZF2001 (7.5%); Ad5-nCoV (0.7%)
Studies have shown that the effectiveness of all types of SARS-CoV-2 vaccines decreased to some extent in relation to the Omicron variant and that the Omicron variant has shown lower neutralizing sensitivity than other VOCs to immune sera elicited by boosters [9][35][36][37][38], even if the booster and the fourth dose can reduce the incidence of breakthrough infection and the risk of severe infection [39][40][41][42]. This indicates that some measures are needed, such as developing a second-generation vaccine, in order to prevent and control the pandemic.

This entry is adapted from the peer-reviewed paper 10.3390/medicina58121733

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