The COVID-19 pandemic has led to unprecedented levels of morbidity, mortality, and economic disruption worldwide. Several non-pharmaceutical interventions have been implemented worldwide to curb the spread of SARS-CoV-2, including social distancing, home isolation, and centralized quarantine [
1]. Nevertheless, these interventions cannot be sustained over the long-term. Current hopes of controlling the pandemic rely heavily on vaccination, which remains the best tool available for preventing infection and symptomatic illness. As of November 2022, about 13 billion doses of the COVID-19 vaccine have been administered worldwide, and 68.6% of the world’s population has received at least one dose [
2]. It is estimated that COVID-19 vaccines prevented an estimated about 20 million deaths from COVID-19 in 185 countries and territories between December 8, 2020, and December 8, 2021 [
3].
As the number of SARS-CoV-2 infection caused by Omicron variants has rapidly increased in vaccinated populations since the first Omicron variant was reported in South Africa on November 2, 2021, increasing concerns have been raised about the effectiveness of current vaccines. The results of some real-world studies indicated limited protection against symptoms caused by the Omicron variant following primary immunization with two doses of either mRNA [
4,
5] or an adenoviral vector [
5,
6] vaccine. Despite the fact that protection waned over time, a booster dose significantly improved protection following either the mRNA or adenoviral vector vaccine primary course [
7]. Moreover, though inactivated vaccines have been widely used in developing countries and account for almost half of COVID-19 vaccine doses delivered globally [
8], their effectiveness against Omicron variant in real-world settings has not been adequately studied.
It is critical for a vaccine to be able to prevent infection or disease in older individuals, who are at higher risk of severe disease or mortality and should be offered vaccination as a priority [
9]. However, COVID-19 vaccination coverage in the elderly varies substantially by country due to vaccine hesitancy, barriers to global vaccine equity, and other factors [
10]. More than 90% of people over the age of 60 years in some developed countries have received a booster dose (such as Japan, Belgium, Italy) as of November 2022 [
2], while in most African countries, more than 50% of people over the age of 60 years have not yet received any dose [
11]. In China, about 86% of people over 60 years have completed the initial COVID-19 vaccination protocol by November 2022, but less than 70% of people over 80 years have been vaccinated [
12]. In light of the findings of the study, it is recommended that vaccination coverage for the elderly be improved as soon as possible. In addition, older individuals demonstrate a significantly lower immune response but higher tolerability to the COVID-19 vaccine compared with younger individuals [
13]. Due to this, it is imperative to elucidate whether current vaccines are effective in the elderly.
In this issue of
Frontiers of Medicine, Fu and colleagues reported findings from a real-world study that assessed the effectiveness of SARS-CoV-2 prototype-inactivated vaccines against severe/critical COVID-19 and characterized the pathophysiological features of the Omicron BA.2.2 sub-lineages in different age groups [
14]. Herein, clinical laboratory tests and immunization records were analyzed for 9911 patients with symptomatic COVID-19, including 9638 mild/moderate cases and 273 severe/critical cases in Shanghai, China, during the outbreak in the spring of 2022. In light of the study analysis, important findings deserve to be valued. First, the severity of COVID-19 was positively related to age, while vaccine-protected people were less likely to experience severe/critical disease than non-vaccinated people (Fig.1 and 1B). Second, the severity of COVID-19 has also been found to be associated with some laboratory indicators in previous studies [
15,
16]. It is critical to identify those infected people who are at a higher risk of severity through the laboratory indicators, and then to implement a series of intervention measures to prevent severity. Fu
et al. [
14] explored the associations of multiple laboratory indicators (including host immune response, multi-organ function and damage, coagulation, etc.) at the early stage of BA.2.2 infection with the risk of severe/critical cases. It was found that the severe/critical cases were related to abnormal functions such as liver damage and kidney injury (Fig.1 C), as well as decreased levels of some host immune response. These findings suggest more attention and intervention for the infected individuals with abnormal laboratory indicators, thus reducing their risk of severity. Additionally, among people 60 years of age and older, 2 to 3 doses of prototype-inactivated COVID-19 vaccine resulted in a 90% protection rate against severe/critical COVID-19. The results add evidence for the effectiveness of COVID-19 vaccines against hospitalization and death [
17,
18]. Fu and colleagues [
14] also investigated the relationship between vaccination status and multiple laboratory tests (Fig.1 D), seeking to elucidate the potential mechanism for the lower risk of severe/critical cases among vaccinated individuals. They found that vaccinated individuals were protected against the abnormal bio-analytes in their blood that characterize severe/critical cases, particularly in the elderly. For instance, the lymphocyte counts remained below normal levels during the first 30 days after hospitalization in unvaccinated severe/critical cases, however, their levels returned to a near-normal level within 30 days in the vaccinated group.
