1 Introduction

It all began in December 2019 when many unidentified pneumonia cases were appearing in Wuhan city in the Hubei Province of China. As time went on, this virus continued to spread not only in China but the entire world. On January 30th, 2020 the World Health Organization declared a public health emergency of international importance, and a few weeks later on March 2nd 2020, they declared this a global pandemic naming the disease as Coronavirus Disease 2019 (COVID-19) [1]. Later on, it was renamed as Severe Acute Respiratory Syndrome Coronavirus 2 or SARS-CoV-2 by the Coronaviridae Study Group of the International Committee on Taxonomy of Viruses [2]. COVID-19 has affected more than 750 million people and has reported 7 million death cases worldwide, as of September 2024 [3].

SARS-CoV-2, belongs to the family Coronaviridae and the genus Betacoronavirus [4]. Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS) also belong to the same family. It appears from viral genome analysis that SARS-CoV-2 is a recombinant virus between the bat coronavirus and an unknown-origin coronavirus [5]. The peplomers or the trimeric spike glycoproteins which give the virus its corona-like appearance allow the virus to enter the host cell and are seen to infect mainly humans, mammals, and birds [6].

COVID-19 is highly transmissible and rapidly spreads from human to human via respiratory droplets from coughing or sneezing and also through in-person contact. Common symptoms seen in affected patients are fever, cough, sore throat, fatigue, headache, shortness of breath, loss of sense of smell and taste, phlegm production, and chills [7, 8]. However, many individuals do remain asymptomatic which adds yet another challenge to control the disease. This period has seen the rise of different vaccination strategies to provide immunity against the infection. New vaccine preparations integrated with nanotechnology, such as preparation of chitosan-polyethylene glycol nanocomposite fabricated with antigen of interest, have been proven to enhance immunogenicity and demonstrate stability and efficiency [9].

Since its first appearance, this disease has been a global concern that the world has collectively been combating together. It has been rapidly spreading and many people have been affected by this disease with both minor and major complications including deaths. Therefore, it is vital to have a comprehensive understanding and reflect on all the possible improvements made in the diagnosis, treatment, and management of COVID-19. In this article, we have gathered all the information which is relevant over the past five and half years to address the current risks and challenges. With this updated information, this review aims to help ongoing efforts to manage COVID-19 effectively and helps to understand the unaddressed gaps in response to COVID-19, which is crucial to develop better policies, and strategies, and to prepare for similar threats.

2 Global epidemiology

For a highly contagious disease like COVID-19, which has claimed millions of lives worldwide, understanding the source, causes, and distribution of the disease becomes of utmost importance. In addition, it is important to analyse the fine interplay between political, social, and scientific elements that could worsen the disease risk and provide a better understanding of different measures that can be undertaken to control and manage the pandemic. The pattern of viral infection across various geographical regions has been ever-changing in different waves of the pandemic. The different variants of the virus emerging because of frequent mutations have also posed a challenge in managing the pandemic. Some of the worst affected regions as of 21st May 2020 during the first wave include the United States, followed by Brazil, the United Kingdom, Spain, Italy, France, and China [10]. Apart from developed countries, several developing countries such as Mexico, Indonesia, Nigeria, Argentina, and the Philippines, were also significantly affected by COVID-19. The first wave of COVID-19 appears to have majorly affected people over 30 years, followed by those belonging to the (20-24 years) age group, and finally the (0 –19 years) age group [11]. The economic consequences of the first wave were huge, with the healthcare system experiencing instability, while the tourism sector dropped drastically, leading to a major decline in the economy. This also resulted in significant job losses across industries and other sectors [12]. The second wave was the most devastating and the top countries affected during this wave include, the United States, India, Brazil, Russia, France, Italy, the UK, Spain, and Argentina. The third wave which began in late 2021 infected a large population and people over the age of 30 were the worst affected, following a pattern similar to that of the first wave [11]. The third wave appears to be ongoing in many countries seeing a surge in the number of active cases again. The number of active cases and deaths as of April 13th, 2024, in different regions of the world, is summarized in Table 1. The ongoing wave has triggered newer discussions on all aspects like vaccine distribution, public health, and economic recovery strategies. Collectively, technological advancements and digital transformations have come up with innovative solutions to maintain the industrial economy and assist other sectors during the pandemic [12].

Table 1 Summary of active cases and deaths due to COVID-19 across the globe from March 1st 2020 to April 13th, 2024, categorized under 6 regions-Europe, North America, Asia (with India as a sub-region), South America, Africa, Oceania as well as developing countries [151]
Full size table

3 Variants of SARS-CoV-2

COVID-19 is a rapidly spreading virus that widely circulates among the population increasing the chances of mutation. With the increase in the spread of the virus, there is a higher chance of changes in its structure and genetic composition creating an additional matter of concern. Moreover, these viral mutations do not change how the virus functions and, therefore, do not necessarily impact its ability to cause disease in the host [13]. However, depending upon the exact location of the change in the genetic material it can alter the transmission capability as well as the severity of the disease. These mutations have led to the formation of different variants.

Different genetic variations of SARS-CoV-2 have been reported during the COVID-19 pandemic and their structural variations have created a great concern globally. Countries around the world are struggling with successive new waves of infections due to these different variants. The variants arise through viral replication naturally and can affect vital pathogenic components of the virus, like the receptor-binding domain of the spike protein [14]. The variants which are associated with an increase in transmissibility and virulence can cause some change in the clinical symptoms presented, or reduce the efficacy of available treatments and are termed Variants of Concern (VOCs) [15]. The most reported variants with their structural variations are shown in Figure 1. Three prominent variants- the alpha (B.1.1.7), beta (B.1.351), and gamma (P.1)- were reported towards the late 2020s in the United Kingdom, South Africa, and Brazil, respectively [16]. In the previous summer of 2021, India saw the rise of the delta (B.1.617.2) variant [16]. The next rapidly evolved variant is omicron which has multiple sublineages, each one has specific mutations that contribute to immune evasion and increased transmissibility. The highly transmissible omicron (B.1.1.529) variant also emerged in Africa around late 2021, and this omicron variant possessed over 30 mutations in its spike protein, which imparted it with the ability to surpass antibodies against it [17]. The other notable ones are BA.1, BA.1.1, BA.2, BA.2.12.1, BA.4, and BA.5 [16] . Further evolutionary changes have led to the arrival of other sub-lineages, such as BF.7, and derivatives BQ.1 and BQ.1.1 [18]. These variants show a trend towards enhanced transmission and immune evasion, with each new strain explaining additional genetic advantages. This evolution led to another hybrid variant called XBB.1.5, known for its improved binding affinity and transmissibility compared to its predecessors [19, 20]. The different variants and their representative characteristics are summarized in Table 2.

Fig. 1
figure 1

Variants of SARS-CoV-2. The 5 variants of concern are shown in the figure. The Alpha variant resulting due to 3 mutations is represented with an orange-colored spike protein. The Beta variant with a single mutation is represented with a purple-colored spike protein. The Gamma variant with 3 mutations, one of which is present in the Alpha variant as well, is represented with a green spike protein. The Delta variant with 2 mutations, one of which is also present in the Gamma variant, is represented with a grey spike protein. The latest Omicron variant with the maximum number of mutations is represented with a blue spike protein

Full size image
Table 2 Summary of the variants of COVID-19 [152,153,154,155] [156,157,158,159]
Full size table

4 Current advances in diagnosis and treatment

4.1 Current diagnostic methods

It is remarkable how technology has advanced to a point where we can rapidly detect and identify the causative organism of an unknown infection. In times of medical emergencies, as in a pandemic like COVID-19, multiple clinical priorities are starting from the need to understand the pathology of the disease to provide effective treatment to the patients. [21].Since the beginning of the pandemic, a lot of efforts have been put into developing accurate and rapid diagnostic techniques to detect SARS-COV-2 infection in patients, to reduce the risk of spread of the disease as well to promptly provide treatments for the infected patients [22]. The current diagnostic methods can be understood under two categories: 1) direct detection where the procedure mainly involves the detection of viral proteins or nucleic acids and 2) indirect tests that aim to detect virus-specific antibodies in the patients [23].

Among all the various methods available so far, the two major tests currently in use to detect SARS-COV-2 infection are molecular methods and serological methods, which can be used irrespective of the viral variant causing the disease [24]. Molecular methods, more specifically nucleic acid-based methods generally make use of the genetic material of the virus (single-stranded RNA in the case of Sars-COV-2), and they are based on the principle of high specificity base pairing between homologous strands [25]. Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) is one such method that is widely used with high sensitivity and specificity with the added benefit of quantification of viral RNA [26]. In the developments of RT-PCR, there is an emphasis, on enhancing assay design and automation. This has led to improved efficiency and quicker results. Modern RT-PCR tests not only detect RNA but also measure its quantity providing valuable information, on disease advancement and treatment effectiveness [27]. Additionally, RT-PCR has been vital for evaluating viral load through cycle threshold (Ct) values. Lower Ct values indicate higher viral loads and have been linked with increased infectivity, while higher Ct values generally reflect lower viral loads and a decreased risk of transmission [28]. This quantification has become integral in monitoring disease severity and guiding patient management strategies. Next Generation Sequencing (NGS) is used to obtain the sequence of the viral genome and this way it helps to detect the mutations that have given rise to the variants [25]. Immunological assays like antibody-based assays or antigen-based assays are also in use. However, diagnosing COVID-19 in its early stages using an antibody-based method is challenging because the body takes time to recognize novel foreign antigens and produce appropriate antibodies, which can lead to false-negative test results [24]. Sometimes patients are advised a Computed Tomography scan (CT scan) of the lungs to check for cases of viral pneumonia or other similar abnormalities, however, these scan results cannot on their own be used as a positive confirmation of the infection and need to be accompanied by other nucleic acid or molecular test results because CT scan results are not as sensitive as RT-PCR [26].

Imaging, such as CT scans, helps diagnose lung abnormalities typical of COVID-19 cases, but sometimes results can be false-positive or false-negative. False positives can occur due to bacterial pneumonia, or chronic lung diseases whereas False negatives can happen in the early stages of infection or technical factors [29]. Therefore, imaging results should be interpreted alongside other diagnostic data to ensure a more accurate diagnosis. The different methods of detection and identification of COVID-19 are currently in use as shown in Figure 2.

Fig. 2
figure 2

Different diagnostic methods currently in for COVID-19. Nucleic acid-based RT-PCR is the most commonly used technique to detect SARS-CoV-2 infection. Serological methods like antigen assays are also used, however they are not as accurate as of the RT-PCR method. Computer Tomography (CT) scan is also generally advised to patients along with an RT-PCR test to confirm COVID-19 infection. The electrochemical sensor-based technique is relatively new and with further development, it can be brought into use

Full size image

Despite all the diagnostic methods for COVID-19, they are not completely reliable and can result in false positive/negative results. False-positive COVID-19 cases occur in antigen tests due to non-clear sample placement, cross-reactions with other antigens, or the detection of inactivated virus particles, among other factors. Antibody tests can result from cross-reactions with other antibodies or exogenous factors like high concentrations of nasal spray or chemical substances. On the other hand, False negative COVID-19 cases occur in antigen tests due to poor sampling, sample degradation, or the presence of mutations that evade detection. Antibody tests may often give false negative results if the test is conducted too early, i.e., even before sufficient antibody is produced or due to exogenous factors that interfere with the test [30]. Furthermore, it should be noted that patients with underlying medical conditions such as blood malignancy tend to show false negative results due to endogenous factors such as hematocrit, triglycerides, cholesterol, and other blood substances [31].

Additionally, the severity of COVID-19 can range from asymptomatic to mild or severe cases. What is often considered 'asymptomatic' cases may result from testing done during the pre-symptomatic or post-symptomatic phases [32]. Since testing often reflects a random sample taken at an unpredictable time relative to the initial infection, this can lead to false assumptions about true asymptomatic cases [33]. This subject is relevant when we use molecular tests like RT-PCR, which, although highly specific, may not always detect the virus at different stages of infection.

4.2 Biomarkers of COVID-19

It is important to know the different biomarkers of COVID-19, especially in immunological, inflammatory, coagulation, haematological, cardiac and biochemical pathways, as it aids in early identification, prognosis, diagnosis and specific treatment of the disease [34]. As of studies performed till 2020, the various biomarkers identified include haematological (lymphocyte count, neutrophil count, Neutrophil–Lymphocyte Ratio (NLR)), inflammatory (C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), procalcitonin (PCT)), immunological (interleukin (IL)-6) and biochemical (D-dimer, troponin, creatine kinase (CK), aspartate aminotransferase (AST)), especially those related to coagulation cascades in Disseminated Intravascular Coagulation (DIC) and Acute Respiratory Distress Syndrome (ARDS) [35]. Leukopenia and lymphopenia act as early diagnosis biomarkers as they are correlated with disease severity. A study showed that 40 percent of patients with increased LDH levels have ARDS, which substantially needs high care and leads to mortality [36]. Another diagnostic marker is the NLR ratio as concluded in a systematic review of 6 studies. These studies showed that an elevated NLR ratio resulted in worsening clinical symptoms. Overall, leukopenia, lymphopenia, high NLR and LDH are relatively specific and accurate biomarkers for diagnosis of COVID-19 disease [37]. The CRP plasma levels are higher in COVID-19 patients as compared to healthy individuals; IL-6 levels also undergo a sharp rise in COVID-19 patients; the patients also show an increase in leukocyte count but the levels of lymphocytes, monocytes, basophils and eosinophils were less, resulting in a greater neutrophil-to-lymphocyte ratio [38]. The elevation of CRP depends on various physiological processes and is also based on each individual. For example, the CRP level is elevated when it is involved with immune response and is also helpful in checking the severity of inflammation. Additionally, individuals with cancer or obesity experience high CRP levels because CRP is often reflected as a sensitive indicator [39].

Studies have shown that an increase in LDH levels could also be a potential biomarker of COVID-19 [40]. Other biomarkers identified and studied include D-dimer, urea, creatinine and cardiac troponin which seem to show increased levels in patients, and platelet count which shows decreased levels in patients [38]. Though multiple biomarkers have been identified, their levels may fluctuate depending on the severity of COVID-19 and hence, more experimental studies are required for their complete validation and standardisation. These biomarkers should be carefully integrated with other diagnostic evaluations to provide appropriate treatment to patients.

4.3 Potential drug targets

It has been observed that there isn’t a prescribed regimen to follow while treating COVID-19 as patients can exhibit a spectrum of clinical symptoms. However, understanding the structure of the virus as well as its mechanism of entry and infection of host cells has led to the discovery of various drug targets that have been effective in the treatment of disease. Essentially, the enzymes and proteins that are crucial for viral replication and the control of the host cellular functions can serve as potential drug targets [41]. Thus, new drugs or antagonists need to be developed that inhibit these enzymes, proteins, and receptors which are solely required for the survival and multiplication of viruses. Various drug targets that can be targeted for therapy are discussed below.