In the same way as the elderly, individuals with comorbidities, such as diabetes mellitus, respiratory disease, chronic kidney disease, cardiovascular disease, obesity, and mental health conditions are at an increased risk of developing severe COVID-19 [
19]. Risks are higher for people with diabetes, obesity, and anxiety related disorders, and relatively lower for those with cardiovascular disease [
20]. It has been recommended that COVID-19 vaccines should be administered to individuals with high-risk comorbidities in the interim guidelines published by the WHO Strategic Advisory Group of Experts on Immunization [
21]. It should be noted, however, that vaccination rate in people with comorbidities was still lower than that in healthy people, owing to safety concerns and vaccine hesitancy [
22]. Several recent studies indicated that the COVID-19 vaccine appeared safe for individuals with comorbidities, and adverse effects were not different between individuals with and without comorbidities [
23,
24]. Based on the results of the reported clinical studies so far, COVID-19 vaccination also shows similar efficacy in individuals with comorbidities and those without any underlying medical conditions [
25,
26]. Given the fact that individuals with comorbidities are more likely to progress to severe conditions or even die if infected with COVID-19, the benefits of vaccination outweigh the risks. Moreover, receiving the COVID-19 vaccines could reduce the viral clearance time and symptom duration [
27,
28], which were associated with comorbidities.
As of November 2022, SARS-CoV-2 has infected more than 600 million people globally [
29]. Although SARS-CoV-2 infection may trigger antigen-specific immune responses, due to the gradual decrease in the levels of the humoral and cellular immune response induced by SARS-CoV-2 and the emergence of new SARS-CoV-2 variants, re-infection cases were reported frequently [
30,
31]. However, the individuals with re-infection had significant lower risk of severe case than the individuals with primary infection [
32,
33]. It will be crucial for continued prevention of reinfection to determine whether it is necessary for COVID-19 convalescents to receive vaccinations as well as the number of doses of vaccination that should be administered. A recent study compared the levels of neutralizing antibodies and B cell responses against the Omicron variant in unvaccinated convalescents 18.5 months after infection with those in vaccinated convalescents (one or two doses of inactivated vaccine), and suggested that COVID-19 convalescents would benefit from the administration of inactivated vaccines (one or two doses) [
34]. Two doses of inactivated vaccines were recommended and crucial for controlling COVID-19 and informing vaccination guidelines. Similarly, Carreño
et al. investigated the virus-neutralizing activity of serum from unvaccinated and vaccinated convalescents against the Omicron variant [
35]. They demonstrated that two doses of the mRNA vaccine were sufficient to elicit a significant antibody response in convalescents.
Accumulating evidence has indicated that the existing COVID-19 vaccines have presented a profoundly positive effect in reducing both hospitalization and death, even during a period in which Omicron variants were circulating. Since many governments have loosened public health restrictions, and the focus of the country’s COVID-19 control have shifted to the intervention of potential severe cases, vaccines remain the most important tool for controlling COVID-19 and helping to shift pandemic to the next phase. Increasing vaccine accessibility in resource-poor countries, reducing vaccine hesitancy in groups with relative low vaccine coverage (such as elderly, individuals with stable underlying disease), and further bosting vaccination (such as the fourth dose) help to form immune bulwark against the challenge posed by the rapidly-mutating virus. Besides, to address the continued genetic evolution of SARS-CoV-2, new vaccines (such as bivalent boosters against the emerging variants, broad-spectrum anti-coronavirus vaccine) should be encouraged and sponsored, which also help to reduce the amounts of symptomatic disease and associated heath care.
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