4.3.1 RNA-dependent RNA polymerase (RdRp)

RdRp is coded by the non-specific (Nsp)-12 gene of SARS-CoV-2 [42]. It is one of the most crucial enzymes for the replication and transcription of the virus. Thus, inhibition of this enzyme may be an excellent option for different treatment strategies. A recent study showed that this drug target was associated with a safer profile, less toxicity, and fewer side effects [43]. Drugs such as Ribavirin, Remdesivir, Cortisone, Idarubicin, and Pancuronium bromide have been observed to act upon this protein [44]. In addition, there is a wide array of natural compounds that act on RdRp and have shown anti-COVID activity including Gnidicin from Gnidialamprantha and Betulonal from Cassinexyloacarpa [45]. However, more studies are required to substantiate its efficacy in higher populations.

4.3.2 Angiotensin-converting enzyme-2 (ACE-2)

ACE-2 is the functional receptor of the COVID-19 virus, which is a negative regulator of the Renin-Angiotensin System (RAS) [43]. It is seen that the S protein of the virus will bind to this receptor located on the host cell with great affinity thereby resulting in higher pathogenicity [41]. Therefore, by making use of some sort of inhibitor or blocking agent ACE-2 becomes a potential therapeutic target in the treatment of COVID-19. It is possible to employ viral neutralizing antibodies as they are assumed to be the Receptor-Binding Domain (RBD) specific and can play a role in neutralizing the viral particles [46]. Some natural compounds have displayed a good binding affinity towards ACE-2 such as Amentoflavone, Chrysanthemum, and Biovobin [47].

4.3.3 Papain-like protease (PLpro)

PLpro is found in all the members of the coronavirus family. It plays a major role in the release of non-structural proteins from the N terminal part of the poly proteins 1a and 1ab [48]. It also acts as an antagonist towards interferon and is seen to inhibit the interferon regulatory factor 3 activation [49]. This is important as by targeting this, viral replication can be inhibited and can save the healthy cells from receiving signalling cascades from the infected cells [43]. Drugs such as Disulfiram, Lopinavir, and Ritonavir are known clinical protease inhibitors against MERS and SARS and currently, their effectiveness towards COVID-19 is being tested in clinical trials [42].

4.3.4 Chymotrypsin- like protease (3CLpro)

3CLpro is one of the main proteases involved in the mechanism of viral infection in the host cell. It is also called Nsp5 and is cleaved from the poly proteins and then goes on to cleave further to release Nsp4-Nsp16 which is vital for the life cycle of the virus [50]. Due to its role in the viral mechanism, it would be appropriate to use this as a potential drug target. Doxycycline, Oxytetracycline, Ledipasvir, Lymecycline, and Demeclocycline have exhibited a good binding affinity towards this protease and further studies can be performed to validate their clinical validity [42]. A comparison between various drug targets of COVID-19 studies reported in the past 5 years is shown in Figure 3A.

Fig. 3
figure 3

A Studies carried out on different drug targets for COVID-19 in the past 5 years and B Literature reports on chemical drugs, phytochemical drugs, and nano-based approaches for the treatment of COVID-19 in the past 5 years

Full size image

4.4 Drugs currently in use

4.4.1 Chemical drugs

In the treatment of any disease, it is important to be aware of the different drugs that can be possibly used to combat the illness. In the case of COVID-19 due to the variety of symptoms, there is a range of chemical drugs that could be effective in the specific treatment of the symptoms; hence it is important to understand the drugs that are most effective here. Another strategy is also the repurposing of existing drugs that exhibit desirable effects when administered to patients affected with COVID-19. However, during the start of the pandemic, there have been several in silico studies carried out to discover novel leads for the treatment of COVID-19. Here we will discuss different chemical drugs that are either being currently studied or have shown promising results towards treating or managing the disease.

4.4.1.1 Remdesivir

Remdesivir, also known as GS-5734, is a broad-spectrum antiviral drug [51]. This drug is the most widely researched drug and is commonly used ever since the pandemic began. It is an Adenosine Triphosphate (ATP) analogue and it is a prodrug of Remdesivir triphosphate (RDV-TP) that acts as an RNA-dependent RNA polymerase inhibitor that inhibits the replication of the virus. After entry into the host cell, Remdesivir undergoes cleavage to form the adenosine monophosphate analogue and undergoes phosphorylation giving rise to RDV-TP which resembles ATP [52]. There is competition between RDV-TP and ATP, and RDV-TP gets incorporated into the growing chain thereby causing premature termination of viral RNA transcription [53]. The United States Food and Drug Administration (FDA) on May 1, 2020, declared that Remdesivir could be used for the emergency treatment of hospitalized COVID-19 patients [54]. In addition, Remdesivir has proved to be effective in reducing the severity of COVID–19. In the Canadian treatment of COVID-19 trial, it was shown to lower the chance of using ventilation in patients [55].

4.4.1.2 Favipiravir

Favipiravir is a guanine analogue and is also an antiviral. This drug has been earlier used for the treatment of influenza in Japan [56]. It is administered as a prodrug and it is converted to its active form i.e., Favipiravir ribofuranosyl phosphate after it is taken up by the infected cells [57]. It is seen to inhibit the RNA-dependent RNA polymerase. The possible mechanism of the activity of this drug is that it gets incorporated into the nascent viral RNA or may bind to conserved polymerase domains [52]. As a result, the process of replication and transcription of the viral genetic material is stopped. A recent study on 80 patients conducted in Shenzhen showed that the viral clearance time significantly decreased and it was also observed that chest X-ray imaging improved more quickly [53].

4.4.1.3 Molnupiravir

Molnupiravir was one of the first drugs to be effective in the treatment of mild COVID-19 [58]. It is an anti-viral drug that targets RNA polymerase activity [59]. Molnupiravir has an interesting mechanism of action in that it follows the “error catastrophe” principle [58]. It inhibits RdRp of SARS-CoV-2 and induces RNA mutagenesis in a two-step process [60]. Thus, it increases the rate of mutation in the viral genome and when the number of mutations crosses a certain threshold, the virus is no longer able to replicate and thus becomes extinct [58]. In phase 1 clinical trials of this drug, it was seen that up to 1600 mg daily dose of this drug was safe and tolerated without any adverse effects and phase 2 and 3 clinical trials also led to the conclusion that this drug reduced hospital admissions or death by 50% [58]. However, it was noted that there was no significant benefit of using this drug in cases of late stages of moderate to severe COVID-19 [58]. A recent study conducted by PANORAMIC trials, showed zero benefits for the high-risk COVID-19 patients when given Molnupiravir drug combined with standard therapy [61]. Headache, diarrhoea and nausea were the most commonly reported adverse side effects of using this drug [59]. Though it has been shown as efficient in treating mild COVID-19, NIH COVID-19 has recommended use only if other antiviral drugs are not viable options [58].

4.4.1.4 Lopinavir/Ritonavir

They belong to the group of antiretroviral protease inhibitors and follow a mechanism of competitive inhibition [62]. Different kinds of proteases in SARS-CoV like PLpro, nsp3, 3CLpro or Mpro and nsp5 are important for the post-translational proteolysis of a polyprotein precursor [62]. The normal functioning of the enzyme leads to normal production and release of viral proteins whereas, the inhibition of these enzymes leads to the release of immature virus particles which further prevents their replication and propagation in the host [62,63,64]. These drugs are generally found in combination with each other commercially. Ritonavir is seen to be a boosting agent to Lopinavir and limits the drug’s metabolism thereby improving its bioavailability [7, 65]. They are specific to HIV protease-1 and have been used in the treatment of HIV infection [51]. A recent study conducted by Pandey et al. showed that a combination of Lopinavir/Ritonavir was not effective for the treatment of the Middle East Respiratory Syndrome (MERS) and SARS-COV. However, it showed promising efficacy in the treatment of COVID-19 [66]. Thus, more studies need to be carried out to provide concrete evidence of the use of this combination in the treatment of COVID-19.

4.4.1.5 Chloroquine

Chloroquine falls under the category of aminoquinolines and is a wide-spectrum antiviral drug. It has been used to treat malaria as well as autoimmune diseases such as lupus erythematosus, and rheumatoid arthritis and is an anti-inflammatory agent [67]. In the early phase of the pandemic, it was hypothesized that the drug could mainly inhibit the entry, post-entry, and transport phases of the virus [68] by inhibiting the binding of the S protein to the ACE-2 receptor located on the host cell and hence will inhibit replication of the RNA, the glycosylation of the viral proteins, the assembly of the virus, and finally exocytosis [7, 69]. Based on a small dataset, this drug was given emergency use authorization by the US FDA for the treatment of COVID-19 patients [51]. However, subsequently, the data from clinical trials suggested that both Chloroquine and its derivative hydroxychloroquine were neither effective nor preventative against the treatment of the COVID-19 virus. So, the US FDA revoked the use of this drug due to inefficacy and also evidence of serious heart problems in June 2020 [70].

Furthermore, ongoing trials are exploring new antiviral treatments for COVID-19. Interferon lambda, studied in the TOGETHER trial, significantly lowered emergency visits and hospitalizations, though it is not yet available in the U.S. Other promising antiviral candidates include ensitrelvir, a SARS-CoV-2 protease inhibitor, and oral remdesivir analogues like VV116 and obeldesivir. VV116, in particular, showed similar effectiveness to nirmatrelvir-ritonavir in high-risk patients, with fewer side effects, highlighting advancements in potential COVID-19 therapies [71].

4.4.2 Immunomodulatory therapy

4.4.2.1 Corticosteroids

Corticosteroids are immunomodulating drugs that are generally administered in combination with other antiviral drugs and they play an important role in preventing cytokine storms and thrombotic events [72]. It is recommended by WHO that, when the condition of the patient is not severe then corticosteroids should not be used as it has not shown any major benefits. However, they do seem to improve the status of patients who are in critical condition [73]. Methylprednisolone which is anti-inflammatory and anti-fibrotic in low doses might be able to improve the damaged immune response caused by sepsis which is a complication of COVID-19 and hence effective in its treatment [45]. Though it is widely used, its efficacy in the long term remains controversial. Corticosteroid treatment can cause osteonecrosis and osteoporosis in some patients and the possibility of such complications should be considered by doctors and patients[74]. Various studies have reported the negative effects of use of corticosteroid treatment for COVID-19, which include higher inflammation index, increased hypoxia, severe lymphocytopenia and higher mortality risk [75]. Hence, a lot of considerations need to be taken before corticosteroids can be administered to the patients.

4.4.2.2 Tocilizumab

Tocilizumab is an immunosuppressive drug. This is a recombinant humanized monoclonal immunoglobulin antibody against human IL-6 [68]. It acts as an antagonist towards IL-6activity which is an essential member of the human immune response [54]. Patients with COVID-19 displayed high levels of cytokines (cytokine storm) which included IL-6. This could be attributed to the severity of the disease as well as the inflammation [76]. Therefore, by targeting IL-6 with Tocilizumab this symptom could be overcome and could aid in inhibiting the progress of the disease. This is generally the suggested treatment when there are extensive lung lesions observed in the patient [52].

4.4.3 Phytochemical drugs under study

COVID-19 has made a mark in history as the 5th global pandemic, after the first flu pandemic that broke out in 1918 [77]. The currently available drugs for treatment of COVID-19 like Remdesivir, Lopinavir, Hydroxychloroquine, etc. were identified as a result of the drug repurposing approach, unlike the already available drugs which were screened using specific protocols [78]. The associated benefits of reduced drug discovery time have some serious drawbacks including toxic side effects after treatment with the drug, leading to serious cardiac, neurological and psychiatric side effects, respiratory failure and organ dysfunction [79]. Discovering novel drug moieties to treat SARS-CoV-2, and making it available after FDA approval, remains a time-consuming costly affair, thus driving our focus towards exploring alternative methods and leading us to the option of resorting to a phytochemical-treatment strategy[80]. Phytochemicals, generally known for their reduced toxicity and side effects, easy availability, and cost-effectiveness, provide the most efficient alternative for the treatment of various deadly diseases like COVID-19 [78, 81]. We can broadly classify the phytochemicals which are presently under study to test their anti-SARS-CoV-2 activity into flavonoids, alkaloids, phenolics, essential oils, glycosides, stilbenes, tannins, saponins, and anthraquinones [80]. These phytocompounds are currently at various levels of testing for their efficacy against SARS-CoV-2. Both prevention and treatment of COVID-19 using phytocompounds have gained major attention globally due to their myriad biological properties. Several phytocompounds have been tested for their efficacy against SARS-CoV-2 and various in silico, in vitro, in vivo and clinical studies are being carried out. Here we provide an update on the studies reported for the past 4 years.

4.4.3.1 In silico studies

With the advances in technology now paving the way to computational modelling and simulations of almost every biochemical process, in silico studies have now become a crucial part of the drug development process. Computer Aided Drug Design approaches are gaining wide attention among medicinal chemists, assisting them through every stage of the drug discovery process [82]. By integrating computational methods along with experimental data, it is now possible to study the pharmacodynamics and pharmacokinetics of a drug [83]. In silico studies have many advantages over in vitro and in vivo studies. The former reduces the need to utilize animal models for experimentation, they are more economical especially when the study requires multiple trials for optimization, and increased speed of experiments, and they can also be used in developing personalized treatment for every patient [83, 84]. As useful as in silico studies are, there are some limitations associated with them 1) The applicability of local computational models becomes very narrow and if the model is extended for use in other domains, the predicted results might be inaccurate 2) Many in silico test results have not been validated in vitro and hence the validity of in silico studies is not yet clearly understood 3) developing computational algorithms is a complex procedure involving the integration of different models and a large set of experimental data [83]. In the future, in silico studies can be expected to be highly developed such that they provide realistic and better predictive models that can be used on a wider set of experimental conditions, thus making the screening of various compounds easier. The step-wise procedure of identification of potential drug molecules through in silico studies is summarised in Figure 4.

Fig. 4
figure 4

In silico identification of potential drug molecules from an established ligand database. The ligand database is screened using molecular docking against various drug targets identified in SARS-CoV-2. The ligands that show the highest binding affinity with the drug target and high stability of target-ligand complex are considered for further studies

Full size image

Various phytoconstituents have been effectively screened in silico for their antiviral properties and hundreds of phytocompounds have been reported with inhibitory activity against various COVID-19 targets like Mpro, ACE2, spike glycoproteins, and nucleocapsid proteins amongst others. A variety of phytochemicals like Mangiferin, Azithromycin, Procyanidin-Β-2,7-Dimethox-Yflavan-4′-O-Β-D-Glucopyranoside, Amentoflavone, Hidrosmin, Diosmin, Gallocathechin Gallate, Elsamitrucin, Pectolinaren, Quercetin and Iso-Quercetin have been studied as Mpro inhibitors using computational analyses [80]. Flavonoid based compounds like Rutin, Isorhamnetin-3-O-Β-D and Calendoflaside extracted from Calendula officials have also shown inhibitory activity against Mpro of which Rutin is already in use as a drug and the other two can be expected to be available soon [43]. Based on bioactivity, binding mode and various molecular interaction, Lupeol (–8.6 Kcal/Mol), Lupenone (–7.7kcal/Mol), Hesperetin(–7.4 Kcal/Mol), Apigenin (–7.3 Kcal/Mol) and Castasterone(–7.3 kcal/mol) were identified as probable inhibitors of SARS-CoV-2 main protease (Mpro), and were reported to have better inhibitory activity as compared to Remdesivir and Azithromycin [85]. Physics and knowledge-based methods, computationally intensive studies involving molecular docking, molecular dynamics and QSAR have been performed to understand the characteristics of ligand binding and its affinity toward SARS-CoV-2 main protease Mpro or 3CLpro (Molecular drug target) [86]. Molecular docking studies have shown that alkaloids like Berberine, Tetrahydropalmatine, Tryptanthrine, Indirubin, Indigo, Indican and 5ar-Ethyltryptanthrin are potential COVID-19 inhibitors that majorly target either 3CLpro or Mpro of SARS-CoV-2 [87]. Quinoline and Quinazoline alkaloids like Oxoglyantrypine, NorquinadolineA, 3-Hydroglyantrypine, Deoxytrytoquivaline, Deoxynortryptoquivaline and NeosartoryadinA were reported to exhibit inhibitory activity against COVID-19 using molecular docking studies followed by toxicity and drug-likeness analysis [88]. In addition, Quinacrine, Quinidine and Quinine (from Cinchona officinalis), Chlorogenic acid and Hesperidin extracted from Zingiber officinale [89], Luteolin-7-O-glucuronide extracted from Ocimum sanctum [90], Epigallocatechin-3-gallate (EGCG), Theaflavin gallate, Fisetin[91],Anisotine extracted from Justicia adhatoda [92], Thalimonine, Sophaline D [93], Bromhexine (from Adhatodavasica), Castanospermine (from Castanospermum australe), Cepharanthine (from Stephania spp.), Hernandezine (from Thalictrum podocarpum), Homoharringtonine (from Cephalotoxusharringtonia), Hydroquinidine (from Cinchona officinalis), Isoliensinine and Liensinine (from Nelumbo nucifera), Lycorine (from Amaryllidaceae spp.), Neferine (from Nelumbo nucifera), Oxysophoridine (from Sophora alopecuroides),Reserpine (from Rauwolfia serpentina), Tetrandrine (from Stephania tetrandra) [94], Myristicin extracted from Myristica fragrans, Cannabinoids extracted from Cannabis spp., Rhoifolin and Eugenol extracted from Syzygiumaromaticum, 6-Shogaol from Zingiber officinale and Ethyl cholate from Pangiumedule [54],also form a majority of the compounds that have been studied through molecular docking and dynamics-based simulation analysis. These compounds have shown excellent binding affinity with various SARS-CoV-2 drug targets. However, to test their reported biological properties, validation through in vitro and clinical studies is required.

4.4.3.2 In vitro studies

Parallel to in silico studies, in vitro studies have also been performed to identify potent phytochemical-based anti-SARS-CoV-2 compounds, however, very few phytochemicals have been considered for in vitro analysis. When Homoharringtonine, a plant alkaloid with high antiviral properties, was tested in vitro for its anti-SARS-CoV-2 activity, exhibited SARS-CoV-2 inhibition at an EC50 of 2.10 μM [95]. In addition, Emetine, an isoquinoline derivative that is approved for the treatment of amoebiasis, was also shown to successfully inhibit SARS-CoV-2 at an EC50 of around 0.5 μM [95]. Their study opens avenues for further work to be carried out in the field of combinational therapy using phytoconstituents, which will lead to better clinical outcomes. Another recent in vitro study was conducted specifically to evaluate the anti-SARS-CoV-2 activity of Lycorine, Emetine, and Cephaeline, which demonstrated excellent COVID-19 inhibition. However, owing to their biological toxicity, further research needs to be conducted to modify these compounds to make them safer for consumption [96].

Berberine has already been identified to have good antiviral activity against SARS-CoV-2 through in silico studies, and this is also supported by in vitro studies carried out on Vero E6 cells. The study highlights the potent antiviral activity of Berberine at an EC50 of 9.1 μM, and a continued analysis in infected epithelial cells also reported good viral inhibition at an EC50 of 10.7 μM [97]. This study also throws light on the fact Berberine acts on early as well as later stages of COVID-19 infection and thus represents an excellent candidate for further in vivoand clinical studies. Resveratrol, a type of stilbenoid belonging to polyphenols, with abundant medical benefits, was identified as a powerful SARS-CoV-2 inhibitor. A recent biological assay performed on Vero E6 cells demonstrated a reduction in SARS-CoV-2 replication by 3 logs at 25μM, with an EC50 of 4.48 μM [98]. However, the bioavailability of Resveratrol poses a difficulty, which can be overcome if the drug can be administered through the nasotracheal route, and further research followed by clinical trials is required to ascertain the safety and efficiency of Resveratrol.

A series of in vitro studies performed to test the efficiency of Glycyrrhizin which is a triterpene saponin, identified it to be a good inhibitor of Mpro (SARS-CoV2 main viral protease) [99]. The antiviral active levels of the drug were within the range of that tolerated by humans, indicating that with further in vivo and clinical validation, Glycyrrhizin could also be one of the potential phytocompounds that can be used to treat COVID-19 [99]. An in vitro study reported that EGCG expressed potent antiviral activity against Nsp15 of SARS-CoV-2, thus showing that EGCG-containing compounds could be excellent inhibitors of viral replication [100]. The study also suggests various methods of administration of EGCG in the form of mouthwashes or nasal washes. EGCG is potent even at very low concentrations. Therefore, this phyto compound is pointed out as a powerful lead for further investigation. The method of in vitro evaluation and analysis of biological activity of potential drug molecules is shown in Figure 5.

Fig. 5
figure 5

Process of in vitro analysis to identify the lead compound from the set of potential drug molecules reported after in silico studies. The compounds selected after virtual screening are either purchased or synthesized in the laboratory. Their biological activity is tested on isolated cell cultures and through various biological assays, whose results are analyzed to identify the final lead compound that is considered for studies in animal models

Full size image
4.4.3.3 In vivo and clinical studies

The anti-SARS-CoV2 phytocompounds which are presently under in vivo and clinical studies are very few because it is a costly and time-consuming process. Adding to the difficulty is that the virus is continuously mutating making it harder to find an all-encompassing antiviral phytocompound. However, few phytocompounds are being clinically studied for their efficiency as anti-SARS-Cov-2 drugs. An in vivo study to test the anti-SARS-CoV-2 activity of Agrimonia Pilosa Ethanol Extract (APEE) in a mouse model showed that APEE exhibited potent antiviral activity with an IC50 of 1.1 µg/ml. In addition, extensive biological assays demonstrated that APEE was able to induce a significant reduction in inflammation, apoptosis markers, oxidative stress, and TLR-4 (Toll-Like Receptor 4) expression, along with reducing histopathological abnormalities, highlighting APEE as a potential candidate for further clinical studies [101]. Figure 6 shows the process involved in in vivo validation of identified lead compounds in a mouse model. Resveratrol is one of the phytocompounds that has made it to clinical trials. In its proposed phase 2 study, it was found that the severity of COVID-19 can be reduced using Resveratrol-assisted zinc therapy (Palit et al., 2021).Chlorogenic acid is another phytocompound that has successfully reached clinical trials. In its phase 2 studies, an Açaí Berry extract which contains Chlorogenic acid was administered to COVID-19 patients as a dietary supplement, following which the patients experienced a reduction of inflammation of the lungs and improved disease outcome [102]. The general procedure through which the efficiency and adverse effects of the identified drug molecule are evaluated through clinical trials in humans, is summarized in Figure 7. The studies discussed here show that phytocompounds are gaining major attention for the treatment of COVID-19 as they possess important biological properties that are crucial to fight viral infection. Moreover, we suggest that, if the search for anti-SARS-CoV-2 drugs shifts a little more towards extensive pre-clinical and clinical studies on prospective phytocompounds, then these phytocompounds can easily replace the chemical drugs shortly.

Fig. 6
figure 6

In vivo testing and analysis of lead compound to understand its efficiency and toxicity in a mouse model. The lead compound to be validated is injected into a mouse infected with COVID-19. This mouse is then observed for any changes in the disease condition. If the mouse shows an improvement in the disease outcome, then the drug injected is considered for further evaluation through human trials

Full size image
Fig. 7
figure 7

Testing and evaluation of drug in humans through clinical trials. The drug is administered to an appropriately chosen human population in phases. The human subjects are regularly observed for any benefits or side effects of the drug administered. If the drug proves to be efficient with only minor side effects, then proceedings will start to obtain FDA approval. The drug can then be manufactured and commercialized

Full size image

4.4.4 Ozone therapy treatment

Ozone is a triatomic, highly reactive gas which is generated naturally by lightning and ultraviolet radiation. It acts as a potential treatment option due to its antioxidant, antimicrobial and anti-inflammatory effects [103]. It can be administered through various routes, including major autohemotherapy (MAH), rectal insufflation, and intravenous delivery, making the therapy more advantageous [104]. It is believed that ozone therapy may activate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, enhancing the production of antioxidant enzymes that combat oxidative stress, a significant factor in COVID-19 progression. Additionally, it exhibits antiviral properties by damaging the lipid layer of the COVID-19 virus, significantly inhibiting viral entry and replication [105]. Therefore, it is suggested that ozone therapy has improved the quality of life of COVID-19 patients and can be a potential treatment option with mild to moderate symptoms.

4.4.5 Nanotechnology-based approaches to manage COVID-19

Along with the efforts made in the field of discovering and developing various types of drugs through different approaches, adopting a multidisciplinary perspective by making use of nanomaterials in the field of detection and diagnostics, drug delivery, protective equipment and other preventive strategies can prove to be helpful [106]. Real Time-Polymerase Chain Reaction (RT-PCR) is the widely used diagnostic method for detecting COVID-19 and this process can be made less labour-intensive and less time-consuming by using nanoparticles in the viral extraction procedure [107]. Nanoparticles can help to up-regulate the immune response against the antigen and also increase the specificity of the immune response by directing the antibodies towards the specific antigen [108]. Silver or gold nanoparticles are widely used in point-of-care devices where the viral antigen binds to these nanoparticles and this binding produces a detectable change of colour [109]. Nano biosensors have been developed which can rapidly detect SARS-Cov-2 with good accuracy and cost-effective [110]. Nanotechnology-based solutions can be used to develop highly efficient anti-viral coatings which can further be used in the making of personal protective equipment and face masks, for example, nano fibres developed using copper oxide and graphene oxide can inactivate virus particles and can be incorporated in face masks [107]. The scope of application of nanoparticles in the health sector does not end here. By bringing together the conventional antiviral modalities along with the advantages of nanoscale particles, it is possible to improve detection and treatment methods, thereby helping in improving the COVID-19 management strategy. The applications of nanotechnology in the effective management of COVID-19 are shown in Figure 8.

Fig. 8
figure 8

Nanotechnology approaches for the management of COVID-19. Nanotechnology-based detection and diagnosis kits of COVID-19, nano-based PPE, and face masks based on antiviral coatings, nano-based disinfectants and sanitizers are currently available for use. With further research, other approaches like nanomedicine, nanoimaging, nano-based vaccines, and nano-based clinical and pre-clinical trials can be used in the future

Full size image

There has been a substantial amount of research performed on efficient drugs against COVID-19, and a comparison of the efforts put into finding chemical drugs, phytochemical drugs, and nanotechnology-based approaches in the last 5 years is shown in Figure 3B.

5 Current advances in vaccine development

Besides the aim of developing effective drugs to treat COVID-19, efforts have also been made to develop promising vaccines that can boost immunity and control the viral infection. Globally, 13.6 billion doses have been administered, 67% of the total population had taken their first dose and 32% of the total population had received at least one booster dose as of December 2023 [111]. The process of development of the various vaccines that are available now or those that are under trial has occurred at such an accelerated rate that we now have over 184 vaccine candidates in their preclinical development stage and over 100 vaccine candidates undergoing clinical trials [112]. Of these, almost fifty of them are undergoing human experimentation and some of them have also been approved for administration [113]. There are mainly 4 types of COVID-19 vaccines- (1) whole virus vaccine (2) protein-based vaccine (3) viral vector vaccine and (4) nucleic acid vaccines. All vaccines that are presently in trial are injected vaccines, however, to control an infection that mainly starts in the nasopharynx, nasal vaccines may prove to be more helpful [114]. Lyophilized vaccines can be administered intranasally if it has good aerosol properties [115]. Recently, The Bharat Biotech has developed a one-drop nasal vaccine against SARS-CoV-2, named “CoroFlu”, and it is presently in the animal trials stage [116]. A notable development in recent times is the novel N- protein convacell vaccine, which targets the nucleocapsid protein of the virus. The vaccine demonstrated an efficacy rate of 85.2% in protecting against the COVID-19 virus in its first human trial. This vaccine is promising in preventing virus infection and broadening the scope compared to existing vaccines [117]. Recently, the VLA2001 vaccine from Valneva and Covifenz from Medicago both showed a rate of efficacy of around 70% and they got approved in the UK and Canada respectively in 2022 [118]. A brief description of some of the vaccines currently in phase 3 (human trials) and phase 4 (post-marketing surveillance) study are mentioned in Table 3. The different vaccines that are currently in use are summarized in Table 4.

Table 3 Various COVID-19 vaccines that are currently in phase 3 and phase 4 clinical trials
Full size table
Table 4 Vaccines that are currently in use for the treatment of COVID-19
Full size table

The COVID-19 vaccines currently in use have shown good efficiency and it was seen that they reduced COVID-19 hospitalizations and ICU admissions as well as deaths. [119]. However, these benefits don’t come without risks. The reported side effects of the mRNA-based vaccines in use so far include fever, redness, swelling, injection site pain, myalgia, arthralgia, induration, pruritus, chills, vomiting, fatigue, and headache [120]. It was also reported that the adenovirus-vectored vaccine was associated with higher rates of diarrhoea and arthralgia [120]. Extreme and severe side effects have been rarely reported and those that have been reported do not have any evidence to direct the cause to the vaccine. The relatively rapid and successful development of the vaccines against COVID-19 is to be truly appreciated, however, with the evolving virus, it is equally important to take up an evolving vaccine approach, where vaccines need to be continuously modified to maintain their efficiency.

6 Risks of COVID-19

6.1 Risks in children

The direct effect of COVID-19 on children has not been as pronounced as seen in older adults, but the health and welfare of children have still taken a hit [121]. Studies on the impact of COVID-19 on children’s health and mortality have shown that, in affected children the severity of the infection is considerably lower than in adults. Children typically exhibit mild symptoms such as fever, fatigue, cough, congestion, and occasionally nausea or diarrhoea, with only a rare progression to a stage requiring aggressive treatment [122]. The negative impacts of COVID-19 on children have been majorly due to the sudden and widespread economic and societal disruption following the pandemic, leading to an increase in cases of abuse, neglect, and maltreatment, as well as anxiety and depression [123]. Leaving aside the consequences of the infection as such, cases of psychological distress due to social isolation and deranged education have seen a reported increase since the pandemic [123]. Children with behavioural needs who require regular visits to therapists and other healthcare professionals are one group of children who have been worst affected by the pandemic, as in-person healthcare access has seen a marked decrease during the pandemic [124]. With a pandemic like COVID-19 with its far-reaching impacts, the global economy has taken a hit, and as a consequence, the vulnerable groups in society have sunk even further in their quality of life, which in turn has affected the children belonging to such families, as their difficulties of living have been further exacerbated [122]. Children with medical complexities are also facing a hard time with the reduction of the in-personal health care system [124]. The way to mitigate such risks would be to form and implement virtual strategies to support health care services, child welfare services, educational services, etc. Apart from psychological distress children should also be vaccinated with COVID-19 vaccines to prevent infections among children population and avoid after-effects symptoms that might show up in their later years of life.

6.2 Risks in immunocompromised vaccinated people

The vaccines that are currently available have either not been tested in immunocompromised individuals during phase 3 trials, or there is very limited information about such cases. As per CDC (Centres for Disease Control and Prevention) guidelines, immunocompromised patients include patients with solid tumour and hematologic malignancies, solid organ transplant, hematopoietic stem cell transplant, moderate or primary immunodeficiency, and patients receiving high dose corticosteroids, chemotherapy, and immunosuppressants [125]. Immunocompromised people are at a higher risk of experiencing severe COVID-19 symptoms and even after receiving a vaccination, they might not achieve the same level of protection from the infection as immuno-competent people [126]. There are increasing concerns that in patients who have received an organ transplant and are thus immunocompromised due to the immunosuppressants administered to them, allograft rejection could occur following the administration of COVID-19 vaccination due to the sudden increase in the immune response that can act against the allograft [127]. Immunocompromised individuals are also at a higher risk of developing mucormycosis, which if not diagnosed or misdiagnosed as symptoms of other diseases, could be fatal [128]. For patients who are administered immune checkpoint inhibitors, there is a risk of immune-related adverse effects due to unintentional activation of the immune system following the vaccination [129]. In addition, patients who have undergone hematopoietic stem cell transplants represent a tricky group of people because administering the vaccine to them essentially requires the healthcare provider to balance the risk of a severe COVID-19 infection due to immunocompromised state against the chances of a poor vaccine response [130]. Inactivated vaccines are recommended and live vaccines are generally not advised and the consequences depend on the type of vaccine, the age of the patient, and the time of the infection [129]. Therefore, it is important to plan the vaccination of immunosuppressed patients to avoid drastic consequences and to maximize seroprotection.

6.3 Risks in unvaccinated people

The need for COVID-19 vaccination is apparent. From when the disease made its first appearance back in December 2019, it has taken numerous lives. A cure for the disease is yet to be formulated and currently, strategically managing the spread of the disease is of utmost importance. Adding to the difficulties is the fact that the disease-causing virus is rapidly evolving. Accelerated efforts have resulted in the development of various vaccines that protect against the infection. These vaccinations result in a significant reduction in mortality rates and chances of the infection becoming severe. The unvaccinated population is exposed to higher chances of contracting the infection, for instance, a study reported that unvaccinated people are at 11 times risk of death from the delta variant of COVID-19 as compared to vaccinated people indicating that they are at a higher risk of experiencing a severe episode of the disease [131]. Another recent study that aimed to test the efficacy of Pfizer-BioNTech BNT162b2 and Oxford-AstraZeneca ChAdOx1-S reported that vaccinated individuals had a 44% lower risk of being admitted to a hospital and a 51% lesser risk of death as compared to unvaccinated individuals [132]. It can be inferred from such studies that it is extremely important for unvaccinated individuals to receive the vaccine to avoid severe outcomes of the disease.

6.4 Risks still posed to vaccinated people

Vaccinations help in imparting protection against the disease; however, they come with certain risks and side effects as discussed earlier. The rate of mortality due to COVID-19 infection in vaccinated people is comparatively less and was reported to be 0.4% in the Indian population[133]. Vaccinated people still have the risk of infection with a new variant or re-infection if they are weak and do not follow the COVID-19 protocols. Some reports describe re-infection in many people who were already COVID-19 positive a few months ago, with India having a COVID-19 re-infectivity rate of 4.5% [134]. This suggests the need for booster doses of vaccine that can help in preventing the further spread of disease and better management of COVID-19. Additionally, the issue with the COVID-19 vaccine is that it might give rise to COVID-19 infection and the subject is highly controversial. However, it is worth noting the theoretical aspect of it. Translation of mRNA in the vaccine could lead in two ways: under-translation could give rise to insufficient spike protein production and a weak immune response, Conversely, over-translation could produce too much spike protein, overstimulating the immune system, and leading to COVID-like symptoms. Moreover, these spike proteins lead to virus-induced autoimmunity which can result in inflammation of epithelial cells and thrombosis illness [135].

Discussions of administering booster vaccine doses have started mainly due to two reasons (1) the fact that the levels of serum antibodies produced after vaccination drops after a few months post-vaccination and (2) the rapid evolution of the virus and emergence of variants that can be a breakthrough in the disease epidemiology with a capacity to induce higher viral load even in vaccinated people [136]. A third booster dose has been developed by Moderna, Pfizer–BioNTech, Oxford–AstraZeneca, and Sinovac which can be administered 6 months after the 2ndvaccination dose, and this helps to boost the neutralizing antibody titres, making the vaccination effective against all the variants of the virus [137].

6.5 Risk associated with underlying medical conditions

The majority of people have one or more pre-existing medical conditions, which impact the COVID-19 disease acuteness. These conditions include chronic diseases such as cardiovascular issues, obesity, and chronic lung conditions. Gender differences and age play a role in these conditions [138]. suggested that 56.7% of young adults had reported having these conditions before COVID-19. Additionally, the majority of people exhibit symptoms related to COVID-19 without a confirmed diagnosis, adding to the complexity of the risk profile [139]. These underlying conditions and symptomatology can affect the severity of COVID-19, making it important to address and mitigate the impact of the pandemic.

6.6 Booster vaccination- pros and cons

The vaccination against COVID-19 was administered in three doses- two primary doses and one booster dose has been advised[140]. To ensure a strong immune response against COVID-19, a third dose was deemed necessary [140]. A recent study performed to understand the efficacy of the BNT162b2 vaccine showed that a third dose, if administered approximately 8 months after the second dose, had a high efficacy of almost 90% and was able to neutralise the pathogen [141]. Another study reported that COVID-19 infection, hospitalisation and mortality decreased significantly after administration of the third dose [140]. These facts lead us to believe that the third dose is indeed beneficial to reduce the intensity of the illness and prevent transmission of the disease [141]. The safety and reactogenicity of the third dose were found to be similar to that seen after administering the earlier doses and no new safety signals were reported, however, the long-term risks associated with the third dose are still in the process of being evaluated [141].

7 Acquisition of herd immunity against COVID-19

A society is said to have acquired herd immunity against a disease when a sufficient part of the population is either vaccinated or has naturally recovered from the disease [142]. A common assumption is that, as herd immunity is acquired, the chances of infection in the susceptible fraction of the population should inevitably decrease, and therefore it became important to administer vaccinations until the herd immunity threshold was reached [143]. These thresholds, which are a measure of the part of the population that is immune to the disease, can be mathematically predicted using a factor called the reproductive number which can vary in different populations leading to different thresholds in different populations [143]. Achieving herd immunity without administering vaccines, that are natural, is worth a huge risk, especially in countries like the USA and France where the fatality ratio is 0.3–1.3%, as it would translate into lakhs of deaths [144]. Thus, an effective vaccine is what presents the safest path towards achieving herd immunity. A bottleneck aspect in achieving herd immunity is the ever-emerging variants of the pathogen, which have increasing different viral loads and transmissibility rates associated with them, which causes an increase in the herd immunity threshold [143]. We can say that the current vaccines will help slow down the spread of the infection and reduce its severity, but it is unlikely to lead to a complete eradication of SARS-CoV-2 [143]. The fact that SARS-CoV-2 mutates continuously into new variants capable of escaping immune barriers, can manifest as an asymptomatic disease, does not substantially engage the immune system, and the prolonged protection against the infection (naturally or through vaccination) is not seen, poses a huge challenge in achieving 100% herd immunity against COVID-19 and thus it is near impossible to eradicate the disease like how it was possible to eradicate measles and polio [142].

8 Challenges in the management of COVID-19

The most reliable approach to control the spread of COVID-19 is prevention, treatment and management of the disease. For this, a combined effort from both the public and the government is essential. There are a variety of measures that can be taken to effectively manage the transmission of the virus and each possible way is presented with its challenges.

Due to the rapid transmission rate of the virus, social distancing was immediately implemented with the thumb rule of keeping a distance of 1.5 meters between people as this can help prevent the spread of respiratory droplets and thus most infectious respiratory diseases [145]. This disease is spread through air droplets so it is also essential to wear masks, wash hands often and disinfect with alcohol-based cleaning products. However, with social distancing, the possibility of increased depression and anxiety might increase in people [146]. In addition, wearing masks is advised even now even after most of the population is completely vaccinated or at least vaccinated with one dose. However, there are two challenges observed concerning the wearing of masks, the first being that due to the sudden high demand, there is a shortage observed and the second is spreading awareness on how to use masks properly, understand their necessity, and ensure they are worn [147].

Again, the rapid rate of transmission of the disease causes many people to get infected and the lack of comprehensive understanding of the virus at the cellular and molecular level at the onset of the pandemic led to hospitals being overwhelmed and unable to treat all patients. There was unpreparedness concerning medications and adequate resources including hospital equipment. A variety of resources are required to treat patients such as an ICU bed, ventilators, oxygen supply, PPE kits for the health care workers, etc. Thus, it became a clinical challenge for both clinicians and front-line workers to deal with this.

As this is a disease that affects the respiratory system, ventilators are essential as they provide respiratory support to patients whose lungs are compromised due to the infection. There has been an extreme shortage of ventilators experienced by many of the countries including India, that have been hit hard by the pandemic due to the global supply chain [148]. Hence there is a requirement to escalate the production of ventilators and to find alternative manufacturing processes to deal with the shortage. There was also a massive hospital bed shortage and it was observed that high-income countries had a greater number of bed facilities than low-income regions, which directly affected the quality of the care given to the patients [149].

Moreover, it is essential to also have a preventative measure rather than facing a multitude of problems associated with COVID-19 treatment. This is where vaccines come into the picture. Within less than a year of the start of the pandemic, there were several potential vaccine candidates, and many of them were seen to obtain emergency use authorization as well. There were however many challenges observed such as maintaining R&D incentives, conducting in-depth clinical trials, obtaining the required authorizations, manufacturing, supply, global distribution plans, and post-market surveillance [150]. However, even with all the advancements in technology in the healthcare system, the COVID-19 pandemic is still ongoing due to the emergence of multiple variants of viruses for which the vaccines don’t work. This has created a clinical challenge for both researchers and clinicians. Thus, we suggest that, apart from vaccinating people with booster doses, more research needs to be carried out on emerging variants to understand their mode of transmission and pathogenicity.

In addition to these challenges, the accuracy of diagnostic testing is important as False negatives and false positives can severely impact managing COVID-19. Continuous monitoring and updating diagnostic algorithms to account for new variants are also essential to improve management strategies.

9 Future research directions

It is possible to manage the spread of COVID-19 using an integrated and balanced approach through a fine interplay between academic, scientific, social, political, and economic factors. Lots of efforts have been put into identifying various viral targets that can be used to formulate drugs, however, besides the great potential and benefits offered by phytochemical-based drugs, most of the drugs currently available for use are chemical-based, indicating that there is a growing need for increasing the attempts at bringing a phytochemical-based drug into the market for patient consumption. Nanotechnology seems to be playing an important role in disease-prevention strategies, diagnosis, and treatment. Further research can be performed in incorporating nanotechnology in drug or vaccine delivery to develop more efficient drug delivery systems. The pandemic that seems to have been going on forever has directly or indirectly made its mark on the whole of the global population, however, it seems to have affected children on more than one level. The increasing number of cases of mental health issues arising out of social isolation and economic instability in households is a clear indication that there is a necessity to develop and implement appropriate virtual healthcare systems that can offer maximum health support to children. The different vaccines that are currently available and those that are under different stages of clinical trials are proving to be successful, however, most of them have not considered the effects and consequences of vaccination in the immunocompromised group of the population. There is a lot of ambiguity when it comes to vaccination and its associated risks in this group, and further insight is required along with clinical evidence concerning this issue. Apart from the obvious requirement for overall development in prevention, diagnosis, and treatment strategies, it is of utmost importance to spread awareness regarding the consequences of the disease and where it is headed in the near foreseeable future, and to form protocols and guidelines accordingly. Every country must be prepared for any unexpected turn of events. The major factor that ensures the success of the management and prevention strategies of COVID-19 is the complete cooperation from the people, without which, it will extremely difficult to overcome the pandemic.

10 Concluding remarks

COVID-19 has spread its roots all over the globe. The virus continues to emerge in the form of different variants with different characteristic symptoms and severity of infection. The initial outbreak of the disease wreaked havoc, taking countless lives because the situation was completely unexpected and there were no clear management strategies in place to control the situation. From affecting the health of the population to causing a global economic crisis, the pandemic has shown far-reaching consequences, affecting everyone from infants to adults, mentally, socially, and economically. However, we have come a long way since the first outbreak of the infection, with better control strategies and protocols in place to prevent other waves of the infection. Consistent efforts are being made to identify potential drugs against various drug targets in the SARS-CoV-2 virus, with a major focus now shifting towards phytochemical-based drugs. The fast-tracked approach towards developing vaccines has been successful, many of which have been approved for use and are widely being administered. Even after formulating strict protocols and guidelines regarding the management of COVID-19, directly, or indirectly, there are many risks posed to different groups of population, and completely controlling the spread of the disease continues to remain a challenging task. Close surveillance, monitoring, and reinforcement of the guidelines are required to better manage and control the spread of the infection